Derry Et Al-2016-Cochrane Database of Systematic Reviews

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Fentanyl for neuropathic pain in adults (Review)
Derry S, Stannard C, Cole P, Wiffen PJ, Knaggs R, Aldington D, Moore RA
Derry S, Stannard C, Cole P, Wiffen PJ, Knaggs R, Aldington D, Moore RA.

Fentanyl for neuropathic pain in adults.
Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No.: CD011605.
DOI: 10.1002/14651858.CD011605.pub2.
www.cochranelibrary.com

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 3
BACKGROUND.............................................................................................................................................................................................. 5
OBJECTIVES.................................................................................................................................................................................................. 6
METHODS..................................................................................................................................................................................................... 6
Figure 1.................................................................................................................................................................................................. 9
RESULTS........................................................................................................................................................................................................ 11
Figure 2.................................................................................................................................................................................................. 12
DISCUSSION.................................................................................................................................................................................................. 13
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 15
ACKNOWLEDGEMENTS................................................................................................................................................................................ 15
REFERENCES................................................................................................................................................................................................ 16
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 20
APPENDICES................................................................................................................................................................................................. 22
WHAT'S NEW................................................................................................................................................................................................. 27
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 28
DECLARATIONS OF INTEREST..................................................................................................................................................................... 28
SOURCES OF SUPPORT............................................................................................................................................................................... 28
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 28
NOTES........................................................................................................................................................................................................... 28
INDEX TERMS............................................................................................................................................................................................... 29
Fentanyl for neuropathic pain in adults (Review) i

Informed decisions.
[Intervention Review]
Fentanyl for neuropathic pain in adults
Sheena Derry1, Cathy Stannard2, Peter Cole3, Philip J Wiffen4, Roger Knaggs5, Dominic Aldington6, R Andrew Moore7
1Oxford, UK. 2NHS Gloucestershire CCG, Brockworth, UK. 3Oxford Pain Relief Unit, Churchill Hospital, Oxford University Hospitals NHS
Trust, Oxford, UK. 4Thame, UK. 5School of Pharmacy, University of Nottingham, Nottingham, UK. 6Royal Hampshire County Hospital,
Winchester, UK. 7Plymouth, UK
Contact address: Sheena Derry, Oxford, Oxfordshire, UK. sheena.derry@retired.ox.ac.uk.
Editorial group: Cochrane Pain, Palliative and Supportive Care Group.

Publication status and date: Stable (no update expected for reasons given in 'What's new'), published in Issue 5, 2019.
Citation: Derry S, Stannard C, Cole P, Wiffen PJ, Knaggs R, Aldington D, Moore RA. Fentanyl for neuropathic pain in adults. Cochrane
Database of Systematic Reviews 2016, Issue 10. Art. No.: CD011605. DOI: 10.1002/14651858.CD011605.pub2.
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.
Fentanyl for neuropathic pain in adults (Review) 1
Informed decisions.
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.
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.

SUMMARY OF FINDINGS
Summary of findings for the main comparison.
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Transdermal fentanyl compared with placebo for neuropathic pain
Patient or population: Adults with chronic neuropathic pain
Settings: Community
Better health.
Informed decisions.
Trusted evidence.
Intervention: Fentanyl 1-day adhesive patch 12.5 to 50 µg/h
Comparison: Placebo patch
Outcomes Probable out- Probable out- RR No of studies, partici- Quality of the Comments
come with come with (95% CI) pants evidence
intervention comparator (GRADE)
Moderate benefit: Pain treatment: Pain treatment: Not calculated 1 study, 163 partici- Very low Downgraded three times: single study,
satisfied, very satisfied, very pants, 81 events few participants and events, approxi-
at least 30% reduction in satisfied satisfied mates to prespecified outcome, impu-
pain, or tation for withdrawals not specified,
49/84 32/79 unusual mix of pain conditions
PGIC much or very much
improved
Substantial benefit: No data No data - - - -
at least 50% reduction in

