Clinical Notes : Pharmacology

178. Atypical Opioids : Tramadol


The atypical opioids Tramadol, Tapentadol and Buprenorphine (1)

  • Atypical opioids differ from conventional opioids as they do not rely exclusively on mu-receptor agonism for their analgesic effect.

  • The atypical opioids, buprenorphine, tramadol and tapentadol, have different effects and different adverse effects including toxicity and abuse potential compared with conventional opioids.


  • These differences result in improved outcomes and reduced risks with the use of atypical opioids for individual patients and society as a whole.


  • Atypical opioids are the preferred strong analgesics for chronic pain that requires pharmacological treatment.



  • Tramadol is currently the preferred atypical opioid for the treatment of neuropathic pain, osteoarthritis and cancer pain.

    • 50 mg orally (immediate-release) every 4-6 hours when required, maximum 400 mg/day

    • orally (extended-release) 100-300 mg once daily, maximum 300 mg/day

  • Tapentadol is currently the preferred atypical opioid for the treatment of chronic pain.

    • Palexia 50, 75, or 100 mg every 4 to 6 hours depending on the intensity of pain

    • On the first day, a second dose may be given 1 hour after the initial dose if pain relief is inadequate

    • subsequent doses should be given every 4 to 6 hours, adjusted according to response

    • maximum total dose of 700 mg on the first day and of 600 mg daily on subsequent days


  • Transdermal Buprenorphine is particularly suitable for use in the elderly.

    • Butrans Patch delivers buprenorphine in a range of 5 to 20 micrograms/hour

    • initial dosages should not exceed 5 micrograms/hour in all patients

    • patches should be replaced every 7 days with the new patch being applied to a different site; use of the same area of the skin should be avoided for the next 3 to 4 weeks.




Tramadol is the prototype of the atypical opioid and the first compound to be described with this label in the literature.(2)





In comparative trials with other opioids, tramadol had comparable analgesic efficacy to conventional mu-receptor agonists such as morphine, fentanyl and oxycodone.(3)

However, in clinical practice, it has limited efficacy partially due to a recommended maximum dose of 400 to 600mg daily.


Tramadol has been successfully used in patients with cancer pain as a step-two drug on the WHO ladder, as well as in those with chronic non-cancer pain, where it had also beneficial effects on physical function with reduced disability.(4)


In osteoarthritis specifically, tramadol improved pain scores and function to some extent.(5)


Tramadol is also an effective compound for the treatment of neuropathic pain (6)

It is the only opioid listed as a second-line treatment for neuropathic pain in the guidelines from the Special Interest Group on Neuropathic Pain.(7)



Advantages of tramadol are :

  • the risk of respiratory depression is significantly lower than with the conventional opioids oxycodone and pethidine at equianalgesic doses.(8) (18) (19)

    • However,  can cause respiratory depression, particularly with overdose, and fatalities have been reported, although the number of cases is very low.(9)


  • causes significantly less constipation than conventional opioids primarily due to a less inhibitory effect on gastrointestinal motor function.(10)


  • has been used successfully in opioid withdrawal and was found to be superior to clonidine and comparable with buprenorphine in reducing withdrawal symptoms.(11)



Adverse effects of Tramadol are due to its reliance on a metabolite for its mu-receptor agonist effects and its serotonergic component; these properties make the analgesic effect less reliable and cause a number of adverse effects and drug interactions :


  • Causes more seizures than conventional opioids, particularly with overdose.(9)


  • The serotonergic effects of tramadol lead to an increased risk of serotonergic reactions such as

    • an increased rate of nausea and vomiting in several comparative trials with other conventional opioids such as morphine, fentanyl and oxycodone.(3)

    • in rare cases serotonin syndrome, when combined with medications also having a serotonergic effect such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (M AOIs).(12) (20) (21) (22)


  • Interaction between tramadol and 5-HT(3) receptor antagonist antiemetics, described in particular for ondansetron, leads to reduced efficacy of both drugs.(13)


  • SSRIs that inhibit CYP2D6 such as sertraline, paroxetine or fluoxetine, lead to increased tramadol concentrations.(14)


  • An increased rate of confusion and delirium in elderly patients has also been described.(15)


Dependence, abuse potential and diversion


  • Tramadol can cause physical dependence, but with a lower incidence and lower severity of withdrawal symptoms than conventional opioids.(16)


  • Atypical withdrawal symptoms similar to those observed with SSRIs or SNRIs can occur.(17)


  • Although abuse of tramadol has been reported, the abuse potential is much lower than that of conventional opioids.(18)

cochrane library.jpg

1. Schug SA

The atypical opioids: buprenorphine, tramadol and tapentadol

MedicineToday : Conventional and Atypical Opioids Supplement September 2018


2. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL.

Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic.

J Pharmacol Exp Ther 1992; 260: 275-285.


3. Murphy JD, Yan D, Hanna MN, et al.

Comparison of the postoperative analgesic efficacy of intravenous patient-controlled analgesia with tramadol to intravenous patient-controlled analgesia with opioids.

J Opioid Manag 2010; 6: 141-147.


4. Leppert W.

Tramadol as an analgesic for mild to moderate cancer pain.

Pharmacol Rep 2009; 61: 978-992.


5. Cepeda MS, Camargo F, Zea C, Valencia L.

Tramadol for osteoarthritis: a systematic review and metaanalysis.

J Rheumatol 2007; 34: 543-555.


6. Hollingshead J, Duhmke RM, Cornblath DR.

Tramadol for neuropathic pain.

Cochrane Database Syst Rev 2006; (3): CD003726.


7. Finnerup NB, Attal N, Haroutounian S, et al.

Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

Lancet Neurol 2015; 14: 162-173.


8. Tarkkila P, Tuominen M, Lindgren L.

Comparison of respiratory effects of tramadol and oxycodone.

J Clin Anesth 1997; 9: 582-585.


9. Hassanian-Moghaddam H, Farajidana H, Sarjami S, Owliaey H.

Tramadol-induced apnea.

Am J Emerg Med 2013; 31: 26-31.


10. Grond S, Sablotzki A.

Clinical pharmacology of tramadol.

Clin Pharmacokinet 2004; 43: 879-923.


11. Dunn KE, Tompkins DA, Bigelow GE, Strain EC.

Efficacy of tramadol extended-release for opioid withdrawal: a randomized clinical trial.

JAMA Psychiatry 2017; 74: 885-893.


12. Tsutaoka BT, Ho RY, Fung SM, Kearney TE.

Comparative toxicity of tapentadol and tramadol utilizing data reported to the National Poison Data System.

Ann Pharmacother 2015; 49: 1311-1316.


13. Stevens AJ, Woodman RJ, Owen H.

The effect of ondansetron on the efficacy of postoperative tramadol: a systematic review and meta-analysis of a drug interaction.

Anaesthesia 2015; 70: 209-218.


14. Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R.

Trends in tramadol: pharmacology, metabolism, and misuse.

Anesth Analg 2017; 124: 44-51.


15. Kress HG.

Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine.

Eur J Pain 2009; 13: 219-230.


16. Radbruch L, Grond S, Lehmann KA.

A risk-benefit assessment of tramadol in the management of pain.

Drug Safety 1996; 15: 8-29.


17. Senay EC, Adams EH, Geller A, et al.

Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur.

Drug Alcohol Depend 2003; 69: 233-241.


18. Grond S, Sablotzki A.

Clinical pharmacology of tramadol.

Clin Pharmacokinet 2004; 43: 879-923.


19. Tarkkila P, Tuominen M, Lindgren L.

Comparison of respiratory effects of tramadol and pethidine.

J Anaesthesiol 1998; 15: 64-68.


20. Mildh LH, Leino KA, Kirvela OA.

Effects of tramadol and meperidine on respiration, plasma catecholamine concentrations, and hemodynamics. J Clin Anesth 1999; 11: 310-316.


21. Hassamal S, Miotto K, Dale W, Danovitch I.

Tramadol: understanding the risk of serotonin syndrome and seizures.

Am J Med 2018 May 10. pii: S0002-9343(18)30402-9. doi: 10.1016/j.amjmed.2018.04.025 [epub ahead of print].

22. Jick H, Derby L, Vasilakis C, Fife D.

The risk of seizures associated with tramadol.

Pharmacotherapy 1998; 18: 607-611.


23. Gasse C, Derby L, Vasilakis-Scaramozza C, Jick H.

Incidence of first-time idiopathic seizures in users of tramadol. Pharmacotherapy 2000; 20: 629-634.


Ireland notes.png

The following meds are available in Ireland :

Tramadol (Tradol, Tramadol HCL, Tramake, Tramapine, Xymel, Zydol)

Tapentadol (Palexia)

Transdermal Buprenorphine (Butrans, Transtec)


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