Abstract

Background

This is an update of an earlier review that considered both neuropathic pain and fibromyalgia (Issue 6, 2014), which has now been split into separate reviews for the two conditions. This review considers neuropathic pain only.

Opioid drugs, including oxycodone, are commonly used to treat neuropathic pain, and are considered effective by some professionals. Most reviews have examined all opioids together. This review sought evidence specifically for oxycodone, at any dose, and by any route of administration. Separate reviews consider other opioids.

Objectives

To assess the analgesic efficacy and adverse events of oxycodone for chronic neuropathic pain in adults.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from inception to 6 November 2013 for the original review and from January 2013 to 21 December 2015 for this update. We also searched the reference lists of retrieved studies and reviews, and two online clinical trial registries. This update differs from the earlier review in that we have included studies using oxycodone in combination with naloxone, and oxycodone used as add‐on treatment to stable, but inadequate, treatment with another class of drug.

Selection criteria

We included randomised, double‐blind studies of two weeks' duration or longer, comparing any dose or formulation of oxycodone with placebo or another active treatment in chronic neuropathic pain.

Data collection and analysis

Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and numbers needed to treat for one additional event, using standard methods.

We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table.

Main results

The updated searches identified one additional published study, and one clinical trial registry report. We included five studies reporting on 687 participants; 637 had painful diabetic neuropathy and 50 had postherpetic neuralgia. Two studies used a cross‐over design and three used a parallel group design; all studies used a placebo comparator, although one study used an active placebo (benztropine). Modified‐release oxycodone (oxycodone MR) was titrated to effect and tolerability. One study used a fixed dose combination of oxycodone MR and naloxone. Two studies added oxycodone therapy to ongoing, stable treatment with either pregabalin or gabapentin. All studies had one or more sources of potential major bias.

No study reported the proportion of participants experiencing 'substantial benefit' (at least 50% pain relief or who were very much improved). Three studies (537 participants) in painful diabetic neuropathy reported outcomes equivalent to 'moderate benefit' (at least 30% pain relief or who were much or very much improved), which was experienced by 44% of participants with oxycodone and 27% with placebo (number needed to treat for one additional beneficial outcome (NNT) 5.7).

All studies reported group mean pain scores at the end of treatment. Three studies reported a greater pain intensity reduction and better patient satisfaction with oxycodone MR alone than with placebo. There was a similar result in the study adding oxycodone MR to stable, ongoing gabapentin, but adding oxycodone MR plus naloxone to stable, ongoing pregabalin did not show any additional effect.

More participants experienced adverse events with oxycodone MR alone (86%) than with placebo (63%); the number needed to treat for an additional harmful outcome (NNH) was 4.3. Serious adverse events (oxycodone 3.4%, placebo 7.0%) and adverse event withdrawals (oxycodone 11%, placebo 6.4%) were not significantly different between groups. Withdrawals due to lack of efficacy were less frequent with oxycodone MR (1.1%) than placebo (11%), with a number needed to treat to prevent one withdrawal of 10. The add‐on studies reported similar results.

We downgraded the quality of the evidence to very low for all outcomes, due to limitations in the study methods, heterogeneity in the pain condition and study methods, and sparse data.

Authors' conclusions

There was only very low quality evidence that oxycodone (as oxycodone MR) is of value in the treatment of painful diabetic neuropathy or postherpetic neuralgia. There was no evidence for other neuropathic pain conditions. Adverse events typical of opioids appeared to be common.

Author(s)

Helen Gaskell, Sheena Derry, Cathy Stannard, R Andrew Moore

Abstract

Plain language summary

Oxycodone for neuropathic pain in adults

Bottom line

There is no good evidence that oxycodone works in pain from diabetic neuropathy or postherpetic neuralgia. No studies have reported its use in other types of neuropathic pain.

Background

Neuropathic pain is pain coming from damaged nerves. It is different from pain messages that are carried along healthy nerves from damaged tissue (eg a fall or cut, or arthritic knee). Neuropathic pain is often treated by different medicines (drugs) to those used for pain from damaged tissue, which we often think of as painkillers. For example, medicines that are used to treat depression or epilepsy (fits) can be very effective in some people with neuropathic pain. But sometimes opioid painkillers are used to treat neuropathic pain.

Opioid painkillers are drugs like morphine. Morphine is derived from plants, but many opioids are also made by chemical synthesis rather than being extracted from plants. Oxycodone is a semi‐synthetic opioid, manufactured from the opioid alkaloid thebaine.

This review is part of an update of an earlier review, Oxycodone for neuropathic pain and fibromyalgia in adults, that has now been split into separate reviews for the two conditions. This review focuses only on neuropathic pain.

