Tramadol HCL (Ultram) for Pain

• Generic name: Tramadol Hydrochloride
• Brand/Trade names: Ultram
• Dosages: 50 mg tablets
• Pharmacologic category: Central analgesic
• FDA approved: March 03, 1995
• Manufacturer: Ortho-McNeil
• Habit forming? Yes
• Pregnancy risk factor: C

Tramadol Hydrochloride, a synthetic opioid of the aminocyclohexanol group, is a centrally acting analgesic with weak opioid agonist properties, and effects on noradrenergic and serotonergic neurotransmission. Although Tramadol is a synthetic analog of codeine, it has a significantly lower affinity for opioid receptors than codeine. The drug is available in formulations suitable for oral, rectal and parenteral administration. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration.

Tramadol has been in clinical use in Germany since the late 1970s. After FDA approval in 1995 Tramadol became available in the US under the brand name Ultram.

The most frequently reported adverse effects are nausea, vomiting, dizziness, drowsiness, tiredness, sweating and dry mouth [2].

It is not classified as a controlled substance in the United States.

• Metabolism: Extensively hepatic via demethylation, glucuronidation, and sulfation; has pharmacologically active metabolite formed by CYP2D6 (M1; O-desmethyl tramadol)
• Elimination half-life: 6.3 h
• Excretion: Tramadol and its metabolites are mainly excreted via the kidneys; 30% of a dose is excreted unchanged in urine; 60% is excreted as metabolites.

• low serious side-effect potential
• low respiratory depressant effect [4]
• produce less constipation constipation, than other opioids [12]
• minor cardiovascular side effects [14]
• low dependence and abuse potential [16]
• more effective than NSAIDs for controlling severe pain
• more appropriate than NSAIDs for patients suffering from gastrointestinal and renal problems
• potential antidepressant efficacy [5]
• effective treatment for neuropathic pain [8]
• provides long-term relief of the pain of diabetic neuropathy [9]
• appears to be more effective than other opioids for neuropathic pain
• well tolerated alternative drug for osteoarthritis pain [10]

• high incidence of nausea and vomiting [13]
• possibility of dependence with long term use cannot be entirely excluded
• potential to induce withdrawal of the classical opioid type, and that atypical withdrawal [3]
• can cause seizures when taken in overdose or in combination with serotonergic medications [11]

• premature ejaculation [17]
• fibromyalgia syndrome [6]
• heroin withdrawal [15]
• migraine [18]

Tramadol has a dual mechanism of action: weak mu opioid receptor agonist and a reuptake inhibitor of serotonin and noradrenaline.

The analgesic effect of tramadol is mediated through two distinct but complementary mechanisms of action.

Binds to certain opioid receptors and inhibits reuptake of norepinephrine and serotonin.

Binds to mu-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain; also inhibits the reuptake of norepinephrine and serotonin, which also modifies the ascending pain pathway

Tramadol is a novel analgesic having both opiate agonist activity and monoamine reuptake inhibition that contribute to its analgesic efficacy. Opioid activity is due to both the parent compound and the more active O-desmethylated metabolite. Tramadol acts on the monoamine reuptake systems by inhibiting the reuptake into nerve terminals of both norepinephrine and serotonin.

Tramadol will not produce a positive GC/MS urine test.

• Can Tramadol cause a false-positive drug test and show up in GC/MS test? http://www.netwellness.org/question.cfm/46734.htm
• Pharmaceuticals that can cause positive urine test results using GC/MS confirmation: http://www.norchemlab.com/drugreferences/dt_pharmpos.html

• Ultram / Ultracet / Tramadol discussion: http://www.drugs.com/forum/featured-drugs/ultram-ultracet-tramadol-22123.html
• Tramadol (Ultram) withdrawal:
• Ultram withdrawls: http://www.drugs.com/forum/featured-drugs/ultram-withdrawls-39150.html
• Stopping Ultram ER: http://messageboard.spine-health.com/viewtopic.php?id=15406

• 1. U.S. Food and Drug Administration. Tramadol (Ultram) U.S. Prescribing Information
• 2. Cossmann M, Kohnen C, Langford R, McCartney C. Tolerance and safety of tramadol use. Results of international studies and data from drug surveillance. Drugs. 1997;53 Suppl 2:50-62.
• 3. 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
• 4. 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. PubMed
• 5. Rojas-Corrales MO, Berrocoso E, Gibert-Rahola J, Mico' JA. Antidepressant-like effect of tramadol and its enantiomers in reserpinized mice: comparative study with desipramine, fluvoxamine, venlafaxine and opiates. J Psychopharmacol. 2004 Sep;18(3):404-11. SagePub
• 6. Biasi G, Manca S, Manganelli S, Marcolongo R. Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo. Int J Clin Pharmacol Res. 1998;18(1):13-9.
• 7. 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
• 8. Duhmke RM, Cornblath DD, Hollingshead JR. Tramadol for neuropathic pain. Cochrane Database Syst Rev. 2004;(2):CD003726.
• 9. 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
• 10. 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
• 11. 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.
• 12. Crighton IM, Martin PH, Hobbs GJ, Cobby TF, Fletcher AJ, Stewart PD. A comparison of the effects of intravenous tramadol, codeine, and morphine on gastric emptying in human volunteers. Anesth Analg. 1998 Aug;87(2):445-9.
• 13. Hopkins D, Shipton EA, Potgieter D, Van derMerwe CA, Boon J, De Wet C, Murphy J. Comparison of tramadol and morphine via subcutaneous PCA following major orthopaedic surgery. Can J Anaesth. 1998 May;45(5 Pt 1):435-42.
• 14. Ellmauer S, Dick W, Otto S, Mu"ller H. Different opioids in patients at cardiovascular risk. Comparison of central and peripheral hemodynamic adverse effects. Anaesthesist. 1994 Nov;43(11):743-9.
• 15. Threlkeld M, Parran TV, Adelman CA, Grey SF, Yu J. Tramadol versus buprenorphine for the management of acute heroin withdrawal: a retrospective matched cohort controlled study. Am J Addict. 2006 Mar-Apr;15(2):186-91. PubMed
• 16. Cami J, Lamas X, Farre M. Acute effects of tramadol in methadone-maintained volunteers. Drugs. 1994;47 Suppl 1:39-43.
• 17. 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
• 18. Engindeniz Z, Demircan C, Karli N, Armagan E, Bulut M, Aydin T, Zarifoglu M. Intramuscular tramadol vs. diclofenac sodium for the treatment of acute migraine attacks in emergency department: a prospective, randomised, double-blind study. J Headache Pain. 2005 Jun;6(3):143-8.