Tramadol, sold under the brand nameTramal among others,[17][1] is anopioidpain medication and aserotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderate to severepain.[13][17] When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour.[13] It is also available by injection.[18] It is available in combination withparacetamol (acetaminophen).
Tramadol was patented in 1972 and launched under the brand name Tramal in 1977 by the West Germanpharmaceutical companyGrünenthal GmbH.[17][21] In the mid-1990s, it was approved in the United Kingdom and the United States.[17] It is available as ageneric medication and marketed under many brand names worldwide.[1][13] In 2023, it was the 36th most commonly prescribed medication in the United States, with more than 16million prescriptions.[22][23]
Generic tramadol HCl tablets marketed by Amneal PharmaceuticalsTramadol HCl for injection
Tramadol is used primarily to treat mild to severe pain, both acute and chronic.[24][25] There is moderate evidence for use as a second-line treatment forfibromyalgia, but it is notFDA-approved for this use.[26] Its use is approved for treatment of fibromyalgia as a secondarypainkiller by theNHS.[27]
Itsanalgesic effects take approximately an hour to be realized, and it takes from two to four hours to reach peak effect after oral administration with an immediate-release formulation.[24][25] On a dose-by-dose basis, tramadol has about one-tenth the potency ofmorphine (thus 100 mg is commensurate with 10 mg morphine but may vary) and is practically equally potent when compared withpethidine andcodeine.[28] For moderate pain, its effectiveness is roughly equivalent to that of codeine in low doses andhydrocodone at very high doses. For severe pain, it is less effective than morphine.[24]
Pain-reducing effects last approximately six hours. The potency of analgesia varies considerably as it depends on an individual's genetics. People with specific variants ofCYP2D6 enzymes may not produce adequate amounts of the active metabolite (desmetramadol) for effective pain control.[16][24]
Use of tramadol duringpregnancy is generally avoided, as it may cause some reversible withdrawal effects in the newborn.[32] A small prospective study in France found, while an increased risk ofmiscarriages existed, no major malformations were reported in the newborn.[32] Its use duringlactation is also generally advised against, but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking. No evidence of this dose harming the newborn was seen.[32]
Its use as an analgesic during labor is not advised due to its long onset of action (1 hour).[32] The ratio of the mean concentration of the drug in the fetus compared to that of the mother when it is given intramuscularly for labor pains has been estimated to be 1:94.[32]
Its use in children is generally advised against, although it may be done under the supervision of a specialist.[24] On 21 September 2015, the FDA started investigating the safety of tramadol in use in persons under the age of 17. The investigation was initiated because some of these people have experienced slowed or difficult breathing.[33] The FDA lists age under 12 years old as a contraindication.[34][35]
The risk of opioid-related adverse effects such asrespiratory depression, falls, cognitive impairment, and sedation is increased.[24] Tramadol may interact with other medications and increase the risk for adverse events.[36]
The drug should be used with caution in those with liver or kidney failure, due to metabolism in the liver (to the active molecule desmetramadol) and elimination by the kidneys.[24]
Long-term use of high doses of tramadol causesphysical dependence and withdrawal syndrome.[40] These include both symptoms typical ofopioid withdrawal and those associated withserotonin–norepinephrine reuptake inhibitor (SNRI) withdrawal; symptoms include numbness, tingling,paresthesia, and tinnitus.[41] Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion.[42] In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary.[41] Tramadol withdrawal typically lasts longer than that of other opioids. Seven days or more of acute withdrawal symptoms can occur as opposed to typically 3 or 4 days for other codeine analogs.[41]
The clinical presentation in overdose cases can vary but typically includes neurological, cardiovascular, and gastrointestinal manifestations.[43] The predominant neurological symptoms areseizures and altered levels of consciousness, ranging fromsomnolence tocoma. Seizures are particularly notable due to tramadol's lowering of theseizure threshold, occurring in approximately half of acute poisoning cases.[44] Patients often exhibittachycardia and mildhypertension. Gastrointestinal disturbances such as nausea and vomiting are common, and agitation, anxiety, and cold and clammy skin may also be present.[45]
While less common, severe complications like respiratory depression andserotonin syndrome can occur, particularly inpolydrug overdoses involving other CNS depressants (such asbenzodiazepines, opioids, andalcohol) and agents withserotonergic activity.[46][47] Additionally, individuals with genetic variations leading toCYP2D6 enzyme duplication (rapid metabolizers) may have an increased risk of adverse effects, due to faster conversion of tramadol to its activemetabolite.[48]
