Tramadol

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Tramadol is a common analgesic that provides its effects by acting as an opioid and serotonin-norepinephrine reuptake inhibitor (SNRI). The opioid portion of its effects mainly comes from a metabolite, O-Desmethlytramadol (O-DSMT), while tramadol itself has a greater impact on monoaminergic systems.

Both the opioid and SNRI effects yield pain relief and mood changes.

It does have recreational effects, perhaps more so in those who are efficient at metabolizing tramadol to O-DSMT, but it’s generally viewed as less intense than an opioid like morphine or diamorphine (heroin).


Tramadol = Ultracet; Ultram

PubChem: 33741

Molecular formula: C16H25NO2

Molecular weight: 263.381 g/mol

IUPAC: 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-3H-isoindol-1-one


Dose

Medical

Oral

Instant-release (IR)

A typical dose is 50-100 mg up to four times daily, with administration every 4-6 hours. The max daily dose is 400 mg.

Sustained-release (SR) / Extended-release (XR)

These formulations can be given once or twice per day, with the same maximum dose of 400 mg.

Nonmedical

Oral

Light: 50 – 100 mg

Common: 100 – 250 mg

Strong: 250 – 350 mg


Timeline

Oral

Total: 5 – 8 hours

Onset: 00:30 – 01:30

The onset can be fairly slow and peak effects may not arrive until more than two hours have gone by. This varies between users, but the opioid-like effects in particular tend to have a slower onset than the average orally administered drug.

Its duration is dose-dependent, with some people receiving effects for upwards of 12 hours, mostly with strong+ doses.

Though it may not be as intense as typical opioids a lot of people like its longer duration.


Experience Reports

Erowid


Effects

Recreational

Positive

  • Analgesia
  • Mood improvement
  • Sense of wellbeing
  • Physical euphoria
  • Relaxation
  • Anxiolysis

Negative

  • Drowsiness
  • Nausea and vomiting
  • Irritation
  • Sweating
  • Lightheadedness
  • Itching
  • Dizziness
  • Constipation
  • Urinary retention
  • Dry mouth

It can produce mood enhancing (sometimes euphoric), sedating, and relaxing effects. On average, the physical and mental euphoria is less intense than what can be obtained from a typical pharmaceutical opioid or diamorphine. How intense and pleasurable it is depends on dose and personal factors like genotype. Rarely is it considered an ideal opioid for recreational purposes, so people with access to an alternative opioid will usually prefer it to tramadol, although its tendency to provide a more wakeful and productive state than most opioids is desired by some.

Though it has recreational potential, some people simply do not get pleasurable effects or least not any pleasurable effects that outweigh the negatives enough to justify use. When it lacks mood enhancement and relaxation it may instead just produce restlessness and GI discomfort.

Studies have shown recreational doses of tramadol produce less desirable effects than hydromorphone, but when enough is used (e.g. 350 mg rather than 75-150 mg) it does cause some opioid-type subjective effects (Stoops, 2012 ; Duke, 2011). Tramadol is also associated with more vomiting and less miosis at these doses.

(Stoops, 2012) – Tramadol does have some abuse-related properties, but it’s not nearly as recreational as hydromorphone.

  • 10 participants, all of whom were recreational opioid users but not dependent on opioids. Recent use was confirmed by all of the subjects having positive urine screens.
  • Tramadol at 87.5 mg, 175 mg, and 350 mg oral was studied and compared to hydromorphone at 4 and 16 mg. Oral naltrexone 50 mg was used as a pretreatment to investigate the role of opioid receptors in their properties.
  • Results
    • Hydromorphone 16 mg produced significant prototypical MOR agonist effects that were blocked by naltrexone. Tramadol 350 mg produced miosis and increased ratings of “good effects” and “liking,” while also increasing ratings of “bad effects.” Naltrexone could reverse the miosis from tramadol and actually led to mydriasis, but unlike with hydromorphone, naltrexone administration only partially attenuated the positive subjective effects while increasing several unpleasant subjective effects.
    • The data indicate it has abuse potential but that it is only seen at supratherapeutic doses and the effect profile also includes negative subjective effects.
    • Physiological
      • Miosis generally appeared within 1-1.5 hours of hydromorphone administration vs. 2.5 hours after tramadol. It lasted through the 6 hour post-dosing period.
        • Reduction in pupil size was much smaller after tramadol.
      • Vomiting seemed to occur more often in the tramadol group. A total of 12 instances of vomiting across 120 total sessions. Vomiting occurred in 7 sessions with two higher tramadol doses combined with naltrexone, 4 sessions with the two higher tramadol doses, and 1 session from high hydromorphone dose combined with placebo.
    • Subjective
      • Although it raised VAS ratings of “high” and “good effect,” it did so far less than the 16 mg hydromorphone dose. It was rarely significantly higher than placebo for most measures even though some kind of drug effect was obviously shown and considered to be opioid-like, albeit weak.
  • COI: None. Funding by NIDA and the National Center for Research Resources.

(Duke, 2011) – Tramadol overlaps with hydromorphone in some respects but appears less desirable

  • USA. 8 male volunteers. Participants all had current sporadic opioid and stimulant use, but they were not physically dependent on drugs.
  • Exposed to discriminative training with placebo, hydromorphone 4 and 8 mg, methylphenidate 30 and 60 mg. Testing also included tramadol 50/100/200/400 mg.
  • All drug administration was double-blind. Participants were informed they would receive a monetary bonus for correct identification of the drug they used.
  • Results
    • Placebo was only associated with placebo-appropriate responding. Hydromorphone was significantly associated with hydromorphone-appropriate responding, whereas both doses of methylphenidate were associated with significantly higher methylphenidate-appropriate responding.
    • Higher doses of tramadol were associated with decreased placebo-appropriate responding and increased hydromorphone-appropriate responding. It was not generally associated with methylphenidate, with the exception of the 400 mg dose.
    • Hydromorphone was identified as hydromorphone 75-100% of the time, methylphenidate was identified as such 100% of the time. As the dose of tramadol increased, it was identified as hydromorphone 63-75% of the time. The highest tramadol dose was identified as methylphenidate 25% of the time and as placebo 12% of the time.
    • Subjective and physiological effects
      • Lower doses of tramadol were generally identified as placebo 100% of the time with 50 mg and 75% of the time with 100 mg.
    • VAS ratings of similarity
      • Compared with placebo, both hydromorphone doses and 200 mg tramadol, but not methylphenidate doses, were rated significantly similar to hydromorphone.
    • VAS ratings effects
      • Hydromorphone 8 mg, but not methylphenidate or tramadol, significantly increased ratings of like and good effects. Compared with placebo, hydromorphone 8 mg and methylphenidate 60 mg increased ratings of high and drug effect, though the highest methylphenidate dose significantly raised bad effect ratings. Tramadol did not significantly increase ratings of like or good effects.
    • Adjectives
      • VS placebo, hydromorphone 8 mg increased ratings on the opioid agonist scale, while both methylphenidate doses and tramadol 400 mg significantly increased stimulant scale ratings.
    • Pupils
      • Hydromorphone 8 mg significantly decreased pupil diameter compared with placebo and all tramadol doses.
  • COI: Supported by NIH and NIDA. Author was previously a paid consultant to Grunenthal.

(Cami, 1994) – Showing the acute effects in methadone maintained patients

  • Spain. Methadone maintenance program members given IM tramadol 100 mg, 300 mg, or placebo. Neither tramadol dose produced significant morphine-like effects or precipitated withdrawal syndrome. Subjective, behavioral, and physiological effects similar to placebo.
  • Analog scales of “good effects,” “bad effects,” and pupil diameter were similar to placebo.
  • Participants even classified it as placebo on 3 occasions for each dose. Other misidentifications include benzos, opioids, alcohol, cannabis, and buprenorphine.
    • Staff all classified responses as placebo on 5 occasions for each dose.
  • COI: Grunenthal support.

(Preston, 1991) – Comparing the effects of morphine and tramadol

  • USA. Tramadol 75, 150, and 300 mg vs. morphine 15 and 30 mg vs. placebo. Drugs were given IM in volunteer non-dependent former opioid addicted people.
  • 12 participants who had a mean of 15.6 years of prior illicit narcotic use.
  • Morphine produced typical subjective opioid-like effects and miosis. Tramadol 75/150 mg was not different from placebo, while tramadol 300 mg was identified as an opiate but produced no other morphine-like effects.
  • Tramadol produced minimal pupillary constriction, with diameter decreasing slightly over a 6-hour period after administration.
  • Physiological effects
    • Morphine significantly reduced pupillary diameter and body temperature without affecting cardiovascular measures or RR. Tramadol significantly lowered body temperature, but did not impact pupil size and had a mixed impact of cardiovascular measures with a significant decline in erect SBP at 150 mg and a significant increase in erect and supine DBP at 300 mg.
  • Subjective
    • Morphine 30 mg significantly increased scores on the Feel the Drug, High, and Like the Drug scales. Tramadol 300 mg produced a significant increase in ratings on the Feel the Drug VAS, but without significantly affecting High or Like the Drug scales.
    • Morphine 15/30 mg significantly raised ratings on the morphine-benzedrine scale of the ARCI with no significant impact on the LSD or PCAG scales. Tramadol had no significant ARCI scale effect.
    • Morphine 30 mg significantly increased scores on questionnaire items like skin itchy, nodding, sleepy, need to talk, stomach turning, vision changed, and body feel changed. Tramadol mostly did not significantly affect the scale scores at any of the doses tested, however tramadol 150 mg significantly increased ratings of nervous and tramadol 300 mg significantly increased ratings of stomach turning.
  • COI: Supported by McNeil Pharmaceutical.

Mental

Classic opioid effects like mood enhancement are provided with a slower onset and reduced intensity, including a relative lack of the “rush” provided by some opioids. Users can experience relaxation, giddiness, day dreaming, and they may become somewhat disconnected/dissociated from events. When a user is intentionally relaxing the substance may be more overtly daydreamy and euphoric, whereas those effects can slide into the background when doing something. Waking dream states and nodding are less common with tramadol than with other opioids. Nodding can occur, as can a sense of dissociation or disconnection from your environment and reality, particularly with eyes closed, but those effects are more readily obtained from alternative opioids.

It’s not really stimulating at the physical level, but it is more wakeful than a typical opioid and some users find it reduces the perception of fatigue while working. It can provide relaxation and mood improvement while simultaneously getting people into an attentive, productive mindset. The chance of experiencing productivity enhancement declines as the dose increases. Any potential work enhancement is likely best obtained at low to common doses. For a substantial portion of people it only leads to drowsiness or a desire to do nothing more than low-effort activities. This kind of variability exists with other opioids as well, but the variability in responses could be greater with tramadol.

Tramadol commonly makes people more content doing work they would normally find boring or unfulfilling. Since it provides a more positive valence to nearly everything going on, life is more tolerable and perhaps more enjoyable. Relief of underlying stress, anxiety, or low mood is a typical effect. This quality of the drug, which may be obtained in the absence of significant impairment, is a significant factor in why people become addicted to opioids. Because it can insulate your mind from stressors, a barrier can be constructed between your perception and yourself/the world, which can be positive or negative. It sometimes contributes to emotional blunting, which may interfere with your life. The problematic effects may be a greater issue with chronic use, while the positive aspects of tramadol’s impact on mood could be more substantial with acute use.

Paradoxically, even if someone is in a generally good mood under the influence, they may experience agitation/aggravation and could be more easily irritated than normal. This happens for a minority of users.

Cognitive impairment is not severe at common doses and is usually limited to some brain fog or spaciness. Higher amounts do come with the potential for concentration and memory impairment.

Though it may not always be productive or pro-social, it can make people less anxious and more confident, sometimes contributing to talkativeness.

Sleep can be enhanced or impaired. Some people find it outright makes sleep difficult, though it more often assists with sleep (in the sense of reduced time to sleep onset) but waking up more often through the night is more common. A lot of users report their sleep feels less deep, which is supported by research showing tramadol shifts sleep towards the lighter sleep stages. Although it either doesn’t impact REM or reduces it, dreaming is reported to be more vivid.

Physical

Tramadol commonly changes how your body feels, such as inducing sensations of warmth or tingling, along with floatiness (which is more noticeable when moving). Although some people experience jitteriness or an unpleasant heaviness in their body, it seems more common to experience a general sense of comfort. Sometimes the effect is described as similar to being covered in a warm, comfortable blanket. And things you touch may feel softer.

Libido can increase or decrease. Either way, orgasm is harder to reach, which can be frustrating, although this property also underlies its use in premature ejaculation. It can also sometimes reduce the physical pleasure of sexual activity.

Itchiness is usually less significant than with other opioids, but it can occur. When present it is most noticeable around the head and arms/legs.

Constipation, a common problem with opioids, does occur with tramadol acutely and chronically but it’s less significant and less likely to cause severe problems in the long-term. Urinary retention is also often reported, more so by recreational users than medical users.

Nausea and vomiting are common and occur dose-dependently. Sometimes this property forces people to move slowly or remain stationary to minimize discomfort.

Other potential effects include dizziness, appetite reduction, and coordination impairment.

Perception

Perception is minimally affected aside from dose-dependent vision blurriness and less often slowness, i.e. things appearing to occur more slowly.

After effects

Restlessness and insomnia may occur after the core effects have worn off. Typically it doesn’t have a harsh comedown, but the day after effects can include grogginess, headache/head pressure, dizziness, GI discomfort, and vomiting. Those issues are dose- and time-dependent, occurring more readily with strong+ doses that are taken later in the day.


Medical

Historically it was marketed as offering opioid-level analgesia with a lower risk of abuse, addiction, respiratory depression, and constipation. There is some truth to all of those claims, but there is also good evidence showing it can be taken recreationally, physical dependence can build, overdose deaths are possible, and typical opiod-type side effects like constipation do occur in some users. In general the risk of these is reduced, but it is not eliminated, and for some users it can be nearly the same as exists with a drug like oxycodone or hydrocodone.

People should be aware of its opioid nature before they begin taking it. Some of the problems stemming from its use can be tied to patients and doctors operating under the false assumption that it is drastically safer than other opioids and that relatively little caution is needed.

We know that only a portion of its intended and overdose effects come via an opioidergic mechanism. The other main factors are inhibiting serotonin and norepinephrine uptake, which can directly alter pain transmission and provide antidepressant-like effects.

Analgesia

By far the most common use of tramadol is in pain relief. More studies have been conducted on acute pain than on chronic conditions and unfortunately the chronic pain studies tend to be relatively brief, such as a few months, so it’s not always clear if the effects seen in those studies are going to be the same ones seen after years of treatment.

Acute

The majority of studies show tramadol is either as effective as drugs like pethidine, NSAIDs, and and oxycodone for postoperative pain relief or it makes up for a moderate reduction in efficacy with superior tolerability. It shows superior analgesia to placebo in effectively all of the research, but there are some studies showing superior outcomes with morphine, aspirin/codeine, and pethidine.

Whether it is the right analgesic in a postoperative setting will depend on tolerability (i.e. nausea and vomiting), patient factors like respiratory concerns, and the kind of operation. While 50-100 mg given orally or via injection is the most common way to use tramadol postoperatively, at least one study found ~260 mg was needed to provide an effective dose for 80% of patients (Thevenin, 2008).

Animal evidence has shown it is effective at reducing pain in models of neuropathic pain and it reduces pain sensation (Kaneko, 2014 ; Miranda, 2011).

Reviews

Effective

(Derry, 2016) – Cochrane review showing dexketoprofen plus tramadol is effective for acute postoperative pain in adults

  • 3 studies with 1853 patients were evaluated. Those included patients undergoing surgical removal of impacted wisdom teeth, hip replacement, or hysterectomy.
  • Results
    • Proportion of patients achieving at least 50% pain relief over 6 hours with dexketoprofen 25 mg + tramadol 75 mg was 66%, compared to 32% with placebo, yielding an NNT of 3.0.
    • Response rate with dexketoprofen alone was 53% and response rate with tramadol alone was 45%.
    • A single oral dose of dexketoprofen 25 mg plus tramadol 75 mg appears to provide good pain relief with a long duration of action, with a magnitude similar to other good analgesics.
  • COI: None

 

(Moore, 1997) – Analysis of 3,453 postoperative patients shows tramadol is effective for postoperative analgesia.

  • Patient data from 18 primary trials provided by Grunenthal and Robert Wood Johnson Pharmaceutical Research Institute. Patients were given the study drug if they had a score of 2+ on a 4-point pain scale, indicating moderate or severe pain.
  • Results
    • Tramadol and comparator drugs, namely codeine and combination analgesics, were significantly more effective than placebo.
    • NNT
      • 50 mg tramadol: 7.1 (CI:4.6-18)
      • 100 mg tramadol: 4.8 (CI: 3.4-8.2)
      • 150 mg tramadol: 2.4 (CI:2.0-3.1)
      • Aspirin 650 mg plus codeine 60 mg: 3.6 (CI: 2.5-6.3)
    • The same dose was more effective in postsurgical patients vs. those who had undergone a dental procedure. Side effects were also lower compared to those who had undergone a dental procedure.
  • COI: Supported by Grunenthal.

 

Inferior

(Isiordia-Espinoza, 2014) – Tramadol is significantly less effective than NSAIDs for third molar extraction-related pain.

  • Mexico. DBRCTs analyzing NSAIDs compared to tramadol for third molars.
  • 10 reports of single-dose tramadol vs. NSAIDs in operations on the third molar were located, but only 5 were of adequate quality for inclusion. Tramadol was similar to NSAIDs in 2 reports and less effective in 3 studies.
  • Tramadol had significantly less efficacy and an increased risk of adverse effects. The increase in absolute risk showed 21.8% of patients had adverse effects with tramadol that they would not have had with NSAID.
    • Significantly more nausea and vomiting in particular with tramadol./li>
  • COI: None

 

(Edwards, 2002) – Meta-analysis showing a single dose of tramadol is effective in postoperative pain. Combining it with paracetamol yields more pain relief, though ibuprofen alone is better than either.

  • 7 DBRCTS. All trials compared single-dose oral tramadol (75 mg or 112.5 mg) plus paracetamol (650 or 975 mg) to placebo or other treatment.
  • All cases involved moderate to severe postoperative pain. Pain was studied over 6-8 hours. All studies were on adults.
    • 1376 patients were evaluated after dental surgery while 407 were investigated after other kinds of surgery.
  • Results
    • Combo analgesics, namely tramadol with paracetamol, had a significantly lower NNT.
    • Adverse effects were common between individual drugs and combo, including dizziness, drowsiness, nausea, vomiting, and headache.
    • With control, around 25% of patients improved with at least a 50% decline in pain, while around 45% of tramadol patients and 60% of combo patients improved.
    • Ibuprofen was more effective with the lowest NNT of 2.3.
  • Withdrawal due to lack of efficacy or early remedication
    • Dental
      • 36% with placebo
      • 23% with tramadol
      • 8% with combo
      • 9% with paracetamol
      • 12% with ibuprofen
    • Postsurgical
      • 1% with placebo
      • 3% with paracetamol
      • 0% with tramadol
      • 0% with combo
  • COI: Grant and funding from the Pain Research Unit and from the Pain Research Funds.

 

Ineffective

(Martinez, 2014) – Tramadol is minimally effective at reducing morphine need or pain scores post-surgery

  • The review included papers (on adults or children) with tramadol given via any route, before or after incision, and as a single bolus, continuous, or repetitive.
  • Primary outcome: Cumulative morphine consumption in the 24 hours after surgery and pain during that period.
  • 14 RCTs from 1995 to 2013. Total of 713 patients. Patients had undergone gynecological surgery, abdominal surgery, Cesarean section, cardiac surgery, orthopedic surgery, tonsillectomy, and various types of major surgery.
    • 12/14 used IV tramadol. Tramadol was given before incision in 6 and after incision in 8 studies.
      • Administered as a single bolus in 7, repetitively or continuously in 7.
      • Total dose in the first 24 hours: 50 to 600 mg with a median value of 100 mg.
  • Results
    • 10/14 reported cumulative morphine use at 24 hours. Median value was only 6.9 mg lower in tramadol group at 24 hours, with no differences at 4 and 12 hours.
    • 12/14 reported postoperative pain intensity at rest at 24 hours. No significant difference between groups.
    • No significant difference for opioid-related adverse events.
  • COIO: None

 

Inconclusive

(Schnabel, 2015) – Cochrane review showing minimal and low-quality evidence supporting tramadol for postoperative pain in children.

  • 20 RCTs involving 1170 patients were reviewed. The treatment was 1 to 3 mg/kg tramadol IV.
  • Common surgical procedures including ENT surgery such as adenotonsillectomy or tonsillectomy, lower abdominal surgery, and dental extraction.
  • Results
    • 8 trials compared tramadol to placebo, 5 of which found the need for rescue medication in the postoperative care unit was reduced in those receiving tramadol (RR 0.40; CI of 0.20 to 0.78).
    • 4 trials compared tramadol to morphine. No clear difference in the need for rescue medication in the postoperative care unit (RR 1.25 for tramadol vs. morphine; CI of 0.83 to 1.89).
    • 3 trials comparing tramadol to nalbuphine. No clear evidence of difference (RR 0.63 for tramadol vs. nalbuphine; CI of 0.16 to 2.45).
  • The overall evidence for tramadol in the postoperative setting in children is low or very low.

Humans

Effective

(Chandanwale, 2014) – Significantly more effective for musculoskeletal pain, postoperative pain, and osteoarthritis when combined with diclofenac (an NSAID) vs. when it’s combined with paracetamol.

  • India. 5 day trial. 204 patients with moderate to severe pain from acute musculoskeletal conditions (n=52), acute flare of osteoarthritis (n=52), acute flare of rheumatoid arthritis (n=50), or postoperative pain (n=50).
  • Received tramadol 50 mg with sustained-release diclofenac 75 mg twice daily or tramadol 75 mg w/ paracetamol 650 mg every 3-6 hours, up to four times daily.
  • Results
    • Tramadol/diclofenac showed significantly greater reduction in VAS pain score at Day 3 and Day 5. Though both were significantly effective.
    • There was a concurrent significant reduction in swelling and inflammation scores in tramadol/diclofenac vs. tramadol/paracetamol group.
    • The amount of rescue medication utilized was significantly lower in the tramadol/diclofenac group.
    • Acute pulse, temperature, and BP were similar between groups.
  • COI: Supported by Abbott Healthcare in India.

(Kumar, 2013) – Tramadol is more effective than pregabalin for postoperative pain following lumbar laminectomy.

  • India. 75 patients givenplacebo, tramadol 100 mg oral, or pregabalin 150 mg oral 1 h before anesthetic induction.
  • Results
    • Pregabalin offered significant analgesia, but it was less than seen with tramadol. The need for rescue medication was lowest with tramadol followed by pregabalin and then placebo.
    • Pregabalin had significant anxiolytic effects, but tramadol was more effective.
    • Pregabalin was associated with less sedation vs. tramadol and fewer postoperative instances of nausea, vomiting, and drowsiness.
    • No significant differences for HR or RR preoperatively or after extubation. BP was largely unaffected, but SBP and DBP changes were significantly lower 5 min after intubation and right after extubation in the tramadol group vs. placebo and pregabalin.
  • COI: None

 

(Orbach-Zinger, 2012) – Tramadol is similarly effective to remifentanil for PCA during abortion

  • Israel. 30 patients undergoing second trimester abortion. Analgesia initiated in tramadol group with a loading dose of 1.0 mg/kg with 10 mg metoclopramide followed by PCA bolus 0.3 mg/kg/mL ever 5 min.
  • Remifentanil given via PCA as well.
  • Results
    • No significant pain difference between groups except 16-20 hours after induction of labor, when pain was lower in tramadol group. Average VAS score was low in both. Satisfaction was high in both without a significant difference.
    • The majority of people in either group did not need a higher PCA dose or analgesic supplementation. One patient in both needed conversion to epidural analgesia due to intractable pain.
    • Nausea was a frequent finding in both but most of those affected either needed no treatment or their nausea was responsive to a single metoclopramide dose.
  • COI: Not reported

 

(Karabayirli, 2012) – It is more effective than naproxen for IUD insertion-associated pain.

  • Turkey. Tramadol 50 mg oral compared to naproxen 550 mg or placebo given 1 h before insertion of IUD. After insertion, pain intensity was evaluated.
  • Results
    • Pain scores were significantly lower in tramadol vs. naproxen group (p=0.003) and naproxen group was significantly better than placebo (p=0.001).
    • Patient satisfaction with medication and preference for its use in the future was significantly lower in placebo vs. other groups.

 

(Rahimi, 2010) – Tramadol is effective for postoperative pain management following craniotomy

  • Georgia. Randomized, blinded study. 50 patients given paracetamol alone or tramadol (with narcotic analgesics available).
  • Tramadol group received 100 mg oral twice daily.
  • Results
    • Control group had significantly higher VAS pain scores, increased length of hospital stay, and increased narcotic use vs. the group with tramadol.
  • COI: None

(Akbay, 2010) – Locally applied tramadol is effective in tonsillectomy pain

  • Prospective RDBRCT. 40 children aged 4-15 years old. Either received a 5% tramadol swab (2 mg/kg diluted in 10 mL saline) or a placebo swab. Swabs were applied to both of the tonsillar fossa for 5 min.
  • Paracetamol and amoxicillin were given to all patients orally as per routine clinical procedure.
  • Results
    • Significant intergroup differences seen beginning at 21 hours. Mean daily pain score of 0.34 on Day 1 vs. 0.53 with placebo. And the mean score on Day 4 was 0.11 vs. 0.42. Those differences were significant.
    • No significant difference in morbidity between group.
  • COI: Not reported

 

(Kampe, 2009) – Oxycodone 20 mg XR and tramadol 200 mg XR are equally useful after surgery for breast cancer.

  • Germany. 53 patients. 12-hour dosing schedule in a DBRCT manner. Patients underwent surgery for breast cancer.
  • Results
    • The 90% CI for the mean difference between the two groups postoperatively was within the predefined equivalence margin. Cumulative paracetamol use during the observation period did not significantly differ between groups.
    • No significant differences for nausea, vomiting, or itching. Also no significant differences for patient satisfaction or general perception of postoperative pain management.
  • COI: Study was partly supported by a grant from Bristol-Myers Squibb.

 

(Khooshideh, 2009) – Effective during labor, but less effective than pethidine, while being more tolerable.

  • 160 females in Iran. Either given 50 mg pethidine IM or 100 mg tramadol IM.
  • Results
  • First stage of labor
    • No significant difference between groups for pain scores at 10 min or 1 hour.
    • Second stage of labor
      • Pethidine group had lower VAS pain scores vs. tramadol.
  • Side effects
    • Higher nausea/vomiting in pethidine group (35% vs. 15%) and drowsiness (80% vs. 29%).
  • ~50% of patients rated the analgesia as good to excellent with either, while around 35% were dissatisfied and did not want to use their drug again for pain relief.
  • COI: Not reported

 

(Shen, 2008) – Tramadol preoperatively or intraoperatively is effective for reducing pain after lumpectomy

  • China. 317 patients undergoing lumpectomy were given IV tramadol 100 mg either 15 min before the operation or 15 min before the end of the operation.
  • Results
    • Both preemptive and preventive dosing produced significant analgesia and satisfaction during the first 24 h. A similar amount of additional morphine was used by the groups.
  • COI: Not reported

 

(Thevenin, 2008) – Tramadol is effective postoperatively, but at a dose much higher than is usually given.

  • France. Double-blind prospective trial with 24 participants in the first trial and then a subsequent verification trial with another 24. Patients were scheduled for moderately painful surgery such as inguinal hernia repair or minor ENT surgery.
  • Testing 60, 100, 140, 190, and 260 mg IV.
  • Tramadol was considered effective if the pain scale was equal to or less than 3/10.
  • Results
    • The effective dose in 80% of patients was 260 mg in both trials, with a probability of success at 260 mg of 0.699 or 0.657 (so the ED80 is actually higher).
  • COI: Not reported

 

(But, 2007) – Tramadol is effective for postoperative pain and reduces morphine need.

  • Patients were given tramadol after coronary artery bypass surgery. They received 1 mg/kg IV 1 hour before extubation and then morphine via PCA was available after extubation for 24 hours.
  • Total of 60 patients, with 30 randomized to tramadol and 30 to placebo.
  • Results
    • VAS pain scores were significantly higher at all time points from 30 min to 4 hours after extubation in placebo group. Patient comfort scores were significantly higher in the tramadol group during the same period.
    • Total morphine use was significantly higher with placebo and the number of PCA morphine demands (29.2 demands vs. 36.9) and boluses (23.1 vs. 30.6) were higher.
    • Side effects were similar between groups, though slightly higher in the placebo group, presumably from greater morphine exposure. Almost no patients had respiratory depression postoperatively.

 

(Katsarava, 2006) – A combo of tramadol and paracetamol works for migraine

  • Germany. 305 patients with migraine. They were given either a single dose of tramadol (75 mg) plus paracetamol (650 mg) or placebo within 2 h of the onset of moderate to severe migraine pain.
  • Results
    • Response rate (reduction of pain score from moderate/severe to none/mild) was 55.8% in tramadol+paracetamol and 33.8% in placebo group.
    • Tramadol+paracetamol group was also more likely to be pain-free at 2 h, 6 h, and 24 h after medication and they were less likely to take supplemental medication (22.1% vs. 45.7%).
    • Photophobia (34.6% vs. 52.5%) and phonophobia (34.4% vs. 44.9%) were significantly lower in tramadol/paracetamol group.
    • Migraine-related nausea was significantly greater in tramadol+paracetamol group at 38.5% vs. 29.4%. Treatment-related adverse events in tramadol+paracetamol group were 13.4% with nausea, 10.2% with dizziness, 7.6% with vomiting, and 6.4% with drowsiness. In placebo group, no adverse event was reported by more than 2% of individuals.
  • COI: None

 

(Engelhardt, 2003) – In children, tramadol is as effective for pain and possibly more tolerable than morphine for tonsillectomy-related pain.

  • DBRCT in children undergoing tonsillectomy or adenotonsillectomy. 20 patients in each group: morphine 0.1 mg/kg, tramadol 1 mg/kg, and tramadol 2 mg/kg.
    • All drugs given as a single injection after induction of anesthesia. All patients also received diclofenac 1 mg/kg rectally.
  • Results
    • No significant differences in age, weight, type of operation or induction of anesthesia, 4-h sedation and pain scores and further analgesic requirements. No episodes of respiratory depression. Morphine was associated with a significantly higher incidence of vomiting following discharge, 75% vs. 40% with tramadol, but the antiemetic requirement and nausea incidence were not significantly different.
  • COI: Not reported

 

(Chew, 2003) – Recovery is faster when using tramadol for operative analgesia vs. morphine

  • Singapore. 79 patients given either tramadol 1.5 mg/kg or morphine 0.1 mg/kg for intraoperative analgesia associated with tonsillectomy.
  • Results
    • Patients given tramadol had a faster recovery, shown by earlier eye opening at anesthesia reversal (4.7 min vs. 5.6 min) and nausea was significantly less common (6.8% vs. 28.6%). No other clinically significant differences in response between groups.
  • COI: Not reported

 

(Siddik-Sayyid, 1999) – Epidural tramadol is effective during Cesarean delivery.

  • 60 females in Lebanon. Receiving either 100 mg tramadol epidural, 200 mg tramadol, or control.
    • They could receive diclofenac 100 mg rectally if more pain relief was needed and if no relief was observed they would receive 1 mg/kg IM of meperidine.
  • Results
    • Significantly prolonged time to first analgesic administration (4.5 hours with 100 mg; 6.6 hours with 200 mg; 2.8 hours with control).
    • Mean cumulative dose of meperidine over 24 hours was significantly lower (0.3 mg/kg in 100 mg; 0.3 mg/kg in 200 mg; 0.7 mg/kg in control)
    • Mean total dose of diclofenac over 24 hours was significantly lower (156 mg in 100 mg; 142 mg in 200 mg; 214 mg in control).
    • Side effects
      • Respiratory depression, vomiting, and pruritus were not observed. No significant difference between doses of tramadol for any parameter studied.
  • COI: Not reported

 

(Bosenberg, 1998) – Effective for pain relief in children under halothane anesthesia and it produces less respiratory depression than pethidine

  • South Africa. 88 children split into groups: IV tramadol either 1 mg/kg or 2 mg/kg, vs. IV pethidine 1 mg/kg, vs. placebo.
    • Note: Anesthesia with halothane can depress respiration in children and premedication with trimeprazine can lower respiration, which could leave the children more vulnerable to the impact of an opioid on respiration.
  • Results
    • Decrease in respiratory rate in all opioid groups. Significant difference in max decrease in respiratory rate and increase in end-tidal CO2 between pethidine and tramadol groups. 13 episodes of apnea seen in pethidine group, 11 requiring naloxone.
      • Mean decline was 7.3 breaths per minute with tramadol 1 mg/kg, 11.4 in 2 mg/kg, 31.4 in pethidine, and only 1.7 breaths per minute in placebo.
      • Difference between tramadol and pethidine and between tramadol doses was significant.
      • Prolonged apnea exclusively occurred in the pethidine group. Almost all people given pethidine (20/22) required manual ventilatory support compared to 5/22 in tramadol 2 mg/kg and 3/22 each in the tramadol 1 mg/kg and placebo groups.
    • O2 saturation did not differ in a clinically significant way between groups despite the apnea episodes and decreases in tidal volume.
    • During the first 6 hours, the proportion of patients requiring a further dose of analgesia was highest in placebo and lowest in tramadol 2 mg/kg.
      • 40.9% needed analgesia in tramadol 2 mg/kg, 59.11% in tramadol 1 mg/kg, 63.6% in pethidine, and 68.2% in placebo.
      • Mean time to analgesia need was shortest in the placebo group at 175 min, then tramadol 1 mg/kg at 218 min, pethidine at 223 min, and tramadol 2 mg/kg at 251 min.
    • It’s possible the use of naloxone in the pethidine group led to higher than normal pain scores and need for more analgesia, though comparing the non-naloxone vs. naloxone groups did not reveal a significant difference.
    • Nausea and vomiting were not an issue in any patient, possibly thanks to slow IV injection but more likely because of also using trimeprazine as premedication.
  • COI: Sponsored by Grunenthal GmbH.

 

(Delilkan, 1993) – Effective via epidural administration for postoperative pain

  • 58 patients undergoing abdominal surgery. Split into groups: tramadol 50 mg, tramadol 100 mg, 10 mL bupivacaine 0.25%. All drugs were administered at the patient’s request with each patient allowed four doses in the first 24 hours post-surgery.
  • Surgeries were mostly gynecological or cholecystectomy.
  • Results
    • Pain based on VAS was significantly less at 3, 12, and 24 hours in patients given 100 mg tramadol vs. 50 mg or bupivacaine. The mean interval between doses was 7.40 hours with 50 mg, 9.36 hours with 100 mg, and 5.98 hours with bupivacaine.
    • Nausea and vomiting were significantly higher with tramadol 100 mg vs. bupivacaine. They were reported in 26.3% of patients with 50 mg, 50% with 100 mg, and 15% with bupivacaine.
    • No significant differences in blood pressure, RR, or arterial blood gases. No patient had a respiratory rate under 16 breaths per minute.
  • COI: Grant from Grunenthal and Duopharma.

 

(Viegas, 1993) – It is significantly effective in labor pain.

  • Singapore. Tramadol 50 mg vs. tramadol 100 mg vs. pethidine 75 mg, all administered IM.
  • 90 women in a DBRCT.
  • Results
    • Pain relief was equal with pethidine and 100 mg tramadol, but 50 mg tramadol was not effective.
    • Pethidine was the only drug correlated with a significantly reduced respiratory rate in neonates.
  • COI: Not reported

 

(Vickers, 1992) – Tramadol is effective for analgesia with a reduced risk of respiratory depression.

  • 30 patients each in two studies of people undergoing elective surgery.
  • Results
    • Mean pain score in the pethidine group was higher at rest and on movement, though not significantly so. Near-significant difference for reduced sedation with tramadol vs. pethidine group.
    • No significant differences in HR, RR, or temperature. SBP and DBP increased by a mean of 3.8 mmHg each in tramadol vs. declining by 7.5/2.0 mmHg in pethidine. That was a statistically, though not clinically significant finding.
    • Difference from baseline respiration to minimum respiration under drug effect:
      • 9.7 in morphine 0.143 mg/kg, 4.7 in tramadol 0.5 mg/kg, 3.5 in tramadol 1.0 mg/kg, and 7.7 in tramadol 2.0 mg/kg.
  • COI: Not reported

 

(Lehmann, 1990) – Postoperative analgesia with tramadol is effective.

  • Germany. 40 patients undergoing elective major gynecological or orthopedic surgery. Upon reporting pain in the recovery room, they were given a prophylatic 10 mg metoclopramide dose and titrated to acceptable pain relief with IV tramadol doses of 50 mg up to 200 mg max. PCA was then used with tramadol 20 mg (max 4 hour dose: 500 mg).
  • Results
    • Sufficient to excellent pain relief was achieved in all but two male patients from the orthopedic surgery group.
    • Postoperative circulation and respiration were always normal with respiration ranging from 15 to 20/min.
    • Median minimum effective concentrations were 0.288 μg/mL for tramadol and O-DSMT of 0.0362 μg/mL.
  • COI: Not reported

Inferior

(Iyer, 2015) – Tramadol is less effective for cardiac surgery-related pain than tapentadol

  • 60 adults undergoing cardiac surgery received either tapentadol 50 mg oral or tramadol 100 mg oral TDS. Drugs were given after extubation in a single-blinded manner with data collectors/analyzers blinded.
  • Patients also received oral paracetamol QDS.
  • Results
    • Tapentadol group had significantly better analgesia 3 hours after administration and during cough-aggravated pain. No significant differences in blood creatinine, temperature, hemodynamics, oxygen saturation, and respiratory rate. Tapentadol also produced less drowsiness and vomiting.
  • COI: None. Funded by Chettinad Hospital and Research Institute.

 

(Sudheer, 2007) – Tramadol PCA is less effective than morphine for pain after craniotomy

  • 60 patients allocated randomly to tramadol PCA, morphine PCA, or codeine phosphate 60 mg IM.
  • Morphine PCA: 1 mg boluses with 5 min lockout and 4-h limit of 50 mg
  • Tramadol PCA: 10 mg boluses with 5 min lockout and 4-h limit of 200 mg
  • All patients also received paracetamol 1 g every 6 hours.
  • Intraoperative analgesia provided by fentanyl, remifentanil, or a combo of the two.
  • Results
    • 5/60 had severe enough pain that they required rescue analgesia and were withdrawn from the study.
    • No significant difference in arterial CO2 tension or sedation between groups at any time. Though in all groups some patients had increases in CO2 greater than 1 kPa. Some patients had significant declines in PaCO2, which could have come from hyperventilation.
    • Morphine produced significantly better analgesia at all time points (p<0.005) and better analgesia than codeine at 4, 12, and 18 hours. Patients were also more satisfied with morphine than with tramadol or codeine (p<0.001).
    • Vomiting and retching occurred more often with tramadol at 50% vs. 20% with morphine and 29% with codeine.
  • COI: Not reported

 

(Keskin, 2003) – Effective during labor, but pethidine is superior for pain relief.

  • Patients: 59 females in Turkey. Either given 100 mg pethidine or 100 mg tramadol, both IM.
  • Results
    • Significantly more pethidine patients moved from severe pain to more moderate pain levels.
    • Analgesia was greater with pethidine at 30 and 60 min. Nausea and fatigue were higher in the tramadol group.
    • Decrease in SBP and DBP, with an increase in HR that was significant in both groups.
  • COI: Not reported

 

(Ozer, 2003) – Meperidine is more effective than tramadol in children after adenotonsillectomy

  • Turkey. 50 children aged 4-7 undergoing tonsillectomy received either tramadol 1 mg/kg IV or meperidine 1 mg/kg. Postoperative pain was scored by a blinded observer based on a facial pain scale.
  • Drugs were given after anesthesia induction but before intubation.
  • Results
    • Pain scores were higher in the tramadol group at 0, 10, and 20 min, but not 45 min postoperation. Agitation scores were significantly higher with tramadol vs. meperidine. Time to recovery to spontaneous respiration after atropine and neostigmine was delayed by meperidine vs. tramadol, but it did not cause complications.

 

(Moore, 1998) – It is effective for pain after dental extraction, though ASA/codeine is superior.

