150px 150px
Systematic (IUPAC) name
Clinical data
Trade names Ryzolt, Tramal, Ultram
AHFS/ monograph
MedlinePlus a695011
Licence data US FDA:link
  • AU: C
  • US: C (Risk not ruled out)
Oral, IV, IM, rectal
Pharmacokinetic data
Bioavailability 70–75% (oral), 77% (rectal), 100% (IM)[2]
Protein binding 20%[3]
Metabolism Liver-mediated demethylation and glucuronidation via CYP2D6 & CYP3A4[2][3]
Half-life 6.3 ± 1.4 hr[3]
Excretion Urine (95%)[4]
27203-92-5 7pxY
PubChem CID 33741
DrugBank DB00193 7pxY
ChemSpider 31105 7pxY
UNII 39J1LGJ30J 7pxY
KEGG D08623 7pxY
ChEBI CHEBI:9648 7pxN
Chemical data
Formula C16H25NO2
263.4 g/mol
 14pxN (what is this?)  (verify)

Tramadol (marketed as Ultram, and as generics) is an opioid pain medication which is used to treat moderate to moderately severe pain.[1] When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour.[5] It has two different mechanisms. First, it binds to the μ-opioid receptor. Second, it inhibits the reuptake of serotonin and norepinephrine.[6][7]

Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. Common side effects include: constipation, itchiness and nausea, among others. A change in dosage may be recommended in those with kidney or liver problems. Its use is not recommended in women who are breast feeding or those who are at risk of suicide.[1]

Tramadol is marketed as a racemic mixture of both R- and S-stereoisomers.[2] This is because the two isomers complement each other's analgesic activity.[2] It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.[2] Tramadol is metabolised to O-desmethyltramadol, which is a more potent opioid.[8] It is of the benzenoid class.

Tramadol was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977 in West Germany, and 20 years later it was launched in countries such as the UK, U.S., and Australia.[7]

Medical uses

File:50 mg Tramadol HCl tablets (generic Ultram) marketed by Amneal Pharmaceuticals (rotated).jpg
Generic tramadol HCl tablets marketed by Amneal Pharmaceuticals.
File:Tramadol HCl.jpg
Tramadol HCl for injection

Tramadol is used primarily to treat mild-severe pain, both acute and chronic.[9][10]

Tramadol is recommended for the management of pain in fibromyalgia by the European League Against Rheumatism.[11] Its analgesic effects take about one hour to come into effect and 2–4 hours to peak after oral administration with an immediate-release formulation.[9] On a dose-by-dose basis tramadol has about one-tenth the potency of morphine and is approximately equally potent when compared to pethidine and codeine.[12]

For pain moderate in severity its effectiveness is equivalent to that of morphine; for severe pain it is less effective than morphine.[9] These painkilling effects peak at about 3 hours, post-oral administration and last for approximately 6 hours.[10] These analgesic effects are only partially reversed by naloxone, hence indicating that its opioid action is unlikely the sole contributing factor; tramadol's analgesic effects are also partially reversed by α2 adrenergic receptor antagonists like yohimbine and the 5-HT3 receptor antagonist, ondansetron.[10] Pharmacologically, tramadol is similar to levorphanol and tapentadol in that it not only binds to the mu opioid receptor, but also inhibits the reuptake of serotonin and norepinephrine[2] due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.[13] Available dosage forms include capsules, tablets, including extended release formulations and injections.[9]

Pregnancy and lactation

Its use in pregnancy is generally advised against as it may cause some reversible withdrawal effects in the newborn.[14] A small prospective study in France found that, while there was an increased risk of miscarriages, there were no major malformations reported in the newborn.[14] Its use during lactation 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. There was no evidence of this dose having a harmful effect on the newborn.[14]

Labour and delivery

Its use as an analgesic during labour is generally advised against due to its long-onset of action (one hour).[14] The ratio of the mean concentration of the drug in the foetus compared to that of the mother when it is given intramuscularly for labour pains has been estimated to be 94.[14]


Its use in children is generally advised against, although it may be done under the supervision of a specialist.[9]


There is an increased risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment and sedation.[9]

Liver and kidney failure

It is advised that the drug be used with caution in those with liver or kidney failure, due to the high dependence of the drug on the liver and kidneys for metabolism to O-desmethyltramadol and elimination, respectively.[9]

Adverse effects

File:Side effects of Tramadol.png
Main side effects of tramadol. Red color denotes more serious effects, requiring immediate contact with health provider.[15]

The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness and headache.[16][17] Compared to other opioids, respiratory depression and constipation are considered less of a problem with tramadol.[17]