pain, or
PGIC much improved
Lack of efficacy withdraw- 19/84 39/79 Not calculated 1 study, 163 partici- Very low Downgraded three times: single study,

al in randomised dou- pants, 81 events few participants and events
ble-blind phase
Adverse event withdraw- 14/84 4/79 Not calculated 1 study, 163 partici- Very low Downgraded three times: single study,
al in randomised dou- pants, 81 events few participants and events
ble-blind phase
Serious adverse events 13/258 during 4/79 in ran- Not calculated Titration: 1 study, 258 Very low Downgraded three times: single study,
titration phase domised dou- participants, 13 events few participants and events
ble-blind phase
Randomised dou-
ble-blind phase: 1
3
8/84 in ran- study, 163 partici-
domised dou- pants, 12 events
ble-blind phase
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Deaths None None - 1 study, 258 partici- Very low Downgraded three times: estimated
pants, 0 events incidence not more frequent than 1 in
861
CI: Confidence interval; PGIC: Patient Global Impression of Change; RR: Risk Ratio
Better health.
Informed decisions.
Trusted evidence.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 Eypasch E, Lefering R, Kum CK, Troidl H. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ 1995;311(7005):619-20.

4
Informed decisions.
BACKGROUND combining pharmacological interventions with physical or

cognitive (or both) interventions. Conventional analgesics such
This review is based on a template for reviews of drugs used to as paracetamol and nonsteroidal anti-inflammatory drugs are not
relieve neuropathic pain. The aim is for all reviews to use the thought to be effective, but are frequently used (Di Franco 2010;
same methods, based on new criteria for what constitutes reliable Vo 2009). Some people may derive some benefit from a topical
evidence in chronic pain (Moore 2010a; Appendix 1). lidocaine patch or low-concentration topical capsaicin, although
evidence about benefits is uncertain (Derry 2012; Derry 2014). High-
Description of the condition concentration topical capsaicin may benefit some people with PHN
The 2011 International Association for the Study of Pain definition (Derry 2013).
of neuropathic pain is "pain caused by a lesion or disease of the
Treatment is often by so-called 'unconventional analgesics', such
somatosensory system" (Jensen 2011), and is based on a definition
as antidepressants (duloxetine and amitriptyline; Lunn 2014; Moore
agreed at an earlier consensus meeting (Treede 2008). Neuropathic
2012a; Sultan 2008), or antiepileptics (gabapentin or pregabalin;
pain may be caused by nerve damage, but is often followed by
Moore 2009; Moore 2014b; Wiffen 2013). The proportion of people
changes in the central nervous system (Moisset 2007). The origin
who achieve worthwhile pain relief (typically at least 50% pain
of neuropathic pain is complex (Baron 2010; Baron 2012; Tracey
intensity reduction; Moore 2013a) is small, generally only 10% to
2011; von Hehn 2012), and neuropathic pain features can be found
25% more than with placebo, with numbers needed to treat for
in people with joint pain (Soni 2013).
an additional beneficial outcome (NNT) usually between 4 and 10
Many people with neuropathic pain conditions are significantly (Kalso 2013; Moore 2013b). Neuropathic pain is not particularly
disabled with moderate or severe pain for many years. Chronic different from other chronic pain conditions in that only a small
pain conditions comprised 5 of the 11 top-ranking conditions for proportion of trial participants have a good response to treatment
years lived with disability in 2010 (Vos 2012), and are responsible for (Moore 2013b).
considerable loss of quality of life and employment, and increased
One overview of treatment guidelines pointed out some general
healthcare costs (Moore 2014a).
similarities between recommendations, but guidelines are not
Neuropathic pain is usually divided according to the cause of nerve always consistent with one another (O'Connor 2009). The current
