Background: Chronic musculoskeletal pain is a prevalent condition and a major cause of disability and absence from the workplace worldwide. Opioids are frequently used to treat chronic pain, although adverse effects often restrict their long-term benefits. Tapentadol is an opioid and norepinephrine re-uptake inhibitor, which may cause a lower incidence (and severity) of adverse effects compared to other strong opioids.
Objectives: To determine the efficacy, safety and tolerability of tapentadol extended release for moderate-to-severe pain for at least three months for any musculoskeletal cause.
Search methods: We searched electronic databases (CENTRAL, MEDLINE, EMBASE, Web of Science) to March 2014, unrestricted by language, as well as trials registers and reference lists from retrieved studies. We contacted drug manufacturers for further information.
Selection criteria: Randomised controlled trials (RCTs) of tapentadol in people with chronic musculoskeletal pain, compared to placebo or active control.
Data collection and analysis: Two review authors independently selected trials for inclusion, assessed risk of bias of included studies and extracted data. We performed two meta-analyses for the comparisons tapentadol extended release vs. placebo, and tapentadol extended release vs. active-control (oxycodone). We used random-effects and fixed-effect models according to the presence or not of heterogeneity, respectively. Also, we performed subgroup analyses. The primary efficacy outcome was pain control assessed by change in pain intensity scores and responder's rate (at least 50% pain relief). Primary safety outcome was withdrawal rate due to adverse effects.
Main results: Four parallel-design RCTs of moderate quality including 4094 patients with osteoarthritis or back pain, or both, met the inclusion criteria. Three trials were phase III studies with 12-weeks follow-up and the fourth trial was an open-label safety study of 52-weeks follow-up. All trials were oxycodone-controlled and three were also placebo-controlled. Two trials included patients with knee osteoarthritis, one evaluated patients with low back pain and one enrolled both. All studies reported last-observation-carried-forward (LOCF) as imputation method. We requested baseline-observation-carried-forward (BOCF) imputed analyses and any unpublished data from the manufacturer but the manufacturers denied the request. Two out of the four oxycodone-controlled studies and one out of the three placebo-controlled studies did not provided data on responder's rate. Two studies were considered to be of high risk of bias.In comparison to placebo, tapentadol was associated with a mean reduction of 0.56 points (95% confidence interval (CI) 0.92 to 0.20) in the 11-point numerical rating scale (NRS) at 12 weeks and with a 1.36 increase (95% CI 1.13 to 1.64) in the risk of responding to treatment (number needed to treat for an additional beneficial outcome (NNTB) 16; 95% CI 9 to 57, for 12-weeks). Moderate-to-high heterogeneity was found for the efficacy outcome estimates. Tapentadol was associated with a 2.7 fold increase (95% CI 2.05 to 3.52) in the risk of discontinuing treatment due to adverse effects number needed to treat for an additional harmful outcome (NNTH) 10; 95%CI 7 to 12, for 12 weeks).In comparison to oxycodone, pooled data showed a 0.24 points (95%CI 0.43 to 0.05) reduction in pain intensity from baseline in the 11-point NRS. The two studies that evaluated responder's rate showed a non-significant 1.46 increase (95% CI 0.92 to 2.32) in the risk of responding to treatment among tapentadol treated patients. Tapentadol was associated with a 50% risk reduction (95% CI 42% to 60%) of discontinuing treatment due to adverse effects (NNTB 6; 95% CI 5 to 7, for 12 weeks). Tapentadol was also associated with a 9% reduction (95% CI 4 to 15) in the overall risk of adverse effects (NNTH 18; 95% CI 12 to 35, for 12 weeks) and with a non-significant 43% reduction (95% CI 33 to 76) in the risk of serious adverse effects. Moderate to high heterogeneity was found for most efficacy (except for the primary outcome) and safety outcome estimates. Subgroup analysis showed a higher improvement with tapentadol among patients with knee osteoarthritis and among pooled results from studies of higher quality and shorter follow-up period, although there were no statistical significant differences in the effect size between these subgroups.
Authors' conclusions: Tapentadol extended release is associated with a reduction in pain intensity in comparison to placebo and oxycodone. However, the clinical significance of the results is uncertain due to the following reasons: modest difference between interventions in efficacy outcomes, high heterogeneity in some comparisons and outcomes, high withdrawals rates, lack of data for the primary outcome in some studies and impossibility to use BOCF as imputation method. Tapentadol is associated with a more favourable safety profile and tolerability than oxycodone.