Tramadol - Index

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • Jan. 2022; Nov. 2019; Dec. 2017; Feb. 2016; June 2014; Sept. 2012; Jan. 2011; April 2008; Nov. 2003; Oct. 2002; Nov. 2001; Oct. 2000; Dec. 1999; Nov. 1998; Nov. 1997; Dec. 1996.   
  • Initially developed
    • Nov. 1995

1. Dosage

Tramadol has a nationwide classification as a Schedule IV controlled substance as of August 18, 2014. Key factors contributing to this decision include its potential for abuse and dependence, as well as its link to emergency room visits and deaths related to overdoses1.

1.1. Adults

Tramadol is a centrally acting, opioid-type analgesic that acts as a mu-opioid receptor agonist and a weak inhibitor of serotonin and norepinephrine reuptake. The immediate-release (IR) formulation is FDA-approved for use in the management of acute or chronic moderate to moderately severe pain in adults2-4. Tramadol extended-release (ER) is FDA-approved for use in managing chronic moderate to moderately severe pain in patients requiring continuous pain management2,3,5. The tramadol/acetaminophen combination is FDA-approved for the acute (less than 5 days) management of acute pain2,3,6. Following a titration phase, recommended IR tramadol regimens for pain management include doses of 50 mg to 100 mg administered every 4 to 6 hours as needed. For tramadol ER, the recommended initial dose in tramadol IR-naïve patients is 100 mg once daily, titrated every five days in 100 mg increments until pain relief is achieved. For those patients already managed on tramadol IR, the 24-hour dose should be calculated, and the total daily tramadol ER dose should be rounded down to the closest 100 mg increment. The recommended dose for tramadol in combination with acetaminophen is 2 tablets every 4 to 6 hours as needed for pain relief2-6. Maximum recommended doses for tramadol alone and in combination with acetaminophen are summarized in Tables 1 and 2. Dosages exceeding these recommendations will be reviewed.

Table 1: Maximum Recommended Adult Oral Tramadol Dosages: Monotherapy2-5
Drug Name Dosage Forms/Strengths Maximum Recommended Dose
tramadol immediate-release (Ultram®, generics) 50 mg tablets

400 mg/day, in divided doses every 4-6 hours

elderly*: 300 mg/day, in divided doses every 4-6 hours
tramadol extended-release (generics) 100 mg, 200 mg, 300 mg tablets 300 mg/day in single daily doses
tramadol extended-release (ConZip®, generics) 100 mg, 150 mg, 200 mg, 300 mg capsules 300 mg/day in single daily doses

Legend

  • * = greater than 75 years of age
Table 2: Maximum Recommended Adult Oral Tramadol Dosages: Combination Therapy2,3,6
Drug Name Dosage Forms/Strengths Maximum Recommended Dose
tramadol/acetaminophen (Ultracet®, generics) 37.5 mg/325 mg tablets 300 mg/2600 mg per day (8 tablets per day), in divided doses every 4-6 hours

 

1.1.1. Elderly Patients

Tramadol dosages exceeding 300 mg per day in elderly patients over 75 years of age are not recommended and will be reviewed. In controlled clinical trials, treatment-limiting adverse events were higher in patients over 75 years of age compared to those less than 65 years of age2-7.

1.1.2. Dosing in Renal and Hepatic Impairment

In patients with a creatinine clearance less than 30 mL/min, the recommended dosing interval for tramadol IR is every 12 hours and the maximum recommended tramadol dose is 200 mg per day. In patients with cirrhosis, the recommended tramadol IR dose is 50 mg every 12 hours. Tramadol ER should not be given to patients with a creatinine clearance less than 30 mL/min or those with severe hepatic impairment. The tramadol/acetaminophen combination should be dosed as 2 tablets every 12 hours in patients with a creatinine clearance less than 30 mL/min and should not be used in patients with hepatic impairment2-6,8.

1.2. Pediatrics

Tramadol IR is FDA-approved for use to manage acute and chronic moderate to moderately severe pain in adolescents 17 years of age and older. Following a titration phase, recommended IR tramadol regimens for pain management include doses of 50 mg to 100 mg administered every 4 to 6 hours as needed. Tramadol ER and tramadol/acetaminophen combination therapy are not FDA-approved for use in pediatric patients as safety and efficacy have not been established and the potential exists for an increased risk of fatal respiratory depression. Pediatric tramadol dosages are summarized in Table 3.