Acute tramadol overdose is generally not life-threatening, with most fatalities resulting from polysubstance overdose.[49] Management includes cardiovascular monitoring,activated charcoal administration, hydration, and treatment of seizures.[50]Naloxone, an opioid antagonist, can partially reverse some effects of tramadol overdose, particularly respiratory depression. However, its use may increase the risk of seizures due to unopposedalpha-adrenergic stimulation.[24] For suspected serotonin syndrome,cyproheptadine, aserotonin antagonist, is considered an effective antidote.[46]
The incidence of tramadol-related overdose deaths has been on the rise in certain regions. For instance, Northern Ireland has reported an increased frequency of such cases.[51] In 2013, England and Wales recorded 254 tramadol-related deaths, while Florida reported 379 cases in 2011.[52][53] In 2011, 21,649 emergency room visits in the United States were related to tramadol.[54] The likely explanation for these observations is due to increase in frequency of prescriptions and use due to easier access due to lighterregulatory scheduling by authorities[55] but this is starting to change. In 2021,Health Canada announced tramadol would be added to Schedule I of theControlled Drugs and Substances Act and to the Narcotic Control Regulations due to tramadol being suspected of having contributed to 18 reported deaths in Canada between 2006 and 2017.[56]
Tramadol is metabolized byCYP2D6 enzymes which contributes to the metabolism of approximately 25% of all medications.[57] Any medications with the ability to inhibit or induce these enzymes may interact with tramadol. These include common antiarrhythmics, antiemetics, antidepressants (sertraline,paroxetine, andfluoxetine in particular),[58] antipsychotics, analgesics, and tamoxifen.[59]
Tramadol increases the risk for seizures by lowering the seizure threshold. Using other medications that lower seizure threshold - such asantipsychotic medications,bupropion (an anti-depressant and smoking cessation drug), andamphetamines - can further increase this risk.[63]
Tramadol induces analgesic effects through a variety of different targets on thenoradrenergic system,serotonergic system, andopioid receptors system.[64] Tramadol affects serotonin and norepinephrine reuptake inhibition similarly to certain antidepressants known as serotonin–norepinephrine reuptake inhibitors (SNRIs), such asvenlafaxine andduloxetine.[65] Tramadol exists as aracemic mixture, the positiveenantiomer inhibits serotonin reuptake while the negative enantiomer inhibits noradrenaline re-uptake, by binding to and blocking the transporters.[66][15] Both enantiomers of tramadol are agonists of theμ-opioid receptor and its M1 metabolite, O-desmetramadol, is also a μ-opioid receptor agonist but is 6 times more potent than tramadol itself.[67] All of these actions may work synergistically to induce analgesia.
Tramadol acts on theopioid receptors through its majoractive metabolitedesmetramadol, which has as much as 700-fold higher affinity for the MOR relative to tramadol.[20] Moreover, tramadol itself has been found to possess noefficacy in activating the MOR in functional activity assays, whereas desmetramadol activates the receptor with high intrinsic activity (Emax equal to that ofmorphine).[76][20][93] As such, desmetramadol is exclusively responsible for the opioid effects of tramadol.[94] Both tramadol and desmetramadol have pronouncedselectivity for the MOR over the DOR and KOR in terms of binding affinity.[77][72][74]
Peak plasma concentrations during treatment with clinical dosages of tramadol have generally been found to be in the range of 70 to 592 ng/mL (266–2,250 nM) for tramadol and 55 to 143 ng/mL (221–573 nM) for desmetramadol.[25] The highest levels of tramadol were observed with the maximum oral daily dosage of 400 mg per day divided into one 100-mg dose every 6 hours (i.e., four 100-mg doses evenly spaced out per day).[25][104] Some accumulation of tramadol occurs with chronic administration; peak plasma levels with the maximum oral daily dosage (100 mgq.i.d.) are about 16% higher and thearea-under-the-curve levels 36% higher than following a single oral 100-mg dose.[25]Positron emission tomography imaging studies have reportedly found that tramadol levels are at least four-fold higher in thebrain than inplasma.[100][105] Conversely, brain levels of desmetramadol "only slowly approach those in plasma".[100] Theplasma protein binding of tramadol is only 4–20%; hence, almost all tramadol in circulation is free, thus bioactive.[106][107][108]
Co-administration ofquinidine, a potent CYP2D6 enzyme inhibitor, with tramadol, a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in human volunteers.[20][107] However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers.[20][94] The analgesic effects of tramadol are only partially reversed bynaloxone in human volunteers,[20] hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic effects are also partially reversed byα2-adrenergic receptor antagonists such asyohimbine, the5-HT3 receptor antagonistondansetron, and the5-HT7 receptor antagonistsSB-269970 andSB-258719.[25][109] Pharmacologically, tramadol is similar totapentadol andmethadone in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine[12] due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.[110]
Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for tramadol's reducing effect on depressive andobsessive–compulsive symptoms in patients with pain and co-morbid neurological illnesses.[80] 5-HT2C blockade may also account for its lowering of theseizure threshold, as 5-HT2Cknockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition ofGABAA receptors at high doses (significant inhibition at 100 μM).[89][66] In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadol's ability to provoke seizures in some individuals, as DOR agonists are well known for inducing seizures.[74]
Nausea andvomiting caused by tramadol are thought to be due to activation of the 5-HT3 receptor via increased serotonin levels.[78] In accordance, the 5-HT3 receptor antagonistondansetron can be used to treat tramadol-associated nausea and vomiting.[78] Tramadol and desmetramadol themselves do not bind to the 5-HT3 receptor.[78][70]
Tramadol is metabolised in theliver via thecytochrome P450isozymeCYP2B6,CYP2D6, andCYP3A4, beingO- andN-demethylated to five different metabolites. Of these,desmetramadol (O-desmethyltramadol) is the most significant, since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours, compared with 6 hours for tramadol itself. As with codeine, in the 6% of the population who have reduced CYP2D6 activity (hence reducing metabolism), a reduced analgesic effect is seen. Those with decreased CYP2D6 activity require a dose increase of 30% to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity.[111][112]
Phase IIhepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used inrenal andhepatic impairment.[25]
Itsvolume of distribution is around 306 L after oral administration and 203 L after parenteral administration.[25]
Tramadol is marketed as aracemic mixture of bothR- andS-stereoisomers,[12] because the two isomers complement each other's analgesic activities.[12] The (+)-isomer is predominantly active as an opiate with a higher affinity for the μ-opiate receptor (20 times higher affinity than the (-)-isomer).[7]
The chemical synthesis of tramadol is described in the literature.[113] Tramadol[2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at thecyclohexane ring. Thus,2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist infour different configurational forms:
(1R,2R)-isomer
(1S,2S)-isomer
(1R,2S)-isomer
(1S,2R)-isomer
The synthetic pathway leads to theracemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from thediastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of thehydrochlorides.The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(−)-enantiomers.The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(−)-isomer] was described[114] employing (R)-(−)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects[115] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals[116] and in humans.[117]
Tramadol and desmetramadol may be quantified in blood, plasma, serum, or saliva to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantify these substances. The concentration of desmetramadol in the blood or plasma of a person who has taken tramadol is generally 10–20% that of the parent drug.[118][119][120]
In 2014,Michael Spiteller (Technische Universität Dortmund) and collaborators reported results, also inAngewandte Chemie, that supported the conclusion that the presence of tramadol in those tree roots was the result of tramadol having been ingested by humans and having been administered to cattle (by farmers in the region); Spiteller et al. presented data that tramadol and itsmetabolites were present in animal excreta, which they then argue contaminated soil around the trees.[121] They further observed that tramadol and its mammalian metabolites were found in tree roots in the far north ofCameroon where the commercial drug was in use, but not in the south where it was not being administered.[121]
A news report appearing inLab Times at the time of the latter, 2014 paper, and reporting on its contents, also reported that Michel de Waard (communicating author of the original paper) continued to contest the notion that tramadol in tree roots was the result of anthropogenic contamination.[123] The point was made that samples were taken from trees that grew in national parks, where livestock were forbidden, and it quoted de Waard extensively, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating" would be required to produce the concentrations discovered.[123][better source needed]
In 2016, Spiteller and colleagues followed up their preceding work with aradiocarbon analysis that supported their contention that the tramadol found inN. latifolia roots was of human synthetic origin rather being plant-derived.[124]
Available dosage forms include liquids, syrups, drops, elixirs, effervescent tablets, and powders for mixing with water, capsules, tablets including extended-release formulations, suppositories, compounding powder, and injections.[24]
The U.S.Food and Drug Administration (FDA) approved tramadol in March 1995, and an extended-release (ER) formulation in September 2005.[125] ER Tramadol was protected by US patents nos. 6,254,887[126] and 7,074,430.[127][128] The FDA listed the patents' expiration as 10 May 2014.[127] However, in August 2009, the US District Court for the District of Delaware ruled the patents invalid, a decision upheld the following year by the Court of Appeals for the Federal Circuit. Manufacture and distribution of generic equivalents of Ultram ER in the United States was therefore permitted before the expiration of the patents.[129]
