#228 Tapentadol

FAST FACTS AND CONCEPTS #228

TAPENTADOL

Rohtesh S Mehta MD, MPH and Robert M Arnold MD

Background
Tapentadol is a newly available oral analgesic, approved by the FDA in 2009 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 which also inhibits norepinephrine and serotonin reuptake within the CNS. It is structurally and pharmacologically similar to tramadol.

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 (1).

There are no dosing adjustments required in mild-to-moderate renal or hepatic failure; it has not been studied in patients with severe impairments.


Research Data
The FDA approval was based on two industry-coordinated, randomized controlled studies conducted in patients with osteoarthritis and after bunionectomy. In these studies 50 mg doses 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 (2,3). In another single-dose study involving patients undergoing molar extraction, tapentadol 200 mg demonstrated improved analgesia but higher sedation than 60 mg of oral morphine (4). Total daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been tested, nor has tapentadol been studied in children. Tapentadol has not been tested in cancer pain or in palliative care settings. There are not enough data to comment on whether the drug has a ceiling effect, or on its long-term safety and efficacy (the longest study was only 90 days). Finally, it has not been comparatively studied against tramadol.


Side Effects and Cautions
Tapentadol’s side effect profile is generally similar to opioids’ (although with milder GI side effects): nausea, vomiting, constipation, respiratory depression, pruritus, dizziness and drowsiness. As with tramadol, there is a theoretical increased risk of seizures, as well as serotonin syndrome if given with other serotonergic agents (e.g. antidepressants, drugs with monamine oxidase inhibitory effects). Abuse and addiction are possible as with any opioid agonist. An abstinence syndrome has not yet been described; in one study drug tapering was not required after 90 days of treatment (2).


Dosing and Cost
Tapentadol is available as 50, 75 and 100 mg immediate-release tablets. The initial dose is 50-100 mg every 4 hours (although a second dose can be given one hour after the initial dose). The average wholesale pricing for tapentadol is approximately $2 per 50 mg tab, $2.40 per 75 mg tab, and $3.20 per 100 mg tab. For comparison, tramadol costs $0.07/tab (50 mg), oxycodone costs $0.70 (15 mg tab), and morphine costs $0.18 (15 mg tab).


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, potential ceiling effect, safety concerns with drug interactions, and uncertainty about long-term efficacy and safety limit its current application otherwise, particularly in patients with chronic cancer pain.


References

1. 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.
2. 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
3. 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.

4. 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.
Author Affiliations: University of Pittsburgh Medical Center, Pittsburgh, PA.

Fast Facts and Concepts are edited by Drew A. Rosielle MD, Palliative Care Center, Medical College of Wisconsin. For more information write to: drosiell@mcw.edu. More information, as well as the complete set of Fast Facts, are available at EPERC: http://www.mcw.edu/eperc.


Copyright/Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Rohtesh MS, Arnold RM. Tapentadol. Fast Facts and Concepts. XXXX 2010; 228. Available at: http://www.eperc.mcw.edu/fastfact/ff_228.htm.