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* '''Crispin'''
* '''Crispin'''
* '''Campex''' (in [[Pakistan]])
* '''Campex''' (in [[Pakistan]])
* '''Dolcet''' (in the [[Philippines]])
* '''Dolol''' (in [[Denmark]])
* '''Dolol''' (in [[Denmark]])
* '''Dromadol''' (in [[UK]])
* '''Dromadol''' (in [[UK]])

Revision as of 02:15, 6 August 2008

Tramadol
Clinical data
Pregnancy
category
  • AU: C
Routes of
administration		oral, IV, IM, IV, rectal, sublingual, buccal
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability68–72% Increases with repeated dosing.
Protein binding20%
MetabolismHepatic demethylation and glucuronidation
Elimination half-life5–7 hours
ExcretionRenal
Identifiers
  • (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard100.043.912 Edit this at Wikidata
Chemical and physical data
FormulaC16H25NO2
Molar mass263.4 g/mol g·mol−1
3D model (JSmol)
  • CN(C)C[C@@H]2CCCC[C@@]2(O)c1cccc(OC)c1

Tramadol (INN) (Template:PronEng) is an atypical opioid which is a centrally acting analgesic, used for treating moderate to severe pain. It is a synthetic agent, and appears to have actions on the μ-opioid receptor as well as the noradrenergic and serotonergic systems.[1][2] Tramadol was developed by the German pharmaceutical company Grünenthal GmbH in the late 1970s and marketed under the trade name Tramal.[3] Grünenthal has also cross licensed the drug to many other pharmaceutical companies that market it under various names.

Tramadol is usually marketed as the hydrochloride salt (tramadol hydrochloride) and is available in both injectable (intravenous and/or intramuscular) and oral preparations. It is also available in conjunction with paracetamol (acetaminophen).

Specifically, tramadol comes in capsules, tablets, extended-release tablets, low-residue and/or uncoated tablets which can be taken by the sublingual and buccal routes, suppositories, effervescent tablets and powders, ampoules of sterile solution for SC, IM, and IV injection, powders for compounding, liquid for oral and sublingual administration -- in regular phials and bottles, dropper bottles, bottles with a pump similar to those used with liquid soap and phials with droppers built into the cap -- as well as tablets and capsules containing paracetamol and aspirin. Tramadol has a characteristic taste which is mildly bitter but much less so than morphine and codeine. Oral and sublingual drops and liquid preparations come with and without added flavouring. Its relative effectivness via transmucousal routes (sublingual, buccal, rectal) is around that of codeine and like codeine it is also metabolised in the liver to stronger metabolites (see below).

Doses range from 50–400 mg daily, maximum dose of 400 mg a day (webmed), with up to 600 mg daily when given IV/IM. The formulation containing APAP contains 37.5 mg of tramadol and 325 mg of paracetamol, intended for oral administration with a common dosing recommendation of one or two tabs every four to six hours.

Tramadol can be boosted in its analgesic effect with carisoprodol and meprobamate, benzodiazepines, and most antihistamines, especially promethazine, hydroxyzine, and orphenadrine.

Unlike most other opioids, Tramadol is not considered a controlled substance in many countries (the US and Australia, among others), and is available with a normal prescription. Tramadol is available over the counter without prescription in a few countries.[4] Sweden has as of May 2008 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.[3] Tramadol is sometimes mistakenly classified as a non-opioid analgesic, because its abuse liability is lower than that of other opioids and because it has multiple mechanisms of action (including, but not limited to mu-opioid activity).