Table 3: Maximum Recommended Pediatric Oral Tramadol Dosages: Monotherapy2-6
Drug Name Dosage Forms/Strengths Maximum Recommended Dose
tramadol immediate-release (Ultram®, generics) 50 mg tablets

Greater than 17 years of age:

400 mg/day, in divided doses every 4-6 hours

2. Duration of Therapy

There is no basis for limiting the duration of tramadol therapy as tramadol is promoted for use in chronic pain (e.g., chronic musculoskeletal pain, cancer pain, osteoarthritis, diabetic neuropathy) as well as acute pain events (e.g., postoperative pain, dental extraction pain). However, cases of tramadol abuse and dependence have been reported, especially in patients with a history of substance abuse. Therefore, tramadol should be administered cautiously, if at all, to patients with a history of drug or alcohol abuse and/or dependence.

The tramadol/acetaminophen combination is indicated for use in the short-term management of acute pain and should be limited to five days or less of use. Patient profiles containing tramadol/acetaminophen prescriptions exceeding this treatment duration will be reviewed2-6, 9-23.

3. Duplicative Therapy

Adjunctive administration of multiple tramadol dosage forms may result in significant additive adverse events, including respiratory depression, seizures, and serotonin syndrome. Combined administration of multiple tramadol dosage forms is not recommended and will be reviewed.

Opioid analgesics may enhance the sedative effects as well as other central effects of tramadol. Therefore, the use of tramadol in conjunction with opioid analgesics is recommended cautiously. If tramadol is used concomitantly with another agent that acts upon the central nervous system, the tramadol dosage should be reduced.

Use of tramadol in conjunction with sedative/hypnotics in patients over 75 years of age will be reviewed as these patients may be more sensitive to the additive effects of this drug combination2-6.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for tramadol are summarized in Table 4. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed2-6.

Table 4: Tramadol Drug-Drug Interactions
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level
tramadol barbiturates adjunctive use may result in respiratory depression, hypotension, profound sedation and potentially death due to additive CNS depression; potential as well for decreasing tramadol levels as barbiturates induce CYP3A4 and tramadol is CYP3A4 substrate avoid use, if possible; if combined administration necessary, observe for respiratory depression and loss of tramadol analgesic effects major (DrugReax) 2-major (CP)
tramadol carbamazepine (CBZ) potential for reduced analgesic effect due to CBZ-associated CYP3A4 enzyme induction; potential for additive CNS depressant effects, increased seizure risk with concurrent therapy concurrent use not recommended major (DrugReax) 2-major (CP)
tramadol CYP inducers (e.g., phenytoin, rifampin) potential for reduced tramadol analgesic efficacy as tramadol metabolized by CYP3A4, CYP2D6 monitor for reduced analgesic effects; adjust dosages as necessary moderate (DrugReax) 3-moderate (CP)
tramadol CYP2D6 inhibitors (e.g., amiodarone, propafenone,  ritonavir) potential for enhanced tramadol pharmacologic/ adverse effects as tramadol metabolized by CYP2D6 monitor for enhanced analgesic effects, increased adverse effects (including seizures); adjust dosages as necessary moderate (DrugReax) 3-moderate (CP)
tramadol CYP3A4 inhibitors (e.g., amiodarone, erythromycin,  ritonavir) potential for enhanced tramadol pharmacologic/ adverse effects as tramadol metabolized by CYP3A4 monitor for enhanced analgesic effects, increased adverse effects (including seizures); adjust dosages as necessary moderate (DrugReax) 3-moderate (CP)
tramadol MAOIs+/MAOI-like compounds (e.g., phenelzine, selegiline, rasagiline, linezolid) potential for additive effects on serotonin and norepinephrine reuptake inhibition; increased risk for seizures, hypertensive reactions, serotonin syndrome (e.g., nausea, vomiting, hypertension, hyperthermia, cardiovascular collapse) concurrent administration or prescribing within 14 days of MAOI discontinuation contraindicated contraindicated, major (DrugReax) 1-severe, 2-major (CP)
tramadol neuroleptics (e.g., thioridazine, risperidone) increased seizure risk (mechanism unknown), and potential for increased CNS, respiratory depression avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together major (DrugReax) 2-major (CP)
tramadol opioid analgesics increased seizure risk avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together 2-major (CP)
tramadol serotonergic drugs (e.g., SSRIs/ SNRIs, milnacipran) increased seizure risk, increased risk of serotonin syndrome (e.g., nausea/vomiting, hypertension, hyperthermia, cardiovascular collapse) due to additive increases in serotonin concentrations avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together major (DrugReax) 2-major (CP)
tramadol TCAs^ (e.g., imipramine, cyclobenzaprine) increased seizure risk (TCAs lower seizure threshold), increased risk of serotonin syndrome (e.g., nausea/vomiting, hypertension, hyperthermia, cardiovascular collapse) as both compounds inhibit serotonin/norepinephrine reuptake avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together major (DrugReax) 3-moderate (CP)
tramadol warfarin increased prothrombin time with increased bleeding risk; mechanism unknown closely monitor for INR changes, bleeding; adjust doses as necessary moderate (DrugReax) 2-major (CP)

