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).
IUPAC: 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-3H-isoindol-1-one
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.
These formulations can be given once or twice per day, with the same maximum dose of 400 mg.
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.
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.
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.
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 is minimally affected aside from dose-dependent vision blurriness and less often slowness, i.e. things appearing to occur more slowly.
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.
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.
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.
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).
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.
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).
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).
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).
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.
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.
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.
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.
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)
Tramadol at 1 mg/kg IV and above removed postanesthetic shivering following the administration of general anesthesia, which can lower body temperature (Witte, 1997).
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.
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.
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.
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.
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.
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.
Tramadol is cross-reactive with the EMIT II+ PCP immunoassay (Hull, 2006).
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.
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.
(Wentland, 2009) – CHO cells expressing human opioid receptors.
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.
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.
There is some evidence for a role of adenosine receptors, either directly or indirectly, in the effects of tramadol.
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.
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.
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).
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).
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.
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).
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.
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.
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.
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.
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.
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.
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.
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).
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).
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.
Absorption begins in a few minutes and the absolute bioavailability appears somewhat higher at ~77% (Grond, 2004).
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).
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.
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.
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:
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.
Common CYP2D6 inhibitors include SSRIs (e.g. fluoxetine, paroxetine, sertraline), methadone, and quinidine.
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).
Clearance is reduced and the half-lives of tramadol and O-DSMT double with renal impairment (Miotto, 2016).
Synthesized by Grunenthal in Germany.
Tramadol became available for analgesia in West Germany. It was sold by Grunenthal as “Tramal.”
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.
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.
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.
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).
Dr. Mahoud Khozendar:
Dr. Taysir Diab, psychiatrist at Gaza Community Mental Health Programme:
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.
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:
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.
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.
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:
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.
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.
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.
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.
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.
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.
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).
Tramadol somewhat increases orofecal and colonic transit time, but gastric emptying is not delayed at normal doses, unlike with morphine (Murphy, 1997).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)
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