Uses

Tramadol is used to treat moderate and severe pain and most types of neuralgia, including trigeminal neuralgia.[citation needed] It has been suggested that tramadol could be effective for alleviating symptoms of depression and anxiety because of its action on the noradrenergic and serotonergic systems, the involvement of which appear to play a part in its ability to alleviate the perception of pain. However, health professionals have not yet endorsed its use on a large scale for disorders such as this.[5][6]

Off-label and investigational uses

Veterinary

Tramadol is used to treat post-operative, injury-related, and chronic (e.g. cancer-related) pain in dogs and cats [4] as well as rabbits, coatis, many rodents including rats and flying squirrels, guinea pigs, ferrets and raccoons. Tramadol comes in ampoules in addition to the tablets, capsules, powder for reconstitution and oral syrups and liquids; the fact that its characteristic taste is not very bitter and can be masked in food and diluted in water makes for a number of means of administration. No data which would lead to a definitive determination of the efficacy and safety of tramadol in reptiles or amphibians is available at this time, and following the pattern of all other drugs it appears that tramadol can be used to relieve pain in marsupials such as North American opossums, Short-Tailed Opossums, sugar gliders, wallabies, and kangaroos amongst others.

Mechanism of action

The mode of action of tramadol has yet to be fully understood, but it is believed to work through modulation of the noradrenergic and serotonergic systems in addition to its mild agonism of the μ-opioid receptor. The contribution of non-opioid activity is demonstrated by the analgesic effects of tramadol not being fully antagonised by the μ-opioid receptor antagonist naloxone.

Tramadol is marketed as a racemic mixture with a weak affinity for the μ-opioid receptor (approximately 1/6th that of morphine). The (+)-enantiomer is approximately four times more potent than the (-)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (-)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (+)-tramadol exhibiting 10-fold higher analgesic activity than (-)-tramadol (Goeringer et al., 1997).

The serotonergic modulating properties of tramadol mean that it has the potential to interact with other serotonergic agents. There is an increased risk of serotonin syndrome when tramadol is taken in combination with serotonin reuptake inhibitors (e.g. SSRIs) or with use of a light box, since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism. Tramadol is also thought to have some NMDA-type antagonist effects which has given it a potential application in neuropathic pain states.

Metabolism

Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2D6, being O- and N-demethylated to five different metabolites. Of these, M1 (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. In the 6% of the population who have slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble and they are excreted by the kidneys. Thus reduced doses may be used in renal and hepatic impairment.

Adverse effects

The most commonly reported adverse drug reactions are nausea, vomiting, sweating and constipation. Drowsiness is reported, although it is less of an issue than for other opioids. Respiratory depression, a common side effect of most opioids, is not clinically significant in normal doses. By itself, it can decrease the seizure threshold. When combined with SSRIs, tricyclic antidepressants, or in patients with epilepsy, the seizure threshold is further decreased. Seizures have been reported in humans receiving excessive single oral doses (700 mg) or large intravenous doses (300 mg). There is anecdotal evidence that when used recreationally, an oral dose as low as 200 mg can cause seizures. An Australian study found that of 97 confirmed new-onset seizures, eight were associated with Tramadol, and that in the authors' First Seizure Clinic, "Tramadol is the most frequently suspected cause of provoked seizures" (Labate 2005). Seizures caused by tramadol are most often tonic-clonic seizures. Dosages of coumadin/warfarin may need to be reduced for anticoagulated patients to avoid bleeding complications. Constipation can be severe especially in the elderly requiring manual evacuation of the bowel.

Pregnancy and breastfeeding

Tramadol is in FDA pregnancy category C; animal studies have shown its use to be dangerous during pregnancy and human studies are lacking. Therefore, the drug should not be taken by women who are pregnant unless "the potential benefits outweigh the risks".[18]

Tramadol may also cause serious or fatal side effects in a newborn, including neonatal withdrawal syndrome, if the mother uses the medication during pregnancy or labor. Use of tramadol by nursing mothers is not recommended by the manufacturer because the drug passes into breast milk.[18] However, the absolute dose excreted in milk is quite low, and tramadol is generally considered to be acceptable for use in breastfeeding mothers.[19]

Dependency

Some controversy exists regarding the dependence liability of tramadol. Grünenthal has promoted it as an opioid with a lower risk of opioid dependence than that of traditional opioids, claiming little evidence of such dependence in clinical trials. They offer the theory that since the M1 metabolite is the principal agonist at μ-opioid receptors, the delayed agonist activity reduces dependence liability. The noradrenaline reuptake effects may also play a role in reducing dependence.