injury. There may be many causes, but some common causes of National Institute for Health and Care Excellence (NICE) guidance
neuropathic pain include diabetes (painful diabetic neuropathy suggests offering a choice of amitriptyline, duloxetine, gabapentin,
(PDN)), shingles (postherpetic neuralgia (PHN)), amputation or pregabalin as initial treatment for neuropathic pain (with the
(stump and phantom limb pain), neuropathic pain after surgery or exception of trigeminal neuralgia), with switching if the first,
trauma, stroke or spinal cord injury, trigeminal neuralgia, and HIV second, or third drugs tried are not effective or not tolerated (NICE
infection. Sometimes the cause is unknown. 2013).
In systematic reviews, the overall prevalence of neuropathic pain Description of the intervention
in the general population is reported to be between 7% and Fentanyl was first synthesised in the 1950s and was found to be
10% (van Hecke 2014), and about 7% in a systematic review of significantly more potent than commonly used opioids, such as
studies published since 2000 (Moore 2014a). In individual countries, morphine. It was initially used for intravenous anaesthesia and
prevalence rates have been reported as 3.3% in Austria (Gustorff analgesia in the 1960s and became a mainstay of intraoperative
2008), 6.9% in France (Bouhassira 2008), and up to 8% in the UK and perioperative analgesia and both conscious and deep sedation
(Torrance 2006). Some forms of neuropathic pain, such as PDN and in the in-hospital setting. Peak analgesic effects of intravenous
postsurgical chronic pain (which is often neuropathic in origin), are fentanyl last for 30 to 60 minutes, but onset of analgesia is
increasing in prevelance (Hall 2008). rapid. Fentanyl is approximately 80 to 100 times more potent
than morphine, is highly lipophilic, and binds strongly to plasma
Estimates of incidence vary between individual studies for
proteins (Trescot 2008). Fentanyl is associated with possible
particular origins of neuropathic pain, often because of small
hypoxaemia (low oxygen levels in the blood) after surgery (McQuay
numbers of cases. In primary care in the UK, between 2002 and
1979).
2005, the incidences (per 100,000 person-years' observation) were
28 (95% confidence interval (CI) 27 to 30) for PHN, 27 (26 to 29) Fentanyl undergoes extensive metabolism in the liver, and is
for trigeminal neuralgia, 0.8 (0.6 to 1.1) for phantom limb pain, subject to first-pass metabolism in the liver and possibly small
and 21 (20 to 22) for PDN (Hall 2008). Others have estimated intestine, though hepatic extraction from blood may be more
an incidence of 4 in 100,000 per year (Katusic 1991; Rappaport complicated (Bullingham 1984). Various formulations of fentanyl
1994) for trigeminal neuralgia, and of 12.6 per 100,000 person- have been studied, including a rapid transmucosal formulation for
years for trigeminal neuralgia and 3.9 per 100,000 person-years for buccal absorption or intranasal sprays for acute breakthrough pain,
PHN in a study of facial pain in the Netherlands (Koopman 2009). and transdermal formulations for chronic pain (Lötsch 2013; Nelson
One systematic review of chronic pain demonstrated that some 2009). The transdermal formulation has a lag time of 6 to 12 hours
neuropathic pain conditions, such as PDN, can be more common to onset of action after application, and typically reaches steady
than other neuropathic pain conditions, with prevalence rates up state in three to six days. When a patch is removed, a subcutaneous
to 400 per 100,000 person-years (McQuay 2007). reservoir remains, and drug clearance may take up to 24 hours.
Neuropathic pain is difficult to treat effectively, with only a minority Fentanyl patches are available as generic formulations, and brand
of people experiencing a clinically relevant benefit from any names include Fentalis®, Matrifen®, Mezolar®, Osmanil®, Tilofyl®,
one intervention. A multidisciplinary approach is now advocated,
Victanyl®, Durogesic®, and DTrans®. They are available as 12, 25, 50,

