Tramadol versus Tapentadol

Based on "Essential Pain Pharmacology"
written by Howard S. Smith, MD; Marco Pappagallo, MD

Difference between Tramadol and Tapentadol

Table 1. Comparison of tramadol and tapentadol

  Tramadol Tapentadol
Brand names Ultram®, Ultram® ER Nucynta®, Nucynta® ER
Drug class Centrally acting synthetic analgesic
Legal status Controlled Substance Schedule IV Controlled Substance Schedule II
FDA-approved Indications for Immediate-release formulation Moderate to moderately severe pain in adults. Moderate to severe acute pain in patients aged > or =18 years.
FDA-approved Indications for Extended-release formulation • Moderate to moderately severe chronic pain in adults, requiring around-the-clock, long-term treatment • Severe pain requiring daily, around-the-clock, long-term opioid treatment and for which alternative treatments are inadequate;

• Severe diabetic peripheral neuropathic pain in adults requiring daily, around-the-clock, long-term opioid treatment and for which alternative treatments are inadequate
Mechanism of action Dual mechanism of action:
weak µ-opioid receptor agonism,
and norepinephrine and serotonin reuptake inhibition
Dual mechanism of action:
µ-opioid receptor agonism and norepinephrine reuptake inhibition
Onset of action 1 hour 20-40 min
Duration of action 4-6 hours 4-6 hours
Half-life 6.3 hours
(7.4 hours for metabolite)
4 hours
Oral bioavailability
Metabolism, Elimination Undergoes CYP3A4- and CYP2D6 metabolism in the liver.
Excreted primarily through liver metabolism and the metabolites are eliminated primarily by the kidneys.
Predominantly metabolized by liver by phase 2 glucuronidation.
Excreted in urine 99%.
Analgesic efficacy is not altered by metabolic factors.
Contraindications • Hypersensitivity to tramadol
• Acute intoxication with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs5
• Hypersensitivity to tapentadol
• Significant respiratory depression
• Acute or severe bronchial asthma or hypercarbia
• Paralytic ileus
• Monoamine oxidase (MAO) inhibitors therapy4
Warnings & precautions • Abuse potential
• Interactions with alcohol, other opioids, CNS depressants
• Patients with increased intracranial pressure or head injury
• Serotonin syndrome risk
• Withdrawal symptoms
• Impairment of mental or physical abilities
• Respiratory depression
• Seizures risk - seizures have been reported with the recommended dosages
• Suicide risk
• Concomitant use with MAO inhibitors and SSRIs
• Anaphylactoid reactions have been reported
• Renal and hepatic disease - dosing reduction is recommended
Life threatening respiratory depression; elderly and debilitated patients are particularly vulnerable
• Seizures risk - has not been studied in patients with patients with a predisposition to seizures
• Chronic pulmonary disease
• Hypotensive effect
• Hepatic impairment - avoid in severe hepatic impairment; dosing reduction is recommended in moderate hepatic disease
• Renal impairment - avoid tapentadol in severe renal impairment
• Spasm of the sphincter of Oddi risk
Abuse potential Low risk of physical/psychological dependence Physical/psychological dependence similar to schedule II potent opioids
Drug interactions • CYP2D6 and CYP3A4 inhibitors (e.g. ketoconazole, erythromycin) may affect the metabolism of tramadol.
• Carbamazepine significantly increases tramadol metabolism.
• Quinidine
• Does not inhibit or induce cytochrome P450 enzymes.
Minimal potential for pharmacokinetic drug interactions.
• Anticholinergics may increase the risk of urinary retention.
Monoamine oxidase inhibitors, serotonergic medications
Pregnancy category
Generic availability
Molecule • Racemic mixture
• Prodrug
• Single enantiomer
• Active molecule, not a prodrug


Tapentadol and Tramadol are similar in that they are considered “different” than the classic opioids. Both tramadol and tapentadol are centrally-acting analgesics that combine opioid and non-opioid activities, which synergistically produce analgesia. In contrast to pure opioid agonists, both drugs have lower risks of respiratory depression, tolerance, and dependence.

tramadol vs tapentadol molecule

Tapentadol has an open-chain molecule, while tramadol has a 2-ring cyclic structure, resulting in distinct pharmacological properties.

