Tapentadol – a new opioid with a unique, dual mechanism of action and wide possibilities of application Review article
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Published:
Jun 30, 2025
Keywords:
mu-opioid receptor agonist, MOR, norepinephrine reuptake inhibitor, pain treatment, synergism, tapentadol
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Abstract
Tapentadol is a new drug classified as a strong opioid, a representative of a new class of centrally acting analgesics called MOR-NRI. It is a drug with a unique, dual mechanism of action: it is an agonist of the μ-opioid receptor (MOR) and norepinephrine reuptake inhibitor (NRI). This drug, despite its 50-fold lower affinity for the μ-opioid receptor compared to morphine, has an analgesic effect that is only three times weaker than morphine, which is a consequence of the synergism of its two mechanisms of action. It is believed that the noradrenergic mechanism of action of tapentadol is largely responsible for its effectiveness in relieving various neuropathic pain syndromes, while its action on μ-opioid receptor for analgesic effect of tapentadol in nociceptive pain. Many clinical studies have confirmed good analgesic effect of tapentadol in treatment of acute postoperative pain and many chronic pain syndromes, including pain in the course of osteoarthritis, spinal pain syndrome (with or without a neuropathic component) or neuropathic pain in the course of painful diabetic polyneuropathy. Available studies and everyday clinical practice also confirm the efficacy and safety of tapentadol in the treatment of severe pain in cancer patients.
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Zajączkowska, R. (2025). Tapentadol – a new opioid with a unique, dual mechanism of action and wide possibilities of application. Medycyna Faktow (J EBM), 18(2(67), 253-259. https://doi.org/10.24292/01.MF.0225.13
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References
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2. Gressler LE, Hammond DA, Painter JT. Serotonin syndrome in tapentadol literature: systematic review of original research. J Pain Palliat Care Pharmacother. 2017; 31(3-4): 228-36.
3. Tzschentke TM, De Vry J, Terlinden R et al. Tapentadol hydrochloride. Drugs Fut. 2006; 31: 1053-61.
4. Zajączkowska R, Przewłocka B, Kocot-Kępska M et al. Tapentadol – A representative of a new class of MOR-NRI analgesics. Pharmacol Rep. 2018; 70(4): 812-20.
5. Tzschentke TM, Christoph T, Kögel B et al. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther. 2007; 323(1): 265-76.
6. Kögel B, De Vry J, Tzschentke TM et al. The antinociceptive and antihyperalgesic effect of tapentadol is partially retained in OPRM1 (μ-opioid receptor) knockout mice. Neurosci Lett. 2011; 491(2): 104-7.
7. Schroder W, De Vry JD, Tzschentke TM et al. Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain. Eur J Pain. 2010; 14(8): 814-21.
8. Palexia SR (tapentadol) prolonged-release oral tablets [summary of product characteristics]. Buckinghamshire, UK, Grunenthal Ltd., 2011.
9. Zajączkowska R, Kocot-Kępska M, Dobrogowski J et al. Tapentadol – stan wiedzy 2017. Terapia. 2017; 8: 1-8.
10. Etropolski M, Kuperwasser, B., Flügel, M. 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: 604-20.
11. Wild JE, Grond S, Kuperwasser B, Flügel M et al. Longterm safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract. 2010; 10(5): 416-27.
12. van der Schrier R, Jonkman K, van Velzen M et al. An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers. Br J Anaesth. 2017; 119(6): 1169-77.
13. Webster L, Rauck RL. Atypical opioids and their effect on respiratory drive. J Opioid Manag. 2021; 17(7): 109-18.
14. Biondi D, Xiang J, Etropolski M et al. A post hoc pooled data analysis to evaluate blood pressure (BP) and heart rate (HR) measurements in patients with a current or prior history of hypertension who received tapentadol ER, oxycodone CR, or placebo in chronic pain studies. J Pain. 2011; 12(4 Suppl): P55.
15. Oh C, Rengelshausen J, Mangold B et al. A thorough Qt/QTc study of multiple doses of tapentadol immediate release in healthy subjects. Int J Clin Pharmacol Ther. 2010; 48(10): 678-87.
16. Eichenbaum G, Gohler K, Etropolski M et al. Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency. J Opioid Manag. 2015; 11(3): 211-27.
17. Coluzzi F, Pergolizzi J, Raffa RB et al. The unsolved case of bone-impairing analgesics: the endocrine effects of opioids on bone metabolism. Ther Clin Risk Manag. 2015; 11: 515-23.
18. Hartrick CT, Rozek RJ. Tapentadol in pain management. CNS Drugs. 2011; 25(5): 359-70.
19. Pergolizzi J, Alegre C, Blake D et al. Current considerations for the treatment of severe chronic pain: the potential for tapentadol. Pain Practice. 2012; 12(4): 290-306.
20. Franchi S, Moschetti G, Amodeo G et al. Do All Opioid Drugs Share the Same Immunomodulatory Properties? A Review From Animal and Human Studies. Front Immunol. 2019; 10: 2914.
21. Kneip C, Terlinden R, Beier H et al. Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes. Drug Metab Letters. 2008; 2: 67-75.