Informed decisions.
75, and 100 μg/h transdermal patches. The 25, 50, 75, and 100 μg/ The standards used to assess evidence in chronic pain trials have
h patches were first licensed in 1994, and a 12 μg patch followed in evolved substantially in recent years, with particular attention
2005. Transdermal fentanyl provides 'rate controlled' drug delivery being paid to trial duration, withdrawals, and statistical imputation
over 72 hours, although shorter and longer delivery periods are following withdrawal, all of which can substantially alter estimates
under development. A 24-hour patch has been licensed for some of efficacy. The most important change is the move from using
pain conditions in Japan. Surface area exposed, skin permeability, mean pain scores, or mean change in pain scores, to the number of
and local blood flow determine absorption (Heiskanen 2009). people who have a large decrease in pain (by at least 50%) and who
Absorption was impaired in 10 cachectic (weak and underweight) continue in treatment, ideally in trials of 8 to 12 weeks' duration or
compared with 10 normal weight cancer patients, (Heiskanen longer. A pain intensity reduction of 50% or more correlates with
2009). The 'reservoir patch' is being phased out and replaced with improvements in comorbid symptoms, function, and quality of life.
a matrix design, as it was likely to leak if damaged or cut. Trials These standards are set out in the Cochrane Pain, Palliative and
have demonstrated no difference in pain intensity reduction or Supportive Care Group (PaPaS) Author and Referee Guidance for pain
overall adverse effects between the reservoir and matrix patches. studies (PaPaS 2012).
Satisfaction was improved, and wearability, adhesion, and comfort
were improved with the matrix patches (Cachia 2011). This Cochrane review assessed evidence using methods that make
both statistical and clinical sense, and used developing criteria for
Fentanyl patches have been suggested to have some benefits what constitutes reliable evidence in chronic pain (Moore 2010a).
over more traditional opioids such as oral morphine. There is a To be included, trials had to meet a minimum of reporting quality
favourable safety profile in people with renal insufficiency, as this (blinding, randomisation), validity (duration, dose and timing,
does not affect fentanyl elimination, while renal insufficiency or diagnosis, outcomes, etc.), and size (ideally at least 500 participants
failure cause a build-up of active metabolites of opioids such as in a comparison in which the NNT is 4 or above; Moore 1998). This
morphine. Fentanyl is also considered to cause less constipation approach sets high standards for the demonstration of efficacy and
than morphine. However, fentanyl patches are not generally marks a departure from how reviews were conducted previously.
recommended in clinical practice for people who are opioid naïve.
Moreover, exposure to heat through fever, sunbathing, hot showers Taking this newer, more rigorous approach is particularly important
or baths, and warm weather can cause more fentanyl to be released for opioids in chronic non-cancer pain. Opioids in clinical trials in
into the skin and cause serious, or even fatal, adverse events. non-cancer pain are associated with very high withdrawal rates of
up to 60% over about 12 weeks (Moore 2010b). Many withdrawals
How the intervention might work occur within the first few weeks, when participants experience pain
relief but cannot tolerate the drug. The common practice of using
Opioids such as fentanyl bind to specific opioid receptors in the the last observed results carried forward to the end of the trial
nervous system and other tissues; there are three principal classes many weeks later (last observation carried forward (LOCF)) can,
of receptors (mu, kappa, and delta) though others have been therefore, produce results based largely on people who are no
suggested, and subtypes of receptors are considered to exist. longer in the trial, and who in the real world could not achieve pain
Binding of opioid agonists such as fentanyl to receptors brings relief because they could not take the tablets. The newer standards,
about complex cellular changes, the outcomes of which include outlined in Appendix 1, would not allow this and can produce very
decreased perception of pain, decreased reaction to pain, and different results. For example, one large analysis of pooled data
