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tramadol (Ultram)

Tradename: Ultram. DEA class 4 agent as of Aug 18, 2014. Indications: - treatment of chronic pain - osteoarthritis* - fibromyalgia [10] - opiate abuse ? [18] - extended-release tramadol may help reduce symptoms of opiate withdrawal * minimal benefit with significant adverse effects in treatment of knee osteoarthritis or hip osteoarthritis [25] * no fewer serious adverse effects than oxcodone or hydrocodone for treatment of postoperative pain after hip arthroplasty or knee arthroplasty [27] Contraindications: - Caution: - avoid in opioid-dependent individuals - avoid in patients with history of seizures [11] - children & adolecents, especially after tonsillectomy [14,17] - lactation [17] Dosage: 1) immediate release a) 50-100 mg PO every 4-6 hours, max 400 mg/day b) elderly (< 75 years): 50 mg every 6 hours, max 300 mg/day 2) extended release a) QD dosing, maximum 300 mg/day b) use with caution in the elderly Tabs: (immediate release) 50 mg Tabs: (extended release) 100, 200, 300 mg Pharmacokinetics: 1) oral doses rapidly absorbed 2) peak serum levels within 2-3 hours 3) bioavailability 60% after a single oral dose, but approaches 100% with regular scheduled use 4) protein binding 20% 5) volume of distribution: 2.5-3 L/kg 6) metabolism in the liver by cyt P450 2D6 a) necessary for conversion to an active analgesic metabolite [3] b) 11 metabolites, only 1 is active 7) t1/2 6.3 hours (parent), 7.4 hours active metabolite 8) excreted in urine (30% as unchanged drug, 60% as metabolites) Dosage adjustment in renal failure: - indicated for creatinine clearance < 30 mL/min a) 50-100 mg BID (immediate release tabs) b) maximum 200 mg QD c) extended release tabs should not be used Adverse effects: 1) central nervous system a) drowsiness b) dizziness c) headache d) fatigue e) restlessness f) seizures [4,11] g) increased risk of dementia (RR=1.06 1-14 day use, 1.18 > 90 day use vs non use) [28] 2) gastrointestinal (GI) system a) nausea/vomiting b) constipation c) dry mouth 3) diaphoresis 4) minimal respiratory depression - dyspnea may be significant in children & adolescents post- tonsillectomy [14] - MKSAP17 presents a case of respiratory depression due to tramadol in a 76 year old woman [15] 5) low potential for producing psychological/physical dependence 6) withdrawal symptoms may occur with abrupt discontinuation a) anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, hallucinations (rarely). b) no specific taper recommendations [5] 7) risk of suicide for patients who are addiction prone, or taking antidpressants or tranquilizers [7,8] 8) increased risk of hospitalization for hypoglycemia [13] - risk highest in 1st 30 days of treatment - maximum absolute risk 0.03% [13] 9) increased 1 year mortality in persons >= 50 years with osteoarthritis (RR=2.0) [19] 10) pruritus through neurologic or histamine-release mechanisms [20] 11) risks for long-term opiate use higher with postoperative tramadol than hydrocodone or oxycodone [21] 12) higher risk of mortality, cardiovascular events, & fractures with tramadol than codeine [22] 13) moderate anticholinergic effects [11] 14) serotonin syndrome Drug interactions: 1) concurrent administration of antidepressants (especially tricyclic antidepressants, bupropion) may induce seizures 2) coadministration with selective serotonin reuptake inhibitors SSRI may result in serotonin syndrome [16,23] 3) any drug that inhibits cyt P450 2D6 may increase levels of tramadol &/or may interfere with analgesic effect 4) coadministration of tranquilizers or antidepressants may increase risk of suicide [7] 5) monitor closely if used in combination with benzodiazepine [22] Laboratory: - Therapeutic range: 100-300 ng/mL (monitoring not required) Mechanism of action: 1) binds to opioid mu receptors in CNS a) inhibits ascending pain pathways b) alters perception & response to pain 2) inhibits reuptake of norepinephrine & serotonin - modifies ascending response pathway

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)

General

opioid receptor agonist (narcotic) serotonin & norepinephrine reuptake inhibitor (SNRI, dual-acting reuptake inhibitor)

Properties

MISC-INFO: elimination route LIVER KIDNEY pregnancy-category C safety in lactation -

