A Model-Based Meta-analysis to Compare Efficacy and Tolerability of Tramadol and Tapentadol for the Treatment of Chronic Non-Malignant Pain

Abstract

Introduction: Pain is a major symptom in many medical conditions which can be relieved thanks to analgesics. The goal of this work was to present an indirect comparison of efficacy and tolerability profiles of two analgesics, tramadol and tapentadol, in patients with chronic non-malignant pain.

Methods: In the absence of a head-to-head comparison between these two opioid drugs, model-based meta-analyses were used to characterize the pain intensity time dynamics and evaluate the proportions of most frequent adverse events (constipation, nausea, vomiting, dizziness, and somnolence) and drop-outs (due to adverse event, as well as due to lack of efficacy) in each treatment group. Using these models, the investigational treatments were compared on the basis of Monte Carlo simulation outcomes.

Results: Data were extracted from 45 Phase II and Phase III studies representing a total of 81 treatment arms, i.e., approximately 13,000 patients. The pain intensity model shows, that after having adjusted for differences in baseline pain intensity and placebo effects, tramadol 300 mg once daily (qd) was slightly more effective in reducing pain than tapentadol 100-250 mg twice daily (bid), with a 46% change from baseline for the former versus 36% for the latter. From a tolerability standpoint, both drugs showed, as expected, increased risks of adverse events compared to placebo. Yet, tapentadol was associated with slightly lower risks of constipation, and nausea than tramadol.

Conclusion: Overall, the analysis showed that the benefit-risk profiles of tramadol 300 mg qd and tapentadol 100-250 mg bid were approximately even. The amount of data to characterize dose-response relationships was sufficient only in the tramadol group; public access to tapentadol efficacy and tolerability readouts across a wide dose range in chronic non-malignant pain would allow a comparison of therapeutic indices, a straight quantitation of the benefit-risk ratio. Knowing that their side-effects have been identified as potential hindrance to prescription, a broad and open access to clinical trial data in this indication is encouraged in order to facilitate the evaluation of the opiate analgesics clinical utility.

Figures

Fig. 1

Pain intensity (normalized to a 0–10 scale) over time, in patients treated for chronic non-malignant pain, with placebo, tapentadol, or tramadol. Each circle represents the arm-level average score, with a diameter proportional to the sample size in the arm. The outer curves give the 95% predictive interval and the bold curve the predicted median, using the final pain intensity model

Fig. 2

Distribution of 1,000 differences in predicted group-level pain intensity (normalized to a 0–10 scale) after 12 weeks of treatment with tramadol (300 mg one daily) versus tapentadol (100–250 mg twice daily) (ΔPI). Predictions of pain intensity were simulated from the final model, assuming 1,000 patients per arm. The plain and dashed vertical lines materialize the median and 95% prediction interval, respectively

Fig. 3

From left to right number of arms (Narms), frequency of adverse event, odds-ratio (with 95% confidence interval) for the active groups versus placebo and odds-ratio (with 95% confidence interval) for tramadol (300 mg once daily) versus tapentadol (100–250 mg twice daily), for each type of adverse event (Constip. constipation, Dizzin. dizziness, Somnol. somnolence)

Fig. 4

From left to right number of arms (Narms), proportion of drop-out patients, odds-ratio (with 95% confidence interval) for the active groups versus placebo, and odds-ratio (with 95% confidence interval) for tramadol (300 mg once daily) versus tapentadol (100–25/0 mg twice daily), per reason of withdrawal (DO.AE, drop-out due to adverse event; or DO.LoE, drop-out due to lack of efficacy)