  • DBRCT. Tramadol 100 mg vs. tramadol 50 mg vs. codeine 60 mg vs. ASA 650 mg with codeine 60 mg vs. placebo.
  • Third molar extraction. 192 patients enrolled in a 6-hour evaluation after a single dose of the study drug.
  • Results
    • ASA/codeine was significantly superior to placebo for all measures of efficacy (TOT-PAR, MaxPAR, sum of pain intensity difference scores, peak pain intensity difference, remedication, and global evaluations.)
    • Tramadol 100 mg was superior to placebo for TOTPAR, sum of pain intensity difference scores, and time of remedication. Tramadol 50 mg was only superior to remedication time.
    • Codeine was not superior to placebo for any measure.
    • There was a greater TOTPAR response with ASA/codeine during the first 3 hours compared to all other active drugs. The 6-hour TOTPAR scores for tramadol and ASA/codeine were not significantly different.
    • Rescue medication
      • 144/192 patients required a rescue analgesic before the conclusion of the 6-hour assessment. 85.2% receiving placebo, 80% receiving codeine, 73.7% receiving ASA/codeine, 72.9% receiving tramadol 100 mg, and 69.4% receiving tramadol 50 mg required a rescue analgesic.
      • Based on time to remedication, all treatments other than codeine were superior to placebo.
    • GI side effects like nausea, dysphagia, and vomiting were more common with tramadol 100 mg, ASA/codeine, and codeine vs. placebo.
  • COI: Not reported

Ineffective

(Grace, 1995) – Small trial in which epidural tramadol was ineffective for postoperative analgesia after total knee replacement

  • Northern Ireland. Tramadol 50 mg bolus followed by infusion of 5 mg/h for 12 hours then another 12 hours of 2.5 mg/h vs. tramadol 100 mg bolus with infusion of 10 mg/h for 12 hours and 5 mg/h for another 12 vs. morphine sulphate 2 mg bolus followed by 12 hours of 0.2 mg/h and 0.1 mg/h for another 12.
  • Supplemental PCA with pethidine was available.
  • The study was discontinued after only 12 patients because of poor analgesia in those given tramadol.
  • Results
    • Based on pain scores and PCA consumption, tramadol performed significantly worse.
  • COI: Supported by the Department of Health and Social Services for Northern Ireland.

Animal research

Effective

(Kaneko, 2014) – Effective in models of neuropathic pain and fibromyalgia

  • Anti-allodynic effects measured with injection (10 or 30 mg/kg IP) and oral (10 or 30 mg/kg) administration following neuropathic pain induced by sciatic nerve ligation (PSL) and reserpine-induced myalgia (RIM).
  • Results
    • In PSL rats, the threshold for response from tactile stimulation was much lower seven days post-operation, suggesting tactile allodynia.
    • Tramadol produced a potent and dose-dependent reduction in allodynia. The same was seen in RIM rats. IP injection led to a significantly higher mean threshold at 1 hour, while the threshold was higher from Hours 1 to 4 in oral administration.
    • Naloxone (1 mg/kg SC) partially, but not completely, antagonized the efficacy of tramadol.
  • COI: None

 

(Flor, 2013) – Effective with metamizole for severe chronic pain in cancer.

  • Brazil. 69 dogs with various forms of cancer and a sufficiently elevated pain score despite being given NSAIDs.
    • Tramadol given at 2 mg/kg every 8 hours.
  • Results
    • Metamizole-only group had significantly less analgesia at Day 7 and Day 14 compared to those given metamizole, tramadol, and NSAIDs, or metamizole and tramadol.
    • Quality of life scores were significantly better in groups receiving tramadol.
    • Side effects more common in metamizole-only group.
  • COI: Supported by a grant from Fundacao de Auxilio a Pesquisa do Estado de Sao Paulo.

 

(Meymandi, 2012) – It is effective on its own for analgesia and it also enhances pregabalin at some doses.

  • Rats were studied using the hot plate test, with the impact of drugs investigated 30 and 60 minutes post-administration.
  • Results
    • Antinociception was seen with both. Pregabalin worked at 200 and 400 mg/kg IP, while tramadol worked at 20 to 80 mg/kg IP in a dose-dependent manner. ED50 was calculated to be 69 mg/kg for tramadol.
    • Unlike pregabalin, the maximum possible effect of tramadol was significantly lower at 60 min vs. 30 min, while it was higher for pregabalin.
    • The interaction studies showed co-administration of a non-analgesic 10 mg/kg dose of pregabalin with a low 30 mg/kg dose of tramadol led to synergism, whereas all other combo groups actually showed sub-additive results.
      • Particularly if non-analgesic doses of 10 mg/kg were given for both drugs, the effect was significantly lower than either drug alone.
  • COI: This work was supported by Tehran University of Medical Sciences.

 

(Miranda, 2011) – It’s synergistic with fentanyl in tonic inflammatory pain in rats

  • Background
    • The injection of diluted formalin can cause tissue injury and it generates behavioral response.
  • Rats were exposed to the orofacial formalin test, which provides a model of persistent cutaneous nociception in the region innervated by the trigeminal nerve.
  • Phase 1 of the test corresponds to the 5-min period beginning immediately after formalin exposure; it represents tonic acute pain due to peripheral nociceptor interaction. Phase 2 is the 10-min period beginning 20 min after formalin injection and it represents inflammatory pain.
  • Results
    • IP tramadol and fentanyl both induced dose-dependent antinociception in Phase 1 and Phase 2. Tramadol’s ED50 was 2.97 mg/kg for Phase 1 and 1.79 mg/kg in Phase 2, while fentanyl was more potent at 0.062 mg/kg for Phase 1 and 0.041 mg/kg for Phase 2.
    • Coadministration of those drugs was synergistic.
  • COI: Supported by a project at Universidad Andres Bello.

 

(Loram, 2007) – More effective than or as effective as morphine and amitriptyline for acute ischemic pain but not thermal pain.

  • Measured the effect via motor function impairment and response latencies to noxious thermal and ischemic challenges. Rats given tramadol via IP route at 1, 5, 15, and 25 mg/kg. Morphine was given at 0.01, 0.1, 1, and 5 mg/kg. While amitriptyline was used at 1, 3, and 10 mg/kg.
  • Measured tail flick latency to noxious thermal challenge. Also measured response latency to noxious ischemia induced by a tourniquet inflated at the base of the tail.
  • Results
    • Noxious thermal challenge
      • Tramadol 15 mg/kg caused a 107% increase in response latency. 25 mg/kg was 79%
      • Morphine 1 mg/kg impact was 85%, 5 mg/kg was 138%, and amitriptyline 10 mg/kg was 46%.
    • Noxious ischemia
      • Morphine and amitriptyline effects were not dose-dependent, while the impact of tramadol over the 1-25 mg/kg range increased.

Chronic

Tramadol has shown efficacy in chronic pain conditions including neuropathic pain, cancer-related pain, fibromyalgia, and musculoskeletal pain (MacLean, 2015 ; Finnerup, 2015 ; Schug, 2007). Yet the benefits are sometimes small or inferior to what can be provided by alternative analgesics. The chronic pain studies have usually lasted for only a few months, so it’s unclear if the results are applicable to longer-term use.

Reviews

Effective

(Duehmke, 2017) – Cochrane review of its use for neuropathic pain. Weak evidence supporting efficacy.

  • Only 6 DBRCTs met inclusion criteria and they included 438 participants. The study duration ranged from 4-6 weeks.
  • At least 50% pain intensity reduction was reported in 3 studies with 265 participants. In those, 53% of tramadol patients had a response compared with 30% of placebo patients; NNT of 4.4.
  • Evidence was downgraded to low quality due to small sample sizes and limited duration, along with a risk of bias.

 

(MacLean, 2015) – Review indicating utility in fibromyalgia.

  • (Kaneko, 2014) – Tramadol in an animal model (reserpine-induced myalgia) showed an effect by diminishing tactile allodynia. Administration of naloxone partially blocked the effect.
  • (Biasi, 1998) – 12 humans. Double-blind crossover. Tramadol given 100 mg IV. Results showed a 20.6% reduction in pain from tramadol. But pressure dolorimetry did not clinically differ.
  • (Bennett, 2003) – 315 humans. Tramadol 37.5 mg with 325 mg paracetamol. 48% discontinuation rate compared to 62% with placebo. At study end, tramadol patients reported significantly less pain than placebo patients, with an NNT of 9.
  • (Russell, 2000) – 100 patients. Tramadol 50-400 mg/d. 69% of patients had perceived benefit and tolerated it well. Responders were then enrolled in a double-blind placebo-controlled trial for 6 weeks. 57.1% of patients given tramadol vs. 27% given placebo completed the study with the remainder dropping due to inadequate pain control.
  • COI: None

 

(Finnerup, 2015) – Systematic review indicating tramadol is effective for neuropathic pain in adults.

  • DBRCTs of oral or topical pharmacotherapy for neuropathic pain. Primary outcome measure was NNT for 50% pain relief.
  • 229 studies included. Published studies had greater effects than unpublished studies.
  • Study length: Few lasted longer than 12 weeks and the longest was 24 weeks.
  • Results
    • Trial outcomes tended to be modest.
      • SNRIs: NNT of 6.4
      • Pregabalin: NNT of 7.7
      • Gabapentin: NNT of 7.2
      • Capsaicin high-concentration patches: 10.6
      • Tramadol: 4.7
      • Strong opioids: 4.3
    • Author recommendation
      • Strong recommendation for the use of TCAs, SNRIs, pregabalin, and gabapentin as first-line drugs. Weak recommendation of lidocaine, capsaicin, and tramadol as second-line drugs. And weak recommendation of strong opioids as third-line drugs.
  • COI: Authors have received funding from pharmaceutical companies.

 

(Schug, 2007) – Review of its use in musculoskeletal pain. Recommends tramadol be given, including as an alternative to NSAIDs/paracetamol.

  • Recently there has been a widespread re-examination of the management of musculoskeletal pain, with a general shift away from NSAIDs/paracetamol and towards opioids. NSAIDs are more strongly contraindicated in the elderly and in long-term use.
  • The European League Against Rheumatism recommends opioids as useful alternatives to NSAIDs when those are contraindicated, ineffective, and/or poorly tolerated.
  • The American Pain Society says tramadol can be used alone or with paracetamol/NSAIDs for therapy at any stage of treatment for osteoarthritis.
  • The American College of Rheumatology says the efficacy of tramadol has been found to be comparable to ibuprofen for hip and knee osteoarthritis and that it’s proven efficacious when given alongside NSAIDs in patients who aren’t adequately helped by NSAIDs alone.
  • There is a large body of evidence supporting the use of tramadol, particularly in neuropathic pain, which plays a significant role in low back pain for a large minority of patients.
  • COI: Not reported

Inferior or minimal benefit

(Wiffen, 2017) – Cochrane review. Inadequate evidence for cancer pain with or without paracetamol.

  • Only 10 studies with 958 participants. The studies included people with tumor-related pain who were experiencing moderate to severe pain, with most experiencing at least a 4/10 pain score with current treatment.
  • Study length ranged from one day to 6 months.
  • Doses of 300 to 400 mg/d were most common.
  • Results
    • 9/10 were at a high risk of bias. Results were judged to be very low quality evidence because of widespread lack of blinding of outcome assessment, inadequately described sequence generation, allocation concealment, and small numbers of participants and events.
    • Single comparisons of oral tramadol with codeine/paracetamol or dihydrocodeine or rectal vs. oral tramadol gave no data for key outcomes.
    • 3 studies with 300 participants total compared tramadol with morphine. Only one study combining tramadol, tramadol/paracetamol, and codeine/paracetamol together as “weak opioids” reported results. Weak opioids were linked with a reduction in pain of at least 30% in 47% of participants compared with 82% with morphine. Weak opioids were pain relieving, but less so than morphine.
  • Overall, there is very low quality evidence that it is not as effective as morphine for cancer pain.

 

(Chaparro, 2014) – Cochrane review update. Tramadol is effective for chronic low back pain, but other drugs are more effective.

  • Chronic low back pain. Updating a 2007 review through October 2012 with RCTs from multiple databases. Use of noninjectable opioids for at least 4 weeks was studied and compared with placebo or other treatments.
  • 15 trials with 5540 participants. 12 of those were new.
  • Results
    • Tramadol was significantly better for pain (standard mean difference (SMD) -0.55) and function (SMD -0.18) than placebo.
      • One report of 2 RCTs compared tramadol (200 mg/d) to celecoxib (400 mg/d) and found significantly more celecoxib patients (86% compared to 71%) completed the 6 weeks of follow-up, suggesting tramadol is less effective than celecoxib.
    • Strong opioids (morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol) were all significantly better for pain and function as well.
    • All trials were significantly affected by a high dropout rate. Most studies were over 20% for dropouts; applicable to all opioids, not just tramadol.
  • COI: None

 

(Cepeda, 2006) – Cochrane review of its use in osteoarthritis. It is effective, but it provides a small benefit.

  • Review of 11 RCTs w/ a total of 1019 patients given tramadol or tramadol/paracetamol and 920 patients given placebo or active control. 9 evaluated tramadol alone and two evaluated tramadol plus paracetamol.
    • Around 200 mg tramadol was given or a placebo or an NSAID/different pain reliever.
    • Some of the studies evaluated people for up to three months, others stopped at ~8 weeks.
  • Results
    • Based on the placebo-controlled studies, patients given tramadol had less pain (-8.5 units on 0-100 scale). This is a 12% relative decline in pain intensity from baseline.
      • 50% improved when given placebo, while 69% improve while given tramadol.
    • Patients given tramadol had a 37% increase in the likelihood of reporting moderate improvement (NNT=6). Participants given tramadol had 2.27x the risk of minor adverse effects and 2.6x the risk of developing major adverse effects.
    • Of every 8 people given tramadol, 1 will stop taking the medication due to adverse events, giving an NNH=8 for major adverse events.
      • 18% had minor side effects with placebo compared to 39% with tramadol. And for major side effects it’s 8% vs. 21%.
      • No life-threatening event was reported in tramadol participants.
  • Author conclusion: Tramadol or tramadol/paracetamol decreases pain intensity, produces symptom relief and improves function, but these benefits are small. Benefits are comparable to those seen with paracetamol and they’re coupled with a less favorable safety profile. The side effects greatly disadvantage tramadol compared to other treatments for osteoarthritis.
  • Conflicts – All studies funded by pharmaceutical industry with one exception.

Human research

Effective

(Yoshizawa, 2015) – 12-week-study (uncontrolled) showing it is effective in chronic noncancer pain in Japanese patients.

  • 1316 patients with chronic noncancer pain incurable by non-opioid analgesics.
  • Tramadol was provided at 37.5 mg with paracetamol 325 mg four times per day and that could be increased up to 8 times per day.
  • Results
    • Adverse effects reported in 20.5%, mostly of a non-serious nature (99.4%), including nausea in 6.9%, constipation in 5.0%, dizziness and somnolence in 2.3% each, and vomiting in 1.7%.
      • No event related to drug dependence or respiratory depression was reported.
      • Cardiac disorders in the form of palpitations were reported in 0.2%.
    • 82.8% showed acceptable effectiveness at Week 4 based on physician’s global impression. Numerical rating scale for intensity of pain and EQ-5D utility scores were improved by an average of -2.3 and 0.16 at Week 4, respectively, and the improvement was maintained until Week 12.
      • % assessing tramadol as “effective” was 94.1% at 12 Weeks at 86.3% at last observation.
    • Trend, but not massive, towards lower efficacy ratings in patients with rheumatoid arthritis.
  • COI: Sponsored by Janssen Pharmaceutical.

 

(Norrbring, 2009) – Tramadol is effective in neuropathic pain after spinal cord injury.

  • Sweden. DBRCT. 35 patients randomized to tramadol (n=23) or placebo (n=12). Given either drug for an average of 21 days. Patients were allowed to continue a stable pain medication and they were asked not to change that medication’s dose.
    • Tramadol started at 150 mg/d and that increased every 5 days by 50 mg up to a max of 400 mg/d. If optimal effects were reached or too many adverse effects were noted, patients were told to stop increasing.
    • Pain intensity ratings evaluated on the Borg’s Category Ratio (CR-10) scale.
  • Concomitant drugs present in around 80% of patients, including antiepileptic drugs, antidepressants, and opioids.
  • Results
    • Pain intensity was significantly lower in those given tramadol vs. placebo. Adverse events were substantial and led to withdrawal in 43% of tramadol and 17% of placebo participants.
    • Tiredness, dry mouth, dizziness, and nausea were more common in the tramadol group. While constipation did not significantly differ.
    • Stimulus-evoked pain
      • 10/23 given tramadol and 4/12 given placebo initially had stimulus-evoked pain, i.e. dynamic mechanical allodynia.
      • There were signs based on a small sample size of patients who completed the trial towards reduced allodynia.
  • COI: Grant from the Norrbacka-Eugenia Foundation.

 

(Choi, 2007) – Tramadol is effective at reducing pain when given with paracetamol in osteoarthritis.

  • Korea. 2-week trial of patients with knee osteoarthritis who were stable on NSAIDs and had a mean pain intensity score equal to or greater than 4/10.
  • Randomly received titrated dose or non-titrated dose of 37.5 mg/325 mg TID.
  • 250 patients
  • Results
    • Discontinuation rate significantly lower in titration group: 10.5% vs. 26.2%
      • Discontinuation due to adverse effects was similar until Day 2, but beyond that the rate was much higher in people not titrated.
      • Most common adverse effects: Nausea in 12.1% for titration and 24.6% for non-titration; vomiting in 4% vs. 17.2%; dizziness in 9.7% vs. 22.1%
    • Both associated with a similar decline from baseline in pain: -1.60 vs. -1.68
  • COI: Supported by Janssen.

 

(Boureau, 2003) – Tramadol is effective in postherpetic neuralgia

  • France. Sustained-release tramadol vs. placebo for postherpetic neuralgia in a DBRCT of 127 patients. Duration of 6 weeks.
  • Results
    • Mean pain intensity on Day 43 was significantly lower in tramadol group. The percentage of pain relief through Week 6 was significantly higher in tramadol group and that group also used less rescue medication.
    • No significant difference was found between groups in pain intensity on a 5-point Verbal Scale or in quality of life measurements.
    • Tramadol given at an average of 275.5 mg/d after a 1-week dose adaptation period. No notable difference appeared between groups for adverse events.
  • COI: Not reported

 

(Bennett, 2003) – Tramadol/paracetamol is effective in fibromyalgia.

  • USA. 91-day study comparing tramadol/paracetamol (37.5 mg/325 mg) tablets with placebo.
  • Results
    • Discontinuation for any reason was less common in tramadol/paracetamol group (48% vs. 62%). Tramadol/paracetamol group also had significantly less pain at study end (53 vs. 65 on VAS with a 0-100 scale) and better pain relief (1.7 vs. 0.8 on a -1 to 4 scale).
    • Measures of physical functioning, body pain, and other functional measures were significantly better in tramadol group.
    • Rate of discontinuation due to lack of efficacy was significantly lower at 29% vs. 51%.
    • 42% of tramadol/paracetamol group had at least a 30% reduction in pain score compared with 24% of placebo group. And 35% had at least a 50% reduction, compared with 18%.
    • Mean dose was 4.0 tablets, yielding 151 mg/d tramadol and 1238 mg/d paracetamol.
    • Constipation was the only significantly higher adverse event in the tramadol/paracetamol group, but nausea, drowsiness, and pruritis were numerically higher as well.
  • COI: Funded by Ortho McNeil

 

(Wilder-Smith, 2001) – Tramadol is effective in combination with NSAIDs for osteoarthritis pain that’s not controlled by NSAIDs alone.

  • Open-label trial of tramadol vs. dihydrocodeine in long-acting preparations along with NSAIDs. Patients were unresponsive to NSAIDs alone and had strong pain from osteoarthritis.
  • 60 patients total. 1-month trial.
  • Results
    • Pain at rest and movement declined significantly with both opioids from median pre-treatment verbal ratings over 3 to 1 and below from the second treatment day onwards.
    • Pain at rest was significantly lower with tramadol, but ratings were similar for pain on movement.
    • Dose
      • Mean Day 28 dose: 203 mg for tramadol vs. 130 mg of dihydrocodeine.
    • Change in bowel function and symptoms were minor with both, but frequency of defecation was lower with dihydrocodeine and stools were harder (P=0.04).
    • Sensation and pain thresholds were lower pre-treatment vs. controls (those with NSAID-responsive treatment) and increased w/ treatment. The antinociceptive effects were higher in the tramadol group and distant from the osteoarthritic joint.
  • COI: Supported by research funds from Grunenthal.

 

(Mullican, 2001) – Tramadol/paracetamol is similar in efficacy to codeine/paracetamol, with both being effective for chronic pain

  • USA. 4-week DBRCT. Comparing tramadol/paracetamol (37.5 mg/325 mg) tablets with codeine/paracetamol (30 mg/300 mg) for chronic nonmalignant low back pain, osteoarthritis pain, or both in adults.
  • 462 patients total. 24% had chronic low back pain, 35% had osteoarthritis pain, 41% reported both.
    • 67% received tramadol combo and 33% received codeine combo.
  • Results
    • Mean dose was 131 mg tramadol with 1133 mg paracetamol vs. 105 mg codeine with 1054 mg paracetamol.
    • Total pain relief (11.9 with tramadol and 11.4 with codeine) and sum of pain intensity differences (3.8 for tramadol and 3.3 for codeine) were comparable throughout the study.
    • Adverse event incidence was similar. Though codeine group had a higher drowsiness (24% vs. 17%) and constipation rate (21% vs. 11%).
      • Tramadol group had more headache (11% vs. 7%).
    • Discontinuation
      • Similar rate between groups. 20% of tramadol and 21% of codeine patients withdrew.
    • Neither had clinically significant lab value changes. 11 given tramadol/paracetamol had an increase in liver enzymes from normal to above-normal range, but an equal number had elevated levels before the study that resolved during tramadol/paracetamol therapy.
  • COI: Supported by RW Johnson Pharmaceutical Research Institute and Ortho-McNeil Pharmaceutical.

 

(Harati, 2000) – Maintenance of benefit in diabetic neuropathy for 6 months in an open-label setting.

  • This was a 6-month open extension trial that followed a 6-week DBRCT. Patients had painful diabetic neuropathy and were eligible to continue treatment for 6 months if they completed the DBRCT portion. All received 50-400 mg/d.
  • Total of 117 patients: 56 had been given tramadol initially and 61 had been on placebo.
  • Results
    • At the start of the trial, former tramadol patients had a significantly lower mean pain intensity score of 1.4 vs. 2.2 (p<0.001).
    • By Day 90: Both had a mean pain intensity score of 1.4 and that score was maintained through the story.
    • 4 discontinued due to ineffective pain relief; 13 discontinued due to adverse events. Most common adverse effects: constipation, nausea, and headache.
  • COI: Not reported

 

(Sindrup, 1999) – Tramadol relieves pain and allodynia over a 4-week period l in polyneuropathy.

  • Denmark. DBRCT cross-over. 45 patients given tramadol XR at 200 mg/d and up to 400 mg/d. Patients were tested based on pain scores and mechanical allodynia induced by stimulation with an electronic toothbrush.
  • 34 patients completed the study. 4 weeks with tramadol and 4 weeks with placebo.
    • 50 patients were invited to the study. 2 were not interested. 7 withdrew because of side effects in the first double-blind period (5 on tramadol and 2 on placebo), while 2 withdrew in the second period (both on tramadol).
  • Results
    • Final tramadol dose: 400 mg/d in 23, 300 mg/d in 4, and 200 mg/d in 7.
    • Pain ratings, paresthesia, and touch-evoked pain ratings were significantly lower with tramadol compared to placebo. Allodynia ratings were also significantly lower.
    • NNT for one patient to have at least 50% pain relief: 4.3 (95% CI: 2.4-20).
    • Median consumption of the rescue medication paracetamol was significantly lower in tramadol group.
    • Fraction preferring tramadol to placebo for pain relief alone was 30/34, then 12/34 for side effects alone, and 27/34 overall.
    • Pharmacokinetics
      • 2 were poor metabolizers, the rest were EM. One of the two had no effect while the other had a marked response to tramadol.
  • COI: Not reported

 

(Harati, 1998) – Tramadol is effective for diabetic neuropathy.

  • 131 patients with diabetes and distal symmetric diabetic neuropathy. DBRCT for 42 days. No pain medications other than the study medications were allowed.
  • The dose began at 50 mg/d, escalated to 200 mg/d and could eventually rise up to 400 mg/d depending on response.
  • Results
    • Discontinuation
      • 43/65 tramadol patients finished. 9 left due to it being ineffective, 9 left for adverse events.
      • 39/66 placebo patients finished. 22 left due to it being ineffective, 1 left for adverse events.
    • Efficacy
      • By Day 14, tramadol patients had significantly less pain and that difference was even greater by Day 28. At the final visit, the mean pain intensity was significantly lower and the average dose was 210 mg/d. Mean pain relief was also significantly greater.
      • Patients given tramadol scores significantly better for physical and social functioning.
    • Adverse
      • Tramadol: 23.1% had nausea, 21.5% had constipation, 16.9% had headache, and 12.3% had drowsiness.
      • The most common adverse events w/ tramadol leading to discontinuation were nausea and dyspepsia.
    • Lab values were similar between groups.
  • COI: Not reported

Inferior or minimal benefit

(Leppert, 2010) – Dihydrocodeine is significantly more effective than tramadol for cancer pain.

  • Poland. Randomized study of 40 opioid-naïve cancer patients with nociceptive cancer pain. Tramadol or dihydrocodeine controlled-release tablets given for 7 days then switched for another 7 days.
    • Starting dose of 100 mg BID for tramadol CR vs. dihydrocodeine 60 mg BID titrated to a max of 600 mg tramadol and 360 mg dihydrocodeine.
  • Results
    • 30/40 completed the study.
      • 4 discontinued due to natural deterioration of their condition.
      • 3 treated with tramadol and 2 with dihydrocodeine did not achieve satisfactory analgesia during titration.
    • Dihydrocodeine provided significantly better analgesia and it produced significantly better functional scores, less fatigue, less pain and sleep disturbances, less nausea and vomiting, and better appetite. Tramadol produced less constipation.
    • Daily tramadol dose was 286 mg, dihydrocodeine was 138 mg.
    • 19 patients preferred dihydrocodeine and 4 preferred tramadol and 7 considered them equally effective.
  • COI: Financial support from Poznan University of Medical Sciences.

Depression

There are a couple pharmacological reasons to believe tramadol could alleviate depression. First, it is an SNRI that’s comparable to antidepressants like venlafaxine. Second, opioids are known to have mood-elevating properties, including in the absence of recreational effects.

Little research has been conducted on using tramadol for depression, but there are signs of benefit. One study of people with chronic low back pain and depression found tramadol was significantly more effective than the NSAID celecoxib for alleviating depression, while the treatments were similar for pain and disability scores.

A few case reports have also shown beneficial effects, usually in patients who received tramadol for pain and unexpectedly found it helped with depression. More placebo-controlled research should be carried out to see if the benefits are reliably significant.

Studies in animals found it is antidepressant on its own or when combined with ketamine or SSRIs (Caspani, 2014 ; Yang, 2012). Effects on norepinephrine could be important, since adrenergic antagonists block the beneficial effects of tramadol, while naloxone and serotonergic antagonists do not get rid of the antidepressant properties (Rojas-Corrales, 1998). Other systems, such as imidazoline receptors, could also be involved (Jesse, 2010).

Human research

Effective

(Tetsunaga, 2015) – Effective for pain and depression when cooccurring in low back pain.

  • 70 patients with chronic low back pain and depression based on the Self-Rating Depression Scale (SDS). Randomly assigned to two 8-week periods, one with tramadol-paracetamol and one with NSAIDs (two celecoxoib 200 mg tablets daily).
  • Evaluated using the Numerical Rating Scale (NRS), Oswestry Disability Index (ODI), Pain Disability Assessment Scale (PDAS), Hospital Anxiety and Depression Scale (HADS), SDS, and Pain Catastrophizing Scale (PCS).
  • Results
    • NRS and SDS were significantly lower in tramadol vs. NSAID group. No significant differences for ODI, PDAS, and PCS scores between groups.
    • No significant difference in the anxiety component of the HADS, but a significantly lower depression score with tramadol.
    • Nausea was significantly more common with tramadol, constipation was equal between groups, and drowsiness was similar.
  • COI: None

Case reports

Effective

(Rougemont-Bucking, 2017) – Tramadol may be helpful in depression, based on two case reports

  • Case 1
    • 42-year-old male with depression. He also had many PTSD-like symptoms stemming from interpersonal conflict at work. No history of psychiatric or somatic disease.
    • He received escitalopram 5 mg/d and had clear mood improvement. But 4 months later he withdrew from the drug due to not wanting to be on a psychoactive substance regularly. The workplace stress and other life stressors continued and he reported insomnia, traumatic intrusions, and depressive mood.
      • Additional treatment with zolpidem, oxazepam, and quetiapine was provided but he would only take those drugs on rotation at night for sleep.
    • While travelling he had an injury and received tramadol in the ED. While on tramadol he had marked pain reduction and clear mood improvement. He continued taking tramadol after the low back pain resolved and his psychiatrist agreed to continue the prescription with him receiving 15-35 mg once or twice per day as needed in accordance with mood and the day’s challenges.
      • He never used more than 3 days in a row or 5 days in a week.
    • Mood elevation would be noticeable after an hour and last around 7 hours.
    • For several months: Continued to treat depression as needed with tramadol and he no longer needed the other medications for insomnia.
  • Case 2
    • 53-year-old female. In treatment for many years with many healthcare providers due to recurrent depression and intermittent alcohol abuse, largely stemming from a long history of trauma.
    • At various points she received escitalopram, venlafaxine, mirtazapine, sertraline, fluoxetine, and trazodone. She did not have a durable improvement of mood or functioning from those.
    • She eventually needed surgery and received tramadol for pain. She reported marked mood improvement in the subsequent weeks and said it helped her soothe her suffering more than any antidepressant.
    • Her psychiatrist allowed her to continue the drug and she received 100 mg/d.
    • After 6 months of daily use: Tapered off within 2 months. She reported generally feeling better and she abstained from alcohol.
    • But due to a new life stressor, her depression and alcohol use returned. Her psychiatrist gave her quetiapine 100 mg/d along with alprazolam up to 2 mg/d as needed. Her doctor then remembered the effect of tramadol and prescribed it again. On the first day of restarting tramadol use she reported a marked decline in depression and alcohol craving.
    • In the following months: Daily use of tramadol at 50 to 100 mg and continued to avoid alcohol abuse.
  • COI: None

 

(Reeves, 2008) – Apparent depression relief from tramadol and then from venlafaxine. Alternatively, long-term tramadol use produced persistent depression.

  • 41-year-old female with no personal or family mental illness history underwent surgery and then had chronic low back pain.
  • She was given tramadol 50 mg twice daily as needed, which worked well for pain.
  • 5 years into treatment she had elevated liver enzymes without identifiable liver disease. Tramadol was discontinued; with time her enzymes returned to normal. Treatment switched to tizanidine 4 mg up to three times daily as needed, which worked reasonably well for pain.
  • But within weeks of stopping tramadol she had significant depression with anhedonia, feelings of helplessness, lack of energy, and insomnia. She became suicidal and needed hospitalization for a week.
  • Began on venlafaxine with good response over a 2-3 week period. When she eventually stopped the venlafaxine due to feeling she no longer needed it, her depression returned. Venlafaxine was able to get rid of the depression again when restarting.

 

(Spencer, 2000) – Rapid-onset antidepressant effect from IM tramadol.

  • 25-year-old male admitted with severe, suicidal depression. Due to chronic back pain he was started on IM tramadol. Before starting he was markedly depressed with frequent suicidal thoughts, affect was flattened, and he was very dysphoric.
  • Following tramadol there was a striking difference with depression lifted and he now felt great, was considering his future, and was determined to get better. He then stopped tramadol due to needing to begin cipramil. The next morning he had deteriorated and made a serious overdose attempt, though he survived.
  • Author of this paper believes it’d be worthwhile to study tramadol as a potential rapid-onset IM or IV antidepressant.

Animal research

Effective

(Ubale, 2015) – Effective as an antidepressant in mice

  • Mice. Tramadol 20 and 40 mg/kg IP either alone or with fluoxetine 20 mg/kg IP. Given either once daily for acute (7 days) or chronic (14 days) period.
  • Evaluated using the FST and TST.
  • Results
    • Tramadol at both doses produced a significant antidepressant effect alone or with fluoxetine. Alone, fluoxetine was superior to either tramadol dose, but the combination of tramadol and fluoxetine was better than the single-drug conditions.
    • Tramadol and fluoxetine groups did not significantly differ from control in the open field test to evaluate locomotion.
  • COI: None.

 

(Caspani, 2014) – Reduces anxiety and depression-like symptoms in rats when exposed to chronic constriction injury model of neuropathic pain

  • Rats were exposed to chronic constriction injury (CCI) of the sciatic nerve, a model of neuropathic pain. They were then tested for anxiety symptoms via the elevated plus maze test (EPM) and for depression via the forced swimming test (FST). Pain was also measured.
  • Results
    • CCI rats showed an 82% decline in paw withdrawal threshold in the electronic von Frey test (to measure mechanical sensitivity). Tramadol, on the other hand, increased paw withdrawal threshold by 336% in CCI rats and only increased it by 16% in sham rats.
    • Tramadol increased the time spent on the open arms of the EPM in CCI rats by 67%, while not altering sham rat behavior.
    • FST: CCI rats had 28% longer immobility than sham. Tramadol reduced the immobility time in CCI rats by 22%, while not affecting sham rats.
  • COI: Support from the Innovative Medicines Initiative Joint Undertaking. Financial contribution from the EU’s Seventh Framework Program and EFPIA companies. Some authors are scientific collaborators from Boehringer Ingelheim.

 

(Yang, 2012) – It does not have antidepressant effects of its own but it does potentiate ketamine at 5 mg/kg. Antidepressant effects exist at 10 mg/kg.

  • Background
    • TrkB is a high affinity catalytic receptor for BDNF and mediates the multiple effects of BDNF.
  • Rats tested in the forced swimming test.
  • Results
    • Tramadol 5 mg/kg IP did not have antidepressant effects not did it alter BDNF or TrkB level. Reportedly 10 mg/kg did have antidepressant effects, however.
    • Pretreatment with tramadol 5 mg/kg enhanced the effect of ketamine 10 mg/kg IP and further upregulated BDNF and TrkB levels in the hippocampus.
  • COI: Supported by the National Natural Science Foundation of China.

 

(Jesse, 2010) – It has antidepressant properties that may involve noradrenergic, dopaminergic, and imidazoline systems.

  • Antidepressant-like properties studied in mice with the forced swim test. Tramadol given at 40 mg/kg oral.
  • Results
    • Drugs that were effective at blocking the antidepressant-like effects of tramadol: Yohimbine 1 mg/kg IP (α2 adrenoreceptor antagonist), AMPT 100 mg/kg IP (tyrosine hydroxylase inhibitor), efaroxan 1 mg/kg IP (imidazoline I1/α2 adrenoreceptor antagonist), idazoxan 0.06 mg/kg IP (imidazoline I2/α2 adrenoreceptor antagonist), antazoline 5 mg/kg IP (ligand with high I2 affinity), haloperidol 0.2 mg/kg (nonselective DA receptor antagonist), SCH23390 0.05 mg/kg SC (D1 receptor antagonist), sulpiridine 50 mg/kg IP (D2/D3 antagonist).
    • Drugs that didn’t block the antidepressant effects: Prazosin 1 mg/kg (α1-adrenoreceptor antagonist) and caffeine 3 mg/kg IP (nonselective adenosine receptor antagonist)
    • Also, it was found tramadol did not alter MAO-A or MAO-B enzyme activity in the brain.
  • COI:  “The financial support by the UFSM, FAPERGS, CAPES and CNPq is gratefully acknowledged. This study was supported in part by the FINEPresearchgrant “RedeInstituto Brasileiro de Neurociência (IBNNet)” # 01.06.0842-00.”

 

(Yalcin, 2007) – Antidepressant effects in mice, possibly involving noradrenergic activity.

  • Comparing tramadol to desipramine using the chronic mild stress model.
  • Results
    • Unpredictable chronic mild stress led to a degradation of coat state and decreased grooming behavior. This could be reversed with tramadol 20 mg/kg or desipramine 10 mg/kg.
    • The nonselective β-adrenoreceptor antagonist propranolol and the selective β2 antagonist ICI 118,551 both successfully reversed the antidepressant effects of both drugs.
    • Chronic tramadol and desipramine (brains studied 2 days after last injection) increased the level of norepinephrine and its metabolite MHPG in the locus coeruleus but not in the cerebellum, whereas only MHPG level increased in the hypothalamus. Tramadol increased levels of both in the hippocampus, while desipramine only increased norepinephrine level in that region.
  • COI: Not reported

 

(Rojas-Corrales, 2002) – In rats, tramadol does have an antidepressant effect.

  • Helpless rats were given either tramadol (10 or 20 mg/kg) or (-)-methadone at 2 or 4 mg/kg. Drugs given via IP 20 minutes before each daily testing session.
    • Tested in a learned helplessness model in which rats were exposed to an inescapable shock. 48 hours after the inescapable shock treatment, animals went through three consecutive days of testing in which they could escape the shock or avoid it based on a light cue.
  • Results
    • Tramadol (both 10 and 20 mg/kg) and methadone rats showed a decreased number of failures to avoid or escape the aversive shock stimulus on Days 2 and 3 of testing vs. controls.
    • The effect of tramadol was greater on Day 3 vs. Day 2 (p=0.001 vs. p=0.025). Tendency towards efficacy on Day 1, but not significant.
  • COI: Partially supported by money from Grunenthal.

 

(Rojas-Corrales, 1998) – Antidepressant effects exist in mice and are not opioid-dependent.

  • Forced swim test in mice. Both racemate tramadol and its (-)-enantiomer displayed dose-dependent reduction in immobility. The effect induced by (+)-tramadol was not significant.
  • Phentolamine, an α-adrenoreceptor antagonist, and yohimbine, an α2-adrenoreceptor antagonist, could counter the immobility reduction action of tramadol. Propranolol, a beta adrenoreceptor antagonist, also countered the immobility reducing action.
  • Neither the serotonergic blocker methysergide nor naloxone antagonized the efficacy of tramadol.
  • COI: Not reported

Opioid dependence

Because it has opioid effects, it has been studied for use in opioid dependence, mostly as a medication to provide during detoxification. It is more effective than clonidine in this setting, similarly effective to methadone, and less effective than buprenorphine (Dunn, 2016 ; Zarghami, 2012). It can alleviate withdrawal symptoms and then be tapered on its own to help patients reach abstinence.

In the US there are still legal barriers to using it for this purpose (Williams, 2016). Scheduled drugs can only be provided for opioid detox if a treatment program is registered with the DEA as a narcotic treatment program and if the FDA has specifically approved the substance for that indication. Tramadol is not approved for opioid dependence, unlike methadone and buprenorphine. There is an exception to this rule, but it only covers three days of treatment (Dunn, 2017).

(Dunn, 2016) – It appears somewhat effective (between the efficacy of clonidine and buprenorphine) during opioid withdrawal.

  • Tramadol extended-release was given. 102 opioid-dependent participants were enrolled in a 28-day residential detox study. They were randomly assigned to receive either clonidine (Day 1 dose of 0.4 QID), tramadol (Day 1 dose of 300 mg oral), or buprenorphine (Day 1 dose of 8 mg sublingual) in a double-blind manner.
    • Study drugs were tapered to zero over a 7-day period.
  • Results
    • Tramadol produced withdrawal ratings midway between clonidine and buprenorphine. Participants in the clonidine group were significantly less likely to complete the taper relative to buprenorphine group (61% vs. 93%), while the tramadol group’s 72% rate did not differ significantly from either group.
  • COI: NIDA R01DA018125 (Strain).

(Zarghami, 2012) – Tramadol is similarly effective to methadone in opioid withdrawal

  • Iran. 70 patients randomized to methadone 60 mg/d or tramadol 600 mg/d. Those doses were continued for 3 days followed by an 11-day taper to reach abstinence.
  • Objective Opioid Withdrawal Scale (OOWS) used to assess withdrawal symptoms.
  • Results
    • No significant differences in the OOWS scores between groups. Dropout rate was similar between groups. Side effects in tramadol group were the same or less common than in methadone group, with the exception of perspiration.
  • COI: Not reported

(Lofwall, 2007) – Tramadol is moderately effective in suppressing heroin withdrawal, while lacking strong abuse potential.

