Tapentadol

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.05.2021
Released 10.08.2009
Expires For CME 09.05.2024

Tapentadol

Author: K K Jain MD†

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Tapentadol

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Introduction

Overview

Tapentadol is a novel analgesic with combined opioid and adrenergic activity that was developed to fulfill some of the unmet needs in the management of acute pain and reduce the adverse effects of opioids. It may provide effective analgesic therapy for acute pain with both nociceptive and neuropathic components. Tapentadol immediate-release (Tapentadol IR) was approved by the FDA in 2009 for the treatment of moderate to severe acute pain. It is the first new drug in the centrally acting analgesic class approved in the United States in more than 25 years. Tapentadol is listed in schedule II under the Controlled Substance Act (10). Rates of tapentadol immediate-release (IR) abuse and diversion have been low during the first 2 years after its launch (09).

Pharmacology

The full chemical name of tapentadol HCl is (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride.

Pharmacodynamics. Tapentadol is a centrally acting oral analgesic with a dual mechanism of action, combining mu-opioid receptor agonist and norepinephrine reuptake inhibition in a single molecule. Norepinephrine plays a role in the endogenous descending pain inhibitory system, and the analgesic efficacy of norepinephrine reuptake inhibitors has been shown in neuropathic pain. In a study on patients with diabetic polyneuropathy treated with sustained-release tapentadol, analgesic effect on chronic pain was demonstrated to be dependent on activation of descending inhibitory pain pathways as observed by conditioned pain modulation responses (19).

Analgesic effect of tapentadol has been demonstrated in a wide range of animal models of pain with nociceptive and neuropathic components, and development of tolerance to its analgesic effect was twice as slow as that of morphine. Although tapentadol has a 50-fold lower binding affinity to mu-opioid receptor, its analgesic potency is only 2 to 3 times lower than that of morphine, indicating that the dual mode of action may result in an opiate-sparing effect.

Pharmacokinetics. Important features of the absorption, metabolism, and excretion of tapentadol in humans using oral 3-[14C]-labeled tapentadol hydrochloride are:

	• Drug absorption is rapid, reaching a maximum concentration of 2.45 microg-eq/mL in 1.25 to 1.5 hours.
	• The drug is present mainly in the form of conjugated metabolites.
	• Excretion is renal and complete within 5 days.

The absolute oral bioavailability of tapentadol is approximately 32%, which is comparable to that of morphine.

Clinical trials

Various clinical trials of tapentadol during the past decade are summarized in Table 1.

Table 1. Clinical Trials of Tapentadol

Trial design and method	Results
Randomized study of oral, twice-daily doses of tapentadol extended-release or oxycodone controlled-release for up to 1 year in patients with moderate to severe chronic knee or hip osteoarthritis or low back pain.	Tapentadol extended-release was associated with better gastrointestinal tolerability than oxycodone and provided sustainable relief of pain over the study period (24).
A phase 3, multicenter, double-blind, randomized study of tapentadol IR on Korean adults with moderate-to-severe pain following foot surgery.	Tapentadol IR reduced acute pain intensity, significantly more than placebo (17).
A retrospective, single-center, open-label study in Japan on patients with advanced cancer who were resistant to opioids, such as tramadol, oral oxycodone, and transdermal fentanyl for relief of pain.	Tapentadol was effective in relieving cancer-related neuropathic pain that was refractory to first-line opioid treatment and produced less adverse effects than opioids (23).

Gastrointestinal tolerability demonstrated in clinical trials is expected to improve patient compliance and satisfaction. Tapentadol immediate-release may offer a better option compared with other currently available analgesics for the relief of moderate to severe acute pain. Tapentadol immediate-release has reduced opioid-related gastrointestinal adverse events while maintaining adequate analgesia, but further studies are required to establish its clinical usefulness in relation to that of tramadol and opioids other than oxycodone (13). Tapentadol immediate-release has been evaluated in clinical trials in patients with postoperative pain after bunionectomy, and results show that it has better gastrointestinal tolerability than oxycodone immediate-release at doses that provide comparable analgesia (08).

In well-designed short-term (15 week) clinical studies in adult patients with moderate to severe chronic pain associated with knee osteoarthritis, low back pain, or diabetic neuropathy, extended-release tapentadol 100 to 250 mg twice daily provided more effective pain relief and significantly improved functional outcomes compared with placebo (15). In longer-term studies (> 24 months) analgesic efficacy was maintained without development of tolerance. Results of an observational study have shown the long-term effectiveness, safety, and tolerability of oral prolonged-release tapentadol for the treatment of refractory chronic low back pain in a real-life clinical setting (12).

