Tapentadol Effective and Safe for Relief of Moderate-to-Severe Chronic Pain Due to Osteoarthritis of the Knee: Presented at EULAR
By Chris Berrie
BARCELONA, SPAIN -- June 17, 2007 -- The novel centrally-acting analgesic tapentadol shows good tolerability and is effective in the treatment of patients with moderate-to-severe chronic knee pain due to osteoarthritis, according to a multicentre, randomized, double-blind, placebo-controlled trial.
Researchers presented the findings here on June 16th at EULAR 2007, the 8th Annual European Congress of Rheumatology, of the European League Against Rheumatism.
While opioids are effective for treatment of chronic pain, such as that in osteoarthritis, they also show increased incidence of gastrointestinal and nervous system adverse effects.
Tapentadol was developed in the search for better analgesics to treat chronic pain in osteoarthritis. It has a dual mode of action, both as an agonist of the mu opioid receptor (MOR) and as a noradrenaline reuptake inhibitor.
"There is a potential benefit in the side effects [of tapentadol] because the affinity to the mu receptor is lower than for morphine, so the typical mu-receptor side effects are lower than for morphine-like drugs," said Claudia Lange, MD, PhD, clinical project leader, Grünenthal GmbH, Aachen, Germany.
Thus, its successful use in preclinical pain models is believed to arise through this dual mode of action.
The objective of the research was to determine the efficacy and tolerability of an extended-phase form of tapentadol in comparison with placebo and a positive control of controlled-release oxycodone HCl.
The main inclusion criteria were patients 40 years and older with a body mass index no greater than 45 kg/m2 who showed moderate-to-severe chronic pain due to arthritis of the knee, defined as American College of Rheumatology (ACR) criteria. There were also a number of standard general exclusion criteria indicated.
The flare state was defined as a treatment-washout period of 3 to 7 days, as mean pain intensity during the preceding 24 hours of 50 mm or greater on a visual analogue scale (VAS) from 0 mm (no pain) to 100 mm (worse pain imaginable), and a increase of 18 mm or greater relative to the VAS at the start of the washout.
Patients were randomized to one of four treatment groups: placebo (n = 167; mean age, 57.4 years; male, 41%) or the up-titrated maintenance doses of 100 mg (n = 162; mean age, 56.8 years; male, 39%) or 200 mg (n = 167; mean age, 58.1 years; male, 35%) tapentadol, or 20 mg oxycodone HCl (n = 169; mean age, 57.8 years; male, 36%), with each agent taken twice daily over a total of 28 days. The drug tapers over the first 14 days were: 25, 50 and 100 mg and 100, 150, 200 mg for tapentadol, and 10, 10, 20 mg for oxycodone HCl.
As rescue medication, patients were allowed up to 1,000 mg/day acetaminophen, except during the 24 hours prior to each weekly visit.
The primary endpoint was mean pain intensity over the preceding 24 hours according to the VAS scale, as evaluated on day 29 (end of trial).
Accordingly, the higher of the tapentadol doses provided significant improvement in pain intensity over placebo, as mean changes from baseline of average pain intensities: -45.3 versus -36.8 (P =.021). Significance was not reached over placebo for 100 mg tapentadol and 20 mg oxycodone HCl (-42.9 and -41.8, respectively).
Treatment tolerability, specifically for gastrointestinal and nervous system disorders, were also assessed. Patient percentages experiencing these tapered off across the treatment groups from oxycodone HCl through 200 mg and 100 mg tapentadol to placebo, respectively: gastrointestinal, 56%, 49%, 30%, 23%; nervous system, 43%, 34%, 24%, 15%.
"Thus, we have shown good efficacy in osteoarthritis patients, and we have also seen a very good side effect profile, so we really hope to bring forward a drug that has a lot of benefit to the patient," said co-investigator Christine Rauschkolb-Loeffler, MD, PhD, project leader and compound development team leader, Johnson & Johnson Pharmaceutical Research and Development, Titusville, New Jersey, United States.
Dr. Lange noted that there was a clearly reduced incidence of constipation seen in not just the placebo group but also at both 100 mg and 200 mg tapentadol, with respect to that seen for oxycodone HCl (5%, 7%, 10% and 20%, respectively).
Thus, when tapered up to 200 mg, tapentadol was effective in the primary efficacy endpoint for up to 4 weeks in this treatment of patients with moderate-to-severe chronic pain due to osteoarthritis of the knee. It was also noted that the lower dose of tapentadol (100 mg) was as effective as 20 mg oxycodone HCl, although the benefits of both of these treatments did not reach significance over placebo.
Use of tapentadol also showed an interesting improved tolerability when compared with oxycodone HCl, while also showing unexpectedly large reductions in the incidence of constipation.
This research was sponsored by Grünenthal GmbH and Johnson & Johnson.
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