There are suggestions that chronic opioid administration may induce a state of immune tolerance,[18] although tramadol, in contrast to typical opioids, may enhance immune function.[19][20][21] Some have also stressed the negative effects of opioids on cognitive functioning and personality.[22]


Tramadol interacts, potentially fatally, with such serotonergics, monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin antagonist and reuptake inhibitors, certain analgesics (pethidine (meperidine), tapentadol, oxycodone, dextromethorphan and fentanyl), certain anxiolytics (such as the SSRIs and buspirone), certain antibiotics (namely, linezolid and isoniazid), certain herbs (e.g. St. John's wort, passiflora, etc.), amphetamines/substituted amphetamines, phenethylamines/Substituted phenethylamines, phentermine, lithium, methylene blue as well as numerous other therapeutic agents.[4][9] As it is a substrate of CYP3A4 and CYP2D6, hence any agents with the ability to inhibit or induce these enzymes will likely interact with tramadol. A pressor response similar to the so-called "cheese effect" was noted in combinations of amphetamine and tramadol, which appears to cause dysfunction of or toxicity to epinephrine/norepinephrine receptors.[9][17]


Its use is not advised for people deficient in CYP2D6 enzymes which accounts for about 6–10% of Caucasians and 1–2% of Asians, as they are crucial to the therapeutic effects of tramadol, by means of enabling tramadol's metabolism to O-desmethyltramadol.[9]


Fatalities with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of these overdoses involve other drugs including alcohol.[23] Recognised risk factors for tramadol overdose include depression, addiction and seizures.[23] Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.[9]

Physical dependence and withdrawal

Long-term use of high doses of tramadol may be associated with physical dependence and a withdrawal syndrome.[24][25] These include both withdrawal symptoms typical of opiate withdrawal and those associated with SSRI withdrawal, including numbness, tingling, paresthesia, and tinnitus.[26] Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion.[27] In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary.[26] Tramadol withdrawal lasts longer than that of other opioids; seven days or more of acute withdrawal symptoms can occur as opposed to typically three or four days for other codeine analogues.[26]

Psychological dependence and recreational use

Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous.[28] Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opiates, which could deter abuse.[29] Compared to hydrocodone, fewer persons choose to abuse tramadol.[30]

It may also have a large effect on sleeping patterns and high doses may cause insomnia, especially for those on methadone, both for maintenance and recreation. Though there is no scientific proof tramadol lessens effects of opiates or is a mixed agonist-antagonist, some people get the impression it is, while someone else might benefit being prescribed both for pain and breakthrough pain.[31]

Detection in biological fluids

Tramadol and O-desmethyltramadol may be quantified in blood, plasma or serum to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or 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 quantitate these substances. The concentrations of O-desmethyltramadol in the blood or plasma of a person who has taken tramadol are generally 10–20% those of the parent drug.[32][33][34]


Synthesis and stereoisomerism

(1R,2R)-Tramadol   (1S,2S)-Tramadol
(1R,2R)-Tramadol     (1S,2S)-Tramadol
(1R,2S)-Tramadol   (1S,2R)-Tramadol
(1R,2S)-Tramadol     (1S,2R)-Tramadol

The chemical synthesis of tramadol is described in the literature.[35] Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

  • (1R,2R)-isomer
  • (1S,2S)-isomer
  • (1R,2S)-isomer
  • (1S,2R)-isomer

The synthetic pathway leads to the racemate (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 the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. 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[36] 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[37] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals[38] and in humans.[39]

Mechanism of action

Tramadol acts as a μ-opioid receptor agonist,[40][41] serotonin reuptake inhibitor and releasing agent,[42][43][44][45] norepinephrine reuptake inhibitor,[41] NMDA receptor antagonist (IC50=16.5 μM),[46] 5-HT2C receptor antagonist (EC50=26 nM),[47] (α7)5 nicotinic acetylcholine receptor antagonist,[48] TRPV1 receptor agonist,[49] and M1 and M3 muscarinic acetylcholine receptor antagonist.[50][51]

Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for tramadol's reducing effect on depressive and obsessive-compulsive symptoms in patients with pain and co-morbid neurological illnesses.[47] 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout 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 of GABAA receptors at high doses.[46] In addition, tramadol's major active metabolite, O-desmethyltramadol, is a high-affinity ligand of the δ- and κ-opioid receptors, and activity at the former receptor could be involved in tramadol's ability to provoke seizures in some individuals, as δ-opioid receptor agonists are well known to induce seizures.[52]


Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6 and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, O-desmethyltramadol is the most significant since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. As with codeine, in the 6% of the population that have reduced CYP2D6 activity (hence reducing metabolism), there is therefore a reduced analgesic effect. Those with decreased CYP2D6 activity require a dose increase of 30% in order to achieve the same degree of pain relief than those with a normal level of CYP2D6 activity.[53][54]

Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment.[10]

Its volume of distribution is approximately, 306 L after oral administration and 203 L after parenteral administration.[10]

Society and culture

Legal status

The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-release (ER) formulation in September 2005.[55] It is covered by U.S. patents nos. 6,254,887[56] and 7,074,430.[57][58] The FDA lists the patents as scheduled for expiration on 10 May 2014.[57] However, in August 2009, U.S. District Court for the District of Delaware ruled the patents invalid, which, if it survives appeal, would permit manufacture and distribution of generic equivalents of Ultram ER in the United States.[59]

Effective August 18, 2014, Tramadol has been placed into Schedule IV of the federal Controlled Substances Act.[60][61] In addition, several states, including Arkansas, Georgia, Kentucky, Illinois, Mississippi, New York, North Dakota, Ohio, Oklahoma, South Carolina, Tennessee, West Virginia, Wyoming and the U.S. military have already classified Tramadol as a schedule IV controlled substance under state law.[62][63][64]

Thus, tramadol is classified as a Schedule IV in the US, Schedule 4 in Australia rather than as a Schedule 8 Controlled Drug like opioids.[9]

Sweden, as of May 2008, has chosen to classify tramadol as a controlled substance in the same way as codeine and dextropropoxyphene. This means that the substance is a scheduled drug. But unlike codeine and dextropropoxyphene, a normal prescription can be used at this time.[65]

The UK government has decided that tramadol will become a Schedule 3 controlled drug (CD) on 10 June 2014, but will have exemption from the safe custody requirement.[66]

Brand names

Grünenthal GmbH, which still owns the patent on tramadol, has cross-licensed the drug to pharmaceutical companies internationally. Thus, tramadol is marketed under many trade names around the world, including:

  • Acugesic (Malaysia, Singapore)
  • Adolonta (Spain)
  • Algifeno (Bolivia)
  • Algesia (Philippines)
  • Anadol (Bangladesh, Thailand)
  • Astadol (combined with paracetamol)(Pakistan)
  • Boldol (Bosnia, Herzegovina)
  • Calmador (Argentina)
  • Campex (Pakistan)
  • Citra 50 (Mexico)
  • Contramal (Belgium, France, India, Italy, Turkey, Sudan, Hungary)
  • Conzip (United States)
  • Crispin
  • Cramol (Nepal)
  • Dolcet (combined with paracetamol)(Philippines)
  • Dolol (Denmark)
  • Dolzam (Belgium, Luxembourg)
  • Dromadol (United Kingdom)
  • Durela (Canada)
  • Exopen (South Korea)
  • Hovid (Malaysia)
  • Ixprim (combined with paracetamol) (France, Ireland)
  • Lumidol (Bosnia, Herzegovina, Croatia)
  • Mabron (Bahrain, Bangladesh, Bulgaria, Czech Republic, Estonia, Iraq, Jordan, Latvia, Lithuania, Malaysia, Oman, Romania, Singapore, Sri Lanka, Sudan, Yemen)
  • Mandolgin (Denmark)
  • Mandolgine
  • Mosepan
  • Matrix (combined with paracetamol) (Honduras, Guatemala)
  • Mavidol TR (combined with Ketorolac) (México)
  • Nobligan (Argentina, Denmark, Iceland, Mexico, Norway, Portugal, Sweden)
  • Nomal (Oman)
  • Osteodol (India)
  • Oxxalgan PR (Greece)
  • Pazital (combined with paracetamol) (Spain)
  • Palitex (India)
  • Poltram (Poland)
  • Pyredol (combined with paracetamol) (Vietnam, Bolivia)
  • Ralivia (Canada)
  • Ryzolt (United States)
  • Sinergix (combined with ketorolac) (Mexico)
  • Sintradon (Serbia)
  • Siverol (Philippines)
  • Tandol (South Korea)
  • Tiparol (Sweden)
  • Tonoflex (Pakistan)
  • Topalgic (France)
  • Trabar (Cameroon)
  • Tradol (Bangladesh, Ireland, Mexico, Singapore, Venezuela)
  • Tradolan (Austria, Denmark, Finland, Iceland, Romania, Sweden)
  • Tradolgesic (Thailand)
  • Tradonal (Belgium, Indonesia, Italy, Luxembourg, Netherlands, Philippines, Spain, Switzerland)
  • Tralgit (Czech Republic, Georgia, Romania, Slovakia)
  • Tralodie (Italy)
  • Tramacet (combined with paracetamol) (Canada, Mexico, Costa Rica, South Africa)
  • Tramacip (India)
  • Tramadex (Israel)
  • Tramadin (Finland)
  • Trambulance
  • Tramadol HEXAL (Denmark, Finland, Germany, Hungary)
  • Traminol
  • Trampel (Germany)
  • Tram Proxyvon (INDIA)
  • Tranophen (combined with paracetamol) (South Korea)
  • Trexol (Mexico)
  • TRIMIF (India)
  • Trumen (Bangladesh)
  • Tramabol
  • Tramacet (South Africa)
  • Tramadol (Australia, Belgium, Canada, Chile, Egypt, Estonia, France, Netherlands, Romania, New Zealand, Norway, Spain, United Kingdom, United States)
  • Tramadol Stada (Sweden)
  • Tramadol-Sandoz (Hungary)
  • Tramadol-Ratiopharm (Hungary, many European countries)
  • Tramadolor (Austria, Estonia, Germany, Hungary, Latvia, Lithuania, Luxembourg, Romania)
  • Tramadolor ID (Hungary)
  • Tramalgic (Hungary, Czech Republic, Slovakia)
  • Tramagit (Romania)
  • Tramahexal (Australia)
  • Tramake (United Kingdom)
  • Trama-Klosidol (Argentina)
  • Tramal (Slovakia, Costa Rica, Bulgaria, Colombia, Ecuador, Pakistan, Netherlands, Estonia, Finland, Croatia, Morocco, Slovenia, Austria, Poland, Brazil, Chile, Romania, Australia, New Zealand, Germany, Switzerland, Lebanon, Israel, Philippines, Egypt, Thailand, Portugal, Panama)
  • Tramalgic (Hungary)
  • Tramal Gotas (Ecuador)
  • Tramazac (India, Myanmar, Sri Lanka, South Africa)
  • Tramazac Co (combined with paracetamol) (South Africa)
  • Tramed
  • Tramedo (Australia)
  • Tramoda (Thailand)
  • Trasic (Thailand)
  • Tram Sham
  • Tramól (Iceland)
  • Tramundal (Austria)
  • Tridol (South Korea)
  • Tridural (Canada)
  • Trodon (Serbia)
  • Ultracet (combined with paracetamol) (Brazil, United States)
  • Ultradol (Bangladesh)
  • Ultram and Ultram ER (United States)
  • Ultramed (combined with paracetamol) (India)
  • Veldrol (Mexico)
  • VAMADOL PLUS (India)
  • Volcidol (Thailand)
  • Zafin (combined with paracetamol) (Chile)
  • Zaldiar (combined with paracetamol) (Australia, Belgium, Chile, Croatia, the Czech Republic, France, Mexico, Poland, Portugal, Slovenia, Spain, Switzerland, Russia, Panama)
  • Zaledor (combined with paracetamol) (Chile)
  • Zamadol (United Kingdom)
  • Zamudol (France)
  • Zodol (Chile, Ecuador, Peru)
  • Zoftadol (India)
  • Zydol (United Kingdom, Ireland, Australia)
  • Zytram (Canada, Iceland, New Zealand, Spain)
  • Zytrim (Spain)