Tapentadol has no active metabolites and does not require metabolic activation to exert its analgesic effects. Tramadol requires metabolism by the CYP450 complex to its active metabolite O-desmethyltramadol to be completely effective.

The µ-opioid receptor agonist activity of tapentadol is several-fold greater than that of tramadol. Also, tapentadol exerts noticeable norepinephrine reuptake inhibition but minimal serotonin effect 2. Tramadol notably inhibits both norepinephrine and serotonin reuptake.

Tramadol is a good choice for pain conditions for which a strong opioid action is not necessary. On the other hand, tapentadol is a suitable choice for pain conditions requiring a strong opioid action2.

Main Tapentadol advantages over Tramadol:

  • Lack of cytochrome P450 drug interactions
  • Lower risk of seizures (no listed risk of idiopathic seizures in the FDA labeling4)
  • Lower risk of serotonin syndrome6
  • Better analgesia thanks to stronger binding affinity for µ-opioid receptors
  • Earlier onset of action
  • No individual variation in drug response
  • Lesser incidence of nausea and vomiting

Main Tramadol advantages over Tapentadol:

  • Lower risk of respiratory depression, drowsiness, and lethargy7
  • Less abuse potential
  • Not contraindicated in patients with asthma, hypercarbia, and paralytic ileus
  • Inexpensive - wide availability of generic formulations


Indirect Comparison of Tramadol and Tapentadol

Tolerability: According to the indirect comparison1 between oral tramadol and oral tapentadol patients treated with tramadol have a significantly higher risk of constipation and vomiting; patients treated with tapentadol have a slightly higher risk of dizziness.

Effectiveness: Recent 2014 meta-analysis1 suggests that tramadol provides slightly better pain management than tapentadol. However, as mentioned above, tramadol opioid analgesia depends on CYP2D6 genotype.

Head-to-head comparisons of Tramadol and Tapentadol

Analgesia after cardiac surgery
Tapentadol is a better analgesic than tramadol8.

Low back pain
Tapentadol provides better control of low back pain9.

Further reading


  • 1. Mercier F, Claret L, Prins K, Bruno R. A Model-Based Meta-analysis to Compare Efficacy and Tolerability of Tramadol and Tapentadol for the Treatment of Chronic Non-Malignant Pain. Pain Ther. 2014 Jun;3(1):31-44. PubMed
  • 2. Raffa RB, Buschmann H, Christoph T, Eichenbaum G, Englberger W, Flores CM, Hertrampf T, Kögel B, Schiene K, Straßburger W, Terlinden R, Tzschentke TM. Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother. 2012 Jul;13(10):1437-49. PubMed
  • 3. Vadivelu N, Timchenko A, Huang Y, Sinatra R. Tapentadol extended-release for treatment of chronic pain: a review. J Pain Res. 2011;4:211-8 PubMed
  • 4. Prescribing Information for NUCYNTA® (tapentadol) Revised 12/2016 PDF
  • 5. Prescribing Information for ULTRAM® (tramadol hydrochloride) PDF
  • 6. T.L. Lemke, D.A. Williams Foye's Principles of Medicinal Chemistry. 7th ed. Philadelphia, Wolters Kluwer/Williams; p.689
  • 7. Tsutaoka BT, Ho RY, Fung SM, Kearney TE. Comparative Toxicity of Tapentadol and Tramadol Utilizing Data Reported to the National Poison Data System. Ann Pharmacother. 2015 Dec;49(12):1311-6. PubMed
  • 8. Iyer SK, Mohan G, Ramakrishnan S, Theodore S. Comparison of tapentadol with tramadol for analgesia after cardiac surgery. Ann Card Anaesth. 2015 Jul-Sep;18(3):352-60. PubMed
  • 9. Guillén-Astete CA, Cardona-Carballo C, de la Casa-Resino C. Tapentadol versus tramadol in the management of low back pain in the emergency department: Impact of use on the need for reassessments. Medicine (Baltimore). 2017 Nov;96(45):e8403. PubMed

Published: January 16, 2015
Last updated: August 14, 2018


More Comparisons
Home | Contact Us | Cookies Policy

This website is certified by Health On the Net Foundation. Click to verify. This site complies with the HONcode standard for trustworthy health information: verify here

Copyright 2007-2019 All rights reserved.
All information is for educational purposes only.