Fentanyl for neuropathic pain in adults Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract
Background

Opioid drugs, including fentanyl, 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 fentanyl, at any dose, and by any route of administration. Other opioids are considered in separate reviews.

Objectives

To assess the analgesic efficacy of fentanyl for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to June 2016, together with the reference lists of retrieved articles, and two online study registries.

Selection criteria

We included randomised, double‐blind studies of two weeks' duration or longer, comparing fentanyl (in any dose, administered by any route, and in any formulation) 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. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE.

Main results

Only one study met our inclusion criteria. Participants were men and women (mean age 67 years), with postherpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain. They were experiencing inadequate relief from non‐opioid analgesics, and had not previously taken opioids for their neuropathic pain. The study used an enriched enrolment randomised withdrawal design. It was adequately blinded, but we judged it at unclear risk of bias for other criteria.

Transdermal fentanyl (one‐day fentanyl patch) was titrated over 10 to 29 days to establish the maximum tolerated and effective dose (12.5 to 50 µg/h). Participants who achieved a prespecified good level of pain relief with a stable dose of fentanyl, without excessive use of rescue medication or intolerable adverse events ('responders'), were randomised to continue with fentanyl or switch to placebo for 12 weeks, under double‐blind conditions. Our prespecified primary outcomes were not appropriate for this study design, but the measures reported do give an indication of the efficacy of fentanyl in this condition.

In the titration phase, 1 in 3 participants withdrew because of adverse events or inadequate pain relief, and almost 90% experienced adverse events. Of 258 participants who underwent open‐label titration, 163 were 'responders' and entered the randomised withdrawal phase. The number of participants completing the study (and therefore continuing on treatment) without an increase of pain by more than 15/100 was 47/84 (56%) with fentanyl and 28/79 (35%) with placebo. Because only 63% responded sufficiently to enter the randomised withdrawal phase, this implies that only a maximum of 35% of participants entering the study would have had useful pain relief and tolerability with transdermal fentanyl, compared with 22% with placebo. Almost 60% of participants taking fentanyl were 'satisfied' and 'very satisfied' with their treatment at the end of the study, compared with about 40% with placebo. This outcome approximates to our primary outcome of moderate benefit using the Patient Global Impression of Change scale, but the group was enriched for responders and the method of analysis was not clear. The most common adverse events were constipation, nausea, somnolence, and dizziness.

There was no information about other types of neuropathic pain, other routes of administration, or comparisons with other treatments.

We downgraded the quality of the evidence to very low because there was only one study, with few participants and events, and there was no information about how data from people who withdrew were analysed.

Authors' conclusions

There is insufficient evidence to support or refute the suggestion that fentanyl works in any neuropathic pain condition.

Author(s)

Sheena Derry, Cathy Stannard, Peter Cole, Philip J Wiffen, Roger Knaggs, Dominic Aldington, R Andrew Moore

Abstract

Plain language summary

 Fentanyl for neuropathic pain in adults 

 Bottom line 

There is no good evidence to support or refute the suggestion that fentanyl works in any neuropathic pain condition.

 Background 

Neuropathic pain is pain coming from a damaged nervous system. It is different from pain messages that are carried along healthy nerves from damaged tissue (e.g. from a fall or cut, or an arthritic knee). Neuropathic pain is often treated by different medicines (drugs) from those used for pain from damaged tissue, which we often think of as painkillers. There are different types of neuropathic pain, with different causes. Some medicines that are used to treat depression or epilepsy can be very effective in some people with neuropathic pain. Sometimes opioid painkillers are used to treat neuropathic pain.

Opioid painkillers are drugs such as morphine. Morphine is derived from plants, but many opioids are also made by chemical synthesis rather than being extracted from plants. Fentanyl is one of these synthetic opioids. It is available in numerous countries for use as a painkiller and, when used to treat chronic pain, is usually given through an adhesive patch, so it is taken into the body through the skin.

 Study characteristics 

In January 2016 we searched for clinical trials where fentanyl was used to treat neuropathic pain in adults. We found one small study that did this and met our requirements for the review. The study had a complicated design. Study participants first received fentanyl (as one‐day skin patches) for one month. Those who responded to therapy (achieved a predetermined level of pain relief) were then randomly allocated to continue receiving fentanyl or placebo for 12 weeks. The participants had one of three different types of neuropathic pain and had not taken opioids before. There were only 163 people in the 12‐week comparison with placebo.

 Key results 

The study found that more people taking fentanyl had pain relief than those taking placebo. About 1 in 7 participants stopped taking fentanyl because of side effects, and 1 in 5 did not get a good level of pain relief in the first part of the study. Almost half of those who continued into the second part of the study also stopped. The most common side effects were constipation, nausea (feeling sick), somnolence (feeling sleepy), and dizziness. These are typical side effects with opioids such as fentanyl. There was so little information from this single study that we concluded there was no convincing evidence to support or reject a meaningful benefit for fentanyl over placebo.

 Quality of the evidence 

We rated the quality of the evidence as very low because there was only one study, with few participants and events, and an unusual design. Very‐low‐quality evidence means that we are very uncertain about the results.

Author(s)

Sheena Derry, Cathy Stannard, Peter Cole, Philip J Wiffen, Roger Knaggs, Dominic Aldington, R Andrew Moore

Reviewer's Conclusions

Authors' conclusions

Implications for practice
For people with neuropathic pain

There is insufficient evidence to support or refute the suggestion that fentanyl has any efficacy in any neuropathic pain condition.

For clinicians

There is insufficient evidence to support or refute the suggestion that fentanyl has any efficacy in any neuropathic pain condition.

For policy makers

There is insufficient evidence to support or refute the suggestion that fentanyl has any efficacy in any neuropathic pain condition. In the absence of any supporting evidence, it should probably not be recommended, except at the discretion of a pain specialist with particular expertise in opioid use.

For funders

There is insufficient evidence to support or refute the suggestion that fentanyl has any efficacy in any neuropathic pain condition. In the absence of any supporting evidence, it should probably not be recommended, except at the discretion of a pain specialist with particular expertise in opioid use.

Implications for research

Large, robust, randomised trials with patient‐centred outcomes would be required to produce evidence to support or refute the efficacy of fentanyl in neuropathic pain. The necessary design of such trials is well established, but, for opioids in neuropathic pain, the main outcomes should be those of at least a 30% and at least a 50% reduction in pain intensity over baseline at the end of a trial of 12 weeks' duration in participants continuing on treatment. Withdrawal for any reason should be regarded as treatment failure, and LOCF analysis should not be used. The reason for this is that, in chronic pain, opioids frequently produce withdrawal rates of 50% or more, meaning that LOCF analysis can overstate treatment efficacy to a large extent. BOCF should be used in preference to LOCF as it provides a more relevant estimate of efficacy for the real world.

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