Tramadol (Ultram)

Based on "Essential Pain Pharmacology"
written by Howard S. Smith, MD; Marco Pappagallo, MD

History

Tramadol hydrochloride was invented by the pharmaceutical company Gruenenthal GmbH, located in Stollberg, Germany, in late 1970s. It was launched in Germany in 1977 as an oral immediate-release formulation under the brand name Tramal. Since then, various formulations containing tramadol hydrochloride have been launched in more than 100 countries worldwide.

Grunenthal, founded in 1946 is an independent, family-owned, research-based pharmaceutical company. It was the first company to engage in industrial production of penicillin and to commercialise it. Today analgesics are their main competence. Beside this Grunenthal is active in the marketing of oral contraceptives and the treatment of respiratory tract diseases 3.

In the U.S., immediate-release tramadol, is marketed under the brand name Ultram by Ortho-McNeil, a division of Johnson & Johnson. Ortho-McNeil's primary concentration is on the manufacturing and testing of drugs used to treat pain, acid reflux and infectious diseases.

On August 18, 2014, Tramadol has been scheduled as a Schedule IV substance.FDA approved indications

• management of moderate to moderately severe pain in adults

Tramadol is used to treat the following types of pain:

• dental pain
• osteoarthritis pain 4, 6
• neuropathic pain 17
• posttraumatic pain 11
• postoperative pain 19
• acute musculoskeletal pain
• post-caesarean section pain, labour pain, obstetrical analgesia 18, 33
• renal colic 22
• diabetic neuropathy 5, 20
• postherpetic neuralgia 21
• low back pain 7
• chronic pancreatitis pain 25
• rheumatoid arthritis pain

Off-label & Investigational uses

• premature ejaculation 16
• fibromyalgia 8, 15
• restless legs syndrome 30
• acute myocardial infarct 24
• opiate withdrawal management 27
• migraine headache 31
• opioid withdrawal 35

Tramadol for osteoarthritis
Tramadol may be a useful alternative in patients with osteoarthritis who have not responded to first-line treatment with acetaminophen and in whom nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated, ineffective, or poorly tolerated 6. It appears to be relatively well tolerated for an opioid compound.

Tramadol for postherpetic neuralgia
Tramadol appears to be an interesting therapeutic alternative for pain relief in postherpetic neuralgia, particularly in patients who are not depressed. Tramadol may be a choice for patients with obvious cardiovascular disease in whom antidepressants are contraindicated, and similarly in patients in whom an antidepressant effect is not required 21.

Tramadol for restless legs syndrome
Compared with other treatments for RLS, tramadol seems to be superior in some cases, possibly because of its unique pharmacodynamic profile. In clinical study 12 patients with RLS (some of them treatment resistant or prone to side effects of previous medications) were treated with 50 to 150 mg of tramadol per day. The follow-up lasted from 15 to 24 months. 10 patients reported clear amelioration and 1 reported slight amelioration of their symptoms, while 1 reported no effect. Tramadol was described to be the most effective treatment and free of side effects when compared with several other treatments 30.

Tramadol for fibromyalgia
Tramadol is effective in patients with mild to moderately severe pain. It should be titrated to avoid nausea and dizziness associated with high initial doses. A tramadol/acetaminophen (Ultracet) (37.5/325 mg) combination has been shown to be effective for fibromyalgia pain without any serious adverse effects 8.

Tramadol "pros" and "cons"

Advantages:

• Good tolerability
• Proven efficacy in a broad range of painful conditions
• Respiratory depression is less common and less pronounced than with other opioids 10
• Lesser constipation effect than with other opioids 26
• Withdrawal not considered to be as severe as that produced by other opioids
• Low abuse and dependence potential 29, 28, 34
• More effective than NSAIDs for controlling post operative pain
• Antidepressant-like (mood improving) activity 12
• Local anesthetic activity 14
• Devoid of immunosuppressive activity
• Reasonably priced - available generic formulation
• Helps for pain-induced anxiety

Disadvantages:

• Risk of seizures 23, particularly when tramadol is used other drugs that reduce the seizure threshold.
• Risk of abuse, dependence and tolerance.
• May cause serotonin syndrome when combined with serotonergic medications and medications that alter metabolism of tramadol.
• Relatively high incidence of nausea and vomiting
• Withdrawal symptoms following abrupt discontinuation 2
• Short half-life necessitates dosing of immediate-release formulation every 4 to 6 hours
• Variation of tramadol effects related to CYP2D6 polymorphism 37. Opioid analgesic activity of tramadol requires metabolism to an active metabolite O-desmethyltramadol via cytochrome P450 isoenzymes CYP2D6. So persons, who are "poor metabolizers" -- deficient in CYP2D6 activity, may not get adequate analgesic effect.
• Preliminary data suggests that beginning of tramadol therapy is associated with an increased risk of severe hypoglycemia38.

Mechanism of action

Tramadol is a 4-phenyl-piperidine analogue of codeine. Tramadol is a racemic mixture of 2 enantiomers -- one form is a selective μ agonist and inhibits serotonin reuptake, while the other mainly inhibits norepinephrine reuptake.