  • USA. 10 adult heroin-dependent patients who all tested positive for opiates. Randomized, placebo-controlled, crossover study with subjects initially maintained on morphine 15 mg SC QID and then after at least 7 days of morphine administration the testing began.
  • Oral tramadol (50, 100, 200, and 400 mg), IM morphine (7.5 and 15 mg), IM naloxone (0.1 and 0.2 mg), and placebo were tested.
  • Results
    • Tramadol 50 and 100 mg failed to produce significant VAS ratings for any effect vs. placebo.
    • In the first 120 min, tramadol 200 and 400 mg produced significantly higher ratings vs. placebo for Any Drug Effects, Bad Effects, and Feel Sick, but the majority of these tramadol effects were lower in magnitude than effects from naloxone 0.2 mg.
    • Drug class identification
      • Tramadol 50 and 100 mg were most frequently identified as placebo, while higher doses were increasingly identified as not placebo (over 50% per dose).
      • Some subjects with tramadol 200 mg identified it as an opioid (n=3), antidepressant (n=1), or placebo (n=3).
      • Identifications with 200 mg tramadol failed to reliably predict identifications with 400 mg. Among those identifying 200 mg as an opioid agonist or antagonist, only 50% identified 400 mg more frequently in that same class.
      • There was a time-dependent effect. Subjects first identified doses as opioid antagonist at a mean time of 34 min and as an agonist at 81 min.
    • Opioid adjective rating questionnaire
      • On participant-rated agonist scale, morphine 15 mg produced higher scores vs. placebo. Naloxone and tramadol didn’t produce sustained changed on that scale.
      • On observer-rated antagonist adjective scale, morphine and tramadol showed evidence of withdrawal suppression, however morphine immediately reduced antagonist adjective scale scores while tramadol 200/400 mg only began doing so at 120 and 90 min, respectively.
    • Physiological
      • VS placebo, morphine 15 mg significantly decreased SBP and DBP along with pupil diameter. Tramadol produced few significant differences vs. placebo. When significant effects were seen they were intermittent, such as tramadol 400 mg increasing pupil diameter at 45, 75, and 90 min then decreasing diameter at 210 min.
  • COI: Supported by NIDA.

(Sobey, 2003) – Tramadol is more effective than clonidine in heroin withdrawal.

  • USA. 59 patients detoxed with tramadol compared to 85 with clonidine. Compared based on withdrawal scores and percent who left the program against medical advice.
  • Tramadol given 100 mg orally every 4 hours for one day, then every 6 hours for one day, then every 8 hours for one day. Then decreased to 50 mg oral every 6 hours for one day, every 8 hours for one day, and every 12 hours for one day.
  • Results
    • Mean symptom levels peaked on day 3, with clonidine mean symptom speaking at 1.82 and tramadol peaking at 1.16.
    • Patients given tramadol had only 23% the risk of leaving against medical advice and they scored an average of 0.24 points lower on a 0-3 point withdrawal symptom scale.
  • COI: Not reported

Local Anesthesia

Tramadol may have local anesthetic effects. It was equally effective to lidocaine when locally injected to provide sensory blockade during tendon repair surgery (Kargi, 2008) and patients given tramadol didn’t need postoperative analgesia, unlike those given lidocaine.

When applied locally it prolongs the sensory blockade offered by mepivacaine (Kapral, 1999). The mechanism of this effect is unknown, but a study in rats found naloxone did not block the local effects of tramadol injection, suggesting it is not coming from an opioidergic effect (Sousa, 2015).

Human research

(Kargi, 2008) – It is an effective local anesthetic in tendon repair surgery of the hand.

  • Turkey. Double-blind study. 20 patients given either 5% tramadol plus adrenaline or 2% lidocaine plus adrenaline.
  • Results
    • No difference in the quality of sensory blockade or the incidence of side effects between groups. Only those given tramadol did not require post-operative analgesia.
  • COI: None

 

(Kapral, 1999) – It prolongs the duration of axillary brachial plexus blockade caused by mepivacaine when locally applied

  • USA. RCT comparing mepivacaine, mepivacaine + 100 mg tramadol, and mepivacine + 100 mg tramadol IV.
  • 60 patients scheduled for forearm and hand surgery after trauma who needed brachial plexus anesthesia.
  • Results
    • Duration of sensory and motor block was significantly longer in the mepivacaine + tramadol group compared to mepivacaine alone or mepivacaine combined with IV tramadol.
    • Hemodynamics remained unchanged in all patients.
  • COI: Not reported

Animal research

(Sousa, 2015) – Tramadol is a local analgesic via a non-opioidergic pathway

  • Rats received 5 mg tramadol either IV or intraplantar and some also received naloxone 200 μg.
  • The plantar incision model is a postoperative pain model that’s been used for decades.
  • Results
    • Mechanical hyperalgesia was not observed in the intraplantar tramadol group. Naloxone given via the same route did not block that beneficial effect.
    • In the IV tramadol group, analgesia was only seen starting 45 min later and it was absent in rats also given naloxone.
    • Intraplantar administration gave an effect during the entire 60-min observation period and the benefit was greater than with IV administration.
  • COI: Not reported

Sexual function

Tramadol has been investigated as a treatment for premature ejaculation (Abdel-Hamid, 2015 ; Kaynar, 2012). Like some antidepressants, it does increase the time to ejaculation, but those benefits could be accompanied by reduced pleasure, anorgasmia, or erectile dysfunction in some people.

Its effect on ejaculation latency could be coming from multiple mechanisms. Opioids are known to inhibit ejaculation, as are serotonergic drugs.

Long-term use of opioids is associated with hormonal changes, including low testosterone, which could potentially inhibit the benefit of long-term daily tramadol use.

Humans

Effective

(Abdel-Hamid, 2015) – Review of its use for sexual function. Inadequate research in that area, though signals of benefit.

  • Benefit was evaluated in 11 clinical trials and 6 systemic reviews (incl. 3 meta-analyses). Tramadol is prescribed off-label for premature ejaculation.
  • Results
    • Evidence is inadequate with a trend towards benefit for premature ejaculation.
      • The studies lasted 3-24 weeks. Overall effect size when excluding an outlier report from a questionable author who had 3 clinical studies retracted in the past few years was 1.02 minutes.
    • Risks
      • Inadequate evidence of impact on erectile dysfunction, decreased libido, hypogonadism, anorgasmia, and risky sexual behaviors.
      • Opioids in chronic pain are linked to increased risk of low testosterone and erectile dysfunction.
  • COI: None

 

(Kaynar, 2012) – It is effective for premature ejaculation

  • Turkey. Single-blind placebo-controlled crossover study with 60 lifelong patients with premature ejaculation, defined as intravaginal ejaculation latency time (IELT) under 60 seconds in 90% of intercourse episodes. Efficacy evaluated via IELT, ability of ejaculation control, and sexual satisfaction.
  • 8-week treatment period. Tramadol 25 mg was taken 2 hours before sexual activity.
  • Results
    • At study end, the tramadol group had significantly superior values on all three measures of effect. Increase in IELT from 30.66 sec to 55.83 sec in placebo group vs. 38.83 to 154.67 sec in tramadol group.
    • 20% had mild nausea and headache with tramadol, and 6.5% had mild drowsiness, whereas no side effects were reported in placebo group.
  • COI: Not reported

 

(Bar-Or, 2011) – Two DBRCTs showing tramadol does prolong ejaculation time in premature ejaculation

  • Two 12-week DBRCT Phase 3 trials of healthy men with a history of lifelong premature ejaculation. They had intravaginal ejaculation latency time (IELT) of 2 minutes or less.
    • Patients needed to have a stable, monogamous, heterosexual relationship at least 6 months in length.
    • They took the study medication 2-8 hours before engaging in vaginal intercourse, with an interval between uses of at least 20 hours.
  • 604 ITT subjects randomized to placebo, 62 mg orally disintegrating tramadol (Zertane), or 89 mg tramadol.
  • Results
    • Median IELT compared to placebo increased significantly, with a rise of 0.6 min in placebo, 1.2 min in tramadol 62 mg, and 1.5 min in 89 mg tramadol.
    • Tramadol was well-tolerated. Discontinuation in 0% of placebo, 1% of 62 mg, and 1.6% of 89 mg patients.
    • Female partners
      • Baseline PEP scores show a large % of women had poor or very poor satisfaction with intercourse (69%), partner’s control over ejaculation (86%), and quite a bit or extreme distress related to partner’s speed of ejaculation (52%), and interpersonal difficulty (40%).
      • With tramadol there was a significantly greater improvement in those categories, such as 67% vs. 53% for satisfaction with sexual intercourse.
  • COI: Funded by Ampio Pharmaceuticals.

Inferior or minimally effective

(Alghobary, 2010) – Paroxetine is more effective than tramadol for improving premature ejaculation.

  • Egypt. Measured the effect using the intravaginal ejaculatory latency time (IELT) and the Arabic Index of PE (AIPE).
  • 35 cases with lifelong premature ejaculation. Patients were randomized to either tramadol on-demand at 50 mg (2-3 hours before intercourse) or daily paroxetine at 20 mg, then they were switched.
  • Results
    • Tramadol and paroxetine significantly increased IELT at 6 weeks. Tramadol’s increase was 7-fold, while paroxetine’s was 11-fold.
      • After 12 weeks, a decline of IELT to 5-fold was seen with tramadol, whereas paroxetine became more effective, increasing IELT to 22-fold.
      • Tramadol improved AIPE score significantly after 6, but not 12 weeks. Paroxetine was significantly effective at both times.
    • Well-tolerated. No serious side effects apart from mild headache and gastric upset with paroxetine, and mainly gastric upset with tramadol.
    • No significant impact from either on libido. Significantly less erection was recorded at both times for tramadol. Paroxetine was associated with significantly better erection than with tramadol at 6 weeks.
  • COI: None

Neuroprotection

It protects against ischemia-reperfusion brain damage in animals and is associated with a reduction in inflammatory processes and oxidative stress (Akkurt, 2018 ; Nagakannan, 2012). Ischemia causes damage in large part from excitotoxicity and oxidative stress. Exactly how tramadol yields these benefits is unknown. One possibility is that opioid receptor agonism activated PI3K/AKT signaling, which has been associated with neuroprotection.

(Akkurt, 2018) – Protective in rats exposed to ischemia reperfusion injury

  • Rats exposed to ischemia-reperfusion insult. Tramadol was given four hours after blocking blood flow. After sacrifice, levels of pyknotic and necrotic neurons in hippocampal CA1, CA2, CA3, and parietal cortical regions were examined.
    • Also, IL-1β, IL-10, MDA, NO, TNF-α, caspase-3, beclin-1, Atg12, LC3II/LC3I levels were measured.
  • Acute group was given tramadol for 3 days and then sacrificed, while the chronic group was given tramadol for 10 days and then sacrificed.
  • The injury was caused by totally occluding bilateral internal carotid arteries for 30 min. Tramadol was then given at 0.6 mg/kg/d infused via IP route.
  • Results
    • Injury was linked to severe edema and significant inflammatory cell infiltrates were seen. The inflammatory process was somewhat lighter in the chronic vs. acute group.
    • Pyknotic and necrotic neuron numbers were significantly lower in the tramadol acute group and chronic group vs. animals not given tramadol.
    • Tramadol inhibited perivascular edema, intercellular organization disorder, parietal and hippocampal neuronal necrosis, inflammatory cell infiltration in both periods of I/R injury.
  • COI: None

(Takhtfooladi, 2013) – Neuroprotective in a model of ischemia-reperfusion injury in rats

  • Tramadol animals received 20 mg/kg IV immediately before reperfusion. Animals were killed 24 hours after reperfusion for further examination.
    • Hind limb ischemia was induced by clamping the femoral artery. Ischemia was caused for 2 hours followed by 24 hours of reperfusion.
  • Results
    • Brain water content
      • Tramadol group had significantly lower brain water content, indicating less edema. (p<0.002 w/ 61.90% vs. 66.78%)
    • Lipid peroxidation
      • Significantly lower lipid peroxidation (p<0.004). 1.50 nM/mg protein vs. 2.21 nM/mg protein
    • Histological analysis
      • Pathological changes included inflammatory cell infiltration, nerve cells with different levels of swelling, perivascular edema formation, partial destruction of cerebral parenchymal architecture. Pathological changes were significantly lower in the tramadol group.
      • Significant difference between groups (p=0.006).
  • COI: Not reported

(Nagakannan, 2012) – Neuroprotective against transient forebrain ischemia in rats.

  • Rats were pretreated with tramadol at 10 and 20 mg/kg IP for 4 days and then subjected to 30 min occlusion of bilateral common carotid arteries followed by 24 h of reperfusion.
  • Results
    • Tramadol attenuated the postischemic motor impairment that could be seen in sensorimotor test performance. It also significantly reduced lipid peroxidation in the brain (p<0.001).
  • COI: None

Cardioprotection

Tramadol can reduce myocardial injury, inflammatory responses, and oxidative stress in animals under ischemic conditions like those caused by myocardial infarction or in some clinical procedures, such as cardiac surgery (Zhang, 2009). However, in patients undergoing coronary artery bypass, tramadol use was associated with worse outcomes as seen by a higher troponin level, indicating greater cardiac damage (Wagner, 2010). The negative finding in the Wagner (2010) paper could be associated with a problematic level of serotonin activity (the dose was fairly high at two administrations of 200 mg and a couple patients showed serotonin toxicity symptoms), which could constrict diseased coronary arteries and exacerbate ischemic damage.

If cardioprotective effects are possible, they may be associated with opioid activity or noradrenergic effects. In rats, KOR and DOR are found on atrial and ventricular tissue, while MOR is absent. Tramadol might have agonist effects at KOR and DOR, providing a potential mechanism of efficacy, since there is evidence that those receptors are therapeutic targets.

Zhang (2009) showed a reduction in NF-κΒ activation. NF-κΒ activation is involved in cardiac ischemia-reperfusion damage.

Humans

Ineffective

(Wagner, 2010) – Tramadol was associated with worse cardiac surgery outcomes, with indications of higher ischemic damage.

  • Background
    • Remote ischemic preconditioning involves brief ischemia of one organ or tissue that then offers protection to another organ against sustained ischemia-reperfusion injury.
  • Czech Republic. Patients were undergoing coronary artery bypass grafting with cold-crystalloid cardioplegia. Patients were exposed to late phase of remote ischemic preconditioning (L-RIPC) or preoperative tramadol.
    • L-RIPC involved three five min cycles of upper limb ischemia and 3 five min pauses using blood pressure cuff inflation 18 h prior to operation.
    • Tramadol dose was 200 mg the day before the operation and six hours prior to the operation.
  • 101 adults assigned to the L-RIPC, control, or tramadol groups.
  • Results
    • L-RIPC was linked to significantly lower cardiac injury, beyond the level of reduction seen with cold-crystalloid cardioplegia. Tramadol, on the other hand, worsened myocardial injury with a higher troponin level.
    • iNOS expression significantly increased in control and L-RIPC groups, while being dampened in tramadol group. L-RIPC did not augment iNOS.
  • COI: Not reported

Animals

Effective

(Zhang, 2009) – Tramadol can reduce myocardial infarct size and NF-κβ activation in rats

  • Rats were exposed to coronary artery occlusion with or without pretreatment with tramadol 12.5 mg/kg IV.
  • Results
    • Infarct size was reduced from 44.9% to 31.6% with tramadol. Expression of NF-κβ and its mRNA and intercellular adhesion molecule-1 mRNA was significantly lowered by tramadol. Flow cytometry assay revealed tramadol attenuated NF-κβ activation by 13.4%.
    • No significant change in BP or HR following tramadol administration.
  • COI: Not reported

 

(Bilir, 2007) – Tramadol can reduce ischemia-reperfusion injury in isolated rat hearts.

  • Isolated rat hearts were exposed to 60 min of global ischemia followed by 60 min of reperfusion. Tramadol infusion was given at 0.0001 M/L for 10 min either before injury, after, or both.
  • Results
    • Hemodynamic
      • Peak systolic pressure was significantly higher in the group with pre- and post-administration vs. other groups.
    • Significant differences were seen between tramadol and saline groups for glutathione peroxidase levels (higher), SOD levels (higher), and lactate dehydrogenase (LDH) levels (lower).
  • COI: Not reported

Other tissue protection

Similar to the studies on cardioprotection, tramadol reduced ischemia-reperfusion-related damage to muscle tissue and testicular tissue in rats (Asghari, 2016 ; Takhtfooladi, 2014). This was associated with a reduction in oxidative stress.

(Asghari, 2016) – Tramadol reduces testicular damage from ischemia-reperfusion in rats and it reduces oxidative damage.

  • Ischemia-reperfusion injury was induced. Tramadol was given at 20 mg/kg/d for 1 week prior to injury or at 40 mg/kg/d.
  • Animals were exposed to midline laparotomy with occlusion of the infrarenal aorta for 1 h ischemia followed by 24 h reperfusion. After that 24 h, the abdomen was opened and the left testis was extracted for histopathological studies.
  • Results
    • 40 mg/kg tramadol protected against testicular ischemia-reperfusion injury. Administration of that dose led to higher SOD levels and glutathione peroxidase levels while diminishing malondialdehyde levels.
    • 20 mg/kg/d was ineffective.
  • COI: Not reported

 

(Takhtfooladi, 2014) – It is protective during ischemia-reperfusion in muscles

  • Background
    • Reperfusion causes more muscular injury than ischemia alone because the re-introduction of oxygenated blood to ischemic tissues causes free oxygen radicals to be released and neutrophils to be activated.
  • Rats exposed to either a sham procedure, ischemia-reperfusion, or ischemia-reperfusion with tramadol. Ischemia-reperfusion involved left femoral artery clipping for 2 h followed by 24 h of reperfusion. Tramadol 20 mg/kg IV given immediately before reperfusion.
  • Results
    • Muscle changes significantly less pronounced in the tramadol group. In comparison with other groups, the ischemia-reperfusion only group had much higher serum and tissue MDA levels and much lower GSH, SOD, and catalase levels, indicating an oxidative burden on the tissues.
    • Wet/dried weight ratio was significantly higher ischemia-reperfusion, suggestive of edema that is protected against by tramadol.
  • COI: None

Seizures

In humans, tramadol is primarily considered a cause of seizures, especially in overdose. Despite this, it appears to have anticonvulsant properties at low doses in animals, yet those do give way to proconvulsant properties at higher doses.

Though some efficacy may exist for reducing seizures, it’s unlikely to be utilized in humans.

This effect is antagonized by selective KOR antagonists and by naloxone at higher doses (Manocha, 2005)

(Manocha, 2005) – Anticonvulsant properties in maximal electroshock model

  • Mice tested in maximal electroshock seizure test. Seizure severity measured by duration of tonic hindlimb extensor (THE) phase and by mortality from electroconvulsions.
  • Results
    • Tramadol 10-50 mg/kg IP dose-dependently decreased duration of THE phase of the maximal electroshock.
      • Compared to control, these doses led to straub’s tail, hyperreactivity to sound and touch, and drowsiness.
      • Over 50 mg/kg produced occasional running, jumping, and circling.
    • Mortality declined from 40% to 0% across doses.
    • The effect was antagonized by naloxone at a high but not low dose and by the selective KOR antagonist MR2266, but not by the DOR antagonist naltrindole.
    • Coadministrations
      • GABAergic drugs like diazepam, muscimol, and baclofen or the NMDA antagonist MK801 augmented the anticonvulsant effect of tramadol.
      • Flumazenil, a BZD receptor antagonist, counteracted diazepam’s facilitation and DAVA, a GABAB antagonist, abolished the faciliatory effect of baclofen.
  • COI: Supported by the Council of Scientific and Industrial Research in New Delhi.

 

(Potschka, 2000) – It has anticonvulsant effects at analgesic doses in animals, but proconvulsant effects at higher amounts.

  • Studied rats in the amygdala kindling model of epilepsy or in normal conditions. Kindling model involved constant current stimulations to the amygdala once daily until 10 sequential fully kindled seizures were caused.
  • Evaluation of seizure threshold was made based on afterdischarge threshold, a sensitive measure of anticonvulsant activity against focal seizure activity in kindled rats.
  • Results
    • At analgesic doses, racemate tramadol and its enantiomers induced anticonvulsant effects in kindled rats. Yet at slightly higher 30 mg/kg IP doses, generalized seizures occurred in most kindled, but not non-kindled, rats.
      • Significant difference in seizure occurrence between kindled and non-kindled rats.
    • The (-)-Tramadol enantiomer induced myoclonic seizures at 30 mg/kg IP in most kindled but not non-kindled rats. Seizures were also observed after the (+)-enantiomer and the (+)-O-DSMT enantiomer, but experimentation was limited with those drugs due to marked respiratory depression.
  • COI: Supported by Grunenthal.

 

(Manocha, 1998) – Tramadol has an anticonvulsant effect in mice in the maximal electroshock model

  • Maximal electroshock test in mice. Drug administration was completed 30 min before seizure testing.
    • In the naloxone tests, tramadol was first given at 50 mg/kg IP and then 20 min later a dose of naloxone was provided.
    • In MR2266 studies, mice were concurrently given the drugs.
  • Results
    • IP administration of tramadol was shown to be dose-dependently effective with an ED50 of 33 mg/kg. The effect was antagonized by low doses of 0.05 or 0.1 mg/kg SC of MR2266, a selective KOR antagonist, whereas only higher doses (1-5 mg/kg IP rather than 0.1-0.25 mg/kg) of naloxone were effective.
  • COI: Supported by Council of Scientific and Industrial Research, New Delhi.

Postanesthetic shivering

Tramadol at 1 mg/kg IV and above removed postanesthetic shivering following the administration of general anesthesia, which can lower body temperature (Witte, 1997).

(Witte, 1997) – Tramadol reduces shivering after anesthesia

  • Belgium. DBRCT assessing tramadol 0.5 mg/kg, 1 mg/kg, and 2 mg/kg IV on shivering after standardized general anesthesia in 40 adults and also in another group of 64 adults without specific general anesthesia or ASA physical status parameters.
  • Mean central temperature before extubation was 35.6°C.
  • Results
    • 1 mg/kg or more abolished shivering entirely 5 min post-administration in all patients for both groups. Tramadol 0.5 mg/kg was significantly slower and less efficacious overall.
  • COI: Supported partly by Searle Continental Pharma Inc.

OCD

A very small open-label trial showed a benefit effect in treatment-resistant OCD (Shapira, 1997). Some evidence indicates the endogenous opioid system is involved in that condition. Naloxone, for example, makes symptoms worse.

(Shapira, 1997) – Open-label trial showing efficacy with tramadol in treatment-resistant OCD

  • This study looked at patients meeting OCD criteria for at least 6 months and who had treatment-resistant OCD, defined as having an inadequate response to an 8-week therapeutic dose of at least one SRI.
  • Studied using the Structured Clinical Interview for DSM-IV Patient Version (SCID-P), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Hamilton Rating Scale for Depression (HAM-D), and Clinical Global Impression Scale (CGI).
  • Followed for a 6-week open-label period. Initially 50 mg QID for the first week, rising to a max of 400 mg/d.
  • Only 7 patients. 2 study dropouts, one because of nausea and exacerbation of trichotillomania and the other due to experiencing a panic attack (the patient had preexisting panic disorder).
  • Results
    • All patients had a decline in Y-BOCS score. Mean dose of 254 mg/d for the 6 patients completing at least 2 weeks of treatment.
    • Average baseline Y-BOCS was 27.8, falling to average of 20.7. HAM-D scores, however, nonsignificantly increased.
    • Baseline CGI was 5.2 and endpoint was 2.3.
    • Main side effects were decreased appetite and insomnia, itching and sedation, dizziness, nausea, and flu-like symptoms. Sedation was the main dose-limiting side effect.
    • At the end of six weeks, 3 chose to continue tramadol, 1 chose to discontinue and start a new drug, and 3 chose to discontinue tramadol without starting a new drug.
    • Tramadol withdrawal scores measured for 2 weeks. For the 3 patients stopping tramadol w/ out a new drug, Y-BOCS increased from an average of 14.3 to 19.7.
  • COI: Supported partly by a grant from the Milostan-Kafka Fund, University of Cincinnati Medical Center.

PTSD

A case series of four people showed it was effective for combat-related PTSD (Geracioti, 2014). It significantly reduced PTSD-specific symptoms like hypervigilance, agitation, intrusive thoughts, and trouble sleeping, while also reducing anxiety and depression.

(Geracioti, 2014) – Four cases in which tramadol was useful for combat-related PTSD.

  • Overview: Four patients had a positive response to tramadol after suffering from combat-related PTSD due to serving in Iraq and Afghanistan. The PTSD was typically treatment-resistant.
    • Dosing was twice daily with IR tramadol. Total daily doses ranged from 200 to 300 mg.
  • Case 1
    • Treatment with CBT, SSRIs, and quetiapine failed. Cannabis could hold back his anger but it made his hypervigilance worse.
    • He had severe PTSD with reclusive behavior, intolerance of crowds, emotional numbing, micro-dissociative episodes, hypervigilance, irritability, road rage, homicidal thoughts, dysphoria, intermittent suicidality, insomnia, nightmares, guilty feelings, and intrusive traumatic ideation.
    • Tramadol IR 100 mg twice daily was started and increased to 150 mg twice per day to address residual symptoms two weeks later.
    • 1 month followup: Significant improvement. Social anxiety was less severe, anger and irritability were minimal, feelings of relaxation increased, and mood was improved. Intrusive thoughts and images were greatly reduced and flashbacks were eliminated. Sleep increased to over 6 hours per night with a decline in nightmare frequency. No longer had homicidal, violent, or suicidal thoughts.
    • After 8.5 months of therapy: He was without medication for a week due to it not arriving in the mail. During this time his symptoms greatly increased and the recurrent symptoms began to improve immediately after restarting tramadol. As he described it, “I could feel the anger and anxiety just dying away.”
    • After more than 1.5 years of tramadol: He is still on tramadol 300 mg/d and is doing well.
  • Case 2
    • Citalopram 40 mg/d for over a year with only modest benefit. Symptomatically he showed anger, irritability, ego-dystonic outbursts of yelling, road rage, anxiety with soaking perspiration, hypervigilance, insomnia, nightmares, microdissociative episodes, and marked avoidance of social interactions. He rarely left his house.
    • Started on tramadol IR 100 mg twice daily. He remained on citalopram despite the higher risk of serotonin syndrome.
    • 1 month followup: Substantial improvement with reduced irritability, eradication of rage episodes, reduced avoidance, increased in affectionate behavior, improved concentration, and improved sleep.
    • 4 months: Residual symptoms and return of significant irritability, so the dose was increased to 150 mg twice daily.
      • Eventually 200 mg in the morning and 100 mg in the evening was found to be best.
    • He was without the drug for a month due to a glitch in the mail service and during that time he went from good to being “an asshole,” routinely flying into rages and secluding himself. Restarting tramadol removed those symptoms.
    • The only reported adverse effect has been mild to moderate constipation.
  • Case 3
    • Medication-free and psychopharmacologically naive. He had severe PTSD with major sleep disturbance of just 1-2 hours per night. Nightmares were very common and he had intense hypervigilance. Irritability with daily angry outbursts and road rage almost every time he drove.
    • Tramadol IR 100 mg in the morning was started and then increased to 100 mg twice daily.
    • 2 week followup: Overall improvement with no adverse effects, but he said the positives would wear off before his second dose. Dose increased to 150 mg twice daily.
    • He felt more mellow with anxiety reduction to the point where he could tolerate school and public places without tachycardia, diaphoresis, or internal tremulousness. Hypervigilance was modestly but significantly reduced. Angry outbursts and road rage remained controlled while on the drug.
    • He has remained on tramadol therapy for 1.5 years.
  • Case 4
    • Symptoms included initial and middle insomnia, detachment from others, hypervigilance, and irritability. Tramadol 50 mg was started and then increased to 100 mg twice daily over the next two weeks.
    • 3 week followup: More focused and relaxed, with increased stress tolerance and without angry outbursts. Sleep was much improved. Moderately less hypervigilant. More capable of being in public and doing activities.
    • Remained on tramadol without efficacy reduction for over 1.5 years.
  • COI: Dr. Geracioti receives funding from the Posttraumatic Stress Disorder and Traumatic Brain Injury Clinical Consortium.

Cough

Neurogenic/neuropathic cough, i.e. cough with no pulmonary, GI, allergic, or otolaryngologic etiology, has been managed by CNS drugs, including gabapentinoids and baclofen. A small study with tramadol found it was also effective at reducing cough severity (Dion, 2017). More research is needed to see if tramadol has significant and reliable antitussive properties.

(Dion, 2017) – It appears useful in the treatment of neurogenic cough.

  • USA. Patients received tramadol 50 mg every 8 hours as needed. Uncontrolled study.
  • 16 patients.
  • Results
    • 4/16 reported somnolence and were recommended to reduce their dosage or frequency.
    • Overall, cough severity index (CSI) scores (0-40 scale) declined from 23 to 14. Leicester Cough Questionnaire (LCQ) (0 to 133 scale) improved from 74 to 103.
    • These improvements indicate tramadol may have antitussive properties in neurogenic cough, but controlled research is required.
  • COI: None

Other effects

Tramadol inhibits proliferation, migration, and invasion in breast cancer cells in vitro via a reduction in α2 adrenoreceptor activity (Xia, 2016). The same study showed a beneficial effect in mice with cancer.

(Xia, 2016) – It inhibits proliferation, migration, and invasion in breast cancer cells via α2 adrenoreceptor activity.

  • MDA-MB-231 human breast cancer cell line. Cell proliferation was detected via the methyl thiazolyl tetrazolium (MTT) assay. Wound healing assay and transwell assay were also used to look at migration and invasion ability.
    • Tested after treatment for 0, 7, 14, or 28 days.
    • Yohimbine was used at 50 μM for 48 hours.
  • In vivo test with BALB/c nude mice. Injections given into the right flank of the mouse. After tumor reached 100 cubed mm volume, tramadol 20 mg/kg was given daily for 28 days.
  • Results
    • Tramadol at 2 μM significantly inhibited proliferation, migration, and invasion in a time-dependent manner. It markedly suppressed the growth of xenotransplant tumor in vivo.
    • Protein levels of α2 adrenoreceptor and phosphorylated ERK were decreased by tramadol.
    • Also, a reduction of α2 adrenoreceptor activity by yohimbine could mimic the effect of tramadol treatment.
  • COI: None. Funded by National Key Basic Research Program of China.

Interactions with other drugs

Ondansetron reduces nausea and vomiting via 5-HT3R antagonism, a site where tramadol may have direct and indirect effects. 5-HT3 is among the targets implicated in the pain relieving effects of tramadol. A review found combining it with ondansetron led to both a reduction in analgesia from tramadol and a reduction in the antiemetic action of ondansetron (Miotto, 2016).

De Witte (2001) reported significantly more tramadol use in patients exposed to ondansetron, suggestive of reduced efficacy. Patients given ondansetron used 26-35% more tramadol in a postoperative setting.

(De Witte, 2001) – Analgesia from tramadol is impaired by the use of ondansetron

  • USA. 40 adults undergoing lumbar laminectomy. Randomly assigned to receive 4 mg ondansetron or saline with tramadol 2 mg/kg for 10 min beginning at the discontinuation of remifentanil for anesthesia.
  • Results
    • Cumulative tramadol dose was larger in the ondansetron group vs. control during the first 24 h. Cumulative consumption was between 26% and 35% more in the patients given ondansetron, a significant difference.
    • No significant differences in frequency or severity of side effects, though postoperative nausea and vomiting was numerically greater, occurring in 5% of ondansetron group and 20% of control group.
  • COI: Not reported


Chemistry

Tramadol has two chiral centers around its cyclohexane ring, giving four stereoisomers: (1R,2R), (1S,2S), (1R,2S), and (1S,2R). Tramadol is sold as a 1:1 racemic mixture of two enantiomeric stereoisomers, namely R,R-(+)-Tramadol and S,S-(-)-Tramadol.

Like codeine, tramadol has a methoxy group that contributes to relatively low MOR binding. In both cases, O-demethylation yields metabolites with stronger MOR agonism, namely morphine from codeine and O-DSMT from tramadol.

Drug Testing

Tramadol is cross-reactive with the EMIT II+ PCP immunoassay (Hull, 2006).

(Hull, 2006) – Tramadol is cross-reactive to the PCP immunoassay.

  • 42-year-old male found dead. He had a history of borderline hypertension, hyperchlosterolemia, and obstructive sleep apnea. The decedent had been prescribed tramadol a month earlier.
  • Femoral blood serum level was 14.0 mg/L, at least two orders of magnitude beyond the therapeutic range.
  • EMIT II+ was positive for PCP in urine, but PCP was not identified by HPLC in urine or serum.  Stock solutions of tramadol and O-DSMT were then tested and confirmed to react at 44 mAU/min for tramadol and 27 mAU/min for O-DSMT. That’s lower than the 85 mAU/min cutoff for the PCP test, but they could trigger a false-positive when tramadol along with metabolites are impacting the test together.

Natural presence

Tramadol was reported to be a naturally occurring drug in 2013 when researchers identified it in the roots of Nauclea latifolia, a medicinal plant in Cameroon that is used for pain, malaria, epilepsy, and other conditions (Boumendjel, 2013). Earlier phytochemical analysis had identified alkaloids like the naucleamides, but not tramadol. In this study, a crude extract of the root bark showed potent analgesic activity and was then shown to contain tramadol.

Subsequent studies revealed tramadol is actually a contaminant in the natural environment, not biosynthetically produced (Kusari, 2014). Other research teams were able to confirm its presence in N. latifolia as well as some other plants, but it was exclusively identified in far northern regions and at much lower concentrations than in the Boumendjel (2013) study. When analyzing samples from southern Cameroon, none had detectable amounts of tramadol.

Interviews with farmers in the north revealed it is common to give tramadol to cattle so that they don’t get tired as quickly and it is common for the farmers to take the drug (Kusari, 2014). Tramadol is also given to horses before races. In the southern region this practice is unheard of. The researchers learned that tramadol is available at a very low cost in northern Cameroon, with 12 pills selling for under €1. Further analysis of soil in the the far north revealed the presence of tramadol along with three mammalian metabolites (O-DSMT, N-desmethyltramadol, and 4-hydroxycyclohexyltramadol), all pointing to contamination from mammals in the region.

Lastly, a 2016 study looked at the percent of modern carbon isotope in the tramadol collected from soil in Cameroon (Kusari, 2016). That analysis showed a carbon isotope profile fitting with a synthetic, not natural source. The researchers also found it was impossible to collect enough tramadol in the February 2015 dry season, which followed heavy rains in November 2014. It’s likely that the heavy rains led to leaching of tramadol, a highly water-soluble substance.

(Boumendjel, 2013) – Reporting the presence of tramadol in Nauclea latifolia, which is used to treat pain, malaria, fever, epilepsy, and infantile convulsions in Cameroon.

  • Earlier phytochemical investigations led to the identification of alkaloids, mostly naucleamides, as the main drugs in the plant.
  • This study showed that tramadol could be isolated from the crude extract made of root bark. That extract also showed potent analgesic activity.
  • Tramadol could not be detected in any of the aerial parts of the plant, including leaves, trunk, and branches.
  • Minimal difference was seen in the carbon isotope content between this isolated tramadol and commercial samples.
  • COI: Supported by Inserm and LabEx Ion Channels, Science, and Therapeutics

(Kusari, 2014) – Tramadol does not appear to be a true natural product but is instead present due to contamination.

  • In the paper reporting naturally occurring tramadol, the N and C isotope ratios were in the range of commercial samples.
  • This study included three different field campaigns to investigate N. latifolia plants from two locations in Cameroon, one in the Far North region and one in the central region of Cameroon in the south.
  • Results
    • Tramadol’s presence in the Far North was verified, though with a much lower concentration of 0.0000017% to 0.0001466% in root samples, compared to the 0.4% w/w in the earlier study. There was either a complete absence or detectable amounts in different root tissues of even the same plant.
    • None of the samples from the southern region had any detectable amounts of tramadol.
    • Investigating possible production of tramadol by endophytes associated with N. latifolia:
      • None of the isolated endophytic bacteria and fungi produced tramadol.
    • It was hypothesized that the variable amounts of tramadol in N. latifolia roots came from contamination, so they conducted a series of interviews with farmers and local people.
      • Extensive off-label use of synthetic tramadol both by farmers and farm animals in the Far North region was reported. The farmers use it at 2-3 pills with their morning tea to work all day without getting tired. It is available from the local market or from local street sellers. 12 pills cost under one Euro.
      • Tramadol is fed to cattle so that the animals do not get tired as quickly.
      • Tramadol is given to horses before horse racing, though only on the day of competition and at 500 mg mixed into flour and water to prepare a small cake.
      • In the southern region, the use of tramadol is not known to farmers.
    • Soil was collected in the Far North. Tramadol and three mammalian metabolites (O-DSMT, N-desmethyltramadol, and 4-hydroxycyclohexyltramadol) were found.
    • Plant roots also contained mammalian metabolites along with the parent tramadol compound. And nearby plants like Acacia polyacantha, Acacia sieberiana, Andira inermis, Piliostigma reticulatum, and Ficus sycomorus contained detectable tramadol.
  • COI: Supported by the Welcome to Africa intiative of the German Academic Exchange Service and the German Federal Ministry of Education and Research.

(Kusari, 2016) – Investigating the synthetic origin of tramadol in the environment. The carbon isotope composition fits with a synthetic source.

  • Tramadol had reportedly been found in the roots of a S. latifolius tree, but it was later demonstrated that extensive off-label use of tramadol in humans and cattle in Northern Cameroon had produced its presence not just in S. latifolius but in several other plants, along with sporadic occurrence in soil and surface and ground water.
  • Synthetic molecules use carbon from petroleum-derived precursors, so their carbon isotope content is different from biosynthetic compounds. Therefore carbon-14 content could be measured to see where the tramadol came from in this study.
  • Results
    • The % of modern carbon value confirmed the tramadol traces in soil were of synthetic origin.
    • Plants usually contained too little tramadol to measure, impairing the investigation.
      • The authors grew plants and confirmed tramadol was absent from all plant tissues.
      • When the plant was fed with synthetic tramadol it was taken up by plant roots but none of the known or potential plant metabolites could be detected.
      • The proposed L-phenyl-D-alanine biosynthetic pathway was investigated and although that potential precursor was taken up, neither labelled nor unlabeled tramadol could be found.
    • The authors took multiple trips looking for tramadol-containing plants. Roots of other plants growing near S. latifolius contained tramadol in similar amounts, confirming the point contamination with tramadol in only these particular regions. During a later campaign during the dry season in February 2015 tramadol could not be detected in the exact same plants, confirming the leaching of the highly water-soluble tramadol because of the heavy rain in November 2014.
  • COI: Work was funded by the Welcome to Africa initiative of the German Academic Exchange Service and the German Federal Ministry of Education and Research.


Pharmacology

Tramadol is mostly considered an opioid agonist and an SNRI, but it does have other effects, such as moderate anticholinergic activity and 5-HT2C antagonism. Inhibiting the norepinephrine transporter (NET) and serotonin transporter (SERT) allows it to alter mood, like other SNRIs, as well as pain neurotransmission through the spinal cord.

The enantiomers of tramadol and O-DSMT provide different effects that function together to cause analgesia. R,R-tramadol has the great SERT inhibiting effect, S,S-tramadol has the greatest NET inhibiting effect, and R,R-O-DSMT is the most potent MOR agonist. All three mechanisms alter pain sensation and a person’s psychological/cognitive state. Because of this, at least in the area of pain relief, the racemate of tramadol could be superior to using a single enantiomer of tramadol or O-DSMT, especially in extensive CYP2D6 metabolizers who are able to receive an adequate level of opioid activity.

Affinity

(Grond, 2004)

  • Racemate Tramadol
    • MOR: 2.1 μM
    • DOR: 57.6 μM
    • KOR: 42.7 μM
    • NE uptake inhibition: 0.78 μM
    • Serotonin uptake inhibition: 0.9 μM
  • R,R-Tramadol
    • MOR: 1.3 μM
    • DOR: 62.4 μM
    • KOR: 54.0 μM
    • NE uptake inhibition: 2.51 μM
    • Serotonin uptake inhibition: 0.53 μM
  • S,S-Tramadol
    • MOR: 24.8 μM
    • DOR: 213 μM
    • KOR: 53.5 μM
    • NE uptake inhibition: 0.43 μM **** (most potent NE blocker of the listed drugs)
    • Serotonin uptake inhibition: 2.35 μM
  • R,R-O-DSMT
    • MOR: 0.0034 μM
    • DOR: NR
    • KOR: NR
    • NE uptake inhibition: NR
    • Serotonin uptake inhibition: NR
  • Morphine
    • MOR: 0.00034 μM
    • DOR: 0.092 μM
    • KOR: 0.57 μM
    • NE uptake inhibition: Inactive
    • Serotonin uptake inhibition: Inactive
  • Imipramine
    • MOR: 3.7 μM
    • DOR: 12.7 μM
    • KOR: 1.8 μM
    • NE uptake inhibition: 0.0066 μM
    • Serotonin uptake inhibition: 0.021 μM

(Wentland, 2009) – CHO cells expressing human opioid receptors.

Note: These DOR and KOR affinity values are much higher than have been reported elsewhere, so it is unclear if they are accurate.

  • Tramadol
    • MOR (hot ligand: DAMGO): 1.6 μM
    • DOR (hot ligand: Naltrindole): 0.0094 μM
    • KOR (hot ligand: U69,593): 0.014 μM
  • O-DSMT
    • MOR (hot ligand: DAMGO): 0.0086 μM
    • DOR (hot ligand: Naltrindole): 2.9 μM
    • KOR (hot ligand: U69,593): 0.450 μM

Opioid

Tramadol is only a weak MOR agonist. Though some binding likely exists during therapeutic use, the substantially higher potency of O-DSMT makes it the primary MOR agonist in humans. Gillen (2000) found R,R-O-DSMT had the highest MOR affinity (Ki=3.4 nM), followed by N,O-desmethyltramadol (Ki=100 nM), S,S-O-DSMT (Ki=240 nM), and racemic tramadol (Ki=2,400 nM).

