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Continuing Education Activity

Tramadol is an FDA-approved medication for pain relief. It has specific indications for moderate to severe pain. It is considered a class IV drug by the FDA and has been since July of 2014. Due to possible misuse disorder potential, limitations to its use should be for pain that is refractory to other pain medication, such as non-opioid pain medication. There are two forms of tramadol: extended-release and immediate release. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, toxicity, and monitoring, of tramadol so providers can direct patient therapy where it is indicated as part of the interprofessional team.


  • Identify the mechanism of action of tramadol.
  • Review the various indications for tramadol.
  • Summarize the adverse event profile of tramadol.
  • Describe interprofessional team strategies for improving care coordination and communication to properly use tramadol to improve patient outcomes in the varied scenarios where it can be effective, with an eye towards the ongoing opioid crisis.
Access free multiple choice questions on this topic.


Tramadol is an FDA-approved medication for pain relief. It has specific indications for moderate to severe pain. It is considered a class IV drug by the FDA and has been since July 7th, 2014. Due to possible abuse and addiction potential, limitations to its use should be for pain that is refractive to other pain medication, such as non-opioid pain medication. There are two forms of tramadol: extended-release and immediate release. The immediate-release is not for use as an "as needed" medication; instead, it is for pain of less than a week duration. For pain lasting more than a week, extended-release is the therapeutic choice — the indication for extended-release is for pain control under 24-hour management or an extended period.  

Off-label, the drug is useful for premature ejaculation and restless leg syndrome refractory to other medication.[1][2] For the off-label use of tramadol for premature ejaculation, both sporadic and daily use is effective for treating the condition. Patients indicate a preference for "as needed"therapy for premature ejaculation due to the lack of side effects compared to daily use of tramadol.[3]

Mechanism of Action

Tramadol is an opioid and, like other opioids, selectively bind to different opiate receptors in the central nervous system. The liver enzyme, CYP2D6, converts tramadol to its active metabolite M1, which has a stronger affinity for the mu receptor compared to the inactive form. Tramadol does not bind to the mu receptor as much as morphine. Unlike other opioids, tramadol does not reverse its course completely after the administration of naloxone. Along with the partial agonist activity on the opioid receptors, it also inhibits the reuptake of serotonin and norepinephrine.[4]


There are two different formulations of tramadol: extended-release and immediate release. The extended-release and immediate-release both come in capsule form. For the extended-release formulation, patients should receive counseling on the drug; it should not be chewed, crushed, dissolved, or spit before administration. Administration of both formulations can be without regard to food, but the administration of the extended-release formula should be at a consistent time each day.[5]

  • Half-life: Six hours
  • Time for the drug to reach peak concentration: Extended Release: 12 hours
  • Immediate Release: 1.6 to 1.9 hours
  • Dosages: Extended Release: 100 mg, 200 mg, 300 mg
  • Immediate Release: 50 mg

Adverse Effects

The organs most commonly affected by tramadol are the central nervous system, neuromuscular, and gastrointestinal. The cardiovascular system, dermatologic system, endocrine, genitourinary, and visual system are also affected by tramadol.  

The most prevalent side effects are nausea, dizziness, constipation, vomiting, somnolence, and headache. They tend to occur during the initial treatment rather than maintenance doses of the drug.[6]

Serious side effects include respiratory depression, which may result in death.


Tramadol is contraindicated in patients who have had a hypersensitivity reaction to any opioid. Patients under the age of twelve should not use the medication. Patients under the age of eighteen should not be given the medication if they have had a history of tonsillectomy or adenoidectomy. Because tramadol can cause respiratory depression, patients with a history of severe respiratory depression, or bronchial asthma with the absence of necessary equipment, should avoid taking tramadol. Patients currently on MOAs or people who have been on MOAs in the past fourteen days should not receive tramadol. Patients on tricyclic antidepressants should also not take tramadol.[4] People who have Gl obstruction should not use tramadol.

Due to the potential side effect of respiratory depression, patients should not use alcohol, benzodiazepines, or other CNS depressants at the same time. Concurrent use of these drugs can exacerbate respiratory depression and can lead to coma and death. Because tramadol is hepatically metabolized, concurrent use of other drugs that undergo hepatic metabolism should be avoided. Genetic variations of CYP2D6 can affect the severity of the drug. Using other drugs that are metabolized by these enzymes can also potentiate the side effects.[7]


Prior to administering tramadol, it is essential to get the patient's baseline liver function tests (AST and ALT) because hepatic metabolism of the drug can lead to hepatotoxicity. Recommendations also include psychiatric evaluation for suicidal ideations, abuse, or misuse of tramadol before prescribing the medication.

After administration, the practitioner should continue to monitor the patient’s liver function, blood pressure, respiratory system, and mental status.  Due to the addictive potential of the drug, continued monitoring of the risks and benefits of tramadol use should take place every three months.


The initial treatment primarily is to maintain a patent airway and maintain adequate ventilation through assisted or controlled ventilation.[8] As is the case with other opioids, naloxone can provide partial reversal of the side effects of tramadol.