Tramadol has dual mechanism of action. The results of clinical studies suggest that tramadol-induced antinociception is mediated by opioid (µ, mu) and non-opioid (inhibition of re-uptake of norepinephrine and serotonin) mechanisms 9. There is evidence that, in tramadol, both mechanisms act synergistically with respect to analgesia.

Its major metabolite O-desmethyl tramadol (M1) has a weak affinity at µ-opioid receptors as an agonist. The monoaminergic activity comes through the two stereoisomers of tramadol itself, which act synergistically on serotonergic and noradrenergic mechanisms of pain transmission. More specifically, tramadol enhances spinal pain inhibitory pathways by inhibiting neuronal re-uptake of serotonin (5-HT) and noradrenaline (NA), and stimulating 5-HT release. This added monoaminergic component possibly allows tramadol’s efficacy to stretch over a wider range of painful pathologies than other opioids.

Opioid activity: Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to mu-opioid receptors.

Tramadol’s affinity for the mu-receptor is about 10 times weaker than that of codeine, 60 times weaker than that of dextropropoxyphene, and 6000 times weaker than that of morphine36. In animal models, its active active O-demethylated metabolite M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding.

Non-opioid activity: Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin. These mechanisms may contribute independently to the overall analgesic profile of tramadol.

Tramadol potency

Tramadol has a dose-dependent efficacy that lies between that of codeine and morphine, with a parenteral potency comparable to that of pethidine, i.e. about 10-20% of the gold standard morphine 33.

Time to clear out of the system

Tramadol half-life is 6.3 h and 7.4 h of the metabolite. It may take from 31 to 38 hours to clear out of the system.

Tramadol and its metabolites are mainly excreted via the kidneys.

Onset of action

The onset of analgesia begins approximately within one hour after administration and peaks within 2-3 hours.Duration of action

About 6 hours.

Tramadol and alcohol

Tramadol increases the risk of CNS and respiratory depression when used with alcohol.

Tramadol withdrawal and how to go off

Withdrawal symptoms may occur if tramadol is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, nausea, tremors, diarrhea, chills, piloerection, and rarely hallucinations. Other discontinuation symptoms that have been seen less frequently include panic attacks, severe anxiety, and paresthesias. Withdrawal symptoms may be avoided by tapering tramadol at the time of discontinuation.

Abrupt cessation from tramadol has been associated with two types of withdrawal syndromes 2:

• Opioid-like withdrawal is typical of opioid drugs with flu-like symptoms, restlessness and drug craving. This type is encountered in about 90% of cases of withdrawal from tramadol.
• Atypical withdrawal syndrome (encountered in about 10% of cases of tramadol withdrawal) is atypical of opioids and is associated with hallucinations, paranoia, extreme anxiety, panic attacks, confusion, and numbness and tingling in the extremities.

Further reading

• Tramadol vs Hydrocodone (Vicodin®, Lortab®, Norco®)
• Tramadol vs Ketorolac
• Tramadol vs Oxycodone
• Tramadol vs Tapentadol