Chronic exposure downregulates prodynorphin mRNA expression and biosynthesis much less than morphine (Candeletti, 2006). Although Candeletti (2006) did report tolerance in rats when they were given the drug for seven days, so some neuroadaptations did occur, likely in the opioid or monoamine systems.

Animals

(Candeletti, 2006) – Tramadol given chronically has minimal impact on prodynorphin levels relative to morphine

  • Tramadol given at 10, 20, and 80 mg/kg IP and compared to morphine 10 mg/kg IP. Measuring the effect on the opioid precursor prodynorphin.
  • Results
    • Morphine caused a significant downregulation of prodynorphin mRNA levels in the hypothalamus, striatum, and hippocampus. Tramadol did not cause a significant change in the striatum and did not decrease biosynthesis in the other regions until given at a toxic dose of 80 mg/kg.
    • Analgesia
      • IP administration of either drug produced an elevation of tail-flick latency in a dose-dependent way. On the seventh day of dosing, the antinociceptive ability of both had declined and the impact was no longer significantly better than pre-injection values.
  • COI: Supported by a grant from the Italian Ministry for the University and Scientific Research.

In vitro

(Volpe, 2011) – In vitro study of MOR binding

  • Single binding assay in cell membrane preparation expressing recombinant human MOR. Assays conducted with 2 nM labelled DAMGO.
  • Affinity
    • Tramadol: 12,486 nM
    • Racemic O-DSMT: 18.59 nM
    • R,R-O-DSMT: 3.359 nM
    • S,S-O-DSMT: 674.3 nM

 

(Gillen, 2000) – Tramadol is much less efficacious at MOR compared to O-DSMT

  • Cloned human MOR receptor expressed by membranes from stably transfected Chinese hamster ovary (CHO) cells. Agonist-induced stimulation of GTPγS binding allowed for EC50, efficacy, and relative intrinsic efficacy analysis.
  • Results
    • R,R-(+)-O-DSMT showed the highest affinity for MOR (Ki=3.4 nM) followed by racemic di-N,O-desmethyltramadol (Ki=100 nM), S,S-(-)-O-DSMT (Ki=240 nM), and racemic tramadol (Ki=2.4 μM).
    • GTPγS binding assay showed agonist activity for the metabolites with a rank order of R,R-(+)-O-DSMT, racemic di-N,O-demethyltramadol, and S,S-(-)-O-DSMT.
    • The mono-N-desmethyltramadol, di-N-desmethyltramadol, and tri-N,O-desmethyltramadol metabolites displayed only weak (Ki>10 μM) affinity and had no stimulatory effect on GTPγS binding.
  • COI: Not reported

Monoamines

Unlike morphine, tramadol significantly affects SERT. Barann (2014) reported an IC50 value of 0.93 μM in HEK93 cells. Since micromolar concentrations of tramadol are reached during therapeutic use, this effect is relevant. Low nanomolar affinity exists with O-DSMT (the more potent isomer is R,R-O-DSMT), whereas low micromolar affinity is seen with tramadol (Volpe, 2011 ; Grond, 2004). Significant SERT occupancy is seen in humans, according to Ogawa (2014). Ogawa calculated an ED50 of 98 mg oral (plasma concentration=0.33 μg/mL) for SERT occupancy in the thalamus.

Monoaminergic mechanism seem to contribute to analgesia from tramadol. In healthy volunteers given 100 mg, tramadol increased subjective pain threshold, which was significantly reversed by the α2 adrenoreceptor antagonist yohimbine (Desmeules, 1996). The addition of naloxone to yohimibine effectively abolished tramadol’s effect.

The reported antidepressant properties of tramadol seem to have a serotonergic component. 20 mg/kg IP in rats reversed the physical and behavioral changes cause by chronic mild stress, an effect that was significantly attenuated by a serotonergic lesion (Yalcin, 2008). The tricyclic antidepressant desipramine also lost much of its efficacy in lesioned mice. Yalcin also showed a significant rise in serotonin in the frontal cortex, hippocampus, and raphe nucleus of stressed mice, while not significantly increasing serotonin level in non-stressed mice, indicating it specifically counteracts a stress-induced decline in serotonin.

Some studies have found evidence of increased serotonin release with tramadol (Bamigbade, 1997). This effect was seen with racemic tramadol and its R,R-enantiomer at 5 μM, while S,S-tramadol was ineffective. It appeared to enhance serotonin efflux in a manner that preceded its impact on serotonin reuptake, so although reuptake inhibition occurs at a lower concentration, release could occur at higher concentrations that are still relevant.

Reimann (1998) reported tramadol, like fenflurameine and reserpine, enhanced the basal release of serotonin in rat frontal cortex tissue at 10-100 μM. A selective SERT inhibitor significantly inhibited tramadol’s effect, while abolishing the impact of fenfluramine (Reimann, 1998).

Tramadol 1-10 μM can enhance stimulation-evoked norepinephrine overflow, while not affecting dopamine (Driessen, 1993). O-DSMT has a much weaker facilitatory effect on stimulation-evoked norepinephrine overflow, only increasing it by 17% at 10 μM. Tramadol’s effect was blocked by cocaine (which binds to monoamine transporters), while being unaltered by yohimbine. The effect of tramadol in this study could be coming from reuptake inhibition or from release.

Humans

(Ogawa, 2014) – Significant SERT occupancy is seen in humans via PET imaging.

  • 5 subjects. Received IR capsules orally.
  • Results
    • Mean SERT occupancy in the thalamus was 34.7% at 50 mg and 50.2% at 100 mg, yielding an estimated ED50 of 98.1 mg and plasma concentration of 0.33 μg/mL 2 hours after administration.
  • COI: This work was partially supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT, Japan). Dr Suzuki has received speaker’s honoraria from Pfizer and Eisai within the past 3 yr. Dr Okubo has received grants or speaker’s honoraria from Dainippon Sumitomo Pharma, GlaxoSmithKline, Janssen Pharmaceutical, Otsuka, Pfizer, Eli Lilly, Astellas, Yoshitomi and Meiji within the past 3 yr. For the remaining authors none were declared.

 

(Desmeules, 1996) – Monoaminergic mechanisms contribute to analgesia from tramadol

  • Switzerland. 10 healthy volunteers received 100 mg tramadol orally followed by yohimbine 0.1 mg/kg IV or yohimbine plus 0.8 mg/kg naloxone IV. Subjective pain threshold assessed along with objective pain threshold for 8 hours.
  • Results
    • Tramadol significantly increased both pain thresholds with a peak effect at 3.7 hours. Yohimbine significantly reversed the analgesia for 2.8 hours with a max decrease of 97% for objective score and 67% for subjective. The addition of naloxone abolished tramadol’s effect through the study period with a decline of 90% for objective and 79% for subjective measures.
    • Yohimbine alone did not significantly reduce pain thresholds.
  • COI: Supported by Grunenthal.

Animals

(Yalcin, 2008) – A serotonergic lesion inhibits tramadol’s antidepressant-like effects in mice exposed to chronic mild stress

  • Tramadol tested in mice at 20 mg/kg IP. Some rats were exposed to unpredictable chronic mild stress (UCMS) and some were exposed to a lesion by 5,7-DHT, affecting their serotonergic activity.
    • First 2 weeks of UCMS were drug-free. Treatments began from the third week until 48 hours before the mice were killed. Desipramine was given before the 5,7-DHT injection to prevent destruction of noradrenergic terminals.
    • UCMS began 1-1.5 weeks after lesion operation, continued for 35 days, and then the mice were tested behaviorally and sacrificed by Day 42.
  • Results
    • Tramadol reversed the physical and behavioral changes from chronic stress, yet this was antagonized in lesioned mice, indicating a role of serotonin. Lesion impaired the effect of tramadol on coat state, in the splash test, but not in the resident-intruder test.
    • Serotonin level was reduced in some brain regions by lesion without affecting norepinephrine.
    • There was no significant difference in behavior just between lesioned or non-lesioned non-tramadol groups exposed to stress. Whereas there were significant differences between non-stressed and stressed lesioned or sham mice. The degradation of coat state was significantly improved by chronic tramadol or desipramine in stressed sham mice, yet they failed to work in lesioned mice.
    • UCMS significantly lowered serotonin in control mice vs. non-stressed mice. Neither desipramine nor tramadol significantly altered serotonin level in sham mice vs. vehicle group. UCMS also lowered norepinephrine level.
    • Tramadol significantly increased serotonin in the frontal cortex, hippocampus, and raphe nuclei as well as 5-HIAA level in the striatum and raphe nuclei in sham stressed but not non-stressed mice, indicating the benefit comes from counteracting a stress-induced decline in serotonin.
  • COI: Not reported

In vitro

(Barann, 2014) – Tramadol and pethidine (though tramadol significantly more than pethidine), unlike morphine, significantly affect SERT.

  • In vitro. HEK93 cells or platelets from human blood donated by healthy humans.
  • Results
    • HEK93
      • Citalopram 1 μM suppressed accumulation of serotonin by 93%.
      • Tramadol had an IC50 value of 0.93 μM and pethidine’s was 20.9 μM.
      • Morphine, hydromorphone, fentanyl, and alfentanil didn’t alter reuptake anywhere from 10 nM to 30 μM.
    • Platelets
      • Citalopram 1 μM produced a rise in plasma serotonin to 280% of control.
      • Tramadol 1 μM brought it to 133%; 20 μM brought it to 268%
      • Pethidine 30 μM brought plasma serotonin to 269%
      • Alfentanil, fentanyl, morphine, and hydromorphone at up to 10 μM had no impact on free serotonin concentration in plasma.
  • COI: None

 

(Reimann, 1998) – Tramadol induces serotonin release via a carrier-mediated mechanism and via exocytosis.

  • Rat brain frontal cortex slices. Tramadol was given at 10 or 100 μM. Also testing fenfluramine 1 μM or reserpine 10 μM.
  • Results
    • All drugs enhanced the basal release of serotonin. In the presence of a high 6-nitroquizapine concentration, the effects of tramadol were reduced and fenfluramine’s activity was abolished, while reserpine was enhanced.
    • Tramadol appears to induce both carrier mediated serotonin release and exocytosis.
  • COI: Not reported

 

(Bamigbade, 1997) – Tramadol enhances the release and reuptake of serotonin in rat dorsal raphe nucleus

  • This study utilized fast cyclic voltammetry (FCV) scan, which allows for real time detection of neurotransmitters. Examining the impact in rats on electrically evoked serotonin efflux and uptake in the dorsal raphe nucleus brain slice.
  • Results
    • Racemic tramadol and (+)-Tramadol significantly blocked uptake and increased efflux at 5 μM, a medicinally relevant concentration.
    • The (-)-Tramadol enantiomer and O-DSMT failed to significantly affect serotonin at 5 μM.
    • Both racemic tramadol and its positive enantiomer showed an effect on efflux that preceded the effect on uptake, suggesting uptake block was not the cause of the “efflux.”
  • COI: Supported by Searle.

 

(Driessen, 1993) – Tramadol and O-DSMT have monoamine uptake inhibiting or release-enhancing properties in vitro

  • Tramadol inhibited the uptake of norepinephrine into purified rat hypothalamic synaptosomes with an IC50 of 2.8 μM.
  • Tramadol, 1 and 10 μM, enhanced stimulation-evoked norepinephrine overflow by 25% and 69%, respectively. While tramadol 10 μM had no effect on dopamine release.
  • The effects of tramadol on stimulation-evoked norepinephrine release were blocked by cocaine. Effects were unaltered by blocking the α2 adrenoreceptor with yohimbine.
  • O-DSMT only had a weak faciliatory effect on stimulation-evoked overflow of norepinephrine, 17% at 10 μM.
  • COI: Not reported

Adenosine receptors

There is some evidence for a role of adenosine receptors, either directly or indirectly, in the effects of tramadol.

5-HT1A

Antagonism at 5-HT1A, but not 5-HT1B, significantly enhanced antinociception from tramadol in mice while reducing its antidepressant effect (Berrocoso, 2006). 5-HT1A auto- and heteroreceptors exist in the brain and could differentially be involved in the various properties of tramadol.

Animals

(Berrocoso, 2006) – 5-HT1A antagonism enhances tramadol analgesia while reducing antidepressant effects

  • A study in mice looking at the impact of the 5-HT1A antagonist WAY-100635 or the selective 5-HT1B antagonist SB-216641 on the effects of tramadol in the hot plate test and forced swimming test. Tramadol was administered at 32 mg/kg IP
  • Results
    • 5-HT1A antagonism enhanced antinociception and produced a large decrease in antidepressant-like effect. 5-HT1B antagonism had no significant impact on either.
  • COI: Supported by Fondo de Investigacion Sanitaria and Plan Andaluz de Investigacion.

5-HT2A

Tramadol reduced 5-HT2A-related activity, an effect also seen with morphine (Sun, 2003). This was attenuated by nonselective opioid antagonists and by MOR or KOR selective antagonists, but not DOR selective antagonists.

Animals

(Sun, 2003) – Tramadol lowers 5-HT2A serotonergic activity via MOR and/or KOR.

  • Mice. Studying the impact of tramadol on the head-twitch response caused by 5-HTP, which models activation of 5-HT2A.
    • Single administrations of 5-HTP at 90 to 400 mg/kg SC were given. Tramadol, morphine, or saline were given IP 30 minutes before.
  • Results
    • Tramadol (3.8 to 30 mg/kg IP) was found to dose-dependently attenuate the head twitch response, like morphine (0.5 to 4 mg/kg IP).
    • Naloxone and diprenorphine, nonselective opioid antagonists, blocked the attenuation. A selective DOR antagonist did not block the effect, but a selective MOR antagonist and a selective KOR antagonist did.
  • COI: Supported by China National Narcotic Control Commission.

5-HT2C

At a concentration of 10 μM in vitro, tramadol inhibits 5-HT2C in Xenopus oocytes and competitively inhibits serotonin’s binding to the site (Ogata, 2004).

In vitro 

(Ogata, 2004) – Tramadol seems to competitively inhibit 5-HT2C receptors in Xenopus oocytes

  • Whole-cell voltage clamp was used to look at the impact on serotonin-induced Ca2+-activated chloride currents mediated by 5-HT2C expressed in Xenopus oocytes.
    • Tramadol tested at a concentration of 10 μM
  • Results
    • Tramadol did inhibit serotonin-induced chloride currents at pharmacologically relevant concentrations.
    • A PKC inhibitor did not abolish the inhibitory effects.
    • Tramadol also inhibited the binding of labelled serotonin to the receptor. It appeared to alter the Kd without changing Bmax, indicating competitive inhibition.
    • Based on this, 5-HT2C inhibition may play a role in the activity of tramadol.
  • COI: Not reported

5-HT7

A variety of serotonergic targets, 5-HT7 included, have been implicated in the analgesic effect of tramadol. 5-HT7 receptors are localized in the superficial layers of the dorsal horn of the spinal cord. They are also found in the dorsolateral funiculus, an important source of descending inhibitory signals on spinal pain transmission. In mice with serotonergic lesions caused by intrathecal 5,7-DHT administration, the antinociception from tramadol and O-DSMT was greatly reduced (Yanarates, 2010). Intrathecal administration of a 5-HT7 antagonist also inhibited tramadol/O-DSMT effect, whereas ketanserin and ondansetron did not, suggesting a lack of involvement of spinal 5-HT2 and 5-HT3 receptors (Yanarates, 2010). More research is needed, but the authors hypothesized 5-HT7 receptors localized on spinal inhibitory GABAergic or enkephalinergic interneurons are responsible.

Other studies using different pain models didn’t show an impact of spinal 5-HT7 sites in tramadol’s activity (Sawynok, 2013).

Animals

(Yanarates, 2010) – 5-HT7 receptors in the spinal cord appear connected to the antinociceptive and antihyperalgesic effects of tramadol and O-DSMT

  • Mice. Nociception was assessed via radiant heat tail-flick and plantar incision tests. The serotonergic pathways in some mice were lesioned with intrathecal 5,7-DHT.
    • Selective 5-HT7 , 5-HT2 , and 5-HT3 antagonists were given in some tests.
  • Results
    • Antinociception from both tramadol and O-DSMT was significantly diminished in serotonergic lesioned mice. Intrathecal 5-HT7 antagonist administration blocked tramadol and O-DSMT effects.
    • Whereas ketanserin and ondansestron failed to reverse the antinociceptive and antihyperalgesic effects, indicating a lack of involvement of 5-HT2 and 5-HT3 receptors.
    • Plantar insicion produced significant induction of thermal hyperalgesia. Tramadol and O-DSMT both significantly improved hyperalgesia. 5-HT7 receptors were involved in that action since intrathecal 5-HT7 antagonism failed to influence hyperalgesia on its own, while blocking the effect of tramadol and O-DSMT.
      • Ketanserin, on the other hand, did not change the efficacy.
  • COI: None

Calcium (Ca2+) channels

In mice, the Ca2+ channel blocker amlodipine enhances tramadol’s analgesic effect (Modi, 2013). Combining amlodipine, which blocks L- and N-type channels, can make an otherwise ineffective tramadol dose active.

(Modi, 2013) – In mice, the Ca2+ channel blocker amlodipine enhances tramadol’s analgesia

  • Mice were evaluated via the tail-flick method.
  • Results
    • Amlodipine 2.5 mg/kg and 3 mg/kg IP in combo with a nonanalgesic dose of tramadol (10 mg/kg IP) produced a significant enhancement of antinociceptive effect of tramadol. This effect of amlodipine was dose-dependent.
    • The combo produced no significant antinociception during the first 2 or 6 hours, but significantly increased antinociception at 6.25 hours onward, peaking at 7 hours.
  • COI: None

Adenosine

Adenosine receptors are potentially connected to tramadol’s analgesic effect, either directly or indirectly. Sawynok (2013) reported systemic caffeine (an A1 and A2a adenosine antagonist) inhibited tramadol’s antinociception in mice during the formalin test. Inhibition was also seen with a selective adenosine A1 receptor antagonist (DPCPX), but not with a selective A2a antagonist (SCH58261). DPCPX given spinally was effective for inhibiting systemically administrated tramadol, whereas spinally administered SB269970 (a selective 5-HT7) antagonist failed to alter its effect.

How adenosine is involved is unclear. Research has suggested its effect could be secondary to 5-HT7 agonism, which increases cAMP production and subsequently increases adenosine. Yet this study showed no effect of a 5-HT7 antagonist. Other studies have shown an impact of 5-HT7 antagonists on the effect of tramadol in other nociception tests, which could mean the results are test-specific.

Animals

(Sawynok, 2013) – Spinal and peripheral adenosine A1 receptors contribute to antinociception from tramadol in mice.

  • Studied tramadol’s impact via 5-HT7 and adenosine A1 receptors on antinociception in the formalin test.
  • Systemic tramadol 35 mg/kg IP produced antinociception. Systemic caffeine 10 mg/kg (an adenosine A1 and A2a antagonist) and DPCPX 1 mg/kg IP inhibited antinociception.
    • SCH58261 (selective adenosine A2a antagonist) 3 mg/kg IP did not inhibit antinociception.
  • Spinally, 3 μg DPCPX inhibited systemic tramadol, but spinal SB269970 (selective 5-HT7 antagonist) at 3-10 μg did not significantly alter the effects.
  • In the formalin test, the 5-HT7 site does not appear to play a role, even though the same antagonist doses in other models do block the impact of tramadol. Tramadol could have another mechanism, such as opioid receptor-induced adenosine release, for enhancing adenosine activity that plays a role in antinociception.

Muscarinic acetylcholine receptors (mACh)

Tramadol reportedly inhibits mACh receptors (Shiga, 2002).

State-dependent memory effects caused by tramadol in mice involve muscarinic acetylcholine receptors, although the importance of those receptors (which are known to generally be involved in memory) could be indirect. Physostigmine (an acetylcholine agonist) preadministration reversed the negative effect of tramadol on memory and enhanced the state-dependent memory effect, while atropine (an acetylcholine antagonist) inhibited tramadol’s state-dependent memory effect (Jafari-Sabet, 2016).

Animals

(Jafari-Sabet, 2016) – Tramadol induces state-dependent memory effects that involve hippocampal muscarinic acetylcholine receptors.

  • Mice. Injections of tramadol into the bilateral intradorsal hippocampal area. The impact of physostigmine, an acetylcholinesterase inhibitor, and atropine, a mAChR antagonist, were examined.
  • Posttraining administration was immediate and pre-test administrations were 15 min before testing.
  • Results
    • Post-training administration of tramadol dose-dependently impaired memory retention. If a pretest injection was also given, state-dependent retrieval of memory acquired under the influence of post-training tramadol was induced.
    • A pretest injection of physostigmine reversed the memory impairment induced by post-training tramadol. And pretest physostigmine paired with an ineffective dose of tramadol also significantly restored retrieval.
      • Pretest physostigmine by itself did not affect memory retention.
    • Pretrest atropine 5 min before tramadol dose-dependently inhibited tramadol state-dependent memory.
      • Pretest administration of atropine itself did not affect memory retention.
  • COI: None

Imidazoline

The imidazoline I2 receptor is an analgesic target. Agonists like agmatine, which may be an endogenous ligand for I2, have potential antinociceptive properties in animals and agonists at that site can also boost the effect of opioids. Like with other opioids, I2 agonists complement the antinociception offered by tramadol, though that is not evidence of a direct effect of tramadol on I2.

Animals

(Thorn, 2011) – Imidazoline receptor agonists augment tramadol’s efficacy, increasing antinociception in rats. Though the receptors are not necessarily affected directly by tramadol.

  • Examining, in rats, the effects of morphine (0.1-10 mg/kg), tramadol (3.2-56 mg/kg), the nonselective imidazoline I2 ligand agmatine (10-100 mg/kg), and the selective I2 ligands 2-BFI (1-10 mg/kg) and BU224 (1-10 mg/kg).
    • Studied using the warm water tail withdrawal test.
  • Results
    • Morphine and tramadol alone or in combination increased tail withdrawal latency dose-dependently.
    • Agmatine and 2-BFI, but not BU224, enhanced the antinociception from both drugs, but none of the I2 agonists on their own led to antinociception.
    • The enhancement of antinociception by 2-BFI and agmatine was prevented by BU224, indicating that it may be a lower efficacy ligand and therefore functioning antagonistically when given alongside the other drugs.
  • COI: Not reported

Nitric oxide

Inhibiting nitric oxide might increase the analgesia from tramadol. Mice given an inhibitor of nitric oxide synthase showed greater analgesia (Dal, 2006).

Nitric oxide may also play a role in dependence. NMDAR activation has been implicated in opioid dependence, with many of the relevant NMDAR-associated actions tied to the subsequent activation of nitric oxide synthesis. A study using N. sativa, a natural nitric oxide inhibitor, attenuated tolerance and withdrawal from chronic administration of tramadol in mice (Abdel-Zaher, 2011). This effect was enhanced by giving an NMDAR antagonist (MK-801) or a nitric oxide synthase inhibitor (L-NAME) with N. sativa.

(Abdel-Zaher, 2011) – Nitric oxide appears involved in tramadol dependence and N. sativa can protect against withdrawal/tolerance.

  • Mice. N. sativa oil was tested along with tramadol and in some trials naloxone was given. Antinociceptive efficacy was assessed using the hot plate test.
  • Biochemical testing was performed to look at MDA level and antioxidant markers.
  • Tramadol given at 50 mg/kg SC twice daily for 7 or 15 days. Some mice received 2, 4, or 8 mL/kg N. nativa oil 30 min before tramadol administrations via oral route.
  • Results
    • Dependence/tolerance
      • 50 mg/kg tramadol for 7 days did not produce significant tolerance, but by 11 and 15 days there was a significant decline in analgesic efficacy.
      • Tolerance development was inhibited by N. sativa.
      • MK-801 significantly enhanced N. sativa’s effect, as did the NOS inhibitor L-NAME, whereas l-arginine reduced the effect. The MK-801 and L-NAME combos with N. sativa nearly brought analgesic efficacy back to Day 1 levels.
    • Naloxone-precipitated withdrawal
      • Naloxone did not produce withdrawal after 7 days of tramadol, but after 15 days there were significant withdrawal signs. Those signs were significantly reduced by N. sativa administration at 4 mL/kg.
      • MK-801 and L-NAME enhanced the N. sativa effect. L-arginine did the opposite.
    • After 15 days of tramadol, IP naloxone 5 mg/kg produced a significant increase in brain glutamate and MDA levels and serum nitrite level, along with a significant decline in brain intracellular GSH and GSH-Px activity. Naloxone-induced elevation of brain MDA, elevation of nitrite, reduction of GSH and GSH-Px activity was significantly attenuated by N. sativa.
      • N. sativa did not significantly change the glutamate rise from naloxone.
  • COI: None

(Dal, 2006) – Nitric oxide may inhibit the analgesia caused by tramadol

  • Mice received saline via IP, tramadol 40 mg/kg, L-NAME 10 mg/kg, L-NAME plus tramadol, 7-nitro-indazole 3 mg/kg, or 7-nitro-indazole with tramadol.
    • L-NAME and 7-nitro-indazole are both nitric oxide synthase inhibitors.
  • Mice received those drugs before a hot plate test.
  • Results
    • 7-nitro-indazole had no analgesic effect on its own but it significantly increased the analgesia from tramadol (p<0.001). Whereas L-NAME with tramadol showed no significant difference vs. tramadol by itself.
  • COI: Not reported

Sodium (Na+) channels

Tramadol does block Na+ channels, but the necessary concentration is high. An in vitro study looking at NaV1.2 neuronal Na+ channels from rats showed an IC50 value of 141 μM in neurons at -100 mV, which then increased to 9 μM (note: this was also seen with fentanyl) when the cells were at -70 mV. Although this is still a high concentration for systemic use, it could be relevant when tramadol is injected directly in the vicinity of a nerve.

(Haeseler, 2006) – Tramadol, fentanyl, and sufentanil can block voltage-dependent Na+ channels, while morphine does not

  • HEK 293 cell lines expressing the α subunit of NaV1.2 neuronal Na+ channels from rats.
  • Results
    • IC50 for binding to resting channels at -100 mM was 49 μM for sufentanil, 141 μM for fentanyl, and 141 μM for tramadol.
    • Fast-inactivated state affinity
      • Blocking was significantly increased when at -70 mV compared to -100 mV. Estimates of IC50 for binding to fast-inactivated channels yielded a value of 9 μM for fentanyl and tramadol
    • With exposure to fentanyl and tramadol, a concentration-dependent increase in blocking potency with membrane depolarization was detected, leading to concentration-dependent hyperpolarizing shift of the availability curves.
  • COI: Not reported

Other

Tramadol does not significantly affect glycine receptors, it weakly antagonizes NMDARs, and it weakly inhibits GABA receptors (Hara, 2005). Very large overdoses could perhaps reach a concentration where GABAR inhibition is relevant, such as for contributing to seizures.

(Hara, 2005) – Tramadol doesn’t significantly affect glycine receptors, can impact GABAA at high levels, and does antagonize NMDAR.

  • Human recombinant neurotransmitter-gated ion channels expressed in Xenopus oocytes. Glycine, GABAA, and NMDA receptors expressed.
  • Results
    • Neither tramadol nor O-DSMT had a significant impact on glycine receptors. GABAA receptors were only significantly inhibited at 100 μM.
      • Inhibition of GABAA at high levels could correlate with convulsions in overdose.
    • Tramadol and O-DSMT inhibited the glutamate-concentration response curve without changing the ED50 or Hill coefficient for NMDAR, indicating non-competitive inhibition.
      • Tramadol IC50 of 16.4 μM and O-DSMT IC50 16.5 μM.
    • Neither tramadol nor O-DSMT influenced basal currents of any receptors tested in the study.
  • COI: Partly supported by Grants-In-Aid for Research from the Ministry of Education, Science, and Culture of Japan.

Transient Receptor Potential Ankyrin 1 (TRPA1) and Transient Receptor Potential Vanilloid 1 (TRPV1)

Tramadol and O-DSMT both suppress activity through the TRPA1 target, though they do not impact TRPV1 activity. Tramadol is more potent at TRPA1 as an antagonist. They were found to reduce allyl isothiocyanate (AITC)-induced Ca2+ currents in vitro in cells expressing the human TRPA1 site (Miyano, 2015).

TRPA1 is an ion channel that is involved in pain (including allodynia/hyperalgesia) and noxious stimuli sensation. It could be important in the analgesia/antinociception provided by tramadol. It is active at that target at low millimolar concentrations, which are reached in humans.

Tramadol reduced menthol-evoked cold pain in healthy humans (Altis, 2009). Menthol is a TRPA1 agonist, so antinociception in that test might be mediated by tramadol’s antagonism of TRPA1.

In vitro

(Miyano, 2015) – Tramadol and O-DSMT suppress TRPA1 activity, but not TRPV1. Tramadol is more potent than O-DSMT.

  • Tramadol and O-DSMT at 0.01-10 μM failed to increase intracellular Ca2+ in HEK293 cells on their own, regardless of expression of hTRPV1 or hTRPA1 compared with capsaicin or allyl isothiocyanate (AITC), respectively. Using either as pretreatments before capsaicin did not affect capsaicin’s TRPV1-mediated activity.
  • Pretreatment with tramadol 0.1-10 μM and O-DSMT 1-10 μM significantly suppressed AITC-induced Ca2+ increases in HEK293 cells expressing hTRPA1 and a patch-clamp study confirmed that tramadol and O-DSMT (10 uM) decreased inward cation currents induced by AITC.
    • Neither induced a dose-dependent or large change in Ca2+ on their own, but some doses of tramadol (0.01 and 0.1 μM) and O-DSMT (0.1 and 10 μM) induced a slight increase in Ca2+.
    • Pretreatment was effective with 5 min but not 30 sec of pretreatment.
  • COI: None. Supported by Japanese institutional sources.

Brain activity

Tramadol increases activity in the nucleus accumbens (NAc) associated with reward anticipation (Asari, 2018). How this correlates with abuse potential and impulse-associated risks is unclear since the effects of recreational drugs on NAc activity in an anticipant monetary reward task are variable. Tramadol could be altering dopamine activity in reward-related circuits via opioidergic, serotonergic, and/or noradrenergic effects.

(Asari, 2018) – Enhances NAc brain activity associated with reward anticipation

  • Randomized, double-blind, placebo controlled study. 19 healthy adults. Studied with questionnaires and the monetary incentive delay (MID) task to assess neural response to reward anticipation under fMRI.
  • 50 mg tramadol (oral) compared with placebo.
  • Results
    • Tramadol significantly lowered anxiety (p=0.012), enhanced vigor (p=0.006), increased amicable feelings (p=0.044), increased alertness (p=0.049), and increased contentedness (p=0.030) vs. placebo.
    • Tramadol also significantly increased the % of BOLD signal change in the NAc at the highest monetary reward vs. placebo. This indicates it enhances activity in the reward system.
    • The thalamus and middle frontal gyrus were activated by tramadol (p<0.001 uncorrected and p<0.05 FWE-corrected).
    • No significant difference for task performance in terms of reaction time and hit rate.
    • The results indicate tramadol could drive substance use in populations that are early in their substance use.
  • COI: None

Sleep

Nighttime doses of tramadol increase Stage 2 duration and decrease SWS at 50 and 100 mg. 50 mg did not alter REM, but 100 mg reduced REM duration (Barber, 2011). Since at least part of this change may be coming from a serotonergic mechanism, tramadol’s impact on sleep could normalize with prolonged use, as has been seen with SSRIs.

Important polymorphisms

Polymorphisms in the MOR gene (OPRM1) were shown to predict the response to tramadol in neuropathic pain patients (Liu, 2012). Patients with the A118G variant, which is linked to a reduced response to classic opioids, showed significantly less response to tramadol. Presence of the G allele correlated with a reduction in pain score from 3.1 to 2.6, compared to a reduction from 3.0 to 0.9 in AA patients.

(Liu, 2012) – MOR A118G polymorphism predicts response to tramadol in neuropathic pain

  • 96 ethnic Chinese patients with cancer who were treated with oxaliplatin, leading to neuropathy.
  • Given Ultracet (37.5 mg tramadol with 325 mg paracetamol) orally every 6 hours.
  • Results
    • Mean pain scores were significantly lower with Ultracet treatment.
    • Compared with the 21.1% rate of 118G allele variants in Caucasian populations, the rate in this study was 68.7%, producing a genotype frequency of AA 31.3%, AG 58.3%, and GG 10.4%.
    • Patients with 118G variants had significantly reduced responses. The G allele was linked to a reduction in pain score of 3.1 to 2.6 vs. a 3.0 to 0.9 change in AA patients.
  • COI: None. Supported by a grant from the Taiwan Clinical Oncology Research Foundation.

Pharmacokinetics

The primary metabolite of interest is O-desmethyltramadol (O-DSMT; M1), which is active and is far more potent as a MOR agonist than tramadol. Other metabolites include N-desmethyltramadol, N,N-desmethyltramadol, N,N,O-desmethyltramadol, and N,O-desmethyltramadol (M5). N,O-desmethyltramadol is also active, while N-desmethyltramadol is inactive.

CYP2D6 catalyzes O-DSMT formation, while CYP2B6 and CYP3A4 are involved in the formation of N-desmethyltramadol. Phase 2 metabolites include glucuronides and sulfates. Under normal conditions in CYP2D6 extensive metabolizers, ~80% of tramadol will initially be metabolized by CYP2D6 (Miotto, 2016).

Metabolism is stereoselective and the kinetic profiles of the metabolites differ. For example, O-demethylation to O-DSMT is 2x greater for S,S-O-DSMT compared to R,R-O-DSMT in vitro (Grond, 2004).

Tramadol is transported across the BBB in a concentration-dependent manner and its transport may involve organic cation transporters (specifically the proton-coupled organic cation transporter, or H+/OC antiporter), which are known to be involved in the uptake of oxycodone, diphenhydramine, and nicotine, among others. Kitamura (2014) reported uptake was significantly inhibited by morphine and other cationic substance in vitro. The unbound concentration of tramadol is greater in brain interstitial fluid compared to plasma, yielding a 1.5 to 2.0 μM concentration from a single 100 mg dose (Kitamura, 2014).

P-glycoprotein is not involved in the brain uptake of tramadol in rats, despite it having some characteristics of a potential P-glycoprotein substrate (Sheikholeslami, 2012).

Tramadol Profile

Oral

Tmax (100 mg dose): 2 hours (Dayer, 1994)

Bioavailability: ~70%, increasing to over 90% with multiple dosing. Oral absorption is close to 100%, but bioavailability is reduced by first-pass metabolism. Saturation of first-pass metabolism allows bioavailability to increase with multiple dosing, as seen with a 16% higher Cmax and 36% higher AUC value after dosing 100 mg four times per day compared to a single 100 mg dose (Grond, 2004).

Half-life: 5 to 6 hours

  • Overdose increases the observed half-life of tramadol. Case reports have shown this, as have prospective studies. Khosrojerdi (2015) reported a half-life of 9.24 hours in overdose patients and the half-life increased further with higher doses. Saturation of CYP2D6 is conceivably involved.

Cmax (100 mg dose): 0.3 μg/mL (Grond, 2004)

Plasma concentration and AUC increase linearly from 50 to 400 mg (Grond, 2004). A 17% higher Cmax and 10% higher AUC is obtained by administering the drug alongside a high-fat meal, but this difference is not clinically significant.

Rectal

Absorption begins in a few minutes and the absolute bioavailability appears somewhat higher at ~77% (Grond, 2004).

Intramuscular

Tmax: 0.75 hours

Cmax (50 mg): 0.166 μg/mL

Sustained-Release

Sustained-release formulations yield a slower Tmax of 4.9 hours. Besides having a longer duration of action, these formulations are useful because they reduce the peak-trough fluctuation in steady state plasma concentration from 121% to 66% (Grond, 2004).

Humans

(Khosrojerdi, 2015) – In overdose, half-life is dose-dependent.

  • Prospective cross-section study in Iran’s Imam Reza University Hospital Poison Center. 25 patients admitted with confirmed tramadol overdose.
  • Mean half-life was 9.24 hours, but it dose-dependently increased with higher amounts.
  • COI: None. Supported by Mashhad University of Medical Sciences.

Animals

(Sheikholeslami, 2012) – P-glycoprotein is not involved in the brain uptake of tramadol in rats

  • Rats were given 1 or 10 mg/kg tramadol.
  • Results
    • Brain-to-plasma concentration ratio of more than 1 in all the time points following both the high and low dose (sometimes over 3) indicated brain accumulation.
    • Brain uptake clearance does not change with P-glycoprotein inhibition.
  • COI: Not reported

In vitro

(Kitamura, 2014) – Tramadol is transported across the BBB in a concentration-dependent manner

  • Background
    • Opioids are known to be transported through the BBB via identified and unidentified transporters and receptors. Oxycodone is taken up into rodent brain capillary endothelial cells by the proton-coupled organic cation H+/OC antiporter. Other organic cationic drugs like diphenhydramine, pyrilamine, and nicotine are also transported by the H+/OC antiporter.
    • Tramadol has a pKa of 9.41 and contains a tertiary amine moiety. It is present in cationic form at physiological pH. Tramadol concentration is approximately 5x higher in the brain vs. plasma.
  • Human immortalized brain capillary endothelial cells (hCMEC/D3) were used in this study. They retain much of the morphological and functional characteristics of the human BBB in terms of expression of tight-junction proteins, as well as various ABC and several SLC transporters. They functionally express the H+/OC antiporter.
  • Results
    • Tramadol uptake is not significantly inhibited by TEA (classical substrate and/or inhibitor of OCTs) but it was partially inhibited by carnitine, a substrate and inhibitor of OCTN2.
    • Uptake was inhibited to 58% by morphine and also inhibited by other cationic compounds.
    • The unbound concentration of tramadol in brain ISF was greater than in plasma. As the pKa value of tramadol is 9.41, the proportion of uncharged tramadol can be estimated as 0.098% at pH 6.4, 0.97% at 7.4, and 8.9% at 8.4.
    • Unbound concentration of tramadol in human brain can be estimated as approximately 2-fold higher than in plasma, yielding a 1.5-2.0 μM concentration in the brain from a single 100 mg dose.
  • COI: Supported by a Grant-In-Aid for Scientific Research and by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities provided by the Ministry of Education, Culture, Sports, Science, and Technology in France.

O-DSMT Profile

Half-life: 6.7 hours (Grond, 2004) or 9 hours (Dayer, 1994)

Tmax: 3 hours

Cmax (after 100 mg of tramadol): ~25% of the tramadol concentration, which would be around 0.075 μg/mL. This will vary significantly based on CYP2D6 phenotype.

AUC: ~25% that of the parent drug (Grond, 2004). This will vary significantly based on CYP2D6 phenotype.

Important Polymorphisms

CYP2D6

Because CYP2D6 catalyzes its metabolism to O-DSMT, the highly polymorphic nature of 2D6 contributes to different pharmacokinetic profiles in different users and it’s possible that those with very low O-DSMT formation could receive notably less analgesia and efficacy in general. Ultrarapid metabolizers could receive enhanced efficacy and more opioid-like adverse effects.

The bioavailability of O-DSMT was just 3% of the administered dose of tramadol in PMs, while it was 63% in EMs and 86% in UMs (Miotto, 2016). UMs show greater pain relief, greater miosis, and a higher frequency of nausea.

Though some studies don’t show a correlation between CYP2D6 status and analgesic response (Nasare, 2016), multiple studies have shown a reduction in analgesia and opioid-like effects in people with reduced CYP2D6 activity. Kirchheiner (2008) showed that a significant difference in pharmacokinetics between poor and extensive metabolizers, along with a higher pain threshold and pain tolerance induced by tramadol in healthy people. In a patient population, IV tramadol had a much greater non-response rate in poor metabolizers (Stamer, 2007). Various other studies have shown naturally occurring CYP2D6 PM status or PM status caused by a CYP2D6 inhibitor (e.g. paroxetine) leads to a significant shift in pharmacokinetics and a different effect profile (Gan, 2007 ; Laugesen, 2005 ; Poulsen, 1996).

It’s possible that brain CYP2D6 status is also important, such that peripherally acting inhibitors like quinidine may not impact tramadol’s effect profile as much as centrally active inhibitors like SSRIs.

Demographics

The poor metabolizer (PM) phenotype is found in 6-10% of Caucasians, under 2% of African Americans, and in 1-2% of Asians. PM is the phenotype with the lowest level of CYP2D6 activity, as it stems from two functionally inactive alleles.

