Background: Tapentadol, a novel, centrally acting analgesic with 2 mechanisms of action (µopioid receptor agonism and norepinephrine reuptake inhibition), has been developed in an
immediate-release (IR) and an extended-release (ER) formulation. Determination of the safety and
equianalgesic ratios for conversion between formulations is important for physicians with patients
taking tapentadol IR who may want to switch to tapentadol ER, or vice versa, for any reason.
Objectives: To test whether the total daily dose (TDD) of tapentadol IR may be directly converted into
a comparable TDD of tapentadol ER, and vice versa, with equivalent efficacy and comparable safety.
Study Design: Randomized, double-blind, 2-period (2 weeks each) crossover study.
Setting: Study centers (N = 13) in the United States.
Methods: Patients with moderate to severe chronic low back pain received tapentadol IR 50, 75, or
100 mg every 4 or 6 hours (maximum TDD, 500 mg) during the 3-week open-label period to identify
an optimal, stable dose of tapentadol IR for each patient. Patients were then randomized in a 1:1
ratio to receive, during the first 2-week double-blind period, either the optimal dose of tapentadol
IR identified during the open-label period or a TDD of tapentadol ER (100, 150, 200, or 250 mg
bid) that was as close as possible to the TDD of tapentadol IR from the open-label period. During a
subsequent, 2-week double-blind period, patients received whichever formulation was not received
during the first double-blind period. The primary endpoint was the mean average daily pain intensity
(on an 11-point numerical rating scale) during the last 3 days of each double-blind treatment period.
If the 95% confidence intervals (CIs) of the least squares mean difference between formulations
were within the range of −2 to 2, the formulations were considered equivalent.
Results: Of the 88 patients who were randomized, 72 completed both double-blind treatments,
and 60 were included in the per-protocol analysis. The mean (standard deviation [SD]) pain
intensity score decreased from 7.3 (1.19) pre-treatment to 4.2 (2.13) after 3 weeks of open-label
treatment with tapentadol IR and remained constant throughout double-blind treatment (3.9 or
4.0 each week) for both formulations. The mean (SD) of the average pain intensity scores over
the last 3 days of double-blind treatment was 3.9 (2.17) with tapentadol IR and 4.0 (2.29) with
tapentadol ER, for an estimated difference of 0.1 (95% CI, −0.09 to 0.28). For both tapentadol IR
and tapentadol ER, the median TDD administered was 300.0 mg, and acetaminophen was used by
39.5% and 45.2% of patients, respectively. The incidence of treatment-emergent adverse events
during double-blind treatment was similar between the tapentadol IR and tapentadol ER groups.
Limitations: Use of rescue medication theoretically could have influenced pain measurements,
but in practice, pain measurements did not differ between treatments.
Conclusions: Approximately equivalent TDDs of tapentadol IR and tapentadol ER provided
equivalent analgesic efficacy for the relief of moderate to severe chronic low back pain and were
similarly well tolerated, allowing for direct conversion between the 2 formulations.
Key words: Chronic low back pain, conversion, efficacy, equivalence, extended release,
immediate release, opioid, safety, tapentadol
Measuring Opioid Withdrawal in a Phase 3 Study of a New Analgesic, NKTR-181 (Oxycodegol), in Patients with Moderate to Severe Chronic Low Back Pain