References

• 1. Physicians’ Desk Reference, 59th ed; Thomson PDR: Montvale, NJ; 2005.
• 2. Senay EC, Adams EH, Geller A, Inciardi JA, Mun~oz A, Schnoll SH, Woody GE, Cicero TJ. Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend. 2003 Apr 1;69(3):233-41. PubMed
• 3. Grunenthal GmbH
• 4. Katz WA. Pharmacology and clinical experience with tramadol in osteoarthritis. Drugs. 1996;52 Suppl 3:39-47. PubMed
• 5. Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu CO, Kamin M. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998 Jun;50(6):1842-6.
• 6. Malonne H , Coffiner M, Sonet B, Sereno A, Vanderbist F. Efficacy and tolerability of sustained-release tramadol in the treatment of symptomatic osteoarthritis of the hip or knee: a multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2004 Nov;26(11):1774-82. PubMed
• 7. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. J Rheumatol. 2000 Mar;27(3):772-8. PubMed
• 8. Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med. 2003 May;114(7):537-45. PubMed
• 9. 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 Jan;260(1):275-85.
• 10. Vickers MD, O'Flaherty D, Szekely SM, Read M, Yoshizumi J. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia. 1992 Apr;47(4):291-6.
• 11. Vergnion M, Degesves S, Garcet L, Magotteaux V. Tramadol, an alternative to morphine for treating posttraumatic pain in the prehospital situation. Anesthesia & Analgesia. 2001 Jun;92(6):1543-6. PubMed
• 12. Tayal V, Kalra BS, Chawla S. Evaluation of antidepressant activity of tramadol in mice. Indian J Pharmacol. 2008 Jun;40(3):129-30.
• 14. Pang WW, Huang PY, Chang DP, Huang MH. The peripheral analgesic effect of tramadol in reducing propofol injection pain: a comparison with lidocaine. Reg Anesth Pain Med. 1999 May-Jun;24(3):246-9. PubMed
• 15. Biasi G, Manca S, Manganelli S, Marcolongo R. Tramadol in the fibromyalgia syndrome. Int J Clin Pharmacol Res. 1998;18(1):13-9.
• 16. Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study. J Clin Psychopharmacol. 2006 Feb;26(1):27-31. PubMed
• 17. Sindrup SH, Andersen G, Madsen C, Smith T, Br?sen K, Jensen TS. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain. 1999 Oct;83(1):85-90. PubMed
• 18. Viegas OA, Khaw B, Ratnam SS. Tramadol in labour pain in primiparous patients. Eur J Obstet Gynecol Reprod Biol. 1993 May;49(3):131-5. PubMed
• 19. Sunshine A, Olson NZ, Zighelboim I, DeCastro A, Minn FL. Analgesic oral efficacy of tramadol hydrochloride in postoperative pain. Clin Pharmacol Ther. 1992 Jun;51(6):740-6.
• 20. Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, Donofrio P, Cornblath D, Olson WH, Kamin M. Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications. 2000 Mar-Apr;14(2):65-70. PubMed
• 21. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain. 2003 Jul;104(1-2):323-31. PubMed
• 22. Mortelmans LJ, Desruelles D, Baert JA, Hente KR, Tailly GG. Tramadol drip in controlling renal colic pain. J Endourol. 2006 Dec;20(12):1010-5.
• 23. Ripple MG, Pestaner JP, Levine BS, Smialek JE. Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol. 2000;21(4):370–374.
• 24. Fejfar Z, Vrana J. Self-care in the prevention of sudden cardiac death. Vnitr Lek. 1992 Oct;38(10):937-44. PubMed
• 25. Wilder-Smith CH, Hill L, Osler W, O'Keefe S. Effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis. Dig Dis Sci. 1999;44:1107–1116. doi: 10.1023/A:1026607703352. PubMed
• 26. Freye E, Rosenkranz B, Neruda B. Constipation after tilidine/naloxone and tramadol in comparison to codeine. A dose response study in human volunteers. Schmerz. 1996 Oct 28;10(5):254-60. PubMed
• 27. Sobey PW, Parran TV, Grey SF, Adelman CL, Yu J. The use of tramadol for acute heroin withdrawal. J Addict Dis. 2003;22(4):13-25. PubMed
• 28. Adams EH, Breiner S, Cicero TJ, Geller A, Inciardi JA, Schnoll SH, Senay EC, Woody GE. A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain. J Pain Symptom Manage. 2006 May;31(5):465-76. PubMed
• 29. Das M, Jain R, Dhawan A, Kaur A. Assessment of abuse liability of Tramadol among experienced drug users: Double-blind crossover randomized controlled trial. J Opioid Manag. 2016 Nov/Dec;12(6):421-430. PubMed
• 30. Lauerma H, Markkula J. Treatment of restless legs syndrome with tramadol: an open study. J Clin Psychiatry. 1999 Apr;60(4):241-4. PubMed
• 31. Alemdar M, Pekdemir M, Selekler HM. Single-dose intravenous tramadol for acute migraine pain in adults: a single-blind, prospective, randomized, placebo-controlled clinical trial. Clin Ther. 2007 Jul;29(7):1441-7. PubMed
• 32. Tamaskar R, Parran TV, Heggi A, Brateanu A, Rabb M, Yu J. Tramadol versus buprenorphine for the treatment of opiate withdrawal: a retrospective cohort control study. J Addict Dis. 2003;22(4):5-12. PubMed
• 33. Bredow V. Use of tramadol versus pethidine versus denaverine suppositories in labor--a contribution to noninvasive therapy of labor pain. Zentralbl Gynakol. 1992;114(11):551-4. PubMed
• 34. Cami J, Lamas X, Farre M. Acute effects of tramadol in methadone-maintained volunteers. Drugs. 1994;47 Suppl 1:39-43. PubMed
• 35. Tamaskar R, Parran TV Jr, Heggi A, Brateanu A, Rabb M, Yu J. Tramadol versus buprenorphine for the treatment of opiate withdrawal: a retrospective cohort control study. J Addict Dis. 2003;22(4):5-12. PubMed
• 36. Hennies HH, Friderichs E, Schneider J. Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung. 1988;38:877-880.
• 37. Halling J, Weihe P, Brosen K. CYP2D6 polymorphism in relation to tramadol metabolism: a study of faroese patients. Ther Drug Monit. 2008 Jun;30(3):271-5. PubMed
• 38. Fournier JP, Azoulay L, Yin H, Montastruc JL, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015 Feb;175(2):186-93. PubMed
• 39. Kathwate GH, Karuppayil SM. Tramadol, an Opioid Receptor Agonist: An Inhibitor of Growth, Morphogenesis, and Biofilm Formation in the Candida albicans. Assay Drug Dev Technol. 2016 Dec;14(10):567-572. PubMed

Published: March 31, 2008
Last updated: Januaty 24, 2017