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FDA Approves Tapentadol for Relief of Moderate to Severe Acute Pain

Ellis, Fay Jarosh

doi: 10.1097/01.NT.0000345154.37659.2b

In November, the FDA approved tapentadol hydrochloride, a centrally acting analgesic, for relief of moderate to severe acute pain. The drug was reported to have fewer adverse effects than existing pain therapies such as opioids.

Tapentadol has two mechanisms of action, combining mu-opioid receptor agonism and also inhibition of the reuptake of norepinephrine. Mu-opioid agonists bind to and activate mu-opioid receptors in the CNS, modifying sensory and affective aspects of pain; norepinephrine reuptake inhibitors increase the level of noradrenaline in the brain by inhibiting its absorption into nerve cells.

The FDA based its approval on data from several phase 3 studies reported at the American Pain Society annual meeting last May. In three separate trials involving a total of 2,100 patients, investigators reported significant pain relief compared with placebo for foot surgery; end-stage joint disease; and low backache or osteoarthritis of the hip and knees.

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In one double-blind, randomized, placebo controlled trial, 659 candidates for primary joint replacement surgery for end-stage joint disease were randomly assigned to an oral dose of placebo, tapentadol 50 mg or 75 mg, or oxycodone 10 mg every four to six hours. Oxycodone and tapentadol were similarly effective for pain as compared with placebo (p<0.001) when assessed over five days of treatment. But 52 percent of tapentadol patients had adverse effects, compared with 84 percent of those taking oxycodone.

There were significantly fewer gastrointestinal problems, the lead author Craig T. Hartrick, MD, director of anesthesiology research at William Beaumont Hospital in Royal Oak, MI, reported at the American Pain Society meeting. Dr. Hartrick is a consultant to Johnson and Johnson Pharmaceutical Research & Development, which manufactures the drug and sponsored the study.



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In another phase 3 trial, 878 patients with low back pain or osteoarthritis of the knee or hip were treated with 50 mg or 100 mg of tapentadol every four to six hours, up to a maximum of 600 mg daily, or a flexible dose of 10 mg or 15 mg of oxycodone every four to six hours, up to 90 mg daily for up to 90 days. Both drugs offered pain relief, but those taking tapentadol had significantly fewer adverse events — 76 percent versus 83 percent (for oxycodone). The most common adverse events were nausea, vomiting, dizziness, constipation, headache, and drowsiness.

The rate for discontinuing the drugs due to adverse effect were significantly different — 40 percent for oxycodone and 20 percent for tapentadol, similar to the results of the study for bunionectomy.

Asked to comment on the FDA approval, pain expert Misha-Miroslav Backonja, MD, professor of neurology at the University of Wisconsin-Madison, told Neurology Today that tapentadol represents an incremental improvement over older pharmacological options for treatment of moderate to severe pain — which, in neurological practice, is most commonly associated with neuropathy, spinal disorder, and headache.

Dr. Backonja, who was not involved with any of the studies, said the data comparing tapentadol with oxycodone for back pain for up to 90 days is worth noticing, adding: “One would probably need lesser amount of the mu-opioid effects to get the analgesic effect and consequently there would be fewer gastrointestinal events.”

He noted, however, that tapentadol “has adverse effects similar to those in the drug class for opioids and noradrenergic tricyclic antidepressants (TCAs), which is a lot to be concerned about.” Those adverse effects include respiratory depression, hypoventilation, and intracranial pressure (with opioids), and tremulousness, increased blood pressure and heart rate and seizures (with noradrenergic TCAs).

In addition, he noted that it is assumed to have opioid abuse liability.

Russell Portenoy, MD, who was not involved in the studies, noted that the non-opioid mechanism could also impart a risk of serotonin syndrome if combined with other serotonergic compounds.

“In short, neurologists can soon consider the use of tapentadol in all situations that are now being addressed with other opioid drugs, including tramadol and the pure mu agonists,” said Dr. Portenoy, chairman of the department of pain medicine and palliative care at Beth Israel Medical Center, and professor of neurology and anesthesiology at the Albert Einstein College of Medicine in New York.

“Given the variation in patient response to opioids and other analgesics,” he continued, “it is likely that some patients will respond very well to this compound, and others will not. It is too early to determine whether the drug represents a significant advance in analgesia, but the possibility of a relatively reduced risk of gastrointestinal toxicity is positive and requires further evaluation.”

Dr. Backonja added that although the new drug would be useful for managing intermittent acute pain on a limited basis, it is not yet ready for managing chronic pain. There are multiple mechanisms at work with pain associated with complex neurological conditions, Dr. Backonja explained, so he recommends multimodal, multidisciplinary therapies that target specific disease-related mechanisms.



At press time, tapentadol was being reviewed by the US Drug Enforcement Agency for classification as a controlled substance; after receiving its classification, the new drug will be available for sale.

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• Stegmann JU, Weber H, Daniels S, et al. The efficacy and tolerability of multiple-dose tapentadol immediate release for the relief of acute pain following orthopedic (bunion-ectomy) surgery. Curr Med Res Opin 2008: E-pub 2008 Oct. 10.
    ©2009 American Academy of Neurology