Naloxone is a competitive antagonist of the mu, kappa, and sigma receptor that tramadol and other opioids bind to, with the highest affinity for the mu receptor. It is available in oral or IV formulations. The oral form has low bioavailability compared to the other formulations. The half-life of naloxone is shorter than tramadol, so repeat doses may be necessary. Although this drug may be used to decrease respiratory and central nervous system depression, it may increase the risk for seizures.[9]

Enhancing Healthcare Team Outcomes

Managing opioid overdose such as tramadol requires an interprofessional team effort involving numerous specialties. Without proper management, an overdose of tramadol or other opioids can lead to death. The process of treating tramadol overdose or misuse starts prior to initial administration. The incorrect use of prescriptions is a significant contributor to opioid use disorder, so the proper administration of the drug can help prevent drug use disorder. Management of pain is vital in the treatment of patients, and tramadol can provide valuable relief for this population. Although tramadol has a comparatively low risk of misuse, there are still cases of patients with no history of opioid use disorder developing the condition while taking the medication.[10](Level V) Therefore, reliance upon the whole healthcare team, instead of just the physician, is to prevent the mismanagement of prescriptions. The use of government policy changes that initiated prescription drug monitoring programs has resulted in a decrease in drug misuse as well as drug fatalities.[11] (Level II)

Case managers, clinicians (including mid-level practitioners), pharmacists, and other healthcare team members are essential in preventing the abuse of prescriptions. Case managers and nurses are vital in helping prevent physicians from over-prescribing tramadol and other opioids. These functions are crucial in seeing the potential for use disorder in patients. They can help prevent opioid misuse by doing the following:

  • Assess clinical need for medication
  • Identify treatment and other resources.
  • Provider education and support to the patient and their family
  • Identifying drug-seeking habits[12]

Pharmacists are also critical in the management of tramadol abuse. They can help prevent the misuse of prescriptions by:

  • Providing education on how to take their medication
  • Preventing prescription falsifications
  • Recognizing problematic signs of drug use

Nursing staff are also integral in managing tramadol therapy, serving as initial points of contact for the prescribing clinician, and answering questions regarding dosing, administration, and adverse events.

With an interprofessional team approach, patients will have an increased chance of successful pain management with tramadol and be less apt to experience adverse effects. [Level 5]

Review Questions


Martyn-St James M, Cooper K, Kaltenthaler E, Dickinson K, Cantrell A, Wylie K, Frodsham L, Hood C. Tramadol for premature ejaculation: a systematic review and meta-analysis. BMC Urol. 2015 Jan 30;15:6. [PMC free article: PMC4417346] [PubMed: 25636495]
Lauerma H, Markkula J. Treatment of restless legs syndrome with tramadol: an open study. J Clin Psychiatry. 1999 Apr;60(4):241-4. [PubMed: 10221285]
Khan AH, Rasaily D. Tramadol use in premature ejaculation: daily versus sporadic treatment. Indian J Psychol Med. 2013 Jul;35(3):256-9. [PMC free article: PMC3821202] [PubMed: 24249927]
Dayer P, Desmeules J, Collart L. [Pharmacology of tramadol]. Drugs. 1997;53 Suppl 2:18-24. [PubMed: 9190321]
Xu M, Zheng L, Zeng J, Xu W, Jiang X, Wang L. Physiologically based pharmacokinetic modeling of tramadol to inform dose adjustment and drug-drug interactions according to CYP2D6 phenotypes. Pharmacotherapy. 2021 Mar;41(3):277-290. [PubMed: 33316842]
Langley PC, Patkar AD, Boswell KA, Benson CJ, Schein JR. Adverse event profile of tramadol in recent clinical studies of chronic osteoarthritis pain. Curr Med Res Opin. 2010 Jan;26(1):239-51. [PubMed: 19929615]
Arafa MH, Atteia HH. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with long term tramadol treatment-induced oxidative damage and hepatotoxicity. Toxicol Appl Pharmacol. 2018 May 01;346:37-44. [PubMed: 29555325]
Baldo BA. Toxicities of opioid analgesics: respiratory depression, histamine release, hemodynamic changes, hypersensitivity, serotonin toxicity. Arch Toxicol. 2021 Aug;95(8):2627-2642. [PubMed: 33974096]
Lagard C, Malissin I, Indja W, Risède P, Chevillard L, Mégarbane B. Is naloxone the best antidote to reverse tramadol-induced neuro-respiratory toxicity in overdose? An experimental investigation in the rat. Clin Toxicol (Phila). 2018 Aug;56(8):737-743. [PubMed: 29148295]
Ojha R, Bhatia SC. Tramadol dependence in a patient with no previous substance history. Prim Care Companion J Clin Psychiatry. 2010;12(1):PCC.09100779. [PMC free article: PMC2882815] [PubMed: 20582298]
Johnson H, Paulozzi L, Porucznik C, Mack K, Herter B., Hal Johnson Consulting and Division of Disease Control and Health Promotion, Florida Department of Health. Decline in drug overdose deaths after state policy changes - Florida, 2010-2012. MMWR Morb Mortal Wkly Rep. 2014 Jul 04;63(26):569-74. [PMC free article: PMC4584904] [PubMed: 24990490]
Sortedahl C, Krsnak J, Crook MM, Scotton L. Case Managers on the Front Lines of Opioid Epidemic Response: Advocacy, Education, and Empowerment for Users of Medical and Nonmedical Opioids. Prof Case Manag. 2018 Sep/Oct;23(5):256-263. [PubMed: 30059464]
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