22. Mangold B, Oh C, Jaeger D et al. The pharmacokinetics of tapentadol are not affected by omeprazole: results of a 2-way crossover drug-interaction study in healthy subjects. Pain Pract. 2007; 7(Suppl 1): 55-7.
23. Smit JW, Oh C, Rengelshausen J et al. Effects of acetaminophen, naproxen and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies. Pharmacotherapy. 2010; 30(1): 25-34.
24. Charakterystyka produktu leczniczego Palexia retard.
25. Charakterystyka produktu leczniczego Palexia.
26. Charakterystyka produktu leczniczego Palexia roztwór doustny 4 mg/ml.
27. Charakterystyka produktu leczniczego Palexia roztwór doustny 20 mg/ml.
28. Wade WE, Spruill WJ. Tapentadol hydrochloride: a centrally acting oral analgesic. Clin Ther. 2009; 31(12): 2804-18.
29. Kern KU, Sohns M, Heckes B et al. Tapentadol prolonged release for severe chronic osteoarthritis pain in the elderly: improvements in daily functioning and quality of life. Pain Manag. 2020; 10(2): 85-95.
30. Freo U, Furnari M, Ambrosio F et al. Efficacy and tolerability of tapentadol for the treatment of chronic low back pain in elderly patients. Aging Clin Exp Res. 2021; 33(4): 973-82.
31. Schwittay A, Sohns M, Heckes B et al. Tapentadol Prolonged Release for Severe Chronic Osteoarthritis Pain in the Elderly-A Subgroup Analysis of Routine Clinical Practice Data. Pain Res Manag. 2020; 2020: 5759265.
32. Pierce DM, Shipstone E. Pharmacology Update: Tapentadol for neuropathic pain. Am J Hosp Palliat Med. 2012; 29(8): 663-66.
33. Steigerwald I, Schenk M, Lahne U et al. Effectiveness and Tolerability of Tapentadol Prolonged Release Compared With Prior Opioid Therapy for the Management of Severe, Chronic Osteoarthritis Pain. Clin Drug Investig. 2013; 33: 607-19.
34. Davis MP, Davis A, McPherson ML et al. Opioid conversion in adults with cancer: MASCC‑ASCO‑AAHPM‑HPNA‑NICSO guideline. Supportive Care in Cancer. 2025; 33: 243.
35. Sanchez M, Shenk M, Kern KU et al. Practical Considerations for the Use of Tapentadol Prolonged Release for the Management of Severe Chronic Pain. Clin Ther. 2015; 27(1): 94-113.
36. Viscusi ER, Allard R, Sohns M et al. Tapentadol immediate release for moderate to severe acute post-surgery pain. J Opioid Manag. 2019; 15: 51-67.
37. Baron R, Jansen JP, Binder A et al. Tolerability, Safety, and Quality of Life with Tapentadol Prolonged Release (PR) Compared with Oxycodone/Naloxone PR in Patients with Severe Chronic Low Back Pain with a Neuropathic Component: A Randomized, Controlled, Open-label, Phase 3b/4 Trial. Pain Pract. 2016; 16(5): 600-19.
38. Kress HG, Koch ED, Kosturski H et al. Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain. Pain Physician. 2014; 17: 329-43.
39. Mercadante S, Porzio G, Ferrera P et al. Tapentadol in cancer pain management: a prospective, open-label study. Curr Med Res Op. 2012; 28(11): 1775-9.
2. Gressler LE, Hammond DA, Painter JT. Serotonin syndrome in tapentadol literature: systematic review of original research. J Pain Palliat Care Pharmacother. 2017; 31(3-4): 228-36.
3. Tzschentke TM, De Vry J, Terlinden R et al. Tapentadol hydrochloride. Drugs Fut. 2006; 31: 1053-61.
4. Zajączkowska R, Przewłocka B, Kocot-Kępska M et al. Tapentadol – A representative of a new class of MOR-NRI analgesics. Pharmacol Rep. 2018; 70(4): 812-20.
5. Tzschentke TM, Christoph T, Kögel B et al. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther. 2007; 323(1): 265-76.
6. Kögel B, De Vry J, Tzschentke TM et al. The antinociceptive and antihyperalgesic effect of tapentadol is partially retained in OPRM1 (μ-opioid receptor) knockout mice. Neurosci Lett. 2011; 491(2): 104-7.
7. Schroder W, De Vry JD, Tzschentke TM et al. Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain. Eur J Pain. 2010; 14(8): 814-21.
8. Palexia SR (tapentadol) prolonged-release oral tablets [summary of product characteristics]. Buckinghamshire, UK, Grunenthal Ltd., 2011.
9. Zajączkowska R, Kocot-Kępska M, Dobrogowski J et al. Tapentadol – stan wiedzy 2017. Terapia. 2017; 8: 1-8.
10. Etropolski M, Kuperwasser, B., Flügel, M. 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: 604-20.
11. Wild JE, Grond S, Kuperwasser B, Flügel M et al. Longterm safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract. 2010; 10(5): 416-27.
12. van der Schrier R, Jonkman K, van Velzen M et al. An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers. Br J Anaesth. 2017; 119(6): 1169-77.