Effective August 2014, tramadol has been placed intoSchedule IV of the federal Controlled Substances Act in the United States.[130][131] Before that, some US states had already classified tramadol as a Schedule IV controlled substance under their respective state laws.[132][133][134]
Tramadol is classified in Schedule 4 (prescription only) in Australia, rather than as aSchedule 8 Controlled Drug (Possession without authority illegal) like most otheropioids.[24]
In June 2014, the United Kingdom's Home Office classified tramadol as a Class C, Schedule 3 controlled drug, but exempted it from the safe custody requirement.[8]
In October 2023, New Zealand's Medsafe reclassified tramadol as a Class C2 Controlled Drug (in addition to its existing status as a prescription only medication).[136]
Effective 22 August 2025, the government ofLiberia increased regulations on tramadol. Its use was "strictly limited to licensed hospital settings under the direct supervision of professional medical staff" according to theLiberian Observer. Liberian health authorities claimed that tramadol was the "most widely abused drug" in the country.[137]
Illicit use of the drug is thought to be a major factor in the success of theBoko Haram terrorist organization.[138][139][140] When used at higher doses, the drug "can produce similar effects to heroin."[138] One former member said, "whenever we took tramadol, nothing mattered to us anymore except what we were sent to do because it made us very high and very bold, it was impossible to go on a mission without taking it."[138] Tramadol is also used as a coping mechanism in theGaza Strip.[141] It is also abused in theUnited Kingdom.[142][143]
Tramadol was the most common opioid prescribed by American veterinarians from 2014 to 2019; however, usage has declined in subsequent years due to more recent evidence suggesting that dogs do not metabolise tramadol into O-desmethyltramadol effectively. As metabolisation of tramadol relies oncytochrome P450 enzymes, it is species dependent and even individual genetics can have a profound impact on the efficacy of tramadol.[154] A 2021 meta-analysis of tramadol use in dogs found that although tramadol was more effective thannalbuphine andcodeine, it was less effective thanmethadone,COX inhibitors andmultimodal analgesia with poor evidence to support the use of it is an analgesic for dogs.[155][154] Themean alveolar concentration sparing effect of tramadol is negligible and with a high likelihood of rescue analgesia being required thus tramadol monotherapy is not recommended for the dog.[154] One study looking at tramadol andmeloxicam administered preoperatively provided no benefit compared to meloxican given alone.[156][154] Another study looking atcimicoxib versus tramadol for long-term post-operative pain following atibial-plateau-levelling osteotomy found that although the level of analgesia was similar cimicoxib resulted in better mobility and a lower incidence ofhockoedema.[157][154] These studies and other evidence suggest thatnon-steroidal anti-inflammatory drugs provide superior analgesia to tramadol in dogs.[154]
Tramadol is more effective in cats although oral tramadol is poorly tolerated leading to low compliance. A transdermal gel was formulated to address this but plasma concentrations were undetectable.[154] In cats oral tramadol at 6 mg/kg provides equivalent analgesia to intramuscular tramadol at 4 mg/kg.[154][158] One study comparing tramadol tomeperidine found tramadol to be more effective at providing analgesia for cats undergoing ovariohysterectomy.[159][154] A study looking at treatment ofosteoarthritis in geriatric cats found owner-reported improvements but also significant adverse effects.[160][154] Reported adverse effects of tramadol include:diarrhoea,dysphoria,anorexia,tachycardia,pyrexia,tachypnoea, and increased levels ofsertonin leading to agitation. Tramadol has the potential to causeserotonin syndrome when administered alongsideserotonin re-uptake inhibitors,monoamine oxidase inhibitors, andtricyclic antidepressants.[154]
In horses tramadol is ineffective by itself.[154] Two studies looking at intravenous tramadol found it provided no thermal or mechanicalantinociception,[161][162][154] another study looking at oral tramadol for chroniclaminitis found it provided minimal analgesia,[163][154] and another study looking atintraarticular tramadol found it provided no post-operative analgesia followingarthroscopy;[164][154] however, when administered withparacetamol (acetaminophen) tramadol provides short-acting mechanical antinociception[162][154] and when administered withketamine oral tramadol provides adequate analgesia for chronic laminitis.[163][154] Based on this evidence tramadol is not recommended to be provided on its own for analgesia in horses.[154]
Pharmacokinetics of tramadol across the species[165]
Species
Half-life (h) for parent drug
Half-life (h) for desmetramadol
Maximum plasma concentration (ng/mL) for parent drug
Maximum plasma concentration (ng/mL) for desmetramadol
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