Methodological Issues on a Clinical Trial to Test Tapentadol Prolonged release vs. Oxycodone/Naloxone Prolonged release

To the Editor: A recent article by Baron et al. reports the results of a clinical trial (CT) to compare the effectiveness of tapentadol with oxycodone/ naloxone (Ox/Nal) for the treatment of chronic low back pain of neuropathic origin. This study is a remarkable attempt to progress in this area. We argue, however, that it contains several drawbacks that leave open ground for further trials with more stringent methodological controls. The double-blind design: The preventive effect of double-blinding against the effects of placebo and nocebo has been extensively documented in the literature. The decision to perform an open-label trial runs contrary to the basic rules of CTs. The use of pickup arms: Using “pickup or rescue arms” prevents the evaluation of the superiority of one treatment over another. In the reviewed trial, there are other reasons that render the use of a rescue arm doubly questionable: The first is the asymmetry which allows to use tapentadol under some subjective conditions of lack of efficacy of Ox/Nal, but not the other way around; the second is that the use of this “rescue arm” is combined with the open-label design and prior information to the patient. This leads to unmanageable biases when combined with the use of prior treatments without full equipoise. Dynamics of titration: In CTs aimed at comparing drugs, it is essential to consider pharmacokinetic characteristics of the drugs. In the evaluated study, the comparison was not performed according to this principle because the administration of Ox/Nal did not comply with the established guidelines neither in dose titration nor in titration intervals. They were however adapted to tapentadol guidelines. Criteria for continuation or discontinuation during titration period: The literature favors the use of validated numerical scales sensitive to changes in chronic pain intensity. The use of these scales requires a rigorous control of reproducibility. In the reviewed study, two alternative criteria were formulated to enter the maintenance period, which are based essentially on the same metric, although with different cutoff points. In any case, it is essential to report the quantitative pain reduction achieved up to that point in each trial arm. On the inclusion criteria: The selection of patients not previously exposed (na€ıve) to the use of opioids is a logical criterion. On the same ground, we wonder why the protocol allowed to select patients under treatment with co-analgesics, with lower levels of pain than the rest of patients and with a negative score in the scale painDETECT. The use of the last observation carried forward (LOCF) for imputing the missing data: This method is based on the assumption that the time series is stationary, which does not appear to be a realistic assumption in this trial because it entails the assumption that the patient’s perception of change remains constant.