increased pain tolerance. Opioids from plant sources have been from trials in osteoarthritis and chronic low back pain conducted
used for thousands of years to treat pain. over about 12 weeks judged oxycodone effective, but an analysis
of the same data using the new clinically meaningful standards
Why it is important to do this review
showed it to be significantly worse than placebo (Lange 2010).
One UK survey found that weak and strong opioids were used
frequently for treating neuropathic pain (Hall 2013). Fentanyl One previous Cochrane review demonstrated the limitations of
patches can be useful in people who cannot tolerate oral opioids. our knowledge about opioids in neuropathic pain except in
Titrating the dose of fentanyl patches can be difficult and it is short duration studies of 24 hours or less (McNicol 2013). These
probably better to convert from a dose of morphine or other oral limitations were confirmed by reviews specific to buprenorphine
opioid that is effective but not tolerated. Since the early 2000s, a and oxycodone (Gaskell 2014; Wiffen 2015). A review specific to
marked increase in prescribing of opioids for non-cancer pain in fentanyl is timely.
general, despite a relatively modest evidence base, has in some
countries led to widespread diversion with consequent abuse, OBJECTIVES
misuse, and mortality (Franklin 2014; Weisberg 2014; Zin 2014). To assess the analgesic efficacy of fentanyl for chronic neuropathic
There were 1.2 million prescriptions for fentanyl in primary care in pain in adults, and the adverse events associated with its use in
England in 2014 at a cost of almost GBP57 million (PCA 2015) and clinical trials.
the amount of fentanyl prescribed has been rising substantially (Zin
2014), although not all this prescribing will be for neuropathic pain. METHODS
Concurrently, suspicion has arisen that opioid-induced Criteria for considering studies for this review
hyperalgesia, together with tolerance to the analgesic effects of
opioids, may in reality result in a lesser degree of benefit for opioids Types of studies
in neuropathic pain than previously assumed.
We included randomised controlled trials with double-blind
assessment of participant outcomes following two weeks or more
of treatment, although the emphasis of the review was on studies
Informed decisions.
with a duration of eight weeks or longer. We required full journal improvement on PGIC, withdrawals due to adverse events, serious
publication, with the exception of online clinical trial results adverse events, and death. We used the GRADE approach to assess
summaries of otherwise unpublished clinical trials and abstracts the quality of evidence related to each of the key outcomes listed
with sufficient data for analysis. We did not include short abstracts below (Chapter 12, Higgins 2011), as appropriate.
(usually meeting reports). We excluded studies that were non-
randomised, studies of experimental pain, case reports, and clinical Primary outcomes
observations. 1. Participant-reported pain relief of 30% or greater
Types of participants 2. Participant-reported pain relief of 50% or greater
3. PGIC much or very much improved
We included studies involving adults aged 18 years and above with
4. PGIC very much improved
one or more chronic neuropathic pain condition including (but not
limited to): Secondary outcomes
1. cancer-related neuropathy; 1. Any pain-related outcome indicating some improvement
2. central neuropathic pain; 2. Withdrawals due to lack of efficacy, adverse events, and for any
3. complex regional pain syndrome (CRPS) Type II; cause
4. human immunodeficiency virus (HIV) neuropathy; 3. Participants experiencing any adverse event
5. painful diabetic neuropathy (PDN); 4. Participants experiencing any serious adverse event. Serious
6. phantom limb pain; adverse events typically include any untoward medical
occurrence or effect that at any dose results in death, is life-
7. postherpetic neuralgia (PHN);
threatening, requires hospitalisation or prolongation of existing
8. postoperative or traumatic neuropathic pain; hospitalisation, results in persistent or significant disability
9. spinal cord injury; or incapacity, is a congenital anomaly or birth defect, is an
10.trigeminal neuralgia. 'important medical event' that may jeopardise the person,
or may require an intervention to prevent one of the above
Where studies included participants with more than one type of characteristics or consequences
neuropathic pain, we planned to analyse results according to the 5. Specific adverse events, particularly somnolence and dizziness
