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Practice

Tramadol

James W.S. Young and David N. Juurlink
CMAJ May 14, 2013 185 (8) E352; DOI: https://doi.org/10.1503/cmaj.121592
James W.S. Young
From the Department of Medicine (Young), University Health Network; the Institute for Clinical Evaluative Sciences (Juurlink); and the Department of Medicine (Juurlink), Sunnybrook Health Sciences Centre, Toronto, Ont.
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  • For correspondence: jimmy.young@utoronto.ca
David N. Juurlink
From the Department of Medicine (Young), University Health Network; the Institute for Clinical Evaluative Sciences (Juurlink); and the Department of Medicine (Juurlink), Sunnybrook Health Sciences Centre, Toronto, Ont.
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Tramadol is an analgesic with 2 postulated mechanisms of action

Similar to venlafaxine, tramadol augments serotonergic and noradrenergic neurotransmission, although its main active metabolite, O-desmethyltramadol (M1), is an opioid. Both mechanisms of action are thought to contribute to tramadol’s analgesic effects.1

Tramadol’s metabolism is variable and unpredictable

Conversion of tramadol to M1 is catalyzed by the highly polymorphic cytochrome P450 isoenzyme 2D6 (CYP2D6), the same enzyme responsible for converting codeine to its active metabolite, morphine. People with the “poor metabolizer” phenotype have absent or reduced CYP2D6 activity and form less opioid metabolite for a given dose, which results in less analgesia.1 The same is true of patients receiving medications that inhibit CYP2D6, such as paroxetine and bupropion. Conversely, patients exhibiting the “ultra-rapid metabolizer” phenotype are particularly prone to tramadol’s opioid-like effects.1 The prevalence of these phenotypes varies by ethnic background (Appendix 1, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.121592/-/DC1) and is expected to be widely divergent between ethnic groups in Canada.

Tramadol is a modestly effective analgesic

Canadian guidelines suggest tramadol or codeine as the first-line agent for mild to moderate pain.2 Tramadol has been shown to be modestly effective for osteoarthritis-related pain in placebo-controlled trials.3 In patients with neuropathic pain, tramadol’s efficacy is comparable to that of gabapentin, tricyclic antidepressants and carbamazepine.4

Opioid dependence, withdrawal and toxicity may occur with tramadol use

Canadian guidelines suggest that the risk of addiction is lower with tramadol than with other opioids.2 However, this risk depends on genotype; tramadol abuse is well described in some Middle Eastern countries,5 where the CYP2D6 ultra-rapid metabolizer phenotype is prevalent (Appendix 1). Opioid withdrawal is common following chronic tramadol use.6 As with conventional opioids, tramadol has been linked to apnea and death.5 Despite being metabolized to an opioid, tramadol is not scheduled in the Canadian Controlled Drugs and Substances Act.

Other toxic effects include seizures and serotonin syndrome

Generalized seizures and serotonin syndrome can occur with tramadol use, sometimes with modest doses, and particularly when the drug is combined with other serotonergic or proconvulsant agents such as antidepressants.1,5

CMAJ invites submissions to “Five things to know about …” Submit manuscripts online at http://mc.manuscriptcentral.com/cmaj

References

  1. ↵
    1. Leppert W
    . CYP2D6 in the metabolism of opioids for mild to moderate pain. Pharmacology 2011;87: 274–85.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Kahan M,
    2. Mailis-Gagnon A,
    3. Wilson L,
    4. et al
    . Canadian guideline for safe and effective use of opioids for chronic noncancer pain; clinical summary for family physician. Part 1: general population. Can Fam Physician 2011;57:1257–66.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Cepeda MS,
    2. Camargo F,
    3. Zea C,
    4. et al
    . Tramadol for osteoarthritis [review]. Cochrane Database Syst Rev 2006;(3):CD005522.
  4. ↵
    1. Duehmke RM,
    2. Hollingshead J,
    3. Cornblath DR
    . Tramadol for neuropathic pain [review]. Cochrane Database Syst Rev 2006;(3):CD003726.
  5. ↵
    1. Hassanian-Moghaddam H,
    2. Farajidana H,
    3. Sarjami S,
    4. et al
    . Tramadol-induced apnea. Am J Emerg Med 2013;31:26–31.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Senay EC,
    2. Adams EH,
    3. Geller A,
    4. et al
    . Physical dependence on Ultram® (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend 2003;69:233–41.
    OpenUrlCrossRefPubMed
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Canadian Medical Association Journal: 185 (8)
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Vol. 185, Issue 8
14 May 2013
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Tramadol
James W.S. Young, David N. Juurlink
CMAJ May 2013, 185 (8) E352; DOI: 10.1503/cmaj.121592

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James W.S. Young, David N. Juurlink
CMAJ May 2013, 185 (8) E352; DOI: 10.1503/cmaj.121592
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    • Tramadol is an analgesic with 2 postulated mechanisms of action
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    • Other toxic effects include seizures and serotonin syndrome
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