Veterinary medicine

Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats as well as rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons.[67]

Pharmacokinetics of tramadol across the species[67]
Species Half-life (h) for parent drug Half-life (h) for O-desmethyltramadol Maximum plasma concentration (ng/mL) for parent drug Maximum plasma concentration (ng/mL) for O-desmethyltramadol
Camel 3.2 (IM), 1.3 (IV) 0.44 (IV)
Cat 3.40 (oral), 2.23 (IV) 4.82 (oral), 4.35 (IV) 914 (oral), 1323 (IV) 655 (oral), 366 (IV)
Dog 1.71 (oral), 1.80 (IV), 2.24 (rectal) 2.18 (oral), 90-5000 (IV) 1402.75 (oral), 449.13 (oral), 90–350 (IV)
Donkey 4.2 (oral), 1.5 (IV) 2817 (oral)
Goat 2.67 (oral), 0.94 (IV) 542.9 (oral)
Horses 1.29–1.53 (IV), 10.1 (oral) 4 (oral) 637 (IV), 256 (oral) 47 (oral)
Llama 2.54 (IM), 2.12 (IV) 7.73 (IM), 10.4 (IV) 4036 (IV), 1360 (IM) 158 (IV), 158 (IM)

Pin cushion tree

In 2013, researchers reported that tramadol was found in relatively high concentrations (1%+) in the roots of the African pin cushion tree (Nauclea latifolia).[68] In 2014, however, it was reported that the presence of tramadol in the tree roots was the result of tramadol having been administered to cattle by farmers in the region:[69] tramadol and its metabolites were present in the animals' excreta, which contaminated the soil around the trees. Therefore, tramadol and its mammalian metabolites were found in tree roots in the far North of Cameroon, but not in the South where it is not administered to farm animals.[69]


Investigational uses


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