The ultrarapid metabolizer (UM) is most common in people from the Middle East and Northeast Africa. According to Ingelman-Sundberg (1999), the UM phenotype demographics are as follows:

  • Ethiopia: 29%
  • Saudi Arabia: 21%
  • Mediterranean: 7-12% [Kirchheiner (2008) reports 10% of Italians, Portuguese, and Greeks are UM.]
  • Middle Europe & North America: 4-5%
  • Scandinavia: 1-2%
  • Asia: 0.5-2.5%

Intermediate metabolism (one functionally active and one inactive allele) is most common in Asians. Xu (2014) reports over 50% of the Chinese population has at least an intermediate-level reduction in CYP2D6 activity. The prevalence is similarly high in other Asian countries.

Humans

(Nasare, 2016) – CYP2D6 status does not correlate with response

  • India. 246 patients: including 123 NSAID nonresponders and 123 NSAID responders.
  • Results
    • Tramadol 50-200 mg led to optimum pain relief showed by a significant reduction in NRS scores at Day 14 and Day 28.
    • No significant association between enzyme status and numerical rating scale (NRS) scores, NRS-sleep and global perceived effect (GPE) scores, and genotype was not related to adverse effects.
  • COI: Supported by SRF Fellowship grant.

 

(Xu, 2014) – Effect of CYP2D6 status on the PK of tramadol postoperatively

  • China. Investigating the impact of CYP2D6*10 (coding for reduced enzyme functionality) in 45 postoperative patients who underwent GI tract surgery. Tramadol was given postoperatively.
  • Frequency of CYP2D6*10 alleles was 51%.
  • Results
    • Half-life, mean residence time, and AUC of tramadol was significantly greater and clearance was lower in homozygous *10 patients compared to wild-type.
  • COI: Supported by the Science Technology Department of Zhejiang Province Public Welfare Research and Social Development Projects.

 

(Li, 2010) – CYP2D6 status significantly correlates with metabolic ratio in Chinese volunteers

  • Bacground
    • CYP2D6*10 contains C/T 188 and G/C 4268 mutations that cause a crucial amino acid substitution producing an unstable enzyme with diminished catalytic activity.
  • Oral administration of 100 mg tramadol. Plasma and urine collected for a 32 hour period.
  • Results
    • CYP2D6*1 and CYP2D6*2 allele do not significantly differ for metabolic ratio or formation of metabolites, but CYP2D6*10 is correlated with a significant reduction in 2D6-dependent metabolite formation and homozygotes are more affected than heterozygotes.
    • The 32-hour metabolic ratio of tramadol to O-DSMT was 2.05 for CYP2D6*1/*1, 2.13 for CYP2D6*2/*2, 4.24 for CYP2D6*2/*10, and 6.85 for CYP2D6*10/*10.
  • COI: This work was supported by a grant from the state 863 High Technology Project of China, No. 2002AA2Z3411. This protocol was approved by the ethics committee of Chinese People Liberation Army General Hospital.

 

(Kirchheiner, 2008) – CYP2D6 status correlates with plasma levels of O-DSMT, pain reduction, and miosis.

  • Single dose of 100 mg tested in 11 UM status, 11 EM status, and 3 PM status metabolizers.
  • Results
    • Cmax of R,R-O-DSMT was significantly higher in the UM vs. EM group, with a mean difference of 14 ng/mL. Median R,R-Tramadol AUC was 786 μg*h/L in UM vs. 578 μg*h/L for EM.
    • Significantly higher pain threshold and pain tolerance along with greater miosis from tramadol in UM vs. EM. Pain was tested in healthy people put through a cold pressure test. Differences in pupil diameter change between EM and UM were not significantly different (1.4 mm reduction vs. 2.2 mm).
    • Nearly 50% of UM had nausea compared with 9% of EM.
    • AUC of both tramadol enantiomers was 25% lower in UM vs. EM, but that was not statistically significant.
    • For the few PM individuals, there was no significant change in pain threshold or pain tolerance.
  • COI: Not reported

 

(Stamer, 2007) – CYP2D6 genotype does impact response to tramadol and clearly changes PK.

  • Germany. 174 patients received IV tramadol 3 mg/kg for postoperative analgesia following abdominal surgeries. The effect of PCA tramadol was studied for a 48-hour period after surgery.
  • Demographics: 18 were PM, 93 were IM, 68 were EM, and 8 were UM.
  • Results
    • Median AUC for (+)-O-DSMT was 0 ng*h/mL in PM, 38.6 in IM, 66.5 in EM, and 149.7 in UM.
    • In PM patients, the non-response rate was 4-fold higher compared to the other genotypes, while no significant difference in response was seen between the remaining genotypes.
  • COI: None. Some support from the R. Sackler Research Foundation.

 

(Gan, 2007) – IM metabolizers had lower total clearance and a longer half-life vs. EM or UM in a Malaysian population

  • Background
    • CYP2D6*10 allele leads to IM status and has an allele frequency of around 51% among Asian populations while being present in just 1-2% of Caucasians.
  • Malaysia. IV dose of tramadol 100 mg as their first postoperative analgesic. Genotype testing and blood sampling for 24 hours.
  • Around 50% of patients had the wild-type CYP2D6*1 allele, while most of the rest (40%) had the CYP2D6*10 allele. None of the genotypes predicted poor metabolism. 27% were IM, 2.9% were UM, 70% were EM.
  • Results
    • Mean total clearance predicted by the model was lower (19 L/h) and half-life was longer (5.9 hours) vs. Western populations.
    • UM had a 2.6x faster clearance and EM had a 1.3x faster clearance vs. IM. Clearance was 16 L/h in IM, 18 L/h in EM1, 23 L/h in EM2, and 42 L/h in UM. Mean half-life was 7.1, 6.8, 5.6, and 3.8 hours, respectively.
    • Significant adverse effect differences, with IM group experiencing more adverse effects than the EM group and EM having more adverse effects than the UM group.
  • COI: None. Partly supported by the Ministry of Science, Technology and Environment of Malaysia.

 

(Laugesen, 2005) – The CYP2D6 inhibitor paroxetine significantly alters pharmacokinetics and measures of antinociception in healthy people. This indicates a relevant drug-drug interaction.

  • Background
    • Paroxetine is a potent CYP2D6 inhibitor and during 20-30 mg/d treatment, some though not all EMs become PM.
  • Tramadol was given with or without paroxetine pretreatment at 20 mg/d for 3 consecutive days. 150 mg tramadol was used and administered in a DB placebo-controlled crossover manner.
  • 16 healthy extensive metabolizers
  • Experimental pain models: pressure pain tolerance threshold, electrical sural nerve stimulation, and cold pressor test.
  • Results
    • Paroxetine pretreatment linked to increased plasma AUC for (+)-Tramadol of 37% and (-)-Tramadol of 32%. While AUC of (+)-O-DSMT fell 67% and 40% for (-)-O-DSMT.
    • Paroxetine also significantly reduced some measures of antinociceptive efficacy, while it was maintained on other measures. It appears to have the most impact on opioid-sensitive pain tests.
    • Paroxetine by itself with placebo had no impact on analgesia.
  • COI: Financed by public funds from the Danish Medical Research Council. Authors have received research funding and other funds from Lundbeck Foundation and Grunenthal.

 

(Stamer, 2003) – It is significantly more effective in CYP2D6 EM people

  • Germany. Prospective study looking at 300 patients recovering from abdominal surgery. After titration of an individual loading dose, PCA boluses of tramadol 20 mg, dipyrone 200 mg, and metoclopramide 0.4 mg were available.
  • About 30 min before surgery termination, each patient received a loading dose of tramadol 100 mg, dipyrone 1 g, and metoclopramide 10 mg IV. In the recovery room, patients with sufficient pain could receive another loading dose of tramadol up to a total max dose of 3 mg/kg.
  • Results
    • Percentage of nonresponders was significantly higher in the PM group (46.7%) compared to the EM group (21.6%). Loading dose amounted to 108.2 mg in EM and 144.7 mg in PM. More patients displaying the PM genotype needed rescue medication. Tramadol usage up to the 24th and 48th hours was higher in PM group.
  • COI: Supported in part by the Richard Sackler Research Foundation.

 

(Poulsen, 1996) – CYP2D6 status is correlated with analgesia in humans

  • Denmark. Analgesic effect of 2 mg/kg oral evaluated in 15 EM and 12 PM individuals. DBRCT.
  • Results
    • In EM people, tramadol increased pressure pain detection and tolerance thresholds as well as the threshold for eliciting nociceptive reflexes after single and repeated stimulation of the sural nerve.
    • In PM participants, only thresholds to pressure pain tolerance and nociceptive reflexes after single stimulation were increased and the reflex threshold was increased less than in EM.
    • Serum concentration of (+)-O-DSMT 2 to 10 hours after tramadol ranged from 10 to 100 ng/mL in EM people compared to being below or around the 3 ng/mL detection limit in PM.
  • COI: Not reported

Interactions

Common CYP2D6 inhibitors include SSRIs (e.g. fluoxetine, paroxetine, sertraline), methadone, and quinidine.

(Coller, 2012) – Methadone but not buprenorphine significantly inhibits tramadol metabolism.

  • Australia. Patients had to have been on their current maintenance medication for at least a month, they could not be CYP2D6 PM, and a urine sample had to show no opioids other than buprenorphine or methadone.
  • 16 patients in total: 9 on methadone and 8 on buprenorphine.
  • Participants received a single oral 100 mg dose of tramadol.
  • Results
    • Urinary metabolic ratio for O-DSMT production was significantly lower in the methadone group at 0.071 vs. 0.192. Yet no significant difference in urinary metabolic ratio for N-desmethyltramadol was seen.
    • Significant difference in the % of recovered dose in 4 hour urine samples as O-DSMT (1.8-fold lower) and N-desmethyltramadol (1.5-fold lower) between groups. No difference in total urinary recovery.
  • COI: None

Organic cation transporter 1 (OCT1)

OCT1 mediates the uptake of O-DSMT into the liver, where the transporter is expressed in the sinusoidal membrane of hepatocytes, and therefore OCT1 polymorphisms can affect metabolism. Among Europeans, ~9% have a “poor transporter” profile, which is correlated with a higher plasma level of the cationic drugs taken up by OCT1.

The metabolic path for O-DSMT involves inactivation by glucuronidation in the liver, probably by UGT2B7, which is why the level of hepatic uptake changes the effects of the drug.

OCT1 phenotype was shown to correlate significantly with nausea/vomiting (higher in poor transporters) and exposure to O-DSMT was significantly higher in poor transporters (Stamer, 2016). Greater miosis was also seen in poor transporters in another study (Tzvetkov, 2011).

(Stamer, 2016) – OCT1 function affects O-DSMT PK and effects.

  • 205 patients scheduled for elective open abdominal or urological surgery: 19 had 0 active OCT1 alleles, 82 had 1 functional allele, and 104 had 2 functional alleles
    • Analgesic regimen consisted of 3 mg/kg tramadol (max 250 mg) IV before termination of anesthesia along with dipyrone 1 gram. Then the regimen in post-anesthesia care unit was additional IV tramadol doses as needed and subsequent PCA for a max of 48 hours.
  • Results
    • Cumulative tramadol use via PCA was lowest in patients with 0 active alleles vs. the other groups. Plasma AUC for O-DSMT were 111.8 ng*h/mL with 0 active alleles, 80.2 ng*h/mL with 1 active allele, and 64.5 ng*h/mL with 2 active alleles.
    • Postoperative nausea and vomiting were reported in 47.3% of OCT1 poor transporters in first 24 h compared to 29.3% of intermediate and 28.9% of extensive transporters.
  • COIO: None. Supported by R Sackler Research Foundation and by a grant of the German Research Foundation.

 

(Tzvetkov, 2011) – OCT1 polymorphisms lead to different O-DSMT PK and different tramadol response

  • In vitro test using HEK293 cells and a human study using healthy people.
  • Human study involved 24 healthy volunteers. 14 had two active OCT1 alleles, 8 had one active allele, and 2 had two inactive alleles.
  • In vitro
    • O-DSMT showed low membrane permeability without transporters, while tramadol did show permeability.
    • Tramadol uptake into HEK293 cells was not altered by OCT1 overexpression. While OCT1 overexpression increased O-DSMT uptake 2.4-fold. The increase was reversed by OCT1 inhibitors and absent when inactive non-functional OCT1 variants were overexpressed.
  • Human
    • Concentration of tramadol in plasma was independent of OCT1 genotype. Volunteers with non-functional OCT1 polymorphisms had significantly higher plasma levels of O-DSMT and significantly prolonged miosis.
    • AUC0-24 for (+)-O-DSMT decreased with the number of active alleles:
      • 805.5 μg*h/L with zero
      • 679.4 μg*h/L with one
      • 420.2 μg*h/L with two
  • COI: None

Renal Impairment

Clearance is reduced and the half-lives of tramadol and O-DSMT double with renal impairment (Miotto, 2016).


History

1962

Synthesized by Grunenthal in Germany.

1977

Tramadol became available for analgesia in West Germany. It was sold by Grunenthal as “Tramal.”

1982 – 1990

A drug monitoring system in Germany reported several instances of tramadol abuse, with half involving known street drug addicts (Dayer, 1994). Because there were relatively few reports of abuse during that time period, it was taken as evidence in support of tramadol’s “low” abuse potential, especially among those without a history of recreational drug use or addiction.


1990s

The World Health Organization (WHO) did not recommend a critical review of tramadol in 1992 due to its perceived low abuse liability.

Tramadol launched in Spain in 1992. Between then and 1998, its consumption in the region increased from 2.1 to 570.6 defined daily doses (DDDs) per 1 million people per day. It was one of the only opioids, along with dihydrocodeine and dextropropoxyphene, that didn’t require a special prescription form and that likely contributed to the high usage figures.

It launched in the UK in 1994.

The FDA approved the drug in the mid-1990s and it entered the market in 1995 as an unscheduled opioid. Ortho-McNeil, the American manufacturer of tramadol, ran a postmarketing surveillance program to satisfy a request from the FDA that it carefully monitor tramadol’s use to see if greater restrictions were warranted.

In 1996, Ortho-McNeil released a letter to healthcare professionals advising that “83 domestic reports of an adverse event described as seizures or convulsions” had been reported and that the risk appeared to be higher with SSRIs or TCAs concurrently administered.

Ortho-McNeil’s postmarketing surveillance program found a low abuse rate from 1995 to 1998, with a peak rate of 2 cases per 100,000 exposed patients ~18 months after launch (Cicero, 1999). That rate then declined to 1 case per 100,000 exposed patients. 97% of abuse cases involved someone with a history of drug abuse. The Independent Steering Committee in charge of the program reported in Q1 1996 that it learned from two informants of 6 to 8 impaired physicians who had enrolled in substance abuse treatment due to tramadol use. All of them reportedly described tramadol as a very poor substitute for their drug of choice and they reported using it due to it not being checked for in drug tests and because of its availability.

When the FDA reexamined tramadol’s scheduling in 1998, it didn’t pursue additional restrictions but it did request that the postmarketing surveillance program increase its scope to include data on diversion.


Early 2000s

When the WHO noted a significant number of withdrawal and dependence cases in 2000, it recommend a critical review. But in 2002 it decided the available information was not sufficient to recommend international control of tramadol, though it was adequate for the WHO to keep tramadol under surveillance.

Ortho-McNeil’s Independent Steering Committee did not find an increase in the abuse of tramadol from 1999 to 2004, despite new branded and generic products entering the market (Cicero, 2005). As in earlier evaluations of its abuse potential, the vast majority of reported abuse cases involved people with a history of drug abuse.

The postmarketing surveillance program’s data on diversion showed tramadol was only a minor cause of diversion relative to other opioids (Inciardi, 2006). 102 drug diversion investigators from police agencies around the US were contacted beginning in 2002. Those agencies reported 16,755 drug diversion investigations in 2002. Of those, the majority involved more than one drug and hydrocodone was mentioned in 40.1%, benzodiazepines were mentioned in 27.9%, and oxycodone was mentioned in 20.2%. By comparison, tramadol was only mentioned in 1.5%.

In 2002, Iran’s Drug Selection Committee approved tramadol as an analgesic. It was not long after its entrance on the Iranian market that abuse was reported, often among young people.


Mid to Late 2000s

Global consumption of tramadol increased 42% between 2006 and 2012, according to IMS’ Kilochem data (Abdel-Hamid, 2016). Much of the use has been driven by availability, cost, and allegedly lower risks.

The UK’s Department of Health says prescriptions for the substance nearly doubled between 2006 and 2012 and the National Programme on Substance Abuse Deaths reports there were 2 deaths related to tramadol in 1998, rising to 154 in 2011. Tramadol prescriptions increased 50% in the UK between 2009 and 2011, coinciding with a 77% increase in tramadol-related fatalities (Verri, 2015).

Data from the UK NHS Business Services Authority shows annual tramadol utilization increased from 5.9 to 11.1 million defined daily doses from 2005 to 2012 (Chen, 2017).


A 2008 article in The Guardian discussed the significant use of tramadol by the Gazan population. Students, laborers, and others have reportedly been using the drug at an increasingly high rate, supposedly due to stress. A researcher quoted in the piece, Dr. Mahoud Khozendar of Shifa hospital, estimated up to 30% of males aged 14-30 use the drug regularly. People also turn to the drug to assist with sexual performance. Tramadol is said to be widely available and tablets can be purchased for as little as one shekel ($0.28).

Dr. Mahoud Khozendar:

Every day I see them with symptoms of withdrawal from this drug…Dozens come to emergency telling me that they are suffering vomiting, drowsiness and lack of concentration.

Each tunnel has about 40 labourers, so we are talking about 4,000 to 6,000 people working underground. It’s very hard work and tramadol moves the mood of these people. It gives them some leisure and it removes their fear.

Dr. Taysir Diab, psychiatrist at Gaza Community Mental Health Programme:

It’s a way of avoiding or escaping the political situation — the unemployment, the closure. It’s a huge source of stress.

Professor Mazen al-Sakka, a pharmacologist at al-Azhar university, believes the problem with tramadol increased following Israel’s blockading of Gaza in 2007.


A UN survey after the December 2008 Israeli offensive found increases in risky behavior and drug addiction, including tramadol addiction (Progler, 2010). Tramadol is relatively easy to get through the black market or from fake prescriptions. An escalation in the use of tramadol was highlighted by Al-Jazeera in its 2010 program “Uncomfortably Numb” which described how illicit pharmaceuticals like tramadol enter the country via Gaza’s large underground tunnel network.

Jamil Al Dahshan of the Anti-Drug Task Force in Gaza said there were 1,204 drug cases in 2009, 591 of which were tramadol-related (Progler, 2010). 2.5 million pills were seized, up from 550,000 in 2008. Some of the tramadol shown in the program had the name “Tramajack,” which is an Indian brand, suggesting international sources for the drug.


Early 2010s

A survey of young people in Egypt in 2012 revealed tramadol is a drug of choice (Loffredo, 2015). Tramadol was the most common pharmaceutical drug used recreationally by the group. Its street name is “farawla,” meaning strawberry (referring to the pill’s red color). Around this time, the Ministry of Health released a report on drug addiction in Cairo that estimated 1.4 million people were addicted to drugs, mainly heroin and/or tramadol.

Bassiony (2015) studied its use by adolescents at six schools in 2013. Responses from 204 people were collected, 8.8% of whom tested positive for tramadol. Among those using tramadol, 88.3% used it by itself. Two-thirds of students started with tramadol as their first drug after tobacco. Positive effects included feelings of happiness, having a sense that everything will work out, tension reduction, and relaxation. Negative qualities included lack of concentration, passivity, health problems, anxiety, suicidal thoughts, and becoming inconsiderate.


The UAE cracked down on tramadol use around 2010 in response to an “escalating tramadol phenomenon,” according to a report in Gulf News.

Chief Prosecutor Waleed Ali Khalifa Al Fuqaie, head of Drugs Prosecution at Dubai Public Prosecution:

The phenomenon of selling Tramadol in an unlawful manner has been on the rise. We have probed in 21 cases of trafficking Tramadol since January 2010. I am sending out a serious and stern warning to the public that we will be tailing and prosecuting any individual who sells Tramadol without a proper licence from the concerned authorities or consumes Tramadol excessively. Today I stress and vow that we will be very stringent with illegal traffickers and smugglers of Tramadol. We will also prosecute any person who consumes Tramadol without a medical prescription.

Anti-narcotics police officers have constantly and repeatedly asked us to look into the legality of incriminating suspects who consume Tramadol without prescription. Tramadol is a controlled medicine and could be bought over the counter upon a prescription. Tramadol is a painkiller that if a person uses excessively, it influences the nervous system, causes hallucination and makes one lose awareness or leads to addiction. It has been noticed that Tramadol is common among Emiratis, expatriates and stateless people,


A study using data from the Clinical Practice Research Datalink, the largest verified primary care database of anonymized clinical records in the UK, reported an increase in the monthly prevalence of tramadol users from 23/100,000 people to 93/100,000 from 2000 to 2014 (Chen, 2017). Most prescriptions were to existing users. The proportion of prescriptions going to existing users increased from 69.2% in 2000 to 91.4% in 2015.

Tramadol became a Schedule 3 controlled drug under the Misuse of Drugs Act in the UK in June 2014. Annual utilization of tramadol declined, as did the number of per capita tramadol-related deaths (Chen, 2017).

Tramadol was mentioned in 12% of drug misuse deaths in England and Wales in 2013, making it the third most common opioid behind heroin/morphine in 41% and methadone in 19%. Of the 254 tramadol-related deaths in that region in 2013, tramadol was the only substance mentioned in 100 (39%).


The Global Drug Survey for 2012 received reports of tramadol use from 369 people in the UK (Winstock, 2013). 90 reported using it to get high, 60 of whom said it came from friends or a dealer, while 18 obtained it through a prescription. 28% reported mixing it with alcohol and/or other drugs to enhance its effects.


Prior to its scheduling tramadol had been fairly easy to obtain from online sources, fueling its nonmedical use for around a decade.

In 2013, the number of prescriptions per year in the US was estimated to be over 44 million (Patterson, 2017).

The US placed it in Schedule 4 in 2014. The DEA received 26 comments on its proposal to schedule the drug: 16 were supportive, 9 were oppositional, and 2 didn’t take a position. Some of the supportive comments mentioned tramadol would remain widely available and that state-level restrictions had been effective at curbing abuse. The oppositional comments focused on concerns about restricted access, which could push legitimate patients to the black market. The DEA argued Schedule 4 drugs are easily accessible for legitimate medical use. Schedule 4 was picked based on tramadol having a lower abuse risk than current Schedule 3 drugs, thereby placing it in the same category as propoxyphene.


Mid to Late 2010s

The FDA issued a drug safety communication in August 2015 alerting health care professionals and the public about a higher risk of respiratory depression in children given tramadol. Then in April 2017 a new warning about the use of codeine and tramadol in children/teens was released. It’s recommended they not be used in people under 12-years-old and the FDA has warned against their use in breastfeeding women. For teens 12-18 years old, the FDA warned against their use in patients with a history of obesity, obstructive sleep apnea, or severe lung disease. Neither should be given to children or adolescents following tonsil or adenoid removal. Paracetamol and NSAIDs are recommended as alternative analgesics.

As of 2016, tramadol was being sold alone or in combination with paracetamol in products from ~90 companies.


Its use in professional sports has received some attention. In 2015, the World Anti-Doping Agency (WADA) received information from the United States Anti-Doping Agency (USADA) and other organizations about its use by competitors, but WADA didn’t prohibit the drug. It has been monitoring tramadol since 2012 and according to the WADA Monitoring Program 71-82% of tramadol use from 2012 to 2015 was in cycling. Elite mountain bike racer Ian Mullins says it’s the preferred analgesic for a lot of cyclists and he personally used it to improve training and racing performance. Professional cyclist Michael Barry wrote about using it in his autobiography “Shadows on the Road.” Barry says it made him slightly euphoric and could have improved performance.

USADA science director Matthew Fedoruk says the organization has heard from athletes about tramadol abuse and USADA is now of the opinion that “tramadol abuse threatens athletes’ health and their right to a level playing field.”

A study of young elite cyclists in Italy reported tramadol was commonly considered a doping agent (Loraschi, 2014).


It is said to be the opioid of choice in the Middle East, Northern Africa, and West Africa (Salm-Reifferscheidt, 2018). It is used by workers for its stimulant-like or anti-fatigue effects at lower doses and many people become dependent such that their use is partly driven by the need to avoid withdrawal. It’s a prescription drug in those locations, but it is widely available and cheap outside of medical settings, in part because of a large illicit market that often uses expired or counterfeit pills. Producers, which are frequently located in India or China, have responded to the demand in these regions by raising pill strength to 120, 225, and 250 mg, even though pills usually just contain 50-100 mg.

Thomas Pietschmann, a UNODC drug research expert, noted that the high-strength pills now showing up in the Middle East and Africa don’t make sense from a medical perspective, suggesting they’re being used nonmedically.

Egypt put tramadol under national control, yet in 2015 nearly 70% of people treated at an addiction facility were still using the drug (Salm-Reifferscheidt, 2018). In Nigeria and Benin it’s reportedly mixed with energy drinks for sexual enhancement and it’s prevalent in Gabonese schools, where it’s called “kobolo.”

Attempts to limit its entrance into these countries are limited by relatively porous borders.

In late 2017, the UNODC warned about increasing tramadol trafficking and use. It reported a rise in annual seizures from 300 kg to 3 tonnes since 2013. The major transit or target countries include Benin, Nigeria, Ghana, Togo, Niger, Sierra Leone, Cameroon, and Cote d’Ivoire. Pills tend to originate in South Asia, where they are then trafficked by organized criminal groups to regions of the Sahel that have a notable terrorist presence, with groups like Boko Haram and ISIS. Tramadol trafficking fuels those groups monetarily and fighters frequently consume the drug themselves.


Ghana made an effort to fight tramadol abuse after it increased in 2017.

Olivia Boateng, head of Tobacco and Substances Abuse Department at the Food and Drugs Authority in Ghana:

So far, we have a grip on the listed channels: who is bringing it and where are they taking it. The problem now is to break the markets of the unregistered ones. It is difficult to trace the source. Seized pills give little to no clue on their origin. Sometimes it just states the country they came from, often India–sometimes not even that.


Tramadol seems to be a factor in violence in Nigeria. A study investigating the link between drug use and conflict in Nigeria revealed many civilians and local leaders/authorities believe tramadol contributes to atrocities on both sides of the conflict between Boko Haram and the Civilian Joint Task Force (CJTF) (Mukpo, 2017). Respondents said it’s commonly used by CJTF members and it’s trafficked within camps for internally displaced people. Aside from cannabis, the most commonly used drugs are tramadol, codeine, and benzhexol. In the Borno region, tramadol was described as playing a role in the conflict with Boko Haram and it was perceived by many to be among the most dangerous drugs in the country.

Marcus Ayuba, the leader of a unit run by the Nigerian National Drug Law Enforcement Agency (NDLEA), says the problem with tramadol is “really huge” and the high rate of use can be tied to a decade of war in the country. In an article published by the BBC, a fighter opposed to Boko Haram described how the drug gives him “strength” to fight, while a Boko Haram fighter described using it the same way. At a port in Lagos, Nigeria, NDLEA authorities broke into a shipping container and discovered millions of tablets in a single shipment. The tablets were branded as “Super RolmeX” and said to contain 225 mg. Supposedly they were manufactured by Sintex Technologies in London, England, yet that company shut down in 2012. The packaging described the tablets as having been made in India.


Pierre Lapaque of the UNODC says tramadol use in regions like northern Mali and Niger is “worrying and needs to be addressed as soon as possible.” He notes it has been found in the pockets of terrorists. The UNODC reports customs officials in Cameroon found over 600,000 tablets intended for Boko Haram in August 2017 and 3 million were impounded in September 2017 in Nigeria.

Rebecca Grant, a national security and military analyst with IRIS Independent Research, says opioid trafficking is a major revenue source for terrorist groups.


A drug shipment seized in 2017 by Italian forces in the port of Genoa in northern Italy contained 37 million tablets hidden under a load of fabrics (Santacroce, 2018). The seized contents were worth €75 million and the tramadol was headed to Libya.

Another shipment of tramadol worth €50 million was seized in November 2017 and was also believed to be intended for ISIS in Libya. Italian authorities say the pills were manufactured in India.


India brought the drug under the control of the Narcotic Drugs and Psychotropic Substances Act in April 2018. This move was in response to its abuse and link to criminal groups.

India is the biggest supplier of tramadol in the Middle East and Africa, according to US law enforcement officials, who estimate 1 billion tablets have been seized leaving India by US and international authorities. Libya is one of the major destination countries. Tramadol exports are linked to ISI and Boko Haram, which primarily purchase the drug for resale as a means of funding their activities.


Evidence from 73 treatment-seeking adolescents and young adults in Sweden indicated tramadol is a commonly used drug in that population (Olsson, 2017). Hair analysis showed it was the most commonly detected opioid. 32% of patients overall tested positive for opioids and in all but one they were positive for tramadol.


Misuse of tramadol is said to be a growing problem in Gabonese schools as of 2018, where it’s been blamed for conflicts between students and worse school performance. Children begin using it at 12 or 13 years old. It’s sold for $0.50 to $1.00 per pill. Police in the country seized 5,952 illicit pills in 2017.


A couple studies have shown it’s an adulterant in herbal sexual enhancers sold in Iran (Fard, 2018 ; Dastjerdi, 2018). It’s been detected alongside sildenafil, caffeine, and diazepam, among other drugs.


Legality (As of September 2018)

United States: Schedule 4

Australia: Schedule 4 (Prescription-Only Medicine)

Canada: Prescription-only drug

UK: Class C – Schedule 3


Safety

Therapeutic doses

Adverse effects during therapeutic use (WHO 2014 report):

  • Over 10%: Nausea and dizziness
  • 1-10%: Drowsiness, fatigue, headache, increased sweating, vomiting, dry mouth, constipation
  • 0.1-1%: Diarrhea, cardiovascular dysregulation (palpitations, tachycardia, postural hypotension)
  • 0.01-0.1%: Respiratory depression, convulsions, tremor, bradycardia, hallucinations, anxiety

Langley (2010) reviewed 11 studies on tramadol for osteoarthritis and found the overall rate of adverse events ranged from 45% to 84% with tramadol, compared to 19% to 66% with placebo. The most common adverse effects were GI related (nausea, constipation, vomiting) and CNS-related (dizziness, drowsiness, headache). Two studies found nausea and constipation were significantly more common than with placebo, but neither headache nor vomiting were significantly more common. Most adverse effects appeared in the first four weeks of treatment. Long-acting formulations may reduce the side effect burden.

Respiratory and hemodynamic effects

Adverse effects from therapeutic doses are usually minor or moderate, such as drowsiness, dizziness, headache, nausea, and constipation. It produces a more stable respiratory and hemodynamic profile than classic opioids, minimally affecting vitals at normal doses. Though respiratory depression can be seen, it is less significant than that from classic opioids like morphine or pethidine (Tarkkila, 1998 ; Houmes, 1992). Some studies have failed to show a significant change in respiratory measures. Vickers (1992) reported 0.5 to 2.0 mg/kg IV only caused a non-significant rise in end-tidal CO2, compared to a significant rise from morphine. Overall, there is good evidence that at any of the therapeutic doses, respiration should not be greatly impaired in someone without a preexisting respiratory problem or another risk factor.

At the hemodynamic level, tramadol causes a minor increase or decrease in heart rate and blood pressure. An IV bolus of 100 mg in healthy volunteers caused heart rate to increase by 7 bpm, systolic blood pressure to increase 6 mmHg, and diastolic blood pressure to increase 14 mmHg (Lee, 1993). Whereas 0.75-1.5 mg/kg in children given tramadol postoperatively, the drug caused a decline in heart rate and diastolic blood pressure, but not systolic blood pressure (Lee, 1993).

(Tarkkila, 1998) – Significantly less respiratory depression than pethidine.

  • Respiratory effects of IV pethidine 0.6 mg/kg compared to tramadol 0.6 mg/kg. 36 patients in double-blind controlled trial.
  • Results
    • Pethidine caused significant respiratory depression as seen via increased fractional inspiratory-expiratory oxygen and PETCO2 and as a drop in MV and respiratory rate. Whereas tramadol was similar to placebo with its effects.
    • Hemodynamic effects were similar between groups.
  • COI: Supported by Orion corporation in Finland.

(Houmes, 1992) – Less respiratory depression than with morphine

  • 150 female patients undergoing gynecologic surgery received up to three IV doses of tramadol 50 mg or morphine 5 mg within a 6 h period.
  • Results
    • 13.3% of morphine group vs. 0% of tramadol group had oxygen saturation decrease to under 86%. In 50% of the morphine patients with that response, it occurred after a single 5 mg dose.
    • Both drugs produced acceptable analgesia, although morphine was numerically superior with its effect. No clinically significant adverse event differences.
  • COI: Not reported

GI effects

Tramadol somewhat increases orofecal and colonic transit time, but gastric emptying is not delayed at normal doses, unlike with morphine (Murphy, 1997).

(Murphy, 1997) – It does not delay gastric emptying, unlike morphine.

  • Ireland. 10 healthy participants. Placebo vs. tramadol 1 mg/kg IV in a DBRCT cross-over manner.
  • Results
    • No difference in gastric emptying rate was seen between placebo and tramadol, whereas a prior study found morphine significantly prolonged the emptying time.
    • Side effects
      • No subject vomited with tramadol and HR, BP, and respiratory rate did not differ from placebo. Nausea from rapid IV injection has been noted in other studies, but this study involved IV infusion over a 10 minute period.
  • COI: Not reported

Hypoglycemia

Hypoglycemia occurs at a higher rate in patients receiving tramadol than in patients receiving other opioids (Golightly, 2017). Both MOR agonism and effects on serotonin and norepinephrine can enhance insulin’s effects and promote glucose utilization. The first published case report of hypoglycemia was in 2006 and since then there have been multiple reports showing tramadol sometimes triggers hypoglycemia in both diabetic and non-diabetic people. Blood sugar changes have also been reported in overdose.

Studies/Reviews

(Golightly, 2017) – Hypoglycemia occurs in some patients with a higher rate in those with diabetes

  • Study at the University of Colorado Hospital. Patients given 1 or more tramadol doses orally for acute/chronic pain management. Data from patients seen during a 2-year period. They were included if blood glucose data was available on at least two occasions within 5 days of the initial administration of tramadol.
  • Tramadol was given to 2927 patients meeting inclusion criteria.
  • Results
    • Hypoglycemia (glucose at or under 70 mg/dL) was seen in 22/47 patients with Type 1 Diabetes (46.8%), 113/673 with T2DM (16.8%), and 103/2207 without diabetes (4.7%).
    • In those without diabetes, the causality between hypoglycemia and tramadol use was probable in 77 patients (3.5% overall). By comparison, hypoglycemia was seen in just 8 (1.1%) of 716 matches oxycodone patients without diabetes.
      • With oxycodone as the reference, the relative risk ratio was 3.12 and the NNH was 42.2, meaning for every 42 patients without diabetes who receives tramadol, 1 will develop hypoglycemia when they otherwise wouldn’t have.
  • COI: None

(Fournier, 2015) – Tramadol comes with a higher risk of hypoglycemia-related hospital visits in noncancer pain treatment

  • Using data from the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database. Evaluating all patients newly treated with tramadol or codeine for noncancer pain between 1998 and 2012.
    • The CPRD system includes over 13 million patients from over 680 practices in the UK.
  • Cohort was 334,034 patients. 1105 of them were hospitalized for hypoglycemia during a 5-year follow-up period, yielding an incidence rate of 0.7 per 1000 per year.
  • Tramadol patients had an increased risk of hospitalization for hypoglycemia vs. codeine (OR: 1.52) particularly in the first 30 days of use (OR: 2.61).
  • Use of tramadol increased more than 8-fold during the study period: 25,334 prescriptions in 1999 to 215,709 in 2011.
  • COI: None. Funded in part by research grants from the Canadian Institutes of Health Research and Canada Foundation for Innovation.

(Bourne, 2012) – Tramadol is sometimes linked to hypoglycemia

  • France. Analyzing spontaneous reports of hypoglycemia from tramadol, codeine, and dextropropoxyphene from 1997 to 2010 in French pharmacovigilance database.
  • 72 cases associated with dextropropoxyphene and 43 with tramadol were evaluated. Most patients were elderly and hypoglycemia occurred after a median of 4-5 days of treatment.
  • At least one preexisting risk factor for hypoglycemia was present in most patients, with no significant difference between groups (58.3% with tramadol vs. 58.1%). 31.9% of dextropropoxyphene and 41.8% of tramadol patients had diabetes. 18% of dextropropoxyphene and 16.3% of tramadol patients had renal insufficiency.
  • COI: None

Case reports

(Odonkor, 2016) – Hypoglycemic event triggered by tramadol in someone with Type 1 Diabetes

  • USA. 71-year-old female. After failing to respond to other therapies she was started on tramadol 150 mg/d.
    • She was also on an antihypertensive, novolog, and glargine. She had been on insulin for 36 years without episodes of severe hypoglycemia requiring hospitalization.
  • Took her first dose of tramadol (50 mg) and had symptomatic relief until the evening, when she used her second 50 mg. Her pre-dinner glucose was 93 mg/dL, then her postprandial level was 70 mg/dL. She ate sugar to boost her levels but 3 h later she was hypoglycemic (51 mg/dL). She ate more sugar, but her blood sugar fell further to 42 mg/dL. She reported fatigue and diaphoresis so she used more sugar. Shortly therefore she was still hypoglycemic at 56 mg/dL. She drank significantly more sugar and by 1.5 hours later she was up to 80 mg/dL.
  • She woke up a few hours later with diaphoresis and chills; hypoglycemic at 53 mg/dL. She skipped her morning insulin and had food and some fruit. 4 hours later her hypoglycemia resolved.
  • Patient reported to the clinic the following day, was taken off tramadol. A week off tramadol and she has not had recurrence of blood sugar level issues.

Immune system

Opioids can have a negative effect on immune function; tramadol does not appear as problematic in this regard. Morphine has been shown to reduce natural killer cell activity and T lymphocyte proliferation, whereas tramadol may not impair T lymphocyte function and appears to have a neutral or positive effect on natural killer cell activity (Grond, 2004). Human, animal, and in vitro research has shown less of an effect overall than is seen with typical opioids.

Humans

(Xhihen, 2006) – In vitro and human evidence indicates a better immune system impact profile

  • In vitro study used Jurkat cells, while the human study involved 150 patients randomized to receive either morphine, fentanyl, or tramadol for postoperative analgesia.
  • Results
    • Morphine and fentanyl significantly suppressed NF-κB activation; tramadol did not. IL-2 was significantly decreased in the morphine and fentanyl groups, but it was unchanged 1 h postoperative in tramadol and then it increased significantly at 3 and 24 h postoperative.
  • COI: Not reported

(Sacerdote, 2000) – Tramadol has less of a negative impact on immune function after surgery

  • Italy. Morphine compared to tramadol in terms of pain and immune function during the postoperative period.
  • 30 patients undergoing abdominal surgery for uterine carcinoma. Testing involved looking at phytohemagglutinin-induced T lymphocyte proliferation and natural killer cell activity immediately before vs. immediately after surgery vs. 2 h post-administration of 10 morphine IM or 100 mg tramadol IM.
  • Results
    • Surgical stress led to significantly impaired phytohemagglutinin-induced lymphoproliferation in all patients.
      • In the morphine group, proliferative values remained under basal levels for 2 h after treatment, while in tramadol patients they returned to normal.
    • Natural killer cell activity was not significantly altered by surgery or morphine, while it was significantly increased by tramadol.
    • For pain, the two drugs were similar. VAS for tramadol was 44 vs. 31 for morphine.
    • Comparable sedation scores for the drugs.
  • COI: Not reported

Overdose

Tramadol overdoses exhibit opioid-like and SNRI-like effects. An overdose from tramadol does not tend to look like a classic CNS depressant overdose, as cardiovascular stimulation may be seen and seizures are fairly common. Respiratory depression and coma are often still reported though and they will likely occur more often in those with efficient or abnormally high O-DSMT production.

Other effects seen in overdose are nausea, vomiting, hyper- or hypoglycemia, sweating, serotonin toxicity symptoms like clonus and hyperthermia, and miosis or mydriasis.

Benzodiazepines and naloxone have been used in the event of overdose to address the SNRI-like and opioid-like effects, respectively. Naloxone significantly improves overdose outcomes and is frequently utilized to symptomatically address symptoms even though it is known to only partially antagonize tramadol (Hussien, 2017). Naloxone is usually able to assist with reversing respiratory depression and coma (Marquardt, 2005). Seizure has been reported after naloxone administration, but that seems to be an atypical response (Spiller, 1997).

Fatalities have occurred but are not common, especially with supportive care.