Study characteristics

In December 2015, we updated searches from an earlier Cochrane review to look for clinical trials that used oxycodone to treat neuropathic pain in adults. We found two additional studies to include. The earlier review included three studies that compared oxycodone with placebo over several weeks, and the additional studies added oxycodone to existing treatment with pregabalin or gabapentin. Most of the 687 people in the studies had painful limbs because of damaged nerves caused by diabetes.

Key results

Only very low quality evidence suggested that oxycodone relieved the pain. Compared with placebo, fewer people stopped taking oxycodone because they felt it was not effective, but more people experienced side effects.

Quality of the evidence

We rated the quality of the evidence for both benefit and harm as very low because of small numbers of studies and participants, the outcomes reported, and potential bias from the way the studies were analysed. Very low quality evidence means that we are very uncertain about the results.

Author(s)

Helen Gaskell, Sheena Derry, Cathy Stannard, R Andrew Moore

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Clinical trial evidence on the use of oxycodone in neuropathic pain conditions was limited to five studies in painful diabetic neuropathy and postherpetic neuralgia, all of which we considered at substantial risk of bias and likely to overestimate efficacy.

For people with neuropathic pain

There was very limited evidence that oxycodone (as oxycodone modified‐release (MR)) may provide moderate benefit (equivalent to a 30% reduction in pain) to people with painful diabetic neuropathy or postherpetic neuralgia. There was no evidence for other neuropathic pain conditions. As with other opioids, some adverse events (particularly somnolence or sedation, constipation, and nausea) may limit its clinical usefulness.

For clinicians

There was very limited evidence that oxycodone (as oxycodone MR) may provide moderate benefit (equivalent to a 30% reduction in pain) to people with painful diabetic neuropathy or postherpetic neuralgia. There was no evidence for other neuropathic pain conditions. As with other opioids, some adverse events (particularly somnolence or sedation, constipation, and nausea) may limit its clinical usefulness. It might be expected that, at best, a few people with neuropathic pain will benefit from long‐term use of oxycodone.

For policy makers

There was very limited evidence that oxycodone (as oxycodone MR) may provide moderate benefit (equivalent to a 30% reduction in pain) to people with painful diabetic neuropathy or postherpetic neuralgia. Common opioid adverse events may limit its clinical usefulness. There was no evidence for other neuropathic pain conditions. In the absence of high quality evidence of benefit, it should probably be used only at the discretion of a pain specialist with particular expertise in opioid use, and not as a first line treatment.

For funders

There was very limited evidence that oxycodone (as oxycodone MR) may provide moderate benefit (equivalent to a 30% reduction in pain) to people with painful diabetic neuropathy or postherpetic neuralgia. Common opioid adverse events may limit its clinical usefulness. There was no evidence for other neuropathic pain conditions. In the absence of high quality evidence of benefit, it should probably be used only at the discretion of a pain specialist with particular expertise in opioid use, and not as a first line treatment.

Implications for research 

General

For people with chronic neuropathic pain of moderate or severe intensity, treatment with oxycodone is likely to be more effective than placebo in only a small minority of cases. There may be differences in effect in different types of neuropathic pain. In this circumstance, to be certain of a result in terms of both direction and magnitude of effect would require very large clinical trials. These trials would need to have important design features.

• Be of long duration ‐ a minimum of three months and perhaps longer.
• Use clear outcomes of clinical utility, approximating moderate and substantial benefit using several scoring systems, probably visual analogue scale (VAS) pain intensity and Patient Global Impression of Change scale (PGIC).
• Not use any imputation method, as the outcome desired is that of adequate pain relief in the longer term, and for that people have to continue on therapy. Withdrawal for any reason is treatment failure.
• Be clear from the beginning that treating people with opioid who do not have pain relief is unacceptable, so that there would be built‐in stopping rules linked to pain relief after an adequate trial of therapy.
• Be designed and analysed to assess whether there are any predisposing features linked with treatment success or failure, and to determine stopping rules for adequate trial of therapy.

It may be that a more appropriate trial would be have an enriched enrolment randomised withdrawal design (Moore 2015). Discussion of a study with that design is outside the scope of this review.

Design

Trial designs may need to be radically different to capture answers to the research questions, but the key question is whether there are any people with neuropathic pain who do well on oxycodone in the long term; that is with a substantial reduction in pain maintained, and tolerable adverse events. An alternative to clinical trials might be the use of registry studies in non‐cancer pain; preliminary suggestions for such a study have been published (Kim 2013).

Measurement (endpoints)

A major issue is not in the measurement of pain, as most studies, especially modern ones, have used standard pain intensity and pain relief scales. However, reporting of average pain changes is inadequate, and the use of responder analyses (at least 50% pain intensity reduction, or participants experiencing mild or no pain) is preferred. Long‐term studies should aim to capture data on misuse and abuse of oxycodone.

Comparison between active treatments

Indirect comparisons with carrier are probably as informative as use of an active comparator.

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