A systematic review of clinical trials of chronic pain requiring strong step 3 opioids of the WHO pain ladder and comparison to tapentadol showed a better benefit-risk ratio of tapentadol (20).

A summary of several phase 3 studies has shown that use of tapentadol extended-release in patients with moderate to severe chronic pain was associated with better gastrointestinal tolerability and compliance with therapy than controlled-release oxycodone (01). According to an analysis of prospective data from use in clinical practice, tapentadol prolonged-release is effective and can be considered an alternative to strong opioids in the long-term management of chronic pain (22). A retrospective study has found that tapentadol is effective and well tolerated in opioid-naïve and opioid-tolerant patients with cancer pain of varying pathophysiology, including those with nociceptive and/or neuropathic components, and it may be considered for first-line use in moderate-to-severe pain (21).

Results of an observational retrospective study to comparatively assess the efficacy and tolerability of tapentadol in young and elderly patients with severe chronic low back pain show that tapentadol extended-release maintains efficacy and good tolerability in these patients with advancing age (14).

Special considerations

Tapentadol is not recommended in patients with severe renal or hepatic impairment and should be used with caution in patients with moderate impairment of function of these organs. Tapentadol should be prescribed with care in patients with a history of a seizure disorder. The effect of tapentadol on seizures is unknown as such patients were excluded in clinical trials. Withdrawal symptoms may occur if the drug is discontinued abruptly after use for a prolonged period.

Anesthesia. Patients on tapentadol may exhibit additional CNS depression during general anesthesia.

Pediatric. Most the patients in a retrospective observational study that examined the toxic effects of a single dose of tapentadol in the age group 0 to 17 had no adverse effect from the exposure, and only 2 had life-threatening events (03). The most common adverse effects reported were like those that occur with the use of opioids.

Geriatric. Tapentadol should be administered with caution to elderly, debilitated patients who are more likely to suffer respiratory depression. A pooled analysis of randomized clinical trials shows that elderly patients (75 years of age or older) with moderate to severe low back pain obtained significant pain relief from extended-release tapentadol (100 to 250 mg twice daily) compared with placebo, with a better overall gastrointestinal tolerability than controlled-release oxycodone (02).

Pregnancy. There are no adequate and well-controlled studies of tapentadol use in pregnant women. Tapentadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tapentadol is not recommended for use in women during and immediately prior to labor and delivery. Neonates whose mothers have been taking tapentadol should be monitored for respiratory depression. Tapentadol should not be used during breastfeeding as newborn infants are particularly sensitive to the effects of even small dosages of narcotic analgesics. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped or when breastfeeding is discontinued.

References

01: Afilalo M, Morlion B. Efficacy of tapentadol ER for managing moderate to severe chronic pain. Pain Physician 2013;16(1):27-40. PMID 23340531
02: Biondi DM, Xiang J, Etropolski M, Moskovitz B. Tolerability and efficacy of tapentadol extended release in elderly patients ≥ 75 years of age with chronic osteoarthritis knee or low back pain. J Opioid Manag 2015;11(5):393-403. PMID 26535967
03: Borys D, Stanton M, Gummin D, Drott T. Tapentadol toxicity in children. Pediatrics 2015;135(2):e392-6. PMID 25601980
04: Buynak R, Rappaport SA, Rod K, et al. Long-term safety and efficacy of Tapentadol extended release following up to 2 years of treatment in patients with moderate to severe, chronic pain: results of an open-label extension trial. Clin Ther 2015;37(11):2420-38. PMID 26428249
05: Caputi FF, Nicora M, Simeone R, Candeletti S, Romualdi P. Tapentadol: an analgesic that differs from classic opioids due to its noradrenergic mechanism of action. Minerva Med 2019;110(1):62-78.** PMID 30667206
06: Channell JS, Schug S. Toxicity of tapentadol: a systematic review. Pain Manag 2018;8(5):327-39. PMID 30079795
07: Coluzzi F, Fornasari D, Pergolizzi J, Romualdi P. From acute to chronic pain: tapentadol in the progressive stages of this disease entity. Eur Rev Med Pharmacol Sci 2017;21(7):1672-83. PMID 28429337
08: Daniels SE, Golf M. Clinical efficacy and safety of tapentadol immediate release in the postoperative setting. J Am Podiatr Med Assoc 2012;102(2):139-48. PMID 22461271
09: Dart RC, Cicero TJ, Surratt HL, Rosenblum A, Bartelson BB, Adams EH. Assessment of the abuse of tapentadol immediate release: the first 24 months. J Opioid Manag 2012;8(6):395-402. PMID 23264317
10: Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: placement of tapentadol into schedule II. Final rule. Fed Regist 2009;74(97):23790-3. PMID 19507329
11: Ferri CM, Natoli S, Sanz-Ayan P, et al. Quality of life and functional outcomes with tapentadol prolonged release in chronic musculoskeletal pain: post hoc analysis. Pain Manag 2021;11(2):173-87.** PMID 33241725
12: Finco G, Mura P, Musu M, et al. Long-term, prolonged-release oral tapentadol for the treatment of refractory chronic low back pain: a single-center, observational study. Minerva Med 2018;109(4):259-65. PMID 29947490
13: Frampton JE. Tapentadol immediate release: a review of its use in the treatment of moderate to severe acute pain. Drugs 2010;70(13):1719-43. PMID 20731478
14: Freo U, Furnari M, Ambrosio F, Navalesi P. 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. PMID 32418129
15: Hoy SM. Tapentadol extended release: in adults with chronic pain. Drugs 2012;72(3):375-93. PMID 22316353
16: Ko EY, Tupper MW. Tapentadol and sleepwalking: a case report. J Pharm Pract 2021:897190021996975. PMID 33622091
17: Lee YK, Ko JS, Rhim HY, et al. Acute postoperative pain relief with immediate-release tapentadol: randomized, double-blind, placebo-controlled study conducted in South Korea. Curr Med Res Opin 2014;30(12):2561-70. PMID 25133962
18: Mateos RG, Bernal DS, Morera LM, Ferri CM, Escobar AE. Long-term effectiveness and tolerability of pain treatment with tapentadol prolonged release. Pain Physician 2021;24(1):E75-85.** PMID 33400440
19: Niesters M, Proto PL, Aarts L, Sarton EY, Drewes AM, Dahan A. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. Br J Anaesth 2014;113(1):148-56. PMID 24713310
20: Riemsma R, Forbes C, Harker J, et al. Systematic review of tapentadol in chronic severe pain. Curr Med Res Opin 2011;27(10):1907-30. PMID 21905968
21: Sazuka S, Koitabashi T. Tapentadol is effective in the management of moderate-to-severe cancer-related pain in opioid-naïve and opioid-tolerant patients: a retrospective study. J Anesth 2020;34(6):834-40. PMID 32648017
22: Strick V. Management of severe chronic pain with tapentadol prolonged release - long-term data from pain specialists. Curr Med Res Opin 2014;30(10):2085-92. PMID 24983745
23: Sugiyama Y, Kataoka T, Tasaki Y, et al. Efficacy of tapentadol for first-line opioid-resistant neuropathic pain in Japan. Jpn J Clin Oncol 2018;48(4):362-6. PMID 29506199
24: Wild JE, Grond S, Kuperwasser B, et al. Long-term 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. PMID 20602712
25: Zajączkowska R, Przewłocka B, Kocot-Kępska M, Mika J, Leppert W, Wordliczek J. Tapentadol - a representative of a new class of MOR-NRI analgesics. Pharmacol Rep 2018;70(4):812-20. PMID 29921501

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Tapentadol

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Tapentadol

Tapentadol

Tapentadol

Introduction

Overview

Pharmacology

Clinical trials

Table 1. Clinical Trials of Tapentadol

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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	• Patients with significant respiratory depression, acute or severe bronchial asthma, or hypercapnia in unmonitored settings or in the absence of resuscitative equipment.
	• Patients who have or are suspected to have paralytic ileus.
	• Patients currently using, or within 14 days of using, monoamine oxidase inhibitors due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.

Tapentadol

Introduction

Overview

Pharmacology

Clinical trials

Table 1. Clinical Trials of Tapentadol

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Primary headache associated with sexual activity

Primary cough headache

Medications and substances causing headache

Headache in children: overview and treatment approaches

Alternating hemiplegia of childhood

Late-life migrainous accompaniments

Complex regional pain syndrome

Serotonin syndrome

This is an article preview.
Start a Free Account
to access the full version.