Human research

(Hussien, 2017) – Naloxone significantly improves overdose outcomes

  • Egypt. 30 patients with tramadol intoxication who were given naloxone were compared to 30 patients who did not receive naloxone.
  • Mean dose of tramadol was 1439 mg (+/- 804 mg).
  • Results
    • Mean vitals:
      • Naloxone group: HR 109, SBP 111, DBP 68, RR 14.67, temp 37.37°C
      • Non-naloxone group: HR 92, SBP 110, DBP 67, RR 14.87, Temp 37.3°C
    • Most common symptoms: Sweating 66.7%, cyanosis 61.7%, bradypnea 60%, coma 55%, miosis 50%, tachycardia 46.7%, hyperthermia 41.7%, dizziness and hypotension 35%, nausea and vomiting 31.7%, agitation 26.7%, hypertension 21.7%, cardiac arrest 13.3%, bradycardia 11.7%, seizures 10.2%, and mydriasis 8.3%.
    • Seizure was significantly less common in the naloxone group (6.6% vs. 50%) and death was less common (3.3% vs. 23.3%). Intubation was significantly more common in the non-naloxone group. Mechanical ventilation was needed more in non-naloxone group (40% vs. 13.3%).
  • COI: Not reported

(Alinejad, 2017) – Review of causes of toxicity in Iran; tramadol is a common drug-related cause of overdose and seizures.

  • The Iranian Drug Selecting Committee approved the drug as an analgesic in 2002. In recent years it’s become a major cause of admission to Iranian hospitals, especially among young males who have a history of mental disorders or substance abuse. Important complications include seizures, CNS depression, and respiratory depression, along with renal dysfunction. Tramadol poisoning is deemed the most common cause of drug-induced seizures.
  • One study found tramadol was the leading cause of poisoning, followed by benzodiazepines.
  • A study of 114 intentional tramadol intoxications showed it was sometimes used with illicit drugs, most often benzodiazepines.
  • In Kermanshah, tramadol was mostly used to attempt suicide and 40% of cases had an episode of seizure.
  • A study on 400 college students found nearly 25% reported using tramadol in their lifetime.
  • COI: Not reported

(Stassinos, 2017) – Review of its effects in children at high doses

  • Retrospective evaluation of cases from the National Poison Center Data System from January 2000 to December 2013. Inclusion criteria: under 6 years old and single-substance acute tramadol ingestion.
  • Results
    • 7334 included cases. In the 1,115 children with symptoms, drowsiness and vomiting were the primary ones. Serious clinical effects included respiratory depression (n=36) and seizures (n=24).
    • Respiratory depression came with a median dose of 225 mg and seizure came with a median dose of 525 mg.
  • COI: Not reported

(Kriikku, 2016) – Review of overdoses and fatalities in Finland in 2014

  • There were 22 tramadol-implicated poisonings reported in 2014 and tramadol was the most important finding in 17 of those. 3 poisonings only involved tramadol. Alcohol was a factor in 5 cases.

(Ghamsari, 2016) – ECG abnormalities are common in tramadol overdose

  • Iran. Prospective cross-sectional study of all patients with tramadol poisoning admitted to ED of Logham Hospital from 2012 to 2013.
  • Results
    • 1402 patients with a mean age of 24. Sinus tachycardia in 33%, sinus bradycardia in 0.07%, right axis deviation in 24.2%, QRS widening in 6.5%, long QTc interval in 18.4%, dominant S wave in either I or aVL lead in 28.1%, and right bundle branch block in 5.2%.
  • COI: None

(Hassanian-Moghaddam, 2015) – Review of 20 child cases involving overdose and apnea

  • Iran. Retrospective study looking at all tramadol-exposed hospitalized patients younger than 12 years old from March 2010 to April 2012.
  • Results
    • 20 children with a mean age of 3.7 years were identified. 70% had decreased consciousness level, 15% had apnea, 20% had nausea and vomiting. Witness seizure was not reported for any child.
    • Mean ingested dose was 9.6 mg/kg and there was no significant relationship between apnea and estimated toxic dose. All patients survived. Patients with apnea were managed conservatively with naloxone and they recovered without intubation.
      • 2 symptomatic children failed to respond to naloxone and remained unconscious, yet no other drug was detected, indicating they were still tramadol-only cases.
    • Pupils were often normal or miotic.
  • COI: Supported by Clinical Research Development Center of Loghman Hakim Hospital.

(Ryan, 2015) – Overdose causes seizures and respiratory depression, though serotonin toxicity isn’t a major issue.

  • Australia. Observational case series. Retrospective review of tramadol overdoses admitted to a tertiary toxicology unit. All presentations with 400+ mg tramadol were included regardless of co-ingestants
  • Results
    • 112 admissions were reported, but the dose were unknown in some and under 400 mg in others, leaving 71 studies meeting inclusion criteria.
    • Median dose of tramadol was 1000 mg. Patients co-ingested a number of different medications, including serotonergic drugs and benzodiazepines.
    • Clinical effects
      • Seizures in 11%, with one of those involving over 4000 mg and a total of 6 seizures. Median dose associated with seizure was 2100 mg.
        • One of the patients had a seizure at 750 mg but they were also dealing with benzodiazepine withdrawal. Another patient ingested 1200 mg and had a history of non-drug-related seizure. Besides those cases, the rest had seizures with 2000+ mg.
      • No cases of serotonin toxicity. One used 1000 mg tramadol with 800 mg escitalopram and had ocular clonus, but did not meet criteria for serotonin toxicity.
      • GCS was 15 in 41% of patients. GCS was under 9 in 5 patients, including three people coingesting TCAs and 2 ingesting 3000 mg and 900 mg who had respiratory depression responsive to naloxone.
        • Respiratory depression with oxygen saturation under 94% in 18% of patients with a median dose of 2500 mg.
      • GI effects in 51%, including vomiting in 31 and nausea alone in 5. Cardiovascular effects were common with tachycardia in 38% and mild hypertension in 45%.
    • Outcomes and treatment
      • Median length of stay for patients was 16 h, though it was 19.9 h in those with another medication used. No fatalities.
      • Naloxone was given to 9 with a median dose of 2.2 mg. 7 of those patients had respiratory depression. Naloxone improved oxygen saturation or consciousness level in 6 patients, provided partial improvement in 2, and had no effect in 1.
        • No seizures post-naloxone.
  • COI: None.

(Nasouhi, 2015) – Hypoglycemia and hyperglycemia are fairly common.

  • Iran. Blood glucose level measured in tramadol-overdosed patients.
  • Results
    • 128 patients. 59.4% had seizures. Mean admission blood glucose of 94.88 mg/dL. 14 patients had hypoglycemia in a 12-hour period and hyperglycemia occurred in 8 patients.
    • No significant relation between the dose of tramadol and blood glucose.
    • Admission
      • Mean HR of 90, mean RR of 16, mean SBP of 121, mean DBP of 76, mean temperature of 36.9°C.
  • COI: Supported by a grant from a toxicological research center.

(Rahimi, 2014) – Review of the effects of acute tramadol poisoning

  • Iran. Retrospective study on patients with acute tramadol poisoning referred to Loghman Hakin Hospital from January to April 2012.
    • Exclusion criteria: coingestants, intoxication with an unknown dose, uncertainty about time of ingestion, onset of seizure prior to hospital arrival, past history of epilepsy or drug/substance abuse.
  • 144 patients. Mean ingested dose of 1971.2 mg. In 68.8% of cases, the intention was suicide and it was abuse in 31.2%. No fatalities.
  • Symptoms
    • 88.9% were conscious. 47.9% had seizure, 29.9% with nausea, 22.2% with vomiting, 20.1% with drowsiness, 18.1% with dizziness, 6.3% with lethargy, 5.6$ with apnea, 4.2% with agitation, 1.4% with headache, 1.4% with blurred vision, 0.7% with ataxia, 0.7% with anxiety, 0.7% with sweating, and 0.7% with nystagmus.
  • PCO2 was elevated at 49.6 mmHg. Blood sugar average was not elevated or depressed.
  • COI: Not reported

(Hassanian-Moghaddam, 2013) – Apnea cases linked to tramadol exposure are fairly common, though seizure is much more common.

  • Iran. 2009 to 2010 at Loghman-Hakim Hospital. During a 14-month period there were 732 patients with a history of tramadol exposure, in 525 of those tramadol was the sole agent.
  • The reason for presentation was intentional self-poisoning in 68.4% and abuse in 27.8%. The only route was oral.
  • Tonic-clonic seizures in 46.1%, of those 88.1% had a single seizure. Apnea was observed in 3.6% of patients within 24 hours of ingestion, for which treatment was intubation and ventilation in 84.2% and naloxone administration in the remaining 15.8%.
  • Minimal tramadol dose associated with apnea was 200 mg. Though the mean dose for apnea cases was larger.
  • COI: Not reported

(Shadnia, 2008) – Review of 114 overdose cases

  • Iran. April to May 2007 at Logham-Hakin Hospital Poison Center.
  • 114 patients. The majority were young adults with 50% aged 21-30 years, followed by the 12-20 year old age group. Suicide was the intention in 80.7% of cases, followed by abuse in 18.43% and unintentional in 0.87%.
    • 5.26% had a history of drug addiction.
  • Range of dosage was 100 to 14,000 mg with an average of 1650 mg.
  • HR average 77.06, SBP average 107.4 mmHg, DBP average 69.73 mmHd, respiratory rate average 14.8, temperature average 36.95°C.
  • 23.42% were unconscious. Nausea was present in 76.32%, vertigo was seen in 62.3%, and vomiting occurred in 43.86%.
  • 8 admitted to ICU, all of whom were unconscious and needed intubation for protection of airway. Of those, 2 had cardiopulmonary arrest and there was a mortality rate of 1.75%.
  • COI: Not reported

(Marquardt, 2005) – Review of overdoses reported to a poison control system in California over a 2.5 year period

  • 602 cases retrospectively reviewed. 190 had enough data for analysis. Those with known coingestants were excluded.
    • Suicide represented the largest group of exposures.
  • Symptoms: CNS depression in 27.4%, nausea and vomiting in 21.1%, tachycardia in 17.4%, seizures in 13.7%. Dose ranged from a very small amount to 5000 mg.
    • Seizures were associated with male sex, chronic use, suicide attempts, abuse/intentional misuse, and tachycardia.
  • Smallest amount associated with seizure was 200 mg.
  • No effect in 36.3%, minor in 43.7%, moderate in 19.5%, major in 0.5%. Symptoms resolved within 24 hours in 96.7% of patients.
  • Naloxone improved CNS depression in 7/8 patients in whom a response was documented.
    • One patient became agitated with naloxone but did not have a seizure.
  • COI: Not reported

(Spiller, 1997) – Review of the effects of tramadol in cases of overdose

  • USA. Prospective case series looking at tramadol overdoses reported from 1995 to 1996 to seven poison control centers.
  • 126 cases, of which 87 were tramadol-only.
  • Results
    • Symptoms: lethargy 30%, nausea 14%, tachycardia 13%, agitation 10%, seizures 8%, coma and hypertension 4%, respiratory depression 2%.
    • All seizures were brief. 500 mg was the lowest dose associated with seizure, tachycardia, or agitation, while 800 mg was the lowest dose associated with coma and respiratory depression.
    • Naloxone reversed sedation and apnea in 4/8 patients. 1 patient had a seizure immediately after naloxone.
    • Other treatments: diazepam in 3, phenytoin in 1, lorazepam in 1, nifedipine in 1.
    • 19 patients admitted to ICU.
  • COI: Not reported

Case reports

(Tanne, 2017) – 7 overdoses in pediatric patients

  • France. Intoxication was always confirmed with quantitative blood sampling.
  • Case 1
    • 15.5-year-old female admitted after 2 general convulsive seizures with persistent postictal confusion. 1 dose of diazepam was given after each seizure. She did not have hemodynamic failure and she was intubated due to persistent drowsiness. Moderate hepatic cytolysis.
    • Toxicology: 5.51 μg/mL in blood.
    • After extubation, the patient said the cause was voluntary intoxication. Apneas were still observed so she received naloxone. Discharged on Day 4.
  • Case 2
    • 1-year-old male found with consciousness disturbances rapidly developing. Pediatric GCS was 9 and he had hypoventilation with apneas and bradypnea. Bilateral miosis. Naloxone injection produced rapid improvement.
    • Toxicology: 0.96 mg/L in blood
    • Quickly returned to a proper level of consciousness, he was not intubated, and he was discharged after 1 day in the ICU.
  • Case 3
    • 1-month-old female admitted to ED with tonic-clonic seizures. Pale and hypotonic but she did not present hemodynamic failure. First displayed hypoventilation at a very slow frequency of 10-15/min and ample respiratory movements. Drowsy, did not completely wake up after stimulation, and presented abnormal diffuse clonic movement.
    • Given 0.3 mg/kg diazepam and 15 mg/kg phenobarbital for epileptic episode, but those were ineffective. Management was symptomatic and required invasive respiratory support because non-invasive ventilation failed due to chest wall rigidity.
    • Toxicology (blood)
      • Tramadol: 0.78 mg/L
      • Zolpidem: traces; 0.016 mg/L
    • Neurological recovery was made in the first 24 hours. No injections of naloxone needed. Quickly extubated and discharged from PICU on Day 3.
  • Case 4
    • 13.5-year-old female admitted after a suicide attempt. Appeared to have swallowed tramadol, lansoprazole, ebastine, and paracetamol. Suffered a convulsive tonic-clonic seizure and she was intubated. GCS of 8.
    • Toxicology: 4.68 mg/L of tramadol in blood
    • NAC was quickly administered and recovery was prompt. Extubation possible at Hour 6 and the patient was discharged from the PICU 1 day post-admission.
  • Case 5
    • 4-year-old female prescribed tramadol after thigh abscess surgery. Tramadol was used each day. One month post-surgery, she was found unconscious and had a GCS of 3.
    • Generalized hypertonia with a pediatric GCS of 3. Clonazepam given because of hypertonia, but that was not effective. Patient was intubated due to low chest expansion and respiratory arrest.
    • Toxicology: 4.16 mg/L tramadol in blood. An empty bottle of it was later found in the family home.
  • Case 6
    • 3-year-old formerly premature male with asthma. Tramadol and paracetamol were prescribed. After just 1 administration he was unstable when standing and had moderate breathing difficulties, leading to administration of albuterol. Loss of contact with eye revulsion and staring occurred. Limbs described as hypertensive but no abnormal movements noted.
    • Pediatric GCS was 5 with generalized hypertonia, hypertension, and tachycardia. Diazepam was ineffective. Intubated due to apneas, at which time he inhaled.
    • Presented a first cardiac arrest while being medically transported (occurring about 5 hours post-tramadol administration). Recovered a heartbeat after 8 min reanimation but remained with refractory hypoxia post-inhalation.
    • Admitted to PICU. Second cardiac arrest in the ED, which was fatal after 53 min of resuscitation efforts.
    • Toxicology: 3.49 mg/L.
    • UM metabolizer status was not detected. It was later found that despite them being led to believe he only had one dose, 10 doses were missing, yielding 340 mg.
  • Case 7
    • 17-month-old healthy male presented with a seizure and was drowsy, had a hoarse voice, eye rolling, with clonic contractions of the mouth. Package of tramadol XR 150 mg found nearby.
    • At ED: Hypoventilation and 2 generalized tonic-clonic seizures. The first seizure stopped spontaneously while the second was stopped with 10 μg/kg naloxone. Naloxone was kept at 10 μg/kg/h.
    • 7 hours post-administration: Toxicology showed 5 mg/L in blood
    • Naloxone maintained for under 10 hours due to clinical improvement and he was discharged after 24 hours.
  • COI: Supported by a grant from Biblioteheque scientifique de l’Internat de Lyon and les Hospices Civils de Lyon.

 

(Aliyu, 2016) – Hypoglycemia and seizures in a child with tramadol overdose

  • Nigeria. 4-year-old male exposed to 1200 mg of tramadol from six tablets. The drug was taken an hour before presentation.
  • He vomited several times and convulsed twice on the way to the hospital. Lapsed into unconsciousness. Presented with GCS of 3/15, pupils at 1 mm bilaterally, respiration at 19, oxygen saturation of 85% on room air, pulse of 110, BP 90/60. Hypoglycemic with random blood sugar of 2 mM/L.
  • ECG showed normal sinus rhythm and other lab investigations, including full blood count, electrolytes, urea, creatinine, liver function, were normal.
  • Detrose and intranasal oxygen given for treatment. Regained consciousness 7 hours after admission with no new seizures noted. Discharged after 24 hours.
  • COI: Not reported

 

(Belin, 2016) – Cardiogenic shock from tramadol, alprazolam, and alcohol poisoning

  • France. 50-year-old female found in the woods. She was conscious without confusion and found near six empty bottles of tramadol 100 mg (supposed ingested dose of 18 grams), 2 boxes of alprazolam 0.25 mg (supposed ingested dose of 15 mg) and 1 L of 15% alcohol.
  • ED: Clonus, epileptic seizure with non-reactive bilateral mydriasis, respiratory failure requiring intubation and mechanical ventilation. Early onset of hemodynamic instability required fluids and norepinephrine.
  • Echocardiography showed increased cardiac output with hyperkinetic profile and preserved left ventricular ejection fraction. Lactic acidosis reported.
  • ECG showed first degree atrioventricular block. New seizure treated with thiopental.
  • Rapidly evolved towards cardiogenic shock with a strong reduction in ejection fraction to 20% requiring high doses of epinephrine and norepinephrine, alkalizing with sodium bicarbonate, sedation with midazolam and sufentanyl in association with thiopental.
  • Continuous venovenous hemodiafiltration initiated on Day 4 due to acute renal failure.
  • After 72 h circulatory incompetence with alternating of sustained ventricular arrhythmias and asystole, the patient began recovering effective cardiac activity.
  • Seizures were resistant to treatment during the first four days and they were associated with persistent nonreactive bilateral mydriasis.
  • Recovery of consciousness was slow and gradual, with normal consciousness returning on Day 15.
  • Toxicology
    • Hour 12: tramadol blood concentration of 47 mg/L
    • Day 5: 14.8 mg/L
    • Day 12: 0.6 mg/L
  • COI: None

 

(Ghazimirsaeid, 2014) – Seizure caused by overdose and associated with acute renal failure

  • Iran. 22-year-old male. Exam showed cyanosis in the head and neck, plus mydriasis. He presented 1-2 hours after ingestion. Reportedly took 9400 mg. Admitted while in a deep coma for 2 days and he had 3 seizures during that time. Intubated due to severe respiratory distress. He was hospitalized for 19 days.
  • Days later he had severe dyspnea, increasing HR and RR, feverish, dizzy. Pulmonary edema seen on chest radiograph. No cyanosis or edema. Acute kidney failure diagnosed in kidney sonography and due to severe respiratory distress he was intubated and admitted to ICU.
  • COI: Not reported

 

(Perdreau, 2014) – Cardiogenic shock in a child

  • France. 7-year-old child admitted for generalized seizure and respiratory distress requiring intubation. Acute pulmonary edema with pink, frothy sputum and crackles on pulmonary auscultation associated with hepatomegalia, low BP of 71/36, tachycardia at 140, and oxygen dependence to maintain good saturation. Normal temperature. Chest X-ray supported diagnosis of cardiogenic shock.
  • Initial echocardiography showed impaired left ventricular function with ejection fraction of 20%. Left ventricle was dilated with moderate mitral regurgitation.
  • Elevated troponin and lactate. Child was admitted to cardiac ICU and hemodyanmic support started with inotropic drug infusion and diuretics, associated with curative heparinotherapy due to several impaired cardiac output.
  • Clinical status improved after 2 days of treatment with complete recovery of left ventricular function on echocardiography.
  • Tramadol intoxication suspected due to empty tramadol tablets found near the child.
  • Toxicology
    • Blood
      • Tramadol: over 1 mg/L
      • O-DSMT: 1.5 mg/L
  • COI: None

 

(Lota, 2012) – Significant hyponatremia following overdose

  • 56-year-old male admitted 12 hours after intentionally using 3000 mg tramadol and 20 dihydrocodeine/paracetamol tablets (10/500). Medical history included COPD.
  • Exam: Drowsy with pinpoint pupils and RR of 6. BP 135/80, HR 110. Type 2 respiratory failure.
  • Rapid improvement with boluses of IV naloxone
  • Admission: Serum Na+ of 136 mM/L. Then rehydrated with 3 L of IV normal saline.
  • Next day: Serum Na+ of 132 mM/L
  • Third day: Serum Na+ of 119 mM/L. Patient also became agitated.
  • COI: Not reported

 

(Mugunthan, 2012) – Hypoglycemia from overdose

  • Australia. 54-year-old female presented to ED 2 hours after a suicide attempt involving 3,000 mg tramadol slow-release. In the ED she was given activated charcoal.
  • 30 min after charcoal: Seizures for a minute and consciousness declined to GCS of 3. Blood glucose was low at 52 mg/dL and therefore dextrose was given. Consciousness quickly improved and glucose rose to 68 mg/dL. Given more dextrose and then a dextrose infusion to maintain a higher blood glucose level.
  • 24 hours later: Blood glucose level began to naturally increase and dextrose infusion was discontinued. Discharged the following day.
  • COI: None

 

(Pothiawala, 2011) – Overdose case

  • Singapore. 27-year-old female found by her parents shrieking in her room. The patient was confused and she did not recognize them.
  • Paramedics found 3 strips of tramadol and a total of 14 empty blisters, indicating exposure to 700 mg.
  • Arrival: Alert and rational but without recollection of the preceding events. HR of 142 and RR of 18. Temp was 36.5°C. BP of 130/82. Oxygen saturation at 100%. Tremors in both hands. Neurologic exam was normal; no rigidity or clonus. ECG showed sinus tachycardia with normal QRS/QTc duration. Labs, including liver and blood sugar tests, were normal.
  • She had a background of suffering from headache for the past 3 years. She received tramadol from her GP and she had been taking 2-6 tablets per day over the past year.
    • In this instance she took more than usual, without knowing the exact dose, due to her headache not responding to her typical tramadol dose.
  • Toxicology
    • Blood: 4 μg/mL
    • No other drugs present
  • COI: Not reported

 

(Elkalioubie, 2011) – Near-fatal response in an ultrarapid metabolizer who overdosed

  • France. 22-year-old female who was previously healthy and then found unconscious. Repeated episodes of cardiac arrest required CPR and immediate admittance to ICU where refractory circulatory shock was diagnosed, requiring extracorporeal circulatory support by venoarterial membrane oxygenation. Hypothermia of 35.5°C was noted along with mydriasis.
  • Echocardiography showed severe biventricular failure. Hypoglycemia at 0.57 g/L, lactic acidosis at pH of 6.85 and lactate of 18 mM/L. Renal failure was seen with creatinine of 22 mg/L and urea 0.54 g/L, but normal hepatic and coagulation parameters.
  • Routine tox screen of serum and urine at ICU admission: negative for alcohol, drugs, and other poisons. Only positive for tramadol in both matrices.
  • Despite tramadol identification, naloxone was not used or justified. Within the first 8 h of admission: Patient developed severe liver failure with profound coagulopathy. Signs of liver failure abated after 36 hours and continuous EEG showed no signs of hepatic or post-anoxic encephalopathy.
  • Discharged after 35 days in hospital.
  • Toxicology
    • Initial blood level for tramadol: 3.22 mg/L, which was fairly low considering the reputed dose of 4.5 grams.
    • Apparent elimination half-life was 16 hours, with tramadol persisting over the therapeutic level for 72 hours.
    • Calculation of tramadol/O-DSMT ratio was 2.54 and tramadol/N-desmethyltramadol yielded a ratio of 11.4.
  • Genotyping predicted UM phenotype for CYP2D6. Also, she was on ketoconazole, a CYP3A4 inhibitor, which was present in her system at an enzyme-inhibiting concentration. The data indicate she could have excessively produced O-DSMT, while having a low production of N-desmethyltramadol.
  • COI: Not reported

 

(Khan, 2010) – Tramadol toxicity-induced rhabdomyolysis

  • Qatar. 27-year-old male presented to the ED with lower back ache radiating to the right leg that associated with weakness. Two days earlier he had taken 1000 mg of tramadol to avoid a panic attack during a flight. He fell asleep for 36 hours after the flight and upon waking he could not walk and he had a severe backache radiating to the right leg.
  • Neurological exam showed right lower limb paresis with right proximal muscle tenderness on palpation. CK elevated at 19,926 U/L, AST 680 U/L, ALT 229 U/L, blood urea nitrogen 10.1 nM/L, serum creatinine 375 μM/L, and serum myoglobin was 3,508 ng/mL.
  • Diagnosed with acute renal failure and tramadol toxicity-induced rhabdomyolysis. On the following days his right lower limb pain and weakness resolved.
  • COI: Not reported

 

(Wang, 2009) – Multi-organ dysfunction associated with tramadol overdose

  • China. 19-year-old male found unconscious. 6 g worth of empty tramadol packages found nearby. Sent to the hospital. Vitals were 36.0°C, BP 87/58, HR 125, and RR 15. He was in a deep coma, lips were faintly cyanotic, hypertonia of muscle and Babinski sign positive. GCS 3/15.
  • Mixed respiratory and metabolic acidosis with pH 6.797, PCO2 113.4, PO2 70.9, base excess -8.6. Patient was intubated.
  • Hepatic and renal tests were markedly abnormal with ALT 726 U/L, AST 1493 U/L, CK 3622 U/L, CK-MMB 91.9 U/L, troponin 1 1.32 ng/L, creatinine 190 μM/L, BUN 7.96 mM/L, blood glucose 7.84 mM/L, and potassium 6.9 mM/L.
  • Admission to emergency ICU with mechanical ventilation. Patient showed severe hypoxemia. Chest X-ray fit with pulmonary edema. Dexamethasone given along with ulinastatin and hemoperfusion was performed twice to remove tramadol in the first 24 hours.
  • In the first 2 days, naloxone was given continuously via infusion at 0.25 mg/h.
  • Multiorgan protection like lowering intracranial pressure, protection of liver and kidney, and promotion of myocardial metabolism was commenced in the first 24 h. Vasopressor therapy used to maintain BP and electrolyte imbalances corrected.
  • Day 2: Temp rose to 39.7°C. Fever was considered to be central and from drug or seizures. Physical cooling was used along with antibiotics in case of pneumonia related to mechanical ventilation. Temperature gradually normalized.
  • Seizures after admission. Though phenobarbital was given beginning on Day 3, the seizures worsened. Mild hypothermia and hibernation therapy were used to relieve seizures for 2 days. Seizures then stopped.
  • Day 10: Regained consciousness. Chest x-ray showed disappearance of radiographic infiltrates. Weaned from ventilator the same day and discharged 13 days later.
  • Toxicology
    • Tramadol in blood: 9.5 mg/L

 

(Afshari, 2009) – Seizure and acute renal failure from overdose

  • 19-year-old male made a suicide attempt with an alleged ingestion of 4000 mg tramadol and no other drugs. He had a generalized seizure around 1 hour after administration. He was an ex-opium user.
    • In the past 2 month: Abusing 100 mg tramadol twice daily.
  • Admission: Confused and had a second generalized tonic-clonic seizure that was controlled via diazepam.
  • Physical exam: Slight reactive miosis and deep tendon reflexes were decreased. Tachycardia on ECG. Another episode of seizure after 2 hours of hospitalization. He had a rise in CPK and creatinine that subsided in the following days. Kidneys were normal on ultrasound.
  • Discharged without further seizures or neurological issues 6 days later.
  • COI: Not reported

 

(Daubin, 2007) – Refractory shock and asystole related to tramadol overdose

  • France. 33-year-old male with a history of depression. Found unconscious with seizures, hypotension, and hypoglycemia at 50 mg/dL. Several empty packages of drugs nearby indicating potential exposure to 10 g tramadol, 6 g hydroxyzine, 1 g gabapentin, and 80 mg clonazepam.
  • Intubated and mechanically ventilated. Thiopental, IV glucose, and fluid loading were used and the patient was transferred to ICU.
  • Admission to ICU: GCS of 3 with seizures, mydriasis, no pupillary reflexes. BP 63/38, HR 85, temp 35.9°C.
  • ECG showed sinus rhythm with complete right bundle branch block and QTc 480 msec. EEG showed continuous generalized epileptiform discharge.
  • Elevated creatinine at 22 mg/dL, elevated creatine kinase at 332 U/L, and elevated myoglobin at 1281 μg/L.
  • Despite aggressive therapy w/ thiopental, fluid loading, vasopressors, assisted ventilation, and tight glycemic control, he deteriorated.
  • 12 hours post-admission: Sudden ventricular tachycardia necessitating defibrillation. Followed a few minutes later by a brief asystole, then restoration of spontaneous circulation after 3 mg epinephrine.
  • Repeat echocardiogram showed hypokinetic left ventricular function with 25% ejection fraction. ECLS devise implanted and vasopressors were infused to maintain mean systemic arterial pressure above 70 mmHg. Continuous venovenous hemofiltration was used to treat acute renal failure and to regulate intravascular volume and the overall fluid balance.
  • Gradually improved. Over the following hours vasopressor support and ventilator were adjusted. Weaned off hemofiltration on Day 4, off vasopressors and ECLS on Day 8, and off assisted ventilation on Day 11. Discharged with moderate cerebral disability on Day 12.
  • Toxicology
    • Admission blood analysis was negative for ethanol, benzodiazepines, paracetamol, salicylic acid, barbiturates, and TCAs.
    • GC/MS showed significant peaks of tramadol and O-DSMT. Along with small levels of hydroxyzine, gabapentin, and clonazepam.
    • Tramadol admission level was 23.9 mg/L and was over therapeutic levels for 3 days. Peak O-DSMT was at 12 hours post-admission, at the time of cardiac arrest.
  • COI: Not reported

 

(Mattia, 2004) – Respiratory depression following iatrogenic tramadol overuse in a patient with chronic renal failure

  • 69-year-old male with chronic renal failure. Given tramadol at 75 mg/d. Due to ineffective pain relief that increased to 150 mg/d then 200 mg/d IV.
  • 48 hours after starting the 200 mg/d IV infusion: stuporous, arrhythmic, bradypnea.
    • Pin point pupils, purposeful movements to painful stimuli and no response to verbal stimuli.
  • Revealed that a therapeutic mistake led to the infusion actually containing 400 mg/d.
  • Naloxone 0.4 mg IV given and oxygen therapy started. Regained consciousness, pupils normalized, and respiratory rate increased to 15.
  • New 0.4 mg IV naloxone dose required an hour later then an infusion was given.
  • Clinical conditions eventually improved. And by the next day blood gases normalized, though an oxygen deficit remained.
  • COI: Not reported

 

(Sachdeva, 1997) – Overdose responsive to naloxone

  • USA. 36-year-old male brought by ambulance to ED after being found unresponsive. He had been on tramadol due to pain that was unresponsive to NSAIDs. Found with four recently filled prescription bottles: two with 55x 50 mg tramadol missing from each, one with all 55x 50 mg tramadol tablets still present, and the fourth with four 150 mg amitriptyline tablets missing.
  • Vitals: rectal temp of 99.6°F, BP 101/63, HR 108, RR 10 and shallow. Cardiac, pulmonary, abdominal, and extremity examinations were otherwise unremarkable.
  • IV naloxone 2 mg administered. Immediately became somewhat awake and he was able to answer questions. Reported taking two tablets of tramadol on the way home; denied any recollection of subsequent events and denied suicidal intent.
  • Within 30 min: Became increasingly drowsy with shallow respirations. Again responded to 2 mg naloxone. Required another 2 mg in the next 10 minutes. Then continuous infusion of 6 mg/h was started, titrating up to 12 mg/h due to increasing lethargy.
  • Patient admitted to ICU. Four hours after arrival to ED a slow wean from naloxone began, which was complete by 16 hours later without further depression of mental or respiratory status. Discharged 1 day later due to response to treatment and lack of suicidal ideation.
  • Calculated dose of tramadol was up to 5.5 grams based on the missing tablets.
  • COI: Not reported

 

(Riedel, 1984) – Severe CNS depression in an infant; responsive to naloxone.

  • 6-month-old infant was suffering from a febrile URTI and was erroneously given 100 mg tramadol via suppository by his parents. He was left unattended overnight and found pale and apathetic in the morning. Generalized convulsions began shortly thereafter and were treated by the hospital w/ diazepam.
  • Exam revealed a pale and hypotonic infant with opisthotonic posture, poor peripheral circulation, and noisy breathing. State of awareness varied from sleepiness to unconsciousness. Pin point pupils were noted and they were hardly reactive to light. Mixed acidosis.
  • Artificial ventilation was required due to increasing central hypopnea. Naloxone 10 μg/kg IV was given and this had a remarkable effect, leading to pupil widening a few minutes later and the child became active and started to fight the respirator.
  • The naloxone effect only lasted a short time, but a second dose of the same amount led to the child becoming awake and artificial ventilation was stopped a few hours later.
  • COI: Not reported

Animal research

(Lagard, 2017) – Diazepam + Naloxone is a better overdose treatment than either drug alone.

  • Rats were exposed to 75 mg/kg IP. They were given diazepam 1.77 mg/kg IP, naloxone 2 mg/kg bolus then 4 mg/kg/h infusion, or a combo of the two.
  • Results
    • Naloxone reversed respiratory depression but significantly increased seizures (p<0.01) and prolonged their occurrence time. Diazepam abolished seizures but significantly deepened sedation without improving ventilation.
    • The combination completely abolished seizures and significantly improved rat ventilation by reducing inspiratory time; it did not worsen sedation.
  • COI: None

 

(Lagard, 2016) – Diazepam largely improves aspects of tramadol overdose

  • Tramadol-induced early-onset increases of brain serotonin and norepinephrine in rats was not significantly altered by diazepam/tramadol.
  • Median lethal dose of tramadol (114.5 mg/kg IP) and tramadol with 20 mg/kg diazepam (113.4 mg/kg IP) were not significantly different. But the time to death was significantly longer in combo group at 100.6 min vs. 50.0 min.
  • Test with tramadol 75 mg/kg IP alone or with diazepam 20 mg/kg SC
    • The diazepam/tramadol combo significantly increased sedation, completely prevented seizures and abnormal behaviors, but it didn’t change body temperature. No death was observed in either group.
    • Based on an EEG study, 4/6 tramadol-treated rats experienced electro-clinical and additional electrical seizures, while 2/6 had neither clinical nor electrical seizures. In contrast, diazepam/tramadol-treated rats exhibited no seizures, although EEG was significantly modified.
  • COI: None. Experimental study funded by the Institut national de la sante et de la recherche medicale

Serotonin toxicity

Serotonin toxicity mostly is not a concern with tramadol-only overdoses. It can occur, but it’s more common when combining it with other serotonergic drugs. At therapeutic doses the combination of tramadol and typical antidepressants, including SSRIs, doesn’t appear to be an issue.

Among the symptoms are agitation, anxiety, disorientating, restlessness, clonus, tremor, hypertension, hyperthermia, tachycardia, tachypnea, vomiting, shivering, mydriasis, and hyperreflexia.

Studies have indicated the toxidrome is connected to 5-HT1A and 5-HT2A activity.

Human

(Spies, 2015) – A survey of physicians found a minority are aware of the interaction between tramadol and SSRIs and awareness is not associated with a lower rate of prescribing.

  • Questionnaire sent to 185 physicians at a medical center in The Netherlands, yielding a 46% response rate. They were shown four cases, two of whom used an SSRI among other medications, and asked the respondent to prescribe an opioid in each case.
  • 1/3 of respondents prescribed tramadol and they were aware of the SSRI interaction. About 1/5 deliberately avoided tramadol due to the interaction. No difference in actual tramadol prescriptions, with a rate of 23.8% of SSRI-users receiving tramadol vs. 24.6% of non-SSRI-users.
  • COI: Not reported

 

(Park, 2014) – Serotonin toxicity is not a reason to avoid typical antidepressants and tramadol combo

  • Case reports of serotonin toxicity from a tramadol and an antidepressant (non-MAOI and non-TCA) combo were identified.
  • 10 cases were found with a therapeutic dose of tramadol combined with an antidepressant. Although caution is indicated, the drugs are not contraindicated. Tramadol is only contraindicated with MAOIs, not the antidepressants commonly used today. The case reports indicate a higher risk of serotonin toxicity, but higher doses and pharmacokinetic interactions are relevant.

 

(Nelson, 2012) – Reviewing the literature on recommendations to avoid serotonin toxicity with SSRI/tramadol combo

  • The combination of SSRIs and tramadol does come with a serotonin toxicity risk. There have been 9 published case reports of that issue and they involved variable durations of exposure and dosing, from short-term use of 50 mg/d to long-term use of 400 mg/d. Only 2 case reports were of unintentional tramadol overdose due to uncontrolled pain.
    • In all of the serotonin toxicity cases, the patients fully recovered after stopping the drugs (or at least one of them).
  • An Australian case series from 1036 postmortem coroner reports involving toxicology results for 1 or more drugs: fluoxetine, sertraline, citalopram, paroxetine, venlafaxine, tramadol.
    • Of those, 326 involved a contraindicated (n=26) or inadvisable (n=301) drug combo. 20% of cases involved the combo of tramadol with an SSRI.
    • 5 cases found in which there was not an intentional drug overdose, but rather a major drug interaction that led to death. 2 of those cases involved the combo of tramadol with an SSRI (citalopram, fluoxetine).
  • One of the major issues is PK-related since all SSRIs are inhibitors of CYP2D6, which could enhance the serotonergic activity of tramadol.

 

(Tashakori, 2010) – Case series showing a risk of serotonin toxicity in tramadol overdose

  • Iran. Prospective observational study. All cases admitted with suspected tramadol overdose for a 1-year period were analyzed.
  • Results
    • Tramadol overdose accounted for 1.2% of all poisonings (n=158). It was the only drug present in 65% of those cases.
    • Among tramadol-only cases, 15% had seizure and 6% had elevated CPK. Mortality occurred in 1 case.
    • Seizures occurred more often with tramadol-only use and in cases with mydriasis.
    • 8 treated for possible serotonin syndrome.
    • Concurrent use of CNS depressants, age, alleged dose, consciousness level, respiratory rate, history of drug abuse, and naloxone use were all not correlated.
    • On admission, 6 were unconscious, 133 had some degree of limited consciousness, and 19 were alert.
    • Pupils: 32% miosis, 56% midsize, and 12% mydriasis.
    • Mean RR of 16.8, mean SBP of 115, mean DBP of 75, and mean HR of 79.
  • COI: None

Cases

(Shahani, 2012) – Precipitated by the addition of tramadol in a patient on citalopram and bupropion.

  • 62-year-old Caucasian male. He had a major depressive episode and was on citalopram 40 mg and bupropion 150 mg BID.
  • He was then started on tramadol 50 mg TID for musculoskeletal pain. Three days after starting: Presented to ED with tremor, diaphoresis, and anxiety.
    • He denied excessive medication use or illicit drug use.
  • Exam revealed tachycardia, elevated BP, and presence of clonus in the lower extremities.
  • Diagnosed with serotonin syndrome. Medications (citalopram, bupropion, tramadol) discontinued and supportive care given. Diazepam and labetalol used for anxiety and autonomic stability, respectively.
  • Antidepressants restarted at a lower dose and titrated. Primary care physician was educated about the drug interaction, leading to the implementation of an alternative analgesic therapy.

 

(Peacock, 2011) – Tramadol and citalopram linked serotonin syndrome

  • UK. 78-year-old female was on citalopram and she presented after a fall and commencement of tramadol for pain. Exam showed tachycardia, global myoclonus, increased tone, hyperreflexia, and bilateral upgoing plantars. Serotonin syndrome secondary to tramadol in combination with citalopram was suspected.
  • Symptoms resolved completely on discontinuation of the two drugs.

