Abstract

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 noradrenaline 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 (the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and 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 versus placebo and tapentadol extended release versus active control (oxycodone). We used random‐effects models when there was heterogeneity and fixed‐effect models when there was no heterogeneity. In addition, 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). The primary safety outcome was withdrawal rate due to adverse effects.

Main results

Four parallel‐design RCTs of moderate quality including 4094 participants 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 people with knee osteoarthritis, one evaluated people with low back pain, and one enrolled both. All studies reported last‐observation‐carried‐forward (LOCF) as the imputation method. We requested baseline‐observation‐carried‐forward (BOCF) imputed analyses and any unpublished data from the manufacturers but the manufacturers denied the request. Two of the four oxycodone‐controlled studies and one of the three placebo‐controlled studies did not provide data on responder rate. We considered two studies 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). There was moderate‐to‐high heterogeneity 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 point reduction (95% CI ‐0.43 to ‐0.05) 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 participants. Tapentadol was associated with a 50% risk reduction (95% CI 42% to 60%) of discontinuing treatment due to adverse effects (NNTH 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. There was moderate‐to‐high heterogeneity for most efficacy (except for the primary outcome) and safety outcome estimates. Subgroup analysis showed a higher improvement with tapentadol among people 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 was 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 the impossibility of using BOCF as the imputation method. Tapentadol is associated with a more favourable safety profile and tolerability than oxycodone.

Author(s)

João Santos, Joana Alarcão, Filipa Fareleira, António Vaz Carneiro, João Costa

Abstract

Plain language summary

Tapentadol for chronic musculoskeletal pain in adults

Pain in bones, joints, and muscles is very common and can often be persistent. It is expected that 50% of the general population will suffer from this type of pain for at least three months or longer during their lifetime. This condition is called chronic musculoskeletal pain.

Opioids are a type of strong pain‐killer drug that are used to treat people that have moderate‐to‐severe chronic pain. People taking these drugs frequently have side effects, including severe side effects.

This Cochrane review aimed to assess the effectiveness (reduction in pain intensity) and safety of tapentadol (a new opioid) in moderate‐to‐severe chronic musculoskeletal pain, in comparison to placebo (a pretend medicine) and other drugs that work for such pain.

We performed a literature search in March 2014 for studies that compared tapentadol with placebo or other drugs in adults with musculoskeletal pain.

We found four studies comparing tapentadol with placebo or oxycodone (another opioid) in 4094 adults.

There was moderate‐quality evidence that 3 out of 10 people treated with tapentadol had at least 50% pain reduction (responded to the treatment) while only 2 out of 10 people treated with oxycodone and placebo responded to the treatment.

There was also moderate‐quality evidence that tapentadol‐treated people were at a higher risk of withdrawal from the trial due to side effects in comparison to placebo (2 out of 10 tapentadol‐treated people and 1 out of 10 placebo‐treated people). For oxycodone‐treated people, 4 out of 10 withdrew due to side effects. Constipation, nausea and vomiting, and itching (pruritus) were less with tapentadol than with oxycodone but there was no difference in fatigue, insomnia, sleepiness (somnolence), and headache.

The overall clinical benefit of tapentadol in moderate‐to‐severe chronic musculoskeletal pain found in clinical trials was relatively small (a common conclusion found in all opioids trials for chronic pain). Further studies are needed to find out which people with chronic musculoskeletal pain would benefit the most from this new opioid.

Author(s)

João Santos, Joana Alarcão, Filipa Fareleira, António Vaz Carneiro, João Costa

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Four included trials provided data (of moderate quality) and evidence for the use of tapentadol extended release. There was insufficient evidence to support (or not support) its use and its efficacy in achieving relief from moderate‐to‐severe chronic musculoskeletal pain, in doses of 200 to 500 mg/day.

In this Cochrane review, we found tapentadol to improve pain control slightly in comparison to placebo and oxycodone and to have a better safety and tolerability profile than oxycodone. However, this difference in terms of pain reduction was small. The available evidence showed more consistent results for people with osteoarthritis of the knee than for people with low back pain.

Although a relatively large number of participants were enrolled in the included studies, the number of studies was relatively low, heterogeneity was high for some efficacy and safety outcomes, and withdrawal rates were high in all studies. This may be responsible for some overestimation of tapentadol efficacy. Furthermore, the available evidence did not allow a clear assessment of function and quality of life improvement. Most included studies were of 12‐week duration and further long‐term studies are needed in order to determine tapentadol safety and tolerability in longer periods. Therefore, caution is warranted in making definitive conclusions.

For clinicians treating moderate‐to‐severe chronic musculoskeletal pain, the safety profile of tapentadol may prove advantageous, while the overall clinical benefit of tapentadol in terms of pain reduction will probably be small.

Implications for research 

We did not have access to the full research data produced so far for tapentadol in chronic musculoskeletal pain. Therefore, it is difficult to determine which and how many resources should be invested in future research.

Nevertheless, we suggest that future research evaluates other musculoskeletal conditions associated with chronic pain (eg fibromyalgia or generalised musculoskeletal pain). Currently, we only have data for chronic low back pain and knee osteoarthritis. We need to understand which people benefit most from this treatment or if there is any particular subgroup where the treatment is detrimental. In that sense, further trials of people with osteoarthritis or low back pain may be of use.

Researchers should be demanding with the outcomes, and include, by default, responder's rate (at least 50% pain relief) or pain no worse than mild. These data were not available for all tapentadol trials and should be presented in future trials. It is also important that future trials report their main results using the baseline‐observation‐carried‐forward imputation method for missing data. This is particularly relevant in conditions where withdrawal rate is high, such as chronic pain.

Well‐designed pragmatic studies are also required to characterise long‐term efficacy and safety better, as well as to confirm the clinical benefit in terms of function, quality of life, and other participant‐related outcomes.

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