13. Webster L, Rauck RL. Atypical opioids and their effect on respiratory drive. J Opioid Manag. 2021; 17(7): 109-18.
14. Biondi D, Xiang J, Etropolski M et al. A post hoc pooled data analysis to evaluate blood pressure (BP) and heart rate (HR) measurements in patients with a current or prior history of hypertension who received tapentadol ER, oxycodone CR, or placebo in chronic pain studies. J Pain. 2011; 12(4 Suppl): P55.
15. Oh C, Rengelshausen J, Mangold B et al. A thorough Qt/QTc study of multiple doses of tapentadol immediate release in healthy subjects. Int J Clin Pharmacol Ther. 2010; 48(10): 678-87.
16. Eichenbaum G, Gohler K, Etropolski M et al. Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency. J Opioid Manag. 2015; 11(3): 211-27.
17. Coluzzi F, Pergolizzi J, Raffa RB et al. The unsolved case of bone-impairing analgesics: the endocrine effects of opioids on bone metabolism. Ther Clin Risk Manag. 2015; 11: 515-23.
18. Hartrick CT, Rozek RJ. Tapentadol in pain management. CNS Drugs. 2011; 25(5): 359-70.
19. Pergolizzi J, Alegre C, Blake D et al. Current considerations for the treatment of severe chronic pain: the potential for tapentadol. Pain Practice. 2012; 12(4): 290-306.
20. Franchi S, Moschetti G, Amodeo G et al. Do All Opioid Drugs Share the Same Immunomodulatory Properties? A Review From Animal and Human Studies. Front Immunol. 2019; 10: 2914.
21. Kneip C, Terlinden R, Beier H et al. Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes. Drug Metab Letters. 2008; 2: 67-75.
22. Mangold B, Oh C, Jaeger D et al. The pharmacokinetics of tapentadol are not affected by omeprazole: results of a 2-way crossover drug-interaction study in healthy subjects. Pain Pract. 2007; 7(Suppl 1): 55-7.
23. Smit JW, Oh C, Rengelshausen J et al. Effects of acetaminophen, naproxen and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies. Pharmacotherapy. 2010; 30(1): 25-34.
24. Charakterystyka produktu leczniczego Palexia retard.
25. Charakterystyka produktu leczniczego Palexia.
26. Charakterystyka produktu leczniczego Palexia roztwór doustny 4 mg/ml.
27. Charakterystyka produktu leczniczego Palexia roztwór doustny 20 mg/ml.
28. Wade WE, Spruill WJ. Tapentadol hydrochloride: a centrally acting oral analgesic. Clin Ther. 2009; 31(12): 2804-18.
29. Kern KU, Sohns M, Heckes B et al. Tapentadol prolonged release for severe chronic osteoarthritis pain in the elderly: improvements in daily functioning and quality of life. Pain Manag. 2020; 10(2): 85-95.
30. Freo U, Furnari M, Ambrosio F et al. Efficacy and tolerability of tapentadol for the treatment of chronic low back pain in elderly patients. Aging Clin Exp Res. 2021; 33(4): 973-82.
31. Schwittay A, Sohns M, Heckes B et al. Tapentadol Prolonged Release for Severe Chronic Osteoarthritis Pain in the Elderly-A Subgroup Analysis of Routine Clinical Practice Data. Pain Res Manag. 2020; 2020: 5759265.
32. Pierce DM, Shipstone E. Pharmacology Update: Tapentadol for neuropathic pain. Am J Hosp Palliat Med. 2012; 29(8): 663-66.
33. Steigerwald I, Schenk M, Lahne U et al. Effectiveness and Tolerability of Tapentadol Prolonged Release Compared With Prior Opioid Therapy for the Management of Severe, Chronic Osteoarthritis Pain. Clin Drug Investig. 2013; 33: 607-19.
34. Davis MP, Davis A, McPherson ML et al. Opioid conversion in adults with cancer: MASCC‑ASCO‑AAHPM‑HPNA‑NICSO guideline. Supportive Care in Cancer. 2025; 33: 243.
35. Sanchez M, Shenk M, Kern KU et al. Practical Considerations for the Use of Tapentadol Prolonged Release for the Management of Severe Chronic Pain. Clin Ther. 2015; 27(1): 94-113.
36. Viscusi ER, Allard R, Sohns M et al. Tapentadol immediate release for moderate to severe acute post-surgery pain. J Opioid Manag. 2019; 15: 51-67.
37. Baron R, Jansen JP, Binder A et al. Tolerability, Safety, and Quality of Life with Tapentadol Prolonged Release (PR) Compared with Oxycodone/Naloxone PR in Patients with Severe Chronic Low Back Pain with a Neuropathic Component: A Randomized, Controlled, Open-label, Phase 3b/4 Trial. Pain Pract. 2016; 16(5): 600-19.
38. Kress HG, Koch ED, Kosturski H et al. Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain. Pain Physician. 2014; 17: 329-43.
39. Mercadante S, Porzio G, Ferrera P et al. Tapentadol in cancer pain management: a prospective, open-label study. Curr Med Res Op. 2012; 28(11): 1775-9.