Studies into the dependence liability of tramadol show that patients are no more likely to abuse the drug than normal NSAIDs. Despite these claims, it is apparent in community practice that dependence to this agent may occur, but in higher doses and long-term usage.[20] However, this dependence liability is considered relatively low by health authorities, such that tramadol is classified as a Schedule 4 Prescription Only Medicine in Australia, rather than as a Schedule 8 Controlled Drug like other opioids (Rossi, 2004). Similarly, tramadol is not currently scheduled by the U.S. DEA, unlike other opioid analgesics. Nevertheless, the prescribing information for Ultram warns that tramadol "may induce psychological and physical dependence of the morphine-type". In addition, there are widespread reports by consumers of extremely difficult withdrawal experiences[21] including acute depression and suicidal urges.[22]

A controlled study that compared different medications found "the percent of subjects who scored positive for abuse at least once during the 12-month follow-up were 2.5% for NSAIDs, 2.7% for tramadol, and 4.9% for hydrocodone. When more than one hit on the dependency algorithm was used as a measure of persistence, abuse rates were 0.5% for NSAIDs, 0.7% for tramadol, and 1.2% for hydrocodone. Thus, the results of this study suggest that the prevalence of abuse/dependence over a 12-month period in a CNP population that was primarily female was equivalent for tramadol and NSAIDs, with both significantly less than the rate for hydrocodone". This means that the abuse liability of tramadol was almost the same as that of normal NSAIDs, such as ibuprofen.[21]

Recreational use

As an opioid analgesic, tramadol has been proposed as a possible recreational drug. However, due to the possibility of convulsions at high doses, recreational use is very dangerous. It can, however, via agonism of μ opioid receptors, produce effects similar to those of other opioids (e.g., morphine or hydrocodone), although not nearly as intense due to tramadol's much lower affinity for the receptor. However, the metabolite M1 is produced after demethylation of the drug in the liver. The M1 metabolite has an estimated 200x greater affinity for the mu1, and mu2 opioid receptors. In addition to acting as an opioid, tramadol is also a very weak but rapidly acting serotonin-norepinephrine reuptake inhibitor.[23] When taken in amounts larger than normal therapeutic doses (typically over 400 mg), tramadol can cause seizures (typically tonic-clonic). To prevent seizures, muscle relaxing benzodiazepines (typically diazepam or oxazepam) are often taken together with tramadol, as recreational users often administer doses much larger than 400 mg. Tramadol can also cause severe nausea, which could deter abuse to some extent. Tramadol has been known to produce severe withdrawal symptoms with abrupt cessation after prolonged use. In addition, tramadol can help alleviate withdrawal symptoms from more addictive opiates, and is much easier to lower quantity of usage compared to opiates such as hydrocodone and oxycodone.[21] It may also have large effect on sleeping patterns. High doses may prevent sleeping.

In addition, tramadol is sometimes combined with stronger opiates to potentiate and prolong the effects. Tramadol is a weaker opioid than oxycodone or hydrocodone but has a longer half-life, so when combined it results in a longer duration of the euphoric effects.

Animal treatment

Tramadol for animals is one of the most reliable and useful active principles available to veterinarians for treating animals in pain. It has a dual mode of action: mu agonism and monoamine reuptake inhibition, which produces mild anti-anxiety results. Tramadol may be utilized for relieving pain in cats and dogs. This is an advantage because the use of some non-steroidal anti-inflammatory substances in these animals may be dangerous.

When animals are administered tramadol, adverse reactions can occur. The most common are: constipation, upset stomach, decreased heart rate. In case of overdose, mental alteration, pinpoint pupils and seizures may appear. In such case, veterinarians should evaluate the correct treatment for these events. Some contraindications have been noted in treated animals taking certain other drugs. Tramadol should not be co-administered with Deprenyl or any other psychoactive ingredient such as: serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors. In animals, tramadol is removed from the body via liver and kidney excretion. Animals suffering from diseases in these systems should be monitored by a veterinarian, as it may be necessary to adjust the dose.