Database Correlations

PUBCHEM correlations

References

  1. Drugdex Drug Evaluation
  2. Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
  3. Medications Can Cause Seizures Prescriber's Letter 10(3):16 2003 Detail-Document#: 190320 (subscription needed) http://www.prescribersletter.com
  4. Department of Veterans Affairs, VA National Formulary
  5. Prescriber's Letter 15(12): 2008 Common Oral Medications that May Need Tapering Detail-Document#: 241208 (subscription needed) http://www.prescribersletter.com
  6. Lexi-Comp, Inc 2009
  7. FDA MedWatch Ultram (tramadol hydrochloride), Ultracet (tramadol hydrochloride/acetaminophen): Label Change http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm213264.htm
  8. Prescriber's Letter 17(7): 2010 New Abuse and Safety Warnings for Tramadol Detail-Document#: 260711 (subscription needed) http://www.prescribersletter.com
  9. Prescriber's Letter 19(3): 2012 Drug Interactions with Tramadol Detail-Document#: 280310 (subscription needed) http://www.prescribersletter.com
  10. Deprecated Reference
  11. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  12. Prescriber's Letter 21(8): 2014 Detail-Document#: 300827 (subscription needed) http://www.prescribersletter.com
  13. Fournier JP et al Tramadol Use and the Risk of Hospitalization for Hypoglycemia in Patients With Noncancer Pain. JAMA Intern Med. Published online December 08, 2014 PMID: 25485799 http://archinte.jamanetwork.com/article.aspx?articleid=1984249 - Nelson LS, Juurlink DN Tramadol and HypoglycemiaOne More Thing to Worry About. JAMA Intern Med. Published online December 08, 2014. PMID: 25486516 http://archinte.jamanetwork.com/article.aspx?articleid=1984243
  14. FDA Safety Alert Tramadol: Drug Safety Communication - FDA Evaluating Risks of Using in Children Aged 17 and Younger http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm463499.htm
  15. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  16. Paauw DS Dangerous and Deadly Drug Combinations Medscape. June 30, 2016 http://www.medscape.com/features/slideshow/dangerous-drug-combinations
  17. FDA Safety Alert. 04/20/2017 Codeine and Tramadol Medicines: Drug Safety Communication - Restricting Use in Children, Recommending Against Use in Breastfeeding Women. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm554029.htm
  18. Dunn KE, Tompkins A, Bigelow GE et al Efficacy of Tramadol Extended-Release for Opioid Withdrawal. A Randomized Clinical Trial. JAMA Psychiatry. Published online July 12, 2017. PMID: 28700791 http://jamanetwork.com/journals/jamapsychiatry/fullarticle/2642924
  19. Zeng C, Dubreuil M, LaRochelle MR et al Association of Tramadol With All-Cause Mortality Among Patients With Osteoarthritis. JAMA. 2019;321(10):969-982. PMID: 30860559 https://jamanetwork.com/journals/jama/article-abstract/2727448
  20. Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
  21. Thiels CA, Habermann EB, Hooten WM, Jeffery MM. Chronic use of tramadol after acute pain episode: Cohort study. BMJ 2019 May 14; 365:l1849 PMID: 31088782 Free PMC Article https://www.bmj.com/content/365/bmj.l1849
  22. Xie J, Strauss VY, Martinez-Laguna D et al Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes. JAMA. 2021;326(15):1504-1515 PMID: 34665205 https://jamanetwork.com/journals/jama/fullarticle/2785265
  23. Hassamal S, Miotto K, Dale W et al. Tramadol: understanding the risk of serotonin syndrome and seizures. Am J Med. 2018;131(11):1382.e1-1382.e6. PMID: 29752906 https://www.amjmed.com/article/S0002-9343(18)30402-9/fulltext
  24. tramadol (Rx) Classes: Opioid Analgesics https://reference.medscape.com/drug/ultram-conzip-tramadol-343324
  25. Zhang X et al. Efficacy and safety of tramadol for knee or hip osteoarthritis: A systematic review and network meta-analysis of randomized controlled trials. Arthritis Care Res (Hoboken) 2023 Jan; 75:158. PMID: 34251756 https://onlinelibrary.wiley.com/doi/10.1002/acr.24750
  26. NEJM Knowledge+ Pain Management and Opioids: Recharge - Beakley BD, Kaye AM, Kaye AD. Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review. Pain Physician. 2015 Jul-Aug;18(4):395-400. PMID: 26218943 Free article. Review.
  27. Bosco E, Riester MR, Beaudoin FL et al Comparative Safety of Tramadol and Other Opioids Following Total Hip and Knee Arthroplasty. BMC Geriatr. 2024 Apr 5;24(1):319 PMID: 38580920 PMCID: PMC10996118 Free PMC article
  28. Oh SN, Kim HJ, Shim JY et al Tramadol use and incident dementia in older adults with musculoskeletal pain: a population-based retrospective cohort study. Sci Rep. 2024 Oct 11;14(1):23850. PMID: 39394390 PMCID: PMC11470146 Free PMC article. https://www.nature.com/articles/s41598-024-74817-3

Component-of

acetaminophen/tramadol (Ultracet)