tramadol (Ultram)
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Introduction
Tradename: Ultram. DEA class 4 agent as of Aug 18, 2014.
Indications
- treatment of chronic pain
- 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
Dosage
- immediate release
- extended release
Tabs: (immediate release) 50 mg
Tabs: (extended release) 100, 200, 300 mg
Dosage adjustment in renal failure
- indicated for creatinine clearance < 30 mL/min
- 50-100 mg BID (immediate release tabs)
- maximum 200 mg QD
- extended release tabs should not be used
Pharmacokinetics
- oral doses rapidly absorbed
- peak serum levels within 2-3 hours
- bioavailability 60% after a single oral dose, but approaches 100% with regular scheduled use
- protein binding 20%
- volume of distribution: 2.5-3 L/kg
- metabolism in the liver by cyt P450 2D6
- necessary for conversion to an active analgesic metabolite[3]
- 11 metabolites, only 1 is active
- t1/2 6.3 hours (parent), 7.4 hours active metabolite
- excreted in urine (30% as unchanged drug, 60% as metabolites)
elimination via liver
elimination via kidney
Adverse effects
- central nervous system
- drowsiness
- dizziness
- headache
- fatigue
- restlessness
- seizures[4][11]
- increased risk of dementia (RR=1.06 1-14 day use, 1.18 > 90 day use vs non use)[28]
- gastrointestinal (GI) system
- diaphoresis
- 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]
- low potential for producing psychological/physical dependence
- withdrawal symptoms may occur with abrupt discontinuation
- risk of suicide for patients who are addiction prone, or taking antidpressants or tranquilizers[7][8]
- increased risk of hospitalization for hypoglycemia[13]
- risk highest in 1st 30 days of treatment
- maximum absolute risk 0.03%[13]
- increased 1 year mortality in persons >= 50 years with osteoarthritis (RR=2.0)[19]
- pruritus through neurologic or histamine-release mechanisms[20]
- risks for long-term opiate use higher with postoperative tramadol than hydrocodone or oxycodone[21]
- higher risk of mortality, cardiovascular events, & fractures with tramadol than codeine[22]
- moderate anticholinergic effects[11]
- serotonin syndrome
- drug adverse effects of antidepressants
- drug adverse effects of opiates
- drug adverse effects of psychotropic agents
- drug adverse effects of sedatives
Drug interactions
- concurrent administration of antidepressants (especially tricyclic antidepressants, bupropion) may induce seizures
- coadministration with selective serotonin reuptake inhibitors SSRI may result in serotonin syndrome[16][23]
- any drug that inhibits cyt P450 2D6 may increase levels of tramadol &/or may interfere with analgesic effect
- coadministration of tranquilizers or antidepressants may increase risk of suicide[7]
- monitor closely if used in combination with benzodiazepine[22]
- drug interaction(s) of antidepressant in combination with GLP1-agonist
- drug interaction(s) of tramadol with SSRIs
- drug interaction(s) of triptans with SNRIs
- drug interaction(s) of methylene blue with SNRIs
- drug interaction(s) of linezolid with SNRIs
- drug interaction(s) of benzodiazepines with antidepressants
- drug interaction(s) of antidepressants with benzodiazepines
- drug interaction(s) of NSAIDs with antidepressants
- drug interaction(s) of benzodiazepine with opiates
- drug interaction(s) of antidepressant with opiates
- drug interaction(s) of Z-drugs with opiates
- drug interaction(s) of alcoholic beverage with opiates
- drug interaction(s) of pregabalin with opiates
- drug interaction(s) of gabapentin with opiates
Laboratory
- Therapeutic range: 100-300 ng/mL (monitoring not required)
Mechanism of action
- binds to opioid mu receptors in CNS
- inhibits ascending pain pathways
- alters perception & response to pain
- inhibits reuptake of norepinephrine & serotonin
- modifies ascending response pathway
More general terms
Additional terms
Component of
References
- ↑ Drugdex Drug Evaluation
- ↑ Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
- ↑ 3.0 3.1 Medications Can Cause Seizures Prescriber's Letter 10(3):16 2003 Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=190320&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 4.0 4.1 Department of Veterans Affairs, VA National Formulary
- ↑ 5.0 5.1 Prescriber's Letter 15(12): 2008 Common Oral Medications that May Need Tapering Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=241208&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Lexi-Comp, Inc 2009
- ↑ 7.0 7.1 7.2 FDA MedWatch Ultram (tramadol hydrochloride), Ultracet (tramadol hydrochloride/acetaminophen): Label Change http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm213264.htm
- ↑ 8.0 8.1 Prescriber's Letter 17(7): 2010 New Abuse and Safety Warnings for Tramadol Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260711&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Prescriber's Letter 19(3): 2012 Drug Interactions with Tramadol Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=280310&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 10.0 10.1 Deprecated Reference
- ↑ 11.0 11.1 11.2 11.3 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 - ↑ Prescriber's Letter 21(8): 2014 Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=300827&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 13.0 13.1 13.2 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25485799 <Internet> 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. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25486516 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1984243 - ↑ 14.0 14.1 14.2 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
- ↑ 15.0 15.1 Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
- ↑ 16.0 16.1 Paauw DS Dangerous and Deadly Drug Combinations Medscape. June 30, 2016 http://www.medscape.com/features/slideshow/dangerous-drug-combinations
- ↑ 17.0 17.1 17.2 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
- ↑ 18.0 18.1 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. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28700791 <Internet> http://jamanetwork.com/journals/jamapsychiatry/fullarticle/2642924
- ↑ 19.0 19.1 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: https://www.ncbi.nlm.nih.gov/pubmed/30860559 https://jamanetwork.com/journals/jama/article-abstract/2727448
- ↑ 20.0 20.1 Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
- ↑ 21.0 21.1 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: https://www.ncbi.nlm.nih.gov/pubmed/31088782 Free PMC Article https://www.bmj.com/content/365/bmj.l1849
- ↑ 22.0 22.1 22.2 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: https://www.ncbi.nlm.nih.gov/pubmed/34665205 https://jamanetwork.com/journals/jama/fullarticle/2785265
- ↑ 23.0 23.1 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: https://www.ncbi.nlm.nih.gov/pubmed/29752906 https://www.amjmed.com/article/S0002-9343(18)30402-9/fulltext
- ↑ tramadol (Rx) Classes: Opioid Analgesics https://reference.medscape.com/drug/ultram-conzip-tramadol-343324
- ↑ 25.0 25.1 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: https://www.ncbi.nlm.nih.gov/pubmed/34251756 https://onlinelibrary.wiley.com/doi/10.1002/acr.24750
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/26218943 Free article. Review. - ↑ 27.0 27.1 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: https://www.ncbi.nlm.nih.gov/pubmed/38580920 PMCID: PMC10996118 Free PMC article
- ↑ 28.0 28.1 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: https://www.ncbi.nlm.nih.gov/pubmed/39394390 PMCID: PMC11470146 Free PMC article. https://www.nature.com/articles/s41598-024-74817-3
Database
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- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=63013
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=63014