Background for Fast Fact #228    Tapentadol is a novel oral opioid analgesic, approved by the FDA for the management of moderate to severe acute pain in adults.  This Fast Fact reviews its pharmacology and use.

Pharmacology     Tapentadol is a centrally acting, synthetic, oral mu-opioid receptor agonist. It is pharmacologically similar to tramadol (see Fast Fact #290 for more information on tramadol); however, it has more norepinephrine reuptake inhibition, and unlike tramadol, it does not require metabolic activation (1). This gives potential advantages as an analgesic especially for neuropathic pain with less toxicity. 

• Oral bioavailability ranges from 32% to 42%, with a half-life of 4 ½ hours.
• The drug is metabolized in the liver (97% by Phase-2 conjugation) and excreted in the urine.
• Tapentadol has no known pharmacologically active metabolites, no relevant CYP interactions, and no drug-drug interactions through cytochrome induction or inhibition (2).
• There are no dosing adjustments required in mild-to-moderate renal or hepatic impairment (Child class A or B); it has not been studied in patients with severe hepatic impairment (Child class C).
• It is felt to be 2-3 times more potent than tramadol and 2-3 times less potent than morphine (3).

Research data     The FDA approval was based on industry-coordinated, randomized controlled studies conducted in patients with osteoarthritis and after bunionectomy. In these studies, 50 mg of tapentadol was shown to be non-inferior to 10 mg of oxycodone immediate release in the treatment of pain, but the incidence of nausea, vomiting, dizziness, and constipation was significantly lower (4,5).  In other controlled studies involving patients with chronic low back pain, diabetic peripheral neuropathy, multiple myeloma, and mucositis from head and neck cancer treatment, it has been found to have comparable efficacy to other opioid analgesics but with fewer analgesic effects and a higher potential to reduce neuropathic pain (6-10).  In most studies, it is given 50 mg immediate release as needed or as an extended-release tablet at 100-500 mg/day (11). Total daily doses greater than 700 mg not been tested, nor has tapentadol been studied well in children. Prospective observational studies showed it to be well tolerated and effective for opioid naïve (doses 100 mg per day) and opioid tolerant patients (doses 350 to 450 mg per day) with moderate to severe cancer pain (12-13). There are not enough data to comment on whether the drug has a ceiling effect, nor its long-term safety and efficacy (the longest study is a 1-year safety study). Hence experts feel the level of evidence for the treatment of chronic pain is low (3).

Side effects and cautions    Tapentadol’s side effect profile is generally like other full agonist opioids (e.g., morphine, oxycodone) but is not as well studied. As such, nausea, vomiting, constipation, misuse, opioid use disorder, respiratory depression, pruritus, dizziness, and drowsiness are all described. Pooled analyses of controlled trials suggest that the toxicity profile is similar to tramadol, however, there is a trend toward greater risk for opioid-related side effects and less serotonin related side effects (3,8).  Pooled analyses suggest the risk of opioid-related side effects may be a little than other pure mu opioids (13-14). As with tramadol, there is a theoretical increased risk of seizures. Abuse and dependency are possible as with any opioid agonist (15).  In one study drug tapering was not required after 90 days of treatment (4).

Dosing and cost     Tapentadol is available as 50, 75 and 100 mg immediate-release tablets and 50, 100, 150, 200, and 250 mg extended release tablets. A common initial dose is 50-100 mg every 4 hours as needed. The average wholesale pricing for tapentadol is about four times the cost of comparative dosess of oxycodone and hydromorphone. Its coverage by insurance providers may be less reliable than other full agonist opioids.

Summary    Tapentadol is a novel analgesic, with a 50 mg dose similar in efficacy to 10 mg of oxycodone. Currently its only clearly defined benefit over established opioids is its gentler GI side effect profile.  Its cost and uncertainty about long-term efficacy and safety limit it from being considered a first-line opioid analgesic option.

References 

1. Faria J, Barbosa J, Queiros O, et al. Comparative pharmacology and toxicology of tramadol and tapentadol. European Journal of Pain 2018; 8(5):327-339.
2. Kneip C, Terlinden R, Beier H, Chen G. Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes. Drug Metab Lett. 2008; 2(1):67-75. PMID: 19356073.
3. Roulet L, Rollason V, Desmeules J, et al. Tapentadol versus tramadol: a narrative and comparative review of their pharmacological, efficacy, and safety profiles in adult patients. 2021; 81:1257-1272.
4. Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009; 25(5):1095-104. PMID: 19301989.
5. Daniels S, Casson E, Stegmann JU, Oh C, Okamoto A, Rauschkolb C, Upmalis D. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin. 2009; 25(6):1551-61. PMID: 19445652.
6. Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P. Single dose analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study. Anesth Analg. 2008; 107(6):2048-55. PMID: 19020157.
7. Baron R, Kern U, Müller M, et al. Effectiveness and tolerability of a moderate dose of tapentadol prolonged release for managing severe, chroniclow back pain with a neuropathic component: an open-label continuation arm of a randomized phase 3b Study. Pain Pract. 2015;15(5):471–486.
8. Coluzzi F, Raffa RB, Pergolizzi J, et al. Tapentadol prolonged release for patients with multiple myeloma suffering from moderate-to-severe cancerpain due to bone disease. J Pain Res;2015. 229–238.
9. Mazzola R, Ricchetti F, Fersino S, et al. Erratum: erratum to: effectiveness of tapentadol prolonged release for the management of painful mucositisin head and neck cancers during intensity modulated radiation therapy. Support Care Cancer. 2016;24(10):4457–4465.
10. Freo U, Romualdi P, Kress HG. Tapentadol for neuropathic pain: a review of clinical studies 2019; 12:1537-1551.
11. Alsherhri FS. Tapentadol: a review of experimental pharmacology studies, clinical trials, and recent findings.  Drug Design, Development and Therapy 2023;17:851-61.
12. Mercadante S, Porzio G, et al. Tapentadol in cancer pain management: a prospective open-label study. Curr Med Res & Opinion 2012; 28:1775-1779.
13. Mercadante S, Porzio G, et al. Tapentadol at medium to high doses in patients previously receiving strong opioids for the management of cancer pain. Curr Med Res & Opinion 2014; 30:2063-2068.
14. Etropolski M, Kuperwasser B, et al.  Safety and tolerability of tapentadol extended release in moderate to severe chronic osteoarthritis or low back pain management: pooled analysis of randomized controlled trials. Adv Ther 2014; 31:604-620.
15. Channell JS, Schug S. Toxicity of tapentadol: a systematic review. Pain Management 2018; 5:327-339.
16. Butler SF, McNaughton EC, Black RA. Tapentadol abuse potential: a postmarketing evaluation using a sample of individuals evaluated forsubstance abuse treatment. Pain Med. 2015;16(1):119–130.

Author Affiliations: University of Pittsburgh Medical Center, Pittsburgh, PA.
Version History:   Originally published April 2010; 2nd Edition in August 2015; 3rd Edition in March 2025 by Sean Marks MD. 
Conflicts of Interest: None to report.