primary condition.
Search methods for identification of studies
Types of interventions
Electronic searches
Fentanyl at any dose, by any route, administered for the relief
of neuropathic pain and compared with placebo or any active We searched the following databases, without language
comparator. restrictions.
Types of outcome measures 1. Cochrane Central Register of Controlled Trials (CENTRAL, via the
Cochrane Register of Studies Online database (CRSO)) to 14 June
We anticipated that studies would use a variety of outcome
2016.
measures, with most studies using standard subjective scales
(numerical rating scale (NRS) or visual analogue scale (VAS)) for 2. MEDLINE (via Ovid) from 1946 to 14 June 2016.
pain intensity (where higher numbers indicate more pain) or pain 3. Embase (via Ovid) from 1974 to 14 June 2016.
relief (where higher numbers indicate more relief), or both. We
were particularly interested in Initiative on Methods, Measurement, The search strategies for CENTRAL, MEDLINE, and Embase are listed
and Pain Assessment in Clinical Trials (IMMPACT) definitions for in Appendix 2, Appendix 3, and Appendix 4, respectively.
moderate and substantial benefit in chronic pain studies (Dworkin
Searching other resources
2008). These are defined as:
We reviewed the bibliographies of relevant studies and
1. at least 30% pain relief over baseline (moderate benefit); review articles, and searched two clinical trial registries,
2. at least 50% pain relief over baseline (substantial benefit); (ClinicalTrials.gov (ClinicalTrials.gov) and the World Health
3. much or very much improved on Patient Global Impression of Organization International Clinical Trials Registry Platform (ICTRP)
Change scale (PGIC; moderate benefit); and (apps.who.int/trialsearch/)), to identify additional published or
4. very much improved on PGIC (substantial benefit). unpublished data. We contacted Janssen-Cilag Ltd who were able
to clarify the publication status of the included study shortly before
These outcomes are different from those used in most earlier full publication. We did not contact investigators or other study
reviews, concentrating as they do on dichotomous outcomes where sponsors.
pain responses do not follow a normal (Gaussian) distribution.
People with chronic pain desire high levels of pain relief, ideally Data collection and analysis
more than 50% pain intensity reduction, and ideally having no We planned to perform separate analyses according to particular
worse than mild pain (Moore 2013a; O'Brien 2010). neuropathic pain conditions, combining different neuropathic pain
conditions in analyses for exploratory purposes only.
We have included a 'Summary of findings' table as set out in the
PaPaS author guide (PaPaS 2012), to include outcomes of at least
30% and at least 50% pain intensity reduction, much or very much
Informed decisions.
Selection of studies the remaining studies. Two review authors made the decisions,
reading these studies independently and reaching agreement by
We determined eligibility by reading the abstract of each study
discussion. We did not anonymise the studies in any way before
identified by the search. We eliminated studies that clearly did
assessment. We have included a PRISMA flow chart (Figure 1).
not satisfy the inclusion criteria, and obtained full copies of

Informed decisions.
Figure 1. Study flow diagram.

Informed decisions.
Data extraction and management to 199 participants per treatment arm); or high risk of bias (fewer
than 50 participants per treatment arm).
Two review authors extracted data independently using a standard
form and checked for agreement before entry into Review Measures of treatment effect
Manager 5 (RevMan 2014) or any other analysis tool. We included
information about the pain condition and number of participants We planned to calculate NNTs as the reciprocal of the absolute risk
treated, drug and dosing regimen, control intervention, study reduction (McQuay 1998). For unwanted effects, the NNT becomes
design, study duration and follow up, analgesic outcome measures the number needed to treat for an additional harmful outcome
and results, withdrawals, and adverse events (participants (NNH) and is calculated in the same manner. We planned to use
experiencing any adverse event or serious adverse event). dichotomous data to calculate risk ratios (RRs) with 95% confidence
intervals (CIs) using a fixed-effect model unless we found significant
Assