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Tapentadol Effective and Safe for Relief of Moderate-to-Severe Chronic Pain Due to Osteoarthritis of the Knee
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 multicenter,
randomized, double-blind, placebo-controlled trial.
Researchers presented the findings here on June 16th at the Annual European Congress of Rheumatology (EULAR).
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
(worst pain imaginable), and an 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, 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
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, was 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 coinvestigator Christine Rauschkolb-Loeffler, MD, PhD,
project leader and compound development team leader, Johnson &
Johnson Pharmaceutical Research and Development, Titusville, New
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
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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