Legend:

  • * CP = Clinical Pharmacology
  • +MAOI = monoamine oxidase inhibitor
  • ^TCA = tricyclic antidepressant

5. References

  1. Drug Enforcement Administration. Federal Register Volume 79, Issue 127 (July 2, 2014). Available at https://www.gpo.gov/fdsys/search/pagedetails.action?st=tramadol&granuleId=2014-15548&packageId=FR-2014-07-02. Accessed December 9th, 2021. 
  2. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/. Accessed December 9th, 2021.
  3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/.  Accessed December 9th, 2021.
  4. Tramadol tablets (Ultram®) Package Insert. Janssen Pharmaceuticals, September 2021.
  5. Tramadol extended-release capsules (ConZip®) package insert. Vertical Pharmaceuticals, Inc., September 2021.
  6. Tramadol/acetaminophen tablets (Ultracet®) package insert. Janssen Pharmaceuticals, September 2021.
  7. Vorsanger G, Xiang J, Jordan D, Farrell J. Post hoc analysis of a randomized, double-blind, placebo-controlled efficacy and tolerability study of tramadol extended release for the treatment of osteoarthritis pain in geriatric patients. Clin Ther. 2007;29 (Suppl):2520-35.
  8. Barkin RL. Extended-release tramadol (ULTRAM® ER): A pharmacotherapeutic, pharmacokinetic, and pharmacodynamic focus on effectiveness and safety in patients with chronic/persistent pain. Am J Ther. 2008;15:157-66.
  9. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review and meta-analysis. J  Rheumatol. 2007;34:543-55.
  10. Leppert W, Luczak J. The role of tramadol in cancer pain treatment--a review. Support Care Cancer. 2005;13:5-17.
  11. Leppert W. Tramadol as an analgesic for mild to moderate cancer pain. Pharmacol Rep. 2009;61:978-92.
  12. Hochbert MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):455-74.
  13. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2020;72(2):149-162.
  14. Chou R, Huffman LH. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med. 2007;147:505-14.
  15. Hair PI. Curran MP. Keam SJ. Tramadol extended-release tablets. Drugs. 2006;66:2017-27; discussion 2028-30.
  16. Yates WR, Nguyen MH, Warnock JK. Tramadol dependence with no history of substance abuse. Am J Psychiatry. 2001;158:964.
  17. Miotto K, Cho AK, Khalil MA, et al. Trends in tramadol: pharmacology, metabolism, and misuse. Anesth Analg 2017;124:44–51.
  18. Schug SA. Combination analgesia in 2005 - a rational approach: focus on paracetamol-tramadol. Clin Rheumatol. 2006;25( Suppl 1):S16-21.
  19. Mullican WS, Lacy JR, and the TRAMAP-ANAG-006 Study Group. Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial. Clin Ther. 2001;23:1429-45.
  20. Rodriguez RF, Castillo JM, Castillo MP, et al. Hydrocodone/acetaminophen and tramadol chlorhydrate combination tablets for the management of chronic cancer pain: a double-blind comparative trial. Clin J Pain. 2008;24:1-4.
  21. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85(3 Suppl):S3-14.
  22. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: A position statement by the American Diabetes Association. Diabetes Care. 2017;40:136-54.