 

(Marechal, 2011) – Serotonin syndrome from tramadol in an 8-month-old

  • France. 8-month-old female with no prior medical issues was brought to the pediatric ED because of an episode of epistaxis. The night before she was found playing with her father’s tramadol bottle and she was unable to sleep all night because of extreme agitation.
    • It was discovered a pill was missing, meaning she was exposed to 200 mg tramadol.
  • 12 hours post-ingestion: temp 37°C, HR 141, RR 22, BP 98/69, oxygen saturation 100%.
    • Skin was pale but not diaphoretic. No diarrhea or vomiting. Neurologic exam showed intermediately reactive pupils, ataxia, episodic agitation alternating with drowsiness, GCS of 10, global increase in lower limb tend reflexes.
  • Within the next 2 days her status improved, there was no further myoclonus or seizures, and the initial disturbances went away within 24 hours of admission.
  • Toxicology
    • Tramadol in serum: 680 μg/L
  • COI: Not reported

 

(Kitson, 2005) – Case of serotonin toxicity linked to tramadol and amitriptyline

  • UK. 79-year-old female presented with a two-day history of collapse and confusion. She was on rofecoxib, morphine, coproxamol, and amitriptyline.
    • Three days before arriving she had been started on tramadol for worsening sciatica.
  • Arrival: Delirious and hallucinating with a GCS of 11.
  • Became increasingly unwell over the next 2 days with confusion, sweating, pyrexia, muscular rigidity. Arterial gas showed metabolic acidosis.
  • Day 4: Deteriorated with frequent seizures, increasing pyrexia, increasing rigidity, deepening coma, tachycardia, sweating, diaphoresis.
    • Probable serotonin syndrome was diagnosed.
  • She became unresponsive, hypotensive, and bradycardic with poor respiratory effort. Despite intubation, fluid loading, and high dose epinephrine, her shock state was refractory and she died.
  • COI: Not reported

 

(Houlihan, 2004) – Serotonin toxicity linked to tramadol, venlafaxine, and mirtazapine

  • 47-year-old male with recurrent depression was stable on venlafaxine XR 300 mg/d and mirtazapine 30 mg/d for 4 months. He was also given NSAIDs for chronic pain, but due to increasing intolerance of the adverse GI effects and history of polysubstance dependence (thereby contraindicating classic opioids) he was started on tramadol.
  • Tramadol was titrated to 300 mg/d over 4 weeks and further increased to 400 mg/d.
  • Nearly 2 months after starting 400 mg/d he presented with an 8-day history of increased agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, and mydriasis. Vital signs were unremarkable.
  • Urine drug screen was negative. Labs showed normal CK level. Pill count did not reveal overuse of medication.
  • Presumptive diagnosis of serotonin toxicity was made, so all medications were stopped. Over the next 4 hours he developed tachycardia and 39.2°C temperature. He was given IV hydration and closely monitored.
  • Venlafaxine and mirtazapine were started again a few days later because of the patient’s concern about his mood. Both were titrated over a one week period and the patient has remained symptom-free since.
  • COI: Not reported

 

(Garrett, 2004) – Overdose linked to serotonin toxicity presenting as acute right heart dysfunction

  • Denmark. 37-year-old female presented with weakness, slurred speech, and syncope.
    • History of headaches and chronic pain syndrome treated with tramadol and nitrazepam.
  • She took 2000 mg tramadol XR the prior day.
  • Exam: Relatively undistressed but marked peripheral cyanosis and hypotension. SBP of 68 and HR was 92. Right ventricular heave and loud second heart sound in the pulmonary area.
  • Jugular veins were grossly distended and pulsatile and her face was suffused. RR was 18 and temp was 37.8°C.
  • No peripheral edema. Neurological exam showed disorientatioin but interactive, with tremor, slurred speech, and symmetrically dilated pupils. Muscle tone generally increased. Reflexes were notably brisk with ankle clonus and recurrent symmetrical myoclonic jerks of her limbs when starteld.
  • ECG: First degree heart block, rightward axis, RSR pattern in V1, borderline ST elevation in inferior leads, inverted T waves in V1 and V3 and inferiorly.
  • Blood gas abnormalities: pH 7.15, PaCO2 55 mmHg, PaO2 399 mmHg on non-breather mask oxygen, bicarbonate 18 mM/L, base deficit 9 mM/L, potassium 6.9 mM/L.
  • Echocardiogram: Left ventricle of normal dimensions and systolic function, but dilated right heart chambers with severe functional tricuspid regurgitation, a deviated intraventricular septum, and high pulmonary artery pressures.
  • Diagnosed with acute pulmonary hypertension and right heart failure, confirmed by transthoracic echocardiography. Precipitating event for this appeared to be tramadol.

 

(Mason, 1997) – Possible serotonin toxicity from tramadol and sertraline

  • 42-year-old female presented with atypical chest pain. ECG showed sinus tachycardia at 140 bpm and questionable ST depression. BP of 155/70 and temp of 36.9°C. Symptoms also included confusion, psychosis, sundowning, agitation, diaphoresis, and tremor.
    • She’d been having pain off and on for the last 3 weeks.
  • Medications on admission: metaproterenol, pravastatin, sodium chloride nasal spray, triamcinolone inhaler, chlorzoxazone, metaproterenol, nabumetone, theophylline, sertraline, naphazoline, omeprazole, acetaminophen, terfenadine, and tramadol.
    • Tramadol had been started 3 weeks prior for chronic pain. Given 300 mg/d, titrated from initial dose of 150 mg/d. Good response to tramadol though with increasing GI disturbance.
    • Sertraline was 100 mg/d and she had been on it for over a year.
  • Chest pain resolved 24 hours after admission.
  • Psychiatric consult noted flight of ideas, ideas of reference, and confabulation with mental status which stopped 24-36 hours after admission, when tramadol was discontinued and sertraline lowered to 50 mg/d.
  • Symptoms thought to be from increased sertraline and tramadol addition.
  • After discharge: Sertraline increased again and tramadol restarted with 50-100 mg/d.
  • COI: Not reported

Cardiovascular

A review of the evidence showed tramadol could be associated with an increased risk of QT interval prolongation and Torsades de pointes (Hancox, 2018). This may primarily occur in overdose rather than in therapeutic use. There is some evidence that tramadol can block Na+ channels at high concentrations, which could explain its ability to alter cardiac function.

(Hancox, 2018) – Review of evidence indicating tramadol may be linked to QT interval prolongation and Torsades de pointes

  • In 2018 tramadol was added to the CredibleMeds database as having a possible risk of TdP arrhythmia.
  • (Fanoe, 2009) – 2009 study of 100 patients with chronic non-malignant pain showed methadone was correlated with QTc prolongation, oxycodone was correlated, but tramadol dose was not correlated. But small sample size could have concealed effect.
  • (Emamhadi, 2012) – 479 patients with acute tramadol toxicity. ECG analysis showed QRS widening in 7.5% and QTc prolongation in 24.6%. Since far more had QTc prolongation than QRS, tramadol may have a direct K+ channel inhibitory effect.
  • (Tsai, 2006) – Tramadol shown to inhibit neuronal delayed rectifier K+ channels.
  • (Keller, 2016) – Associated with QTc prolongation in 1270 patients, 1.26% of whom were given tramadol.
  • (Keller, 2016) – QTc prolongation that is correlated with plasma drug concentration. High correlation between change in QTc and plasma concentration.
  • (Alizadeh, 2016) – 2016 study detected prolonged QTc intervals in 18.4% of 1402 patients with tramadol poisoning and QRS widening was seen in 6.5%.
  • (Samanta, 2016) – Case report of male with multiple traumatic injuries who developed ventricular tachycardia and cardiac arrest following IV tramadol. Required magnesium correction and DC cardioversion. QTc interval at restoration sinus rhythm was 480 ms, while pre-tramadol it was 320 ms. Authors suggested tramadol may be associated with K+ channel related delay of repolarization.
  • COI: Author was funded by a University of Bristol Research Fellowship.

 

(Emamhadi, 2012) – ECG data from overdose reports indicates it may cause channel blockade

  • Chart review of 479 patients in Iran with isolated tramadol toxicity. Polydrug use was an excluding factor, but tramadol-only exposure was not confirmed with toxicology testing. Also excluded patients with a known underlying heart condition.
  • Results
    • ECG showed tachycardia in 30.6%, QRS 120 ms or longer in 7.5%, corrected QT over 440 ms in 24.6%, height of R wave over 1 mm in lead aVR in 22.1%, R/S ratio more than 0 in lead aVR in 23.5%, terminal 40-ms frontal plane QRS axis greater than 120° in 31.7%, and complete or incomplete right bundle branch block in 4.6%.
      • T40-ms frontal plane QRS axis over 120° is an indicator of fast Na+ channel blockade.
    • Also, 55.3% of patients had seizures.
  • COI: Not reported

Hepatotoxicity

Human and animal evidence suggests tramadol and O-DSMT could cause hepatotoxicity. It has only been reported in a small portion of patients and it has also been associated with toxicity in some case reports. Given the low frequency of toxicity reports in the millions of patients using tramadol, therapeutic use may not be a major risk factor for developing liver toxicity.

Human research

(Arafa, 2018) – O-DSMT generation from tramadol is associated with hepatotoxicity in long-term use

  • Background
    • α-GST is a sensitive and good hepatic enzyme in the assessment of earlier hepatocellular damage vs. aminotransferases.
    • Hepatotoxicity has been reported as a rare side effect affecting under 0.1% of patients. Some evidence indicates a high rate of tramadol abusers have atypical AST and LDH results indicative of impaired liver function.
  • Egypt. 60 patients given chronic tramadol treatment for a mean of 3.9 years. Dose of 200-400 mg/d. They were compared to healthy, drug-naïve controls. CYP2D6 duplication allele carriers (UM status) followed by EMs had significantly higher levels of O-DSMT in urine along with higher serum lipid peroxidation and lower levels of total antioxidants.
    • Comedications including narcotic analgesics, NSAIDs, local anesthetics, hypnotics, paracetamol, and corticosteroids were excluded.
  • Significant increases in serum hepatic damage markers including α-GST levels and liver function enzyme activities compared to no significant increase vs. controls for PMs.
    • α-GST, ALT, AST, ALP, and GGT were all affected.
  • Tramadol caused more moderate to severe hepatotoxicity in more significant CYP2D6 metabolizers.
  • COI: None

 

(Elmanama, 2015) – Tramadol abuse is associated with liver and kidney toxicity

  • Palestine. 50 male tramadol abusers referred to psychiatric clinics between September 2013 and June 2014. 56% were 21-25 years old and 24% were 26-30 years old.
  • 34% took under 500 mg, 26% took 500-1000 mg, 14% took 1001-1500 mg, 10% used 1501-2000 mg, and 16% used over 2000 mg.
  • Liver function
    • Only those with negative hepatitis virus tests were evaluated. ALT was significantly higher vs. control and about 50% of tramadol abusers showed abnormal AST and LDH results vs. control.
  • Kidney function
    • 6-10% of abusers had abnormal BUN and uric acid values. Those individuals were characterized as long-term abusers of more than five years, suggesting a link to long-term use.
    • Creatinine was not significantly different.
  • COI: Not reported

Animal research

(Sevimli, 2006) – Histopathological changes in animals exposed to morphine or tramadol

  • Rabbits given morphine 1 mg/kg, placebo, or 10 mg/kg tramadol twice daily for 3 days then sacrificed and tissue samples prepared.
  • Results
    • Hepatocyte degeneration, central vein dilation, and mononuclear cell infiltration in the morphine group was more severe than in the control group.
    • Hepatocyte degeneration, sinusoidal dilation, central vein dilation in the tramadal group was more severe than in the control group.
    • Sinusoidal dilation in tramadol group was more severe than in the morphine group.
  • COI: Not reported

Fatalities

Fatalities are possible but single-drug toxicity deaths with tramadol are rare. It is most often a problem when high doses are mixed with other CNS depressants or serotonergic drugs. Tramadol-only fatalities tend to show very high concentrations that would not be reached even with common or strong nonmedical doses.

The fatalities on record have included postmortem findings indicative of an opioid-type overdose, suggesting tramadol can fatally inhibit respiratory and cardiac function, at least in some people.

Reviews

(Tjaderborn, 2007) – Review of fatalities over a 10-year period in Sweden

  • Sweden. 1995 to 2005 data. Cases included forensic autopsy cases in which tramadol was detected, unintentional overdose was suspected, femoral blood concentration exceeded 1 μg/g, and tramadol was considered to have had a major or contributory role in the fatality.
  • 49,700 forensic death investigations during that time. Tramadol was detected in 837 (2%). Of those, 148 (50%) had tramadol listed as a contributing factor. In only 17/148 was the fatality deemed unintentional.
    • During that same period, 124.5 million defined daily doses of tramadol were sold in Sweden, giving an incidence of unintentional fatal intoxications of 0.14 per million DDDs sold.
  • Median femoral blood concentration was 2.0 μg/g for tramadol and 0.3 μg/g for O-DSMT.
  • Other substances were detected in all cases. 94% involved other CNS affecting drugs, most often opioids (53%), benzodiazepines (47%), serotonergic drugs (47%), and/or ethanol (47%).
  • Tramadol was the only drug present at a toxic level in 7/17 cases.
  • Source of tramadol (n=12)
    • 58% prescription, 17% obtained from their partner, 17% obtained it illegally.
  • Documented history of substance abuse seen in 82% of cases.
  • COI: Not reported

(Randall, 2014) – Review of tramadol-related deaths in Northern Ireland from 1996 to 2012.

  • UK. Review of all autopsy reports to the State Pathologist’s Department in Northern Ireland. Total was 127 from 1996 to the end of 2012.
  • Results
    • First death reported in 1996. Gradual rise over time, from 2 in 2001 to 19 in 2012. Highest number of deaths was in 2011 with 23.
    • In 2001, tramadol represented 9% of deaths due to drug misuse. That was up to 40% in 2011. Largest age group for deaths was 41-50 years old.
    • Top fatality location was the Belfast area, accounting for 36% of cases. In a majority of cases death occurred in home or in the community; only 6% reached hospital. 3 of the 8 deaths in hospital were associated with multi-organ or liver failure.
    • In 20%, tramadol was implicated indirectly or as a contributory factor. In those, 17 deaths were caused by aspiration pneumonia, 2 with drowning, 1 with positional asphyxia, 1 with bowel obstruction, 1 with congestive cardiac failure from cardiomegaly, 1 with emphysema, 1 with hemorrhage due to incised radial artery.
    • Tramadol had been prescribed in 46% of cases.
    • Only 23% were due to ingestion of tramadol alone and in this group there was a higher percentage of apparent deliberate overdoses. Alcohol was associated with 28% of deaths and tramadol was most often fatal when used with one other drug, the most common being diazepam.
    • In 63% there was a history of depression with many showing a history of overdose or self-harm. 50% were recorded as suffering from chronic pain, 41% were known to abuse alcohol or drugs, and 15% had mental health problems.
    • Manner of death was most likely suicide in 38%. 27% were thought to be accidents and unknown intentions were responsible for 35%.
    • Highest recorded blood serum level in deaths attributed just to tramadol was 88.8 μg/mL. Lowest level was 1.85 μg/mL. The fatal range of tramadol when used with other drugs was much lower at 0.15 to 39 μg/mL.
  • COI: None

(Iravani, 2010) – Review of trends in tramadol-related fatalities in Tehran, Iran from 2005 to 2008

  • 4-year study period in which toxicological analysis was conducted in 20,000 cases. Of those, 294 cases involved tramadol by itself or with other drugs.
  • Number of cases with tramadol detected increased from 4 in 2005 to 62 in 2006 to 98 in 2007 and to 130 in 2008.
  • Tramadol was detected alone in 51.36% of cases and coingestion was seen in the rest.
  • COI: None

Case reports

(Gioia, 2017) – 2 fatalities from tramadol alone

  • Italy
  • Case 1
    • 48-year-old male found dead. Bilateral pulmonary edema.
    • Toxicology
      • Femoral blood
        • Tramadol: 23.9 μg/mL
        • O-DSMT: 0.2 μg/mL
      • No other CNS depressants or other drugs detected.
  • Case 2
    • 17-year-old male found dead. Relatives said he was using tramadol for pain. Autopsy only showed pulmonary edema.
    • Toxicology
      • Femoral blood
        • Tramadol: 5.8 μg/mL
        • O-DSMT: 0.6 μg/mL
      • No other CNS depressants or other drugs detected.

 

(Barbera, 2013) – Suicidal poisoning from tramadol

  • Italy. 48-year-old female found dead and her doctor stated she had been on different drugs, including carbamazepine and tramadol.
  • Histological exam showed polivisceral congestion. Evidence for the presence of thrombi and blood clots in the chambers of the heart and partly hemorrhagic pulmonary edema, vicarious acute emphysema, very large amount of hemodiserophagic histiocytes, and vocal areas of endoalveolar hemorrhage, signs of low blood flow. No associated pathologies observed.
  • Toxicology
    • Tramadol (blood; femoral): 61.83 μg/mL
    • O-DSMT (blood; femoral): 14.13 μg/mL
    • Carbamazepine has been quantized in femoral blood at 3.2 mg/L.
  • Death blamed on severe depression of fundamental functions (impaired respiration and bradycardia, ultimately cardiac arrest) as a consequence of acute tramadol intoxication and mediated by O-DSMT opioid-like activity.
  • COI: None

 

(Mannocchi, 2013) – Fatality associated with a combination of tramadol and propofol

  • Italy. Middle-aged health care professional admitted to ED with increasing dyspnea and cyanosis. Arrival: RR of 25, ECG showed atrial fibrillation and HR of 100-110, BP of 100/60.
  • Arterial blood showed extreme acidosis. Troponin T and myoglobin elevation indicated cardiac damage. Physicians administered sodium bicarbonate, epinephrine, and atropine. Despite advanced life support the patient died an hour later.
  • Toxicology
    • Heart blood
      • Propofol: 0.20 μg/mL
      • Tramadol: 5.3 μg/mL
    • Blood propofol and tramadol were in the range of previously fatal administrations and were higher than the therapeutic range.
  • Propofol itself cannot be blamed for the toxidrome due to the patient being conscious and alert upon arrival and deceasing an hour later despite ventilatory support and intubation. Though propofol could have contributed to respiratory failure.
  • Clinical, hematochemical, and toxicological findings point to myocardial damage due to unintentional intoxication from tramadol.
  • COI: None

 

(De Backer, 2010) – Two fatal overdoses, one possibly linked to fluoxetine as well.

  • Belgium
  • Case 1
    • 17-year-old male. Died apparently of respiratory depression. Body had evidence of acute pulmonary edema, including foam around the nose and mouth. Drug packages of cetirizine and tramadol were found.
    • Blood concentration: 7.7 mg/L. Tramadol and metabolites also found in urine.
    • Believed to have been suicide.
  • Case 2
    • 75-year-old female. Believed to have died from a combo of tramadol and fluoxetine, with suicide as a factor.
    • Found by husband with apnea and emergency services were called. She received advanced life support and cardiac output was restored, but then she had a further episode of cardiopulmonary arrest a couple hours later, leading to her death.
    • Peripheral blood: 48.3 mg/L.
      • Seproxetine, a metabolite of fluoxetine, was detected at subtherapeutic concentrations.

 

(Gheshlanghi, 2009) – Fatality associated with seizure

  • Iran. 19-year-old male presented after taking 10,000 mg tramadol. 2 hours post-administration: confusion, ataxia, agitation.
  • Admission: Confused with BP of 90/50, HR 140, RR 20, temp 36.8°C. Sudden tonic-clonic seizure occurred; controlled by diazepam 10 mg IV.
  • Because of cyanotic appearance and low O2 saturation of 35.2% and resistance to mask ventilation, endotracheal tube was used and he was moved to ICU.
  • Blood sugar was elevated at 154 mg/100 mL. Severe metabolic acidosis was treated with sodium bicarbonate accompanied by 1 L normal saline. Midazolam infusion was started.
  • 30 min post-seizure cessation: Consciosuness increased and he extubated himself, but his confusion and agitation were unimproved. BP 120/75, RR 20, HR 140. Despite midazolam again, his agitation worsened.
  • Finally he did become temporarily stable but about 3 h post-admission cardiopulmonary arrest occurred, CPR was unsuccessful, and he died.
  • All blood labs pre-death were normal, including CBC, BUN/Creatinine, blood sodium, potassium, CPK, SGOT, SGPT, alkaline phosphatase. ECG were in the normal range.
  • Toxicology was positive for tramadol in all viscera. Ethanol, blood opiates, and carboxy-hemoglobin tests were negative.

 

(Decker, 2008) – Fatality from tramadol overdose alone

  • Belgium. 28-year-old male. Medical history of stress incontinency and Munchausen’s Syndrome. Consulted a psychiatrist regularly and was treated with tramadol for several months due to rather vague abdominal complaints.
  • He reportedly ingested a benzodiazepine before sleeping in the ward (according to other patients) and he snored all night. In the morning, a fellow patient witnessed apnea and alerted medical staff. Asystole was observed and advanced life support was started.
  • Arterial blood gas showed extreme acidosis and hypoglycemia at 5 mg/dL, for which hypertonic glucose and sodium bicarbonate were given.
  • Cardiac output restored within 10 min and patient admitted to intensive care ward. GCS of 3/15, no pupillary reactions or reflexes. ECG showed sinus tachycardia and a transthoracic echocardiography showed no abnormalities. Chest X-ray revealed consolidation of the left lower lobe necessitating bronchoscopy.
  • Lab results indicated acute hepatic as well as renal failure.
  • Because of progressive hepatic failure with ammonia levels as high as 175 IU/L, a liver biopsy was performed the next day and revealed both steatosis and centrolobular necrosis.
  • Progressed to multiple organ failure and he died two days later.
  • Extensive GC-MS analysis of serum at admission to ICU only showed tramadol.
    • Serum at admission to ICU: 8 mg/L
    • Post-mortem serum: 5.2 mg/L
    • N-desmethyltramadol also detected but not quantified.
  • COI: Not reported

 

(Loughrey, 2003) – Fatality following hepatic failure

  • UK. 67-year-old male was on tramadol 100 mg QID for pain associated with rib fracture. He received 84x 50 mg tramadol tablets on the day of his outpatient visit and he requested a further prescription just 4 days later. The ultimate dosage used is unknown.
  • 8 days post-outpatient visit: Admitted to hospital with increasing dyspnea. He was drowsy, centrally cyanosed, and hypotensive. Lab investigations showed markedly altered liver tests with ALT 1739 U/L and AST 1515 U/L.  Hypoxia, lactic acidosis, and hypoglycemia were noted.
  • Soon after admission he had cardiorespiratory arrest and died. Autopsy showed extensive pulmonary fibrosis and histological evidence of extensive fulminant hepatic necrosis with no background cirrhosis.
  • Toxicology
    • Tramadol (blood): 3.7 mg/L
    • Negative for alcohol, paracetamol, barbiturates, antidepressants, and other opioids.
  • COI: Not reported

 

(Clarot, 2003) – Fatal cases involving both a benzodiazepine and tramadol

  • France.
  • Case 1
    • 36-year-old male found dead. Toxicology showed a very high level of tramadol in femoral blood (134 μg/mL) and a toxic bromazepam level (0.867 μg/mL)
  • Case 2
    • 42-year-old male found in cardiorespiratory arrest and he died during transport to the hospital. No evidence of cardiac abnormalities but signs of asphyxia were observed. Toxicology showed a toxic tramadol blood level of 0.880 μg/mL and a toxic bromazepam level of 0.801 ng/mL.
      • However, meprobamate and zopiclone at therapeutic concentrations were also found.
  • Case 3
    • 58-year-old male admitted to ED after dizziness. He was comatose with hypothermia at 34.0°C. Died 2 days later of irreversible coma. Autopsy showed signs of asphyxia.
    • Toxicology showed toxic tramadol level of 3.0 μg/mL and slightly supratherapeutic level of alimemazine at 0.410 μg/mL
  • Case 4
    • 24-year-old male found dead. Toxicology showed a therapeutic blood concentration for phenobarbital and a toxic tramadol level of 1.9 μg/mL.
  • COI: Not reported

 

(Musshoff, 2001) – Fatality just from tramadol

  • Germany. 26-year-old male. Found lying face down and dead. Autopsy and histopathological exam revealed severe edema of the brain and lungs.
  • Toxicology
    • Tramadol, N-desmethyltramadol, and O-DSMT detected. All other tests for ethanol and other drugs of abuse were negative.
    • Femoral blood for tramadol: 9.6 μg/mL
  • COI: Not reported

 

(Lechowicz, 2000) – A case of fatality related to tramadol and tianeptine combo

  • Poland. A middle-aged female fainted on the street and was cared for, but then she was found dead the next day in her flat.
    • Several drugs found nearby, including tianeptine, diclofenac, tetrazepam, ketoprofen, clorazepate, and tramadol.
  • Toxicology
    • Whole blood
      • Tianeptine: 12.5 μg/mL
      • Tramadol: 5.0 μg/mL

 

(Michaud, 1999) – Fatality linked to alprazolam and tramadol

  • Switzerland. 30-year-old female found dead in her home w/ several packages of Tramal (4 empty bottles of 10 mL each containing 100 mg tramadol for oral use) and alprazolam, as well as an empty bottle of wine in the kitchen.
  • Toxicology
    • Tramadol
      • Peripheral blood: 38.3 μg/mL
    • Alprazolam
      • Peripheral blood: 0.21 μg/mL
  • The alprazolam level was higher than the therapeutic range (0.005-0.05 μg/mL) and the level of tramadol was around 100x above the therapeutic level.
  • COI: Not reported

 

(Moore, 1999) – Overdose fatality, possibly just from tramadol.

  • Tramadol overdose was the cause of death. Blood concentration was 20 μg/mL
  • In each tissue/fluid other than urine, tramadol concentration was higher than either metabolite. The O-desmethyl metabolite was at a higher concentration than the N-desmethyl metabolite, going against other postmortem case reports where the N-desmethyl metabolite has been at a higher level.
  • COI: Not reported

 

(Lusthof, 1998) – Suicide from tramadol

  • The Netherlands. 49-year-old male was found dead. Autopsy showed no specific signs of cause of death other than pulmonary edema.
  • Immunoassay test looking for opiates, cocaine metabolite, amphetamines, methadone, benzodiazepines, barbiturates, cannabinoids, and TCAs was negative. Alcohol screening was negative.
  • The only compound besides tramadol found in his blood was a metabolite of flunitrazepam, but the concentration was not quantitated because the estimated concentration was too low to have played a role.
  • Toxicology
    • Tramadol: 13 μg/mL in whole blood

Seizures

Tramadol has a well-known ability to lower seizure threshold. Seizures have frequently occurred in overdose, though they have also occasionally been reported with therapeutic use of 200-400 mg. It is rare for therapeutic use to produce seizures, but because it is a concern you should discuss the risk with your physician if you are using other seizure threshold-reducing drugs or if you have a history of seizures.

Human research and reviews

(Ahmadimanesh, 2018) – There is a significant correlation between tramadol/O-DSMT metabolite plasma concentration and seizure occurrence.

  • Iran. 120 tramadol-intoxicated patients were split into seizure and no-seizure groups. All tramadol poisoned patients referred to the ED of Loghman-Hakim hospital in Tehran during a 3-month period were studied.
  • Seizures were observed in 41.6% of the population, making it a high frequency occurrence. The other common complications were nausea and vomiting in over 40%.
  • Seizures occurred in the first 3 hours in 72% of patients. Seizure was significantly correlated with concentrations of tramadol, O-DSMT, and N-desmethyltramadol, and history of previous seizures.
  • Average concentration of N-desmethyltramadol was significantly higher in males. Higher N-desmethyltramadol concentration in males can be considered a reason for increased incidence of seizures in males.
  • Plasma level of O-DSMT affected the onset of seizure.
  • Median values of the estimated ingested doses were 1000 mg in both groups, with very large SDs of over 1000 mg. The minimum reported dose associated with seizure, which occurred in 3 patients, was 200 mg.
  • Co-ingestion
    • 15 patients co-ingested benzodiazepines. None had seizures despite 3 having a history of seizure due to tramadol poisoning and epilepsy.
    • Co-ingestion of other opioids significantly correlated with a lower risk of seizure.
  • COI: None. The study was fully supported by the Tehran University of Medical Sciences.

 

(Asadi, 2015) – Tramadol is a common cause of first seizure

  • Iran. 1-year cross-sectional study of patients referred to the ED of Poursina Hospital with first seizure.
  • 383 (68.9%) of the 556 patients were experiencing their first seizure. 84 (21.9%) had recently taken tramadol and family history of seizure was less common in tramadol users vs. non-users (3.6% compared to 11%).
  • Mean total tramadol consumption in the preceding hours was 140 mg (50-300 mg). Duration of consumption was under 10 days in 84.5% of patients and 73.8% had seizure within 6 hours of consumption.
  • COI: None

 

(Shadnia, 2012) – Recurrent seizures are sometimes reported in overdose

  • Iran. Loghman Hakim Hospital in Tehran, Iran from March 2008 to July 2008.
  • 100 patients with seizures. 96% had suicidal intent. Mean dose of 1164 mg (100-7000 mg). Average time to admission post-ingestion was 4.7 hours.
  • 15% had co-ingested drugs.
  • Majority of cases had stable vitals through their course. 33% had decreased consciousness level and 13% had nausea, 10% had emesis, and 4% had headache.
  • Only 7% had recurrent seizures. None developed status epilepticus.
  • Mean SBP of 116.6, mean DBP of 76.7, mean HR of 84.5, mean respiration of 16.4.
  • COI: Not reported

 

(Farajidana, 2012) – Seizure is a common issue with overdose

  • Iran. Retrospective study with patients admitted to Loghman Hakim hospital from Feb 2009 to April 2010.
    • Exclusion criteria: Coingestion of other drugs and those with a prior history of convulsive disorders.
  • 232 patients with tramadol-induced seizures were included. Mean dose was 1416 mg (100-6000 mg).
  • 2 patients convulsed with 100 mg. Also, a 3-year-old had a seizure with 150 mg and a 12-year-old had a seizure with 100 mg.
  • COI: Not reported

 

(Taghaddosinejad, 2011) – Evaluating the factors related to seizure in tramadol overdose

  • Iran. 401 patients with a history of tramadol overdose, with 121 (30.2%) having a history of seizure and 14 (3.5%) having a history of unconsciousness. Mean time elapsed between ingestion and blood sampling was 5.2 hours.
  • Intentional overdose was the most common mode of poisoning, being present in 51.9%. Mean dose of 1511 mg. Mean back-extrapolated tramadol concentration in blood was 3843 ng/mL.
  • 95% of seizures occurred in the first 6 h post-ingestion.
  • Back-extrapolated blood concentration correlated with dose as well as blood concentration level. Seizure was significantly correlated with higher reported dose but not with higher blood concentration, time elapsed, age, sex, history of addiction, or observed GCS score.
  • Most patients only experienced one seizure.

 

(Goodarzi, 2011) – Seizures are common in tramadol overdose and usually occur in the first 12 hours.

  • Prospective descriptive study. All patients admitted to the poisoning ward of Shoshtrai Hospital Poison Center in Shiraz, Iran from March 2008 to March 2009 w/ both tramadol poisoning and seizures were included.
  • 54 cases were seen. Seizure onset was 0.5 to 20 hours after administration, mostly in the first couple hours. Most patients presented with coma at admission (57.4%).
  • Half of the cases had one seizure, while 35% had two seizures.
  • All patients took the drug orally. The range of dosing was 200 to 11000 mg, with an average of 3248 mg and an SD of 2515 mg. Most seizures occurred with 200 to 2000 mg (46.3%).
  • Treatment was diazepam alone in 85% of cases. 20.4% required ICU admission. Mortality rate was 7.2%.
  • COI: Not reported

 

(Petramfar, 2010) – Review of 1067 tramadol-induced seizure cases

  • Iran. Nemazee Hospital from 2006 to 2008.
  • 106 patient were studied. 86.8% had new-onset provoked seizure(s) induced by tramadol, while 13.2% had what was considered tramadol-induced provocation of previously known epilepsy.
  • 18.9% had been prescribed the drug while 81.1% abused it.
  • Tramadol dose was 50 to 1500 mg. 80.2% developed seizure with a daily dose equal to or less than 400 mg. Mean dose before seizure was 363.2 mg, though the mean dose specifically in people who had been prescribed the drug was only 133.3 mg.
  • COI: None

 

(Talaie, 2009) – Seizure is not dose-related, but it is common

  • Iran. Cross-sectional study of 215 cases of tramadol users/abusers admitted to Loghman Hakim Hospital from April 2007 to September 2007. Patients with a history of coingestion, addiction, or epilepsy were excluded. This left 132 patients to include.
  • 46.2% had seizure within 24 h of ingestion. Mean tramadol dose was lower in females (1706 mg) compared to males (2413 mg). Of 35 patients with documented seizure type, all had tonic-clonic seizures and 12 had abnormal ECG (35.3%).
  • No significant dose difference between tramadol intake associated with seizures or not.
  • Analysis of seizure patients showed most used in the dose range of 500-1000 mg followed by 1500-2000, then 100-500, then 2500-3000, and 3500-4000 mg.
  • COI: Supported by Loghman Hakim Hospital and the Toxicological Research Center at Shaheed Beheshti University of Medical Sciences and the Iranian National Center for Addiction Study of Tehran University of Medical Sciences.

 

(Jovanovic-Cupic, 2006) – Review of cases involving seizure linked to tramadol abuse.

  • Serbia and Montenegro. Patients included drug addicts and tramadol abusers meeting criteria for tramadol intoxication and abuse. Seizures diagnosed on the basis of the typical description by witnesses and confirmed by a clinical exam suggestive of a post-ictal phase or tongue biting and other injuries during seizures.
  • 57 patients. 31/57 had evidence for generalized tonic-clonic seizures. Seizures occurred multiple times in 55% of cases and occurred in less than 24 hours for 85%.
  • Majority of abusers were heroin addicts and they were substituting it for heroin. Others combined tramadol with benzodiazepines. Just 17% of users took tramadol alone.
  • The last intake dose reported by those experiencing seizures (n=31) was under 500 for 7, 500-100 mg for 13, 1000-1500 mg for 4, and over 1500 mg for 7.
  • COI: Not reported

Case reports

(Ahmadi, 2017) – Case of complex partial seizures and hippocampal atrophy possibly associated with tramadol abuse, potentially aggravating an underlying seizure disorder.

  • Iran. 20-year-old male with recurrent seizures. His seizures began 3 years earlier and he had been taking tramadol 300 mg/d until six months prior, at which point it increased to 2000 mg/d. He was also on sodium valproate and carbamazepine.
  • During examination for a week, seizures occurred one time a day or more with aura, tonic-clonic movements, postictal phase, and caused amnesia about recent events.
  • Urine screen result for substances was negative. MRI showed atrophic left hippocampus and loss of hippocampus interdigitations.
  • Patient treated with carbamazepine. Seizure frequency reduced to once per week after 3 months of treatment.

 

(Nebhinani, 2013) – Seizures associated with high doses and dependence

  • India. 24-year-old male. He began taking tramadol after friends said it would help with fatigue while working in the fields. Used 2-3 tablets containing 37.5 mg tramadol and 375 mg paracetamol each. Tablets were freely available without prescription at a pharmacy.
    • It did relieve fatigue and caused elation. This led to regular use over the next 6-8 months and he began taking 5-6 tablets/d due to tolerance. He also experienced craving and he’d have headache and fatigue when not using.
  • After 3 years of regular use: He once took 14-15 tablets along with alprazolam because a friend said it would increase erection time and time to ejaculation during intercourse.
    • An hour later this led to unresponsiveness and tonic-clonic movement of upper and lower limbs for a minute, associated with clenching of teeth and frothing from mouth, followed by a postictal period of confusion for about 30 min.
  • He noticed over time that whenever he took more Tramadol-Paracetamol than usual he would be jittery and uncomfortable then he’d have a seizure. But he could prevent this with a higher alprazolam dose than usual, so that’s what he would do when needed for sexual purposes. He reported it did let him last longer in intercourse.
  • Eventually he got off the drug and the withdrawal symptoms were non-specific and not the same as typical opioid withdrawal symptoms.
  • COI: Not reported

 

(Raiger, 2012) – Seizures at therapeutic levels in a patient with epilepsy.

  • India. 35-year-old female. History of epilepsy since the age of 13. Seizures previously occurred every 1-2 months; drug treatment led to resolution of seizures. She stopped treatment about 2 years ago and had no episode of seizure within the last 5 years.
  • For an operation she was premedicated with glycopyrrolate 0.2 mg, ondansetron 4 mg, and tramadol 100 mg IV.
    • Within 5 min: Generalized tonic-clonic seizure occurred without aura. Immediately thiopental 75 mg IV was provided.
    • Seizure terminated immediately and she was carefully watched for 30 min. RR 15, BP 130/80, HR in the range of 120 to 140.
    • Eventually the medical staff decided to proceed with the operation without more tramadol and no further episode of seizure occurred.
  • COI: None

 

(Uysal, 2011) – Seizures from therapeutic dosing

  • 42-year-old female in Turkey. She had mental retardation and cerebellar ataxia, the latter of which is a risk factor for seizures, though she had no seizure history. She needed to have a surgery. Operation included anesthesia with IV propofol, fentanyl and rocuronium. Then pain relief was provided with paracetamol and tramadol 100 mg IV beginning 20 min before the end of the surgery.
  • Postoperative analgesia given with tramadol 100 mg IV up to four times daily as needed along with 1 mg paracetamol up to twice daily.
  • 4 hours post-operatively she received 80 mg IV tramadol and at the 10th postoperative hour she was given another 100 mg IV.
    • Following the latter dose she had a generalized tonic-clonic seizure that resolved spontaneously within seconds.
  • Started on phenytoin sodium; tramadol was discontinued and replaced with diclofenac.
  • No subsequent seizures during the clinical follow-up.
  • The patient also had acute hypocalcemia, which is associated with seizures. That along with the 280 mg tramadol that was given during a 10-hour period were believed to have increased the seizure risk.
  • COI: Not reported

Animals

(Rehni, 2010) – Evidence for the involvement of histamine H1 and opioid receptors in seizures

  • Mice. Tested in pentylenetetrazole seizure with various coadministered drugs.
  • Tramadol 50 mg/kg IP significantly potentiated seizure in terms of intensity and time to onset. Prior administration of naloxone, fexofenadine, cetirizine, kelotifen, and sodium cromoglycate all significantly protected against tramadol-induced seizure.
  • Tramadol potentiated the mortality from pentylenetetrazole administration, with the other drugs reverting back the mortality rate.
  • COI: Not reported

(Lesani, 2010) – Nitric oxide plays a role in seizure suppression

  • Rats. Pentylenetetrazole seizure caused via IV administration. Tramadol was given at 0.5-50 mg/kg IP 30 minutes prior to pentylenetetrazole. Effects of nitric oxide synthase inhibitor L-NAME, nitric oxide precursor l-arginine, and naloxone were tested.
  • Tramadol exerted an anticonvulsant effect that was strongest at 1 mg/kg, becoming less significant at higher doses. Acute L-NAME inhibited the anticonvulsant effect, while l-arginine in a noneffective dose range potentiated the seizure threshold when co-administered with a subeffective dose of tramadol.
  • Naloxone partially and dose-independently antagonized the anticonvulsant effect of tramadol 1 mg/kg.
  • COI: Not reported

(Rehni, 2008) – Opioid agonism triggering a reduction in GABAergic activity could play a role in seizure

  • Mice were exposed to tramadol alone or in the pentylenetetrazole 80 mg/kg IP seizure model.
  • Results
    • In the pentylenetetrazole model, prior administration of 50 mg/kg IP tramadol produced a significant potentiation of seizure. Previous administration of 2 mg/kg IP naloxone significantly inhibited that enhancement. And prior administration of gabapentin 25 mg/kg also significantly reduced the potentiation.
      • Tramadol further increased the % mortality, while naloxone and gabapentin reduced that impact of tramadol.
    • Tramadol itself at 50 mg/kg significantly increased seizure, an increase that could be attenuated by naloxone or gabapentin.
  • COI: Not reported

Physical dependence

Dependence does exist with prolonged exposure, leading to opioid-like and SNRI-like withdrawal symptoms upon cessation. It can be very uncomfortable in a dose-dependent manner and in a way that is dependent on how fast you stop your use. Those symptoms can be reduced by tapering the drug slowly.

Tolerance also builds over time, leading to reduced effects and a need for higher doses. Analgesic tolerance may build more slowly with tramadol than with other opioids.

Among the potential withdrawal effects are anxiety, depression, sweating, nausea, insomnia, shakiness, confusion, cognitive impairment, aches, rhinorrhea, hallucinations, increased pain, and GI symptoms like diarrhea and stomach pain.

Withdrawal can sometimes last a week or more, but the worst symptoms tend to persist for under five days, especially if the withdrawal is only stemming from therapeutic doses.

Human research

(Lanier, 2010) – Tramadol does appear to produce opioid-like physical dependence

  • Only people testing positive for opioids who were dependent and needed treatment were studied. Exclusion criteria included any other substance dependence.
  • 20 patients enrolled and 9 completed the trial.
    • 11 left for a variety of reasons: withdrawal discomfort, personal reasons, inconsistent data responses, and minor medical issues.
  • Randomized placebo-controlled within-subject trial. In the first phase people received morphine 15 mg SC QID, then underwent experimental sessions with naloxone exposure to measure their withdrawal response. The second phase involved maintenance on 200 mg/d tramadol or 800 mg/d.  They were also tested with naloxone.
  • Results
    • Withdrawal intensity was related to naloxone challenge dose and tramadol maintenance dose. The highest mean ratings of Any Drug Effects, Bad Effects, and Feel Sick were with 0.5 and 1.0 mg/kg naloxone during 800 mg/kg tramadol. Scores were similar to those in morphine maintenance.
    • During 200 mg/d, only the Bad Effects rating was significantly increased by naloxone at both doses, while Any Drug Effects was significantly elevated in response to 1.0 mg naloxone. Mean scores for Feel Sick and the other categories were numerically higher with 800 mg/d tramadol, although the only significant difference between the two maintenance doses was with 0.5 mg naloxone on the Bad Effects item.
    • Overall, tramadol may exhibit weak opioid-like subjective effects but it comes with opioid-like dependence potential that is responsive to naloxone administration.
  • COI: Paid consultants to Grunenthal and payments from other pharmaceutical companies. This study was supported by NIDA.

