Abstract: We included four studies with 1029 participants. All the studies used a parallel-group design, and included an initial titration phase to determine the maximum effective and tolerated dose, followed by a maintenance phase. Tapentadol medication was taken twice daily and doses ranged from 50 to 500 mg per day. Rescue medication (morphine or oxycodone immediate-release) was available to participants in all studies. Overall, 440 participants were randomised in classically designed RCTs, and 589 participants were enrolled in enriched-enrolment, randomised-withdrawal (EERW) trials. A total of 476 participants were randomised to titration with tapentadol and 338 participants took tapentadol throughout the maintenance phase of their trial. All studies used numerical rating scores, Patient Global Impression of Change scores, and use of rescue medication as measures of efficacy, and all reported on adverse events and withdrawals. All studies enrolled fewer than 200 participants per treatment arm and were therefore at risk of overestimating efficacy. One study was terminated early due to problems with supply of rescue medication, with fewer than 20 participants enrolled per treatment arm in the maintenance phase of the trial. We judged another study at high risk of bias due to an open-label design. There were insufficient data for pooling and statistical analysis. Response rates for pain intensity were comparable across treatment groups in each study. In one EERW study, response rates were high across both treatment and placebo arms during the maintenance phase (62% tapentadol, 69% morphine, 50% placebo). For pain relief, tapentadol is no more and no less effective than oxycodone or morphine (low quality evidence). Treatment emergent adverse event rates were high, approximately 50% to 90%. The most common adverse events were gastrointestinal (nausea, vomiting, constipation) (low quality evidence). There was no advantage of tapentadol over morphine or oxycodone in terms of serious adverse events. The number of people experiencing effects on consciousness, appetite, or thirst was low. Information from RCTs on the effectiveness and tolerability of tapentadol was limited. The available studies were of moderate or small size and used different designs, which prevented pooling of data. Pain relief and adverse events were comparable between the tapentadol and morphine and oxycodone groups.

Plain-language summary: We found four studies with 1029 participants. All four studies compared participants taking tapentadol to participants taking similar medicine, such as morphine or oxycodone. All studies gave participants a period of time to find the best dose to take, before continuing on the medication and comparing their pain levels. All the studies were small or medium sized, so the results are at risk of being influenced by random fluctuations rather than real differences, and they may also overestimate any effects. One trial allowed participants to know what medication they were taking, and one trial was stopped early due administrative problems, so they did not have enough people in the study. We have to be cautious interpreting results from these studies. Because the studies all used different designs, we could not compare the results from one with another. However, each study showed that there was not much difference between the pain levels of people taking tapentadol and people taking morphine and oxycodone. Pain levels were generally well controlled. The studies also showed there was no measurable difference in how many adverse effects people had while taking tapentadol, morphine, or oxycodone. Therefore, we can conclude only that the studies to date show tapentadol was no more or less effective and no more or less well tolerated than morphine and oxycodone.