Dosage and administration of tramadol for animals: in dogs a starting dosage of 1-2 mg/kg twice a day will be useful for pain management. Cats are administered 2-4 mg/kg twice a day.

Proprietary preparations

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

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Template:Multicol-break

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References

  1. ^ Dayer P, Desmeules J, Collart L (1997). "[Pharmacology of tramadol]". Drugs. 53 Suppl 2: 18–24. PMID 9190321.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Opioids.com
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  4. ^ Erowid
  5. ^ Opioids.com
  6. ^ Opioids.com
  7. ^ Harati Y, Gooch C, Swenson M; et al. (1998). "Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy". Neurology. 50 (6): 1842–46. PMID 9633738. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  8. ^ Harati Y, Gooch C, Swenson M; et al. (2000). "Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy". J. Diabetes Complicat. 14 (2): 65–70. PMID 10959067. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  9. ^ Göbel H, Stadler T (1997). "[Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine]". Drugs (in French). 53 Suppl 2: 34–39. PMID 9190323.
  10. ^ Boureau F, Legallicier P, Kabir-Ahmadi M (2003). "Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial". Pain. 104 (1–2): 323–31. doi:10.1016/S0304-3959(03)00020-4. PMID 12855342.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Bennett RM, Kamin M, Karim R, Rosenthal N (2003). "Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study". Am. J. Med. 114 (7): 537–45. doi:10.1016/S0002-9343(03)00116-5. PMID 12753877.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Lauerma H, Markkula J (1999). "Treatment of restless legs syndrome with tramadol: an open study". The Journal of clinical psychiatry. 60 (4): 241–44. PMID 10221285.
  13. ^ Sobey PW, Parran TV, Grey SF, Adelman CL, Yu J (2003). "The use of tramadol for acute heroin withdrawal: a comparison to clonidine". J Addict Dis. 22 (4): 13–25. PMID 14723475.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Threlkeld M, Parran TV, Adelman CA, Grey SF, Yu J (2006). "Tramadol versus buprenorphine for the management of acute heroin withdrawal: a retrospective matched cohort controlled study". Am J Addict. 15 (2): 186–91. doi:10.1080/10550490500528712. PMID 16595358.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Engindeniz Z, Demircan C, Karli N; et al. (2005). "Intramuscular tramadol vs. diclofenac sodium for the treatment of acute migraine attacks in emergency department: a prospective, randomised, double-blind study". J Headache Pain. 6 (3): 143–48. doi:10.1007/s10194-005-0169-y. PMID 16355295. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Goldsmith TB, Shapira NA, Keck PE (1999). "Rapid remission of OCD with tramadol hydrochloride". The American journal of psychiatry. 156 (4): 660–61. PMID 10200754.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, Cleves MA (2007). "Tramadol HCL has Promise in On-Demand Use to Treat Premature Ejaculation". The Journal of Sexual Medicine. (OnlineEarly Articles): 070314061909001. doi:10.1111/j.1743-6109.2006.00424.x. PMID 17362279.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ a b [2]
  19. ^ United States National Library of Medicine
  20. ^ McDiarmid, Todd (2005-01-01). "What is the addiction risk associated with tramadol". Journal of Family Practice. 54 (1). Retrieved 2007-09-17. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  21. ^ a b c Adams, Edgar (May 2006). "A Comparison of the Abuse Liability of Tramadol, NSAIDs, and Hydrocodone in Patients with Chronic Pain" (PDF). Journal of Pain and Symptom Management. 31 (5): 465–76. doi:10.1016/j.jpainsymman.2005.10.006. Retrieved 2007-01-13. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  22. ^ Tramadol
  23. ^ King, Steven A. (2007-06-01). "NSAIDs and Cardiovascular Disease". Psychiatric Times. 24 (7). Retrieved 2007-08-01. {{cite journal}}: Check date values in: |date= (help)
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