 

(Tjaderborn, 2009) – Survey of spontaneously reported tramadol dependence cases in Sweden

  • Sweden. Data from 1995 to 2006. Looking at spontaneous reports that fit the criteria of substance dependence. Spontaneous reporting is required in Sweden for all new, serious, and unexpected reactions to marketed drugs and also reactions that increase in frequency. For new drugs, all reactions except common ones should be reported.
  • Results
    • 41,200 adverse drug reactions reported. 550 (1.3%) involved tramadol. Of those, 18.9% contained one or several of the selected diagnostic terms and fulfilled the other pre-specified criteria for the study, including DSM-IV criteria for substance dependence.
      • 104 reports assessed as tramadol dependence, 36 as withdrawal syndrome, 28 as addiction, 19 as dependence, 11 as increased tolerance, and 30 as withdrawal symptom of tramadol.
    • Tramadol was the only suspected drug in 86.5% of cases.
    • History of substance abuse in 29.8% of people and 39.0% had a documented past or current use of at least one drug of abuse in the past decade, most often an opioid. This history was often unavailable.
    • Benzodiazepine concurrently used by 15.3%, other sedative by 21.3%, 28% were on any psycholeptic drug, and 17.3% were on an antidepressant.
    • Prescribed dose was known in 67.3% of cases. Ingested dose was known in 66.3%.
      • Prescribed amount ranged from 50 to 800 mg, compared to 50-4000 mg for the actual utilized dose. Median dose of 250-300 mg/d for prescription and 400-500 mg for actual use.
      • Reaction was serious in 69.2%. In 50% of cases overall the ADR led to hospitalization, mostly due to admission for detox or admission to a psychiatric clinic.
  • COI: Employee of AstraZeneca, though this paper was completed as part of an assignment at Linkoping University.

 

(Senay, 2003) – Physical dependence produces opioid-like and atypical withdrawal symptoms

  • An independent steering committee was established by Ortho-McNeil with the launch of tramadol in the 1990s in the US. It collected reports of withdrawal from two sources
    • The first was patients, pharmacists, physicians, and the FDA via the MedWatch system.
    • The second was a large national base of key informants including 110 NIDA grantees conducting comprehensive epidemiological and treatment outcome studies of drug-abusing populations and 145 other drug abuse experts. Collectively, the network provided access to approximately 250,000 at-risk individuals.
  • Total report number was 422. Signs and symptoms of typical opioid withdrawal in 367 and atypical in 55. To be “opioid-typical” there had to be at least three usual opioid withdrawal symptoms present.
  • The primary distinction between typical and atypical withdrawal was that atypical cases involved a strong component of other CNS disturbances not usually observed in typical opioid withdrawal. The disturbances included intense anxiety and panic attacks (nearly one-third of patients), confusion, delusional behavior and derealization, unusual sensory phenomena, and hallucinations that were tactile, visual, or auditory.
  • Length of exposure was a weak variable in the withdrawal syndrome. There were many cases with relatively brief exposures of 3-4 days and no clustering in cases with extended exposure. The vast majority of withdrawal cases (92%) occurred at or below the maximal recommended therapeutic level of 400 mg/d.
  • In contrast to the typical cases, 25% of atypical cases involved over 400 mg/d, surpassing the 8% rate in typical withdrawal cases. Atypical cases also tended to be longer lasting and to be more troublesome than typical cases.
  • Most physicians described patients with relatively mild cases and they did not treat the symptoms, with the problem usually resolving on its own in 2-3 days. Sometimes tramadol would be reinstituted so that it could be slowly reduced or benzodiazepines were used. Most of the atypical symptoms responded well to benzodiazepines and/or to slow tapering.
  • Because 1 in 8 Ultram withdrawal cases presented as a mixture of classic opioid withdrawal symptoms and unusual features, they could be misdiagnosed as psychosis or delirium.
  • COI: Supported by a grant from Ortho-McNeil Pharmaceuticals.

Case reports

(Lakhal, 2015) – Psychosis after tramadol withdrawal. This case could have involved tramadol triggering of an underlying mental disorder.

  • Tunisia. 35-year-old male. Past medical history of alcohol dependence and cannabis abuse.
  • Began taking 650 mg/d of tramadol after being admitted for alcoholic pancreatitis. He was put on paracetamol and clorazepate.
  • When he began tapering tramadol he had auditory and cenesthetic hallucinations. Presented to clinic with restlessness, grandiosity thoughts, messianic delusions, and sleeplessness. Treated with antipsychotic medication and he could stop taking tramadol a week after consultation.
  • After 8 days, mental symptoms including hallucinations and delusions were still present. He was diagnosed with tramadol-induced psychotic disorder with onset during withdrawal.

(Lakhal, 2015) – Dependence with withdrawal symptoms

  • Tunisia. 24-year-old male without a history of substance abuse. He was given tramadol for pain after a surgery and then increased his own dose considerably, reaching 250-750 mg via IV per day.
  • He tried to stop several times but always had nausea, muscle aching, dysphoria, and insomnia. The withdrawal symptoms had a negative impact on his life and resulted in family trouble.

(Ahmadi, 2015) – Physical withdrawal can be managed with clonidine, baclofen, and ibuprofen

  • 26-year-old male. For 3 years he was abusing tramadol and had increased the dose to 2000 mg per day. Because tramadol induced convulsions and depression, he was admitted to the psychiatric ward. During hospitalization, he received clonidine 0.3 mg, baclofen 75 mg, and ibuprofen 1200 mg/d for treatment of tramadol withdrawal. He was improved and discharged after 2 weeks of hospitalization.
  • He was in good condition for 5 months then one month before presentation he restarted 2000 mg tramadol and reported occasional methadone use. He was admitted again because of convulsions, agitation, and depression. Urine drug screen was positive for tramadol and methadone.
  • Diagnosed as tramadol-dependent. Began the same clonidine, baclofen, and ibuprofen with success.

(Rahabizadeh, 2009) – Psychosis during tramadol withdrawal

  • Iran. 30-year-old male referred for severe agitation and anxiety in the past week following cessation of tramadol use. He had paranoid ideation and was blaming his anxiety/agitation on delusions. He also had Lilliputian hallucinations, rhinorrhea, epiphora, nausea, diarrhea, musculoskeletal pains, tremors, tic in the shoulders and head, agitation, headache, and sleeplessness.
    • History of heroin and opioid addiction. During cessation he had started taking tramadol. He was using 300 mg/d tramadol until a week before presentation.
  • Exam showed orientation to time, place, and person. Delusional mood. Concentration and attention were reduced. Anxious with normal affect. Restless.
  • Treated with analgesic, sedative, and hypnotic drugs, but not antipsychotics. After 3 days all physical and mental symptoms fully subsided.
  • COI: Not reported

(Pollice, 2008) – Case of severe dependence in a female receiving tramadol initially for pain and without a history of substance abuse

  • Italy. 61-year-old female with no history of substance addiction or abuse. Psychiatric history was unremarkable. She had been taking tramadol 1700 mg/d for five years to control pain following an orthopedic procedure. Her husband (a doctor), along with a neurologist, a psychiatrist, and another physician tried to get her to cease use by giving lorazepam and amitriptyline, but those attempts were unsuccessful.
  • She reported being very agitated when delaying or skipping tramadol. She had learned to recognize the onset of withdrawal and she feared it, so she would take tramadol.
  • One day she didn’t take it twice in a row. She became very nervous, began to have anxiety, anguish, feelings of pins and needles all over her body, sweating, and palpitations.
  • Began detox by gradually lowering the dose. Her beta blocker was stopped and replaced with clonidine. Mirtazapine, an α2 adrenoreceptor antagonist, was also started. Tramadol was stopped fully after 4 months, without further physical or psychological symptoms, nor craving.
  • COI: Not reported

(Ritvo, 2007) – Two cases of physical dependence and addiction responsive to buprenorphine/naloxone

  • Colorado.
  • Case 1
    • 34-year-old female presented with tramadol withdrawal, including pain, muscle stiffness, joint soreness, and lethargy. She had made unsuccessful attempts to discontinue the drug before. History included nicotine dependence and remote history of cocaine use in high school.
    • First given tramadol four years earlier for chronic headache and sinus pain. Continued to use it for improved mood and increased energy. Utilized multiple physicians and pharmacies to get it, then switched to internet pharmacies so she could use up to 1200 mg/d.
    • In the month after starting treatment: She was responsive to buprenorphine. Improved energy and mood. She had not taken tramadol.
  • Case 2
    • 44-year-old female. Tramadol dependence that was discovered after her husband found $7000 in online pharmacy charges related to the drug.
      • History of alcohol abuse and intranasal cocaine use in college, along with nicotine dependence.
    • 3 years prior: Began abusing hydrocodone and oxycodone, obtaining prescriptions from multiple doctors. When they became suspicious, she switched to tramadol from online pharmacies and escalated to 1500 mg/d.
    • Withdrawal symptoms: Anxiety, nausea, vomiting. Made multiple unsuccessful attempts to quit.
    • In the 5 weeks after induction: Buprenorphine/naloxone was successfully used.
    • Over the next year: Improvement in mood, alertness, and family relations. Eventually she was able to weaned the dose to 8/2 mg and had not resumed tramadol.
  • COI: Not reported

(Ripamonti, 2004) – Patient on tramadol for pain who reported withdrawal symptoms that were disabling when missing one or two doses.

  • Italy. 51-year-old female. She had severe pain and was on tramadol for 2 years at 50 mg TID, increasing to 100 mg TID, with 50 mg intramuscular as needed. She avoided switching to a stronger opioid despite still having pain because she became very agitated whenever she missed a tramadol dose, so she did not want to stop the drug.
  • Eventually she missed two doses in a row. After a few hours she had anxiety, anguish, feelings of pins and needles around her body, sweating, and palpitations. She knelt down and rolled on the floor, pressing her hands against her head so as “not to feel and not to understand what was happening.” She begged her husband to take her home so she could have her dose.
  • Tramadol was stopped and replaced with oral methadone.

(Barsotti, 2003) – Withdrawal from therapeutic use

  • USA. 43-year-old female presented to the ED with anxiety, restlessness, and insomnia. Her medical history was significant for rheumatoid arthritis which she’d been given methotrexate, prednisone, folate, and tramadol for. Tramadol was given at 400 mg/d for several months, though 5 days before presentation she switched to 250 mg/d and then stopped entirely 24 hours before ED arrival.
  • Presented with normal vitals, nonfocal exam, and she was discharged with prescriptions for zolpidem and alprazolam for sleep.
  • She returned to ED 2.5 hours later with visual hallucinations, agitation, slurred speech, ataxia, and repeated jerking movements of her extremities. Her husband confirmed she had taken no drugs or medicines since leaving the ED. She was afebrile, HR of 140, BP of 160/90, and oxygen saturation of 95%.
  • 5 mg IV droperidol, 5 mg IV propranolol, and 3 mg IV lorazepam unsuccessfully controlled agitation. Lab evaluation showed negative screen for drugs of abuse, alcohol, salicylate, normal electrolytes, normal urinalysis, and unremarkable blood count.
  • 3 hours later: Recurrence of agitation was controlled with 2 mg IV morphine. Despite some improvement in the agitation and vitals with benzos and narcotics, mental status was still not at baseline. Mental status improved with tramadol 100 mg oral and by evening her mental status completely recovered when she was restarted on her former, scheduled dosing regimen.

(Yates, 2001) – Dependence in someone without a history of substance abuse

  • 29-year-old female presented to hospital requesting detox from tramadol. It had initially been prescribed for pain at 50 mg every 4-6 hours as needed. She started increasing the dose and she was going to multiple physicians and hospitals to obtain more.
    • When analgesics had previously been prescribed she didn’t have any problem with them.
  • 3 years post-initiation of use she was at 1500 mg/d.
  • Day before admission: Two generalized seizures and she stopped taking tramadol.
  • Admission: Severe withdrawal syndrome with blurred vision, dizziness, diarrhea, headache, insomnia. Reported low self-esteem and feelings of guilt. Mild hypertension.
  • Detoxed with tapering doses of tramadol combined with celecoxib, metoprolol, and hydroxyzine. Improved gradually and was discharged after 6 days.
  • Several months post-discharge: Presented to ED twice with suspected self-inflicted lesions trying to obtain tramadol.

(Villamanan, 2000) – Case of withdrawal symptoms upon stopping tramadol in therapeutic use.

  • Spain. 60-year-old female was on tramadol 150 mg for pain. She was on that dose for 7 months.
  • When treatment was discontinued she had an increase in libido, insomnia, panic attacks, pallor, and abdominal discomfort. She experienced no relief with tranquilizers and her symptoms went away when tramadol was restarted.
  • Afterwards the dose was progressively reduced and fully stopped at 3 weeks, with no further symptoms.

(Leo, 2000) – Tramadol dependence with withdrawal. Responsive to methadone.

  • USA. 46-year-old female. Presented to ED with complaints of restlessness, diaphoresis, tremulousness, and anxiety.
    • History of prior opioid dependence and alcohol dependence. She had been abstinent from alcohol for around 10 years and from other opioids for 5 years.
    • Admitted a 1-year history of tramadol abuse. It was initially prescribed for analgesia but she began to use more than was prescribed. When her supply was exhausted she used multiple doctors to get more. She said the doctors were “naïve” and believed tramadol was not addicting, so they simply handed it over.
    • Her abuse of tramadol continued beyond correction of pain. She increased her use to, reportedly, up to 30x 50 mg tablets per day.
    • Initially the benefit to using was mild euphoria and sedation. But she developed tolerance and needed to use more over time to receive those beneficial effects.
  • Recently she had been experiencing dysphoria, vomiting, constipation, dizziness, and malaise associated with use. Tramadol interfered with her functioning. She became reclusive and only left her home to get more tramadol.
  • Upon examination: Anxiety, dysphoria, restlessness, irritability, abdominal cramping, lower extremity cramping. No obvious mydriasis, gooseflesh, or diaphoresis.
    • Mildly tachycardic at 100 and BP of 145/90, therefore mild hypertension.
    • Complained of dysphoria, decreased appetite, decreased sleep, and feelings of guilt associated with her use.
    • Dysphoria was said to have started with tramadol discontinuation. She denied any manic symptoms, delusions, or hallucinations.
  • Methadone was started at 10 mg, but that was ineffective. Raised to a second 10 mg dose and this was successful. Methadone reduced over 8 consecutive days, with taper proceeding well. No clonidine needed as she did not demonstrate significant signs of autonomic arousal during detox.
  • COI: Not reported

(Freye, 2000) – Case study of acute abstinence syndrome after long-term use

  • USA. 45-year-old female demonstrated classical fibromyalgia symptoms and had significant relief from tramadol IR 50-100 mg, usually taken daily in the morning for the past 12 months. Analgesia lasted all day and no other analgesic was required. She had not responded to antidepressant therapy and minimally responded to local anesthetic.
  • While on vacation she lacked access to the drug. After a week, she developed marked and longstanding pain in her back with a VAS of 7.5, making it impossible to walk. She eventually also had depressive mood, moderate tremor, repetitive yawning and sneezing, moderate tachycardia of 95, BP of 145/90, tension through the body, aggressiveness together with greater nervousness, migrating pain, bouts of cephalgia and nausea, intra-abdominal cramps with diarrhea.
  • Acute abstinence syndrome diagnosed. Responsive to loperamide 4 mg/d for abdominal cramps and diarrhea. She also received more fluids. Restless leg syndrome and muscle pain treated with DXM 100 mg/d. Sumatriptane given for headaches and nausea. All these medications led to alleviation of symptoms within 3 days and within a week the patient recovered uneventfully.
  • COI: Not reported

Addiction/Nonmedical use

Because it does have opioid-like properties mixed with other mechanisms that can improve mood and anxiety, it has been used nonmedically, sometimes producing addiction. Part of the problem with the marketing for tramadol is that it was long described as substantially less risky than other opioids in terms of addiction potential, which led to it being relatively easy to access for a long time and to it being prescribed in cases where a patient had a potentially contraindicated history of drug addiction.

It tends to be less pleasurable than classic opioids, yielding a lower level of euphoria, but it can still be satiating, mood improving, and generally enjoyable (Babalonis, 2013). Because it commonly has a more stimulating/productive quality than classic opioids, it may be easier to build a psychological dependence to the drug without noticing it as clearly. In those who produce more O-DSMT it might be more enjoyable and have a higher chance of being involved in an addiction.

Conditioned place preference (CPP) in animals has been shown, though tramadol is generally regarded as less rewarding in that model (Zhang, 2012). Since the research has tended to involve injections of tramadol via routes that get around first-pass metabolism, that could conceivably contribute to a lower perceived reward potential vs. oral use in humans, considering the likely role of opioid activity from O-DSMT in any rewarding effect of the substance.

Human research

(Babalonis, 2013) – Tramadol does come with opioid-like abuse liability

  • USA. Population: Healthy adults with prescription opioid abuse history and confirmed opioid use via urine testing. They were not physically dependent.
  • 4-week inpatient study with a within-subject DBRCT design examining tramadol (200 and 400 mg) vs. oxycodone (20 and 40 mg), codeine (100 and 200 mg), and placebo.
  • 9 people met qualification criteria. All reported primarily using oxycodone products and none reported current heroin use or current tramadol use.
  • Results
    • Physiological
      • Each active drug produced dose-dependent decreases in pupil diameter and peak miotic effects vs. placebo. Oxycodone had the greatest magnitude of effect while tramadol and codeine produced moderate miosis.
        • Peak miosis occurred at 1.1-2.4 hours for codeine and oxycodone whereas the peak for tramadol was at 4.3-4.4 hours.
      • Peak end tidal CO2 concentration significantly increased after both oxycodone doses and the high tramadol dose, while codeine produced modest effects w/ a significant impact at 200 mg.
        • Oxycodone and tramadol led to similar magnitude effects, but with tramadol’s peak occurring at 3.6-4 hours vs. 1.4-1.6 hours for oxycodone.
      • None of the active doses produced significant effects on oxygen saturation, HR, or SBP/DBP.
    • Drug identification
      • All identified oxycodone and tramadol 400 mg as opioid agonists. Most of the participants reported the other drugs and doses were opioids as well.
    • Drug self-administration outcomes (allowing people to earn a dose of drug or a dose of money)
      • Tramadol dose-dependently reinforced, as did oxycodone. 200 mg did not significantly differ from placebo but the high dose was readily self-administered.
    • All active doses significantly increases ratings on measures like “high” “liking” and street value estimates. But tramadol’s impact was numerically much lower on those measures than oxycodone, indicating it is still not preferred.
      • Further, tramadol significantly increased ratings of “bad drug effects” including nausea and flushing.
    • Duration
      • In several instances the participants said the opioid-like effects of tramadol increased or re-emerged after study termination at 6 hours, indicating tramadol’s peak opioid-like effects may occur later on.
  • COI: None. Supported by NIDA and the National Center for Research Resources.

(Adams, 2006) – Comparing the abuse liability of tramadol, NSAIDs, and hydrocodone in chronic pain patients. Hydrocodone was clearly more desirable.

  • Background
    • Estimates of the prevalence of opioid abuse/dependence range from 0% to 30% in chronic pain patients.
  • USA. 12000 subjects total, given either tramadol, NSAIDs, or hydrocodone-containing analgesics.
  • Patients had to have chronic nonmalignant pain.
  • Interviewers asked questions to try and evaluate whether someone was abusing/overusing their medication or had become dependent. Though responses that came merely from therapeutic intent were not counted as abuse/dependence.
  • Results
    • Completion rates were similar between study arms. The rate of abuse appeared to be significantly higher for hydrocodone than NSAIDs or tramadol.
      • 559 cases represented a total of 506 individuals, 102 of whom hit only on tramadol, vs. 176 only on hydrocodone, and 177 only on NSAIDs.
    • The relative abuse of hydrocodone was significantly higher than tramadol or NSAIDs.
    • Most subjects had no known history of drug abuse.
  • COI: Not reported

(Radbruch, 2013) – It doesn’t seem to have a significant abuse risk in Germany generally or compared to tilidine.

  • Germany. The German Federal Government via the Federal Institute for Drugs and Medical Devices evaluated the abuse potential and risk with tramadol and tilidine/naloxone due to reports of misuse.
  • Animal and human studies both showed a low potential for misuse, abuse, and dependency for the drugs. For tramadol, the incidence of abuse or dependency was 0.21 and 0.12 cases per million DDDs, with lower incidences in recent years.
    • The rate was higher with tilidine.
  • Based on an online survey among German pharmacies as well as reports from state pharmacy boards, fraud attempts were more frequent with tilidine/naloxone than with tramadol in the past 2 years. Federal Bureau of Criminal Investigations only reported prescription fraud with tilidine/naloxone.
  • 1/3 of patients surveyed in an addiction clinic reported experiences with one of the drugs, but mostly with duration of under 4 weeks and with a medical prescription based on a reasonable indication.
  • Large-scale survey of 11,000 patients found a misuse rate of 2.7% with tramadol, 2.5% with NSAIDs, and 4.9% with hydrocodone.
  • COI: Not reported

(Schneider, 2005) – Arguing the data indicates it does have some abuse potential

  • DAWN reported from 1995-2002 a 165% rise in drug-related ED visits involving tramadol. Tramadol was mentioned in over 12,000 cases.
  • The validity and generalizability of the data from Ortho-McNeil is limited due to collecting abuse cases in a nonrepresentative population. Tramadol exposure is likely suppressed in addiction communities with access to preferred, more potent or euphoriant opioids. Voluntary case reports of tramadol abuse significant underestimate the actual number of abuse cases in the tramadol-exposed population. Also, their data has a low survey return rate of 49%.
  • 3-year postmarketing cohort study measured its nonmedical misuse rate via urine drug testing among 1601 participants in 4 US state monitoring programs for impaired healthcare professionals. Tramadol exposure reported in 140 (8.7%) and 39% of those were classified as extensive experimentation or abuse of tramadol.
  • Ortho-McNeil’s revised 2001 product package insert for Ultram:
    • “Tramadol may induce psychic and physical dependence of the morphine-type (mu-opioid). Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug are not limited to those patients with prior history of opioid dependence”

(Bush, 2015) – Review of ED visits for drug misuse or abuse involving tramadol.

  • USA. Prescriptions for tramadol increased 88% from 23.3 million in 2008 to 43.8 million in 2013. In 2011, it was ranked 9th in the list of narcotic pain relievers seized in law enforcement operations and analyzed by forensic laboratories.
  • Misuse and abuse appeared to increase from 1995 to 2010. There were 54,397 ED visits involving tramadol in 2011 and 40% of those were attributed to misuse or abuse. The number of tramadol-related ED visits involving misuse or abuse increased about 250% from 6,255 in 2005 to 21,649 in 2011.
  • 29% of tramadol-related ED visits involving misuse/abuse only involved tramadol. Approximately 20% had one other drug, 26% had two other drugs, and 26% had tramadol with three or more other drugs.
  • About 68% of tramadol-related ED visits involving misuse/abuse in 2011 involved tramadol with other pharmaceuticals. 35% involved tramadol with other analgesics, including opioids. About 32% had it with anxiolytic or insomnia medications like benzodiazepines (23%) or zolpidem (7%).
    • 14% had tramadol with alcohol and 12% had it with illicit drugs.

(Skipper, 2005) – Arguing there is a relatively high abuse risk with tramadol.

  • TESS data referenced in (Adams, 2015) by an Ortho-McNeil consultant is misleading because they compared tramadol alone to oxycodone alone + with combinations, therefore making oxycodone substantially more common in the TESS data (which looks at unintentional and intentional toxic exposures). If only looking at single-drug products, the reports for 2001 show 2236 intentional exposures for oxycodone and 2109 for tramadol.
  • The data on the rate of tramadol abuse among physicians in (Knisely, 2002) is misleading since it divides the number of known tramadol abuse cases by a population that includes more than just those exposed to tramadol. It should actually divide the abuse cases (n=15) by those actually exposed to tramadol (n=155), giving a 10% rate of abuse.

(Knisely, 2002) – Postmarketing surveillance study alleging a low rate of abuse by impaired health professionals

  • Focusing on impaired health professions with a history of substance abuse who are a high risk/high access population for drug abuse. Studied between 1995 and 1998.
    • The study included all impaired health care professionals who were active participants in monitoring programs.
  • Total of 1601 people recruited for the study. Tested by urine drug screening.
  • Most common drugs of abuse were alcohol at 39%, opioids 35%, cocaine 11%.
    • Top opioids were hydrocodone 35%, fentanyl 12%, oxycodone 11%, and meperidine 11%.
  • Substances used in addition to a person’s preferred drug were alcohol 26%, opioids 23%, cannabis 18%, sedative hypnotics 15%, and cocaine 10%.
  • Incidence rate for tramadol use (any positive test) was 69 per thousand persons per year (i.e. 6.9%), while the incidence rate for tramadol abuse or dependence was 6.9 per thousand persons per year (i.e. 0.69%).
    • Of the 140 participants with at least one positive urine sample, 87 did not report a legitimate prescription. 35 reported prescription use and never displayed any behavior indicating misuse.
    • Only 24 met the criteria for extensive experimentation.
    • Those using tramadol were more likely to be professionals with prescription privileges specializing in internal medicine, emergency medicine, or family practice.
    • A significant difference was found in the primary substance of abuse, with the most frequent among tramadol users being opioids.
  • Since 51/140 only had one positive test for tramadol and 16 had only two positive samples, it would seem that if they were trying it recreationally, it did not satisfy their demands.
  • COI: Funded by Ortho-McNeil Pharmaceuticals.

Case reports

(Chand, 2017) – Three reports of iatrogenic addiction

  • India.
  • Case 1
    • 20-year-old female presented with abdominal cramps, aches and pains, restlessness, feeling of cold, and lacrimation for the past 3-4 hours. She reported IM injection of tramadol about 6 hours prior. She also had interpersonal problems in her life and poor socioeconomic status.
    • She had been receiving tramadol injections for the past year following a hysterectomy. Initially given 100 mg BID for 2 weeks to relieve postsurgical pain. After stopping the injection she had restlessness, body pain, cold feeling, abdominal cramps, and loose motions, which were relieved by tramadol injection.
      • She continued to inject twice daily to relieve withdrawal. She also reported feeling very happy, relaxed, and more energetic for 30-60 min after injection.
    • Despite multiple abscesses and swellings in the injection site, she continued use. She’d get it from different chemists without a prescription. She had craving whenever use stopped.
    • Urine tox screen negative for other drugs.
  • Case 2
    • 28-year-old female. History of oral tramadol use (37.5 mg tablets with paracetamol 325 mg). She’d been taking it for 5 years. Prescribed by gynecologist after third cesarean delivery. Taking it once a day for a few months then increasing to 3-4 tablets daily for the past 2 years.
      • Later increased use to 6-7 tablets daily despite having no pain. She would have body ache, restlessness, mild lacrimation, rhinorrhea, and abdominal cramps upon stopping.
    • Physical exam showed opioid withdrawal symptoms. Urine screen positive for opioids. No history of any other addiction or emotional problem.
  • Case 3
    • 28-year-old female. Injecting tramadol regularly for the past 2 years. 3 years earlier her GP gave her tramadol and diclofenac for shoulder pain and she was advised to take it whenever she had pain.
    • After 6 months she began injecting by herself and she took it almost daily. She would take both drugs. She began having a sense of relaxation with the tramadol injection and increased the dosage to 300 mg/d. She’d have withdrawal symptoms in the form of severe body ache, lack of interest in work, tremors of hand, easily fatigued, and insomnia when stopping.
  • COI: None

Animal research

(Zhang, 2012) – It induces CPP, like other opioids. Though the CPP is shorter-lasting than morphine or buprenorphine.

  • Rats were conditioned with tramadol at 2-54 mg/kg IP, morphine 0.125 mg/kg SC, buprenorphine, 0.01-0.316 mg/kg SC, or a combo of a subeffective tramadol dose (determined to be 2 mg/kg IP) with a subeffective morphine or buprenorphine dose.
    • CPP regimen involved eight training sessions with drugs or vehicle then testing 1, 14, and 28 days after the last training day for retention.
  • Results
    • All drugs produced dose-dependent CPP. And an otherwise ineffective tramadol dose of 2 mg/kg could enhance the morphine and buprenorphine-induced CPP. Combo also prolonged retention of CPP from those drugs.
    • Tramadol at 6, 18, and 54 mg/kg was effective. Morphine at 2 mg/kg and 8 mg/kg was effective. Buprenorphine at 0.0316, 0.1, and 0.316 mg/kg was effective at producing significant CPP.
    • Tramadol’s CPP failed to reach significance on Days 14 and 28. The other drugs still had significant effects, though they declined over time and were only significant with the highest doses of either drug on Day 28.
  • COI: None. Supported by the National Nature Science Foundation of China, National Basic Research Program of China, and National Key Technology R&D Program.

(O’Connor, 2010) – Tramadol does have reinforcing effects but they are weak relative to other opioids

  • Rats. Tested via self-administration model at 0.3 to 3 mg/kg infusion. Compared to morphine (0.03-0.3 mg/kg/infusion) and remifentanil (0.001-0.03 mg/kg/infusion).
  • Tramadol did have a reinforcing effect at 1 mg/kg, but it was substantially less significant than the other opioids.
  • COI: Sponsored by Pfizer

Other

(Epstein, 2006) – General review of abuse-related info for tramadol

  • Animal studies
    • (Yanagita, 1978) – Three tramadol self-administration studies in rhesus monkeys. Tramadol did not substitute for lefetamine significantly better than saline, although the rate was higher. Response rates compared to morphine and pentazocine were also lower, indicating reduced reinforcing effect.
    • (Sprague, 2002; Tzschentke, 2002) – Effect on CPP in rats was similar in magnitude to morphine.
    • (Ren, 2000) – Fully substituted for morphine in rats, with approximately 96% of responses on the morphine-appropriate lever with tramadol at or above 32 mg/kg. Completely blocked by concomitant administration of naltrexone.
    • (Miranda, 1998) – Tramadol 39.1 mg/kg or 100 mg/kg SC three times per day for 5 days in mice.
      • No evidence of tolerance to antinociceptive effect and few or no signs of withdrawal after administration of naloxone. Comparatively, morphine showed significant tolerance during that period and significant opioid-like withdrawal signs.
      • Almost no cross-tolerance. Antinociceptive response to tramadol was unchanged in morphine group and only a trend towards lower response to morphine in the tramadol group.
    • (Yanagita, 1978) – Some evidence of withdrawal in rhesus monkeys receiving tramadol 32-96 mg/kg/d SC for 59 days. Though few withdrawal signs when naloxone was given 1 mg/kg SC on four occasions during that period, withdrawal signs did emerge in the 5 days after tramadol was discontinued.
  • Human studies
    • (Preston, 1991) – IM tramadol 75, 150, or 300 mg vs. morphine 15 and 30 mg IM vs placebo. 12 non-dependent opioid abusers. On subjective measures of opioid-like and positive mood effects, tramadol 75 and 150 mg was not significantly different from placebo, while 300 mg was identified as an opioid but did not produce classic morphine-like effects.
    • (Jasinski, 1993 and Jasinski, 1994) – IV dose-ranging study in experienced opioid abusers. Tramadol 700 mg IV over 1 min produced a seizure, as did 300 mg IV delivered over 2.5 min. While 200 mg IV administered over 5 min produced no seizures.
      • Comparing placebo, morphine 10 and 20 mg IV, and tramadol 100 and 200 mg IV: Neither dose of tramadol increased ratings of liking or any other subjective measure of opioid-like effects.
      • Very different results when studying tramadol 175, 350, and 700 mg oral vs. placebo vs. oxycodone 20 and 40 mg oral in 12 experienced opioid abusers
        • Tramadol and oxycodone both increased ratings and were identified as opioid-like. Decreased pupil diameter and increased ratings of “feel drug” and “liking.” Supports the role of a metabolite.
    • (Richter, 1985) – Severe pain patients given a mean of 250 mg/d for 3 weeks. No evidence of tolerance to analgesia. Randomized to receive naloxone or placebo 3 hours after last tramadol dose and 3/54 participants showed marginal or slight elevations in opioid withdrawal scores following naloxone vs. 1/55 from placebo, but that was not a significant difference.

COI: Authors supported by NIH and NIDA.

Other

There may be a correlation between tramadol use and psychiatric problems, as well as a minor connection with cognitive impairment (Khalifa, 2017 ; Bassiony, 2016). It’s quite possible the psychiatric disorders are not being cause by tramadol and more research is needed to confirm the connection between both issues and tramadol use.

Its effects in pregnancy are not fully understood. It does not appear teratogenic, but it is not clearly safe in all respects (Bloor, 2012). Since tramadol and O-DSMT readily cross the placenta, that should be considered when it’s being used for analgesia in labor. Neonatal abstinence syndrome is a risk when tramadol is used during pregnancy.

Animal research has indicated the potential for memory impairment, neurotoxicity, and organ toxicity (Baghishani, 2018 ; Faria, 2017)

Human research

(Khalifa, 2017) – Some signs of impaired cognition in tramadol dependence, though the scores were not substantially outside the normal range.

  • Egypt. 30 tramadol-dependent patients vs. 30 healthy controls. The patients needed to have no history of intake of other substances besides nicotine in the past 12 months and they needed to be proven negative for other substances by urine drug screen.
  • Results
    • Tramadol dependent individuals showed impaired memory, visuospatial performance, executive function, and reaction time compared with healthy controls as shown by mini-mental state exam (p=0.003), montreal cognitive assessment scale (p<0.001), brief visuospatial memory test-revised (p=0.016), and P300 latency (p<0.001).
    • Mini-mental state exam was 24.97 in tramadol group vs. 26.67 in control. Scoring reference: Under 24 is abnormal. 24-30 is considered to be no cognitive impairment.
    • Montreal cognitive assessment scale was 23 in tramadol group vs. 25.27 in control group. Scoring reference: Score over 26 is considered normal; mild cognitive impairment average is 22.1; people with Alzheimer’s have a score of 16.2 on average.
  • COI: None

 

(Bassiony, 2016) – Evaluation of psychiatric comorbidity in patients with tramadol addiction.

  • Egypt. 100 patients with tramadol use disorder compared to 100 controls.
  • 24% of users only took tramadol while 76% were polysubstance users.
  • 49% had psychiatric comorbidity: especially mood disorder which was present in 59.2% of those
    • Personality disorders were less common at 24% with borderline and 22% with antisocial
  • Prevalence of psychiatric problems between tramadol-only and polysubstance groups was similar.
  • VS controls
    • Only 24% had psychiatric comorbidity and the most common personality disorders were OCD at 8% and avoidant at 7%.
  • COI: Not reported

 

(El-Hadidy, 2015) – Tramadol is linked to psychiatric problems in long-term use

  • Egypt. Evaluating the impact of chronic use in people with at least 5-years of dependence and over 675 mg/d.
  • Patients at Mansoura University Hospital with solitary tramadol dependence. Exclusion criteria: mental retardation, other drug dependence, any medical illness, and any psychiatric disorders prior to tramadol use.
  • Patients were studied and then treated via abrupt stopping of use and symptomatic treatment with non-opiate analgesics, sympatholytics, and short-term supportive psychotherapy.
  • Results
    • Mean duration of use was 7.15 years and mean daily dose of 1481 mg.
    • Before treatment, 90% of patients had mild anxiety and the rest had moderate anxiety. After detox, depression and anxiety significantly worsened. Though no increase in psychotic symptoms when stopping.
    • Patients dependent on tramadol were angry, hostile, and aggressive.
    • Blood chemistry
      • Lack of significant increases in liver enzymes and lack of other significant changes.
  • COI: Not reported

 

(Bloor, 2012) – Reviewing the evidence of its effects in pregnancy. Tramadol does not appear teratogenic but it is not clearly safe.

  • Pregnant and breastfeeding women were excluded from Phase 1 to 3 studies, yielding limited data on that population. Embryogenesis in the first trimester is the time of greatest risk for teratogenesis and since many women aren’t aware they have conceived, a lot of human embryos have likely been exposed to the substance.
  • Animal studies showed fertility was unaffected by oral tramadol at doses up to 50 mg/kg in males and 75 mg/kg in females. Embryotoxic and fetotoxic effects were only seen when a toxic adult dose was administered. At lower doses no impact was seen. And no teratogenic effects were seen at any dose.
  • Tramadol and O-DSMT readily cross the placenta, which should be considered when used for analgesia in labor.
  • A small prospective study during early pregnancy included 146 pregnancies vs. 292 matched controls and while there was no significant difference in the rate of malformations, the number of spontaneous abortions was higher at 14.4% vs. 3.4%.
  • There have been a few cases of neonatal abstinence syndrome following tramadol exposure in pregnancy.
  • COI: None

Animal research

(Baghishani, 2018) – Tramadol increases hippocampal cell apoptosis and it impairs memory and learning in rats

  • Rats were given tramadol 50 mg/kg oral or tramadol along with crocin 30 mg/kg oral for 28 consecutive days.
  • Memory and learning tested with the morris water maze and passive avoidance tests.
  • Results
    • Tramadol rats spent less time and traveled less distance in the target quadrant of the morris water maze test. The combo group performed better. In the passive avoidance task, tramadol group showed declines in the total time spent in the light compartment and delay for entering the dark, indicating memory impairment (the dark quadrant contains a shock that the rats were previously exposed to). Whereas the combo group showed an increase vs. the tramadol-only group.
    • Tramadol animals had a significant increase in dark neurons and apoptotic cells in the CA1, CA3, and dentate gyrus. (Note: Dark Neurons may not be a great indicator of toxicity.) Crocin protected agaonist the number of dark neurons and apoptotic cells.
  • COI: None.

(Faria, 2017) – Tramadol and tapentadol can damage the brain, lung, and heart in rats

  • Rats were given tramadol or tapentadol at 10, 25, and 50 mg/kg, representing a typical effective analgesic dose, intermediate, and max recommended dose, respectively.
  • 24 hours after IP drug administration, biochemical and oxidative stress analyses were performed in blood and tissue samples.
  • Results
    • Both drugs caused an increase in the AST/ALT ratio, in LDH, CK, and CK-MB activities in serum, and a rise in lactate in serum and brain.
      • AST, AST/ALT ratio, and LDH activity significantly increased with 25 and 50 mg/kg, but not 10 mg/kg of tramadol.
    • Oxidative damage, namely protein oxidation, was shown in heart and lung tissues. In histological analyses, both caused alterations in cell morphology, inflammatory cell infiltrates, and cell death. Tapentadol caused more damage than tramadol.
      • In brain cortex samples from rats, oxidative damage was not detected. At low doses of both drugs (10 and 25 mg/kg) there was a reduction in lipid peroxidation.
      • In lung samples, tramadol and tapentadol did not cause lipid peroxidation changes, but there was a significant rise in carbonyl groups after exposure to 50 mg/kg tramadol and 25 or 50 mg/kg tapentadol.
      • Oxidative damage in the heart was shown, with a rise in protein carbonyl groups from 50 mg/kg tramadol and 25 or 50 mg/kg tapentadol.
    • At 25 mg/kg tramadol, degenerated neurons with darker staining were observed and there was a reduction in definition of the nuclear membrane, which appeared irregular in shape.
  • COI: Supported by grants from CESPU and the Norte Portugal Operational Programme.

(Ahmed, 2014) – Tramadol is associated with oxidative stress and testicular impairment in rats

  • Rats were SC injected with tramadol 40 mg/kg three times per week for 8 weeks.
  • Linked with significantly lower levels of LH, FSH, testosterone, total cholesterol, and higher levels of prolactin and estradiol. Tramadol increased testicular levels of nitric oxide and lipid peroxidation and decreased antioxidant enzyme activity (superoxide dismutase, glutathione peroxidase, catalase) significantly vs. control. Tramadol group also showed decreased sperm count and motility, and numbers of primary spermatocytes, rounded spermatid, and Leydig cells. MDA level significantly increased.
  • COI: Not reported

(Atici, 2004) – Tramadol and morphine are linked to neurotoxicity in rats

  • Rats given morphine IP at 4 mg/kg/d for 10 days, then 8 mg/kg/d for 10 days, then 12 mg/kg/d for 10 days. Alternatively, they received tramadol 20 mg/kg/d for 10 days, then 40 mg/kg, then 80 mg/kg.
  • All rats killed on the 30th day and the brain was removed for histology.
  • Results
    • On the third day of 80 mg/kg/d tramadol, three rats died due to convulsions and were excluded from the study. The dose was then reduced to 40 mg/kg for the remaining rats on the rest of the days.
    • Red neurons were found in the opioid groups, but not in the control group. The total number of red neurons did not differ between drugs, but the numbers of red neurons were significantly higher in the temporal and occipital regions for tramadol group vs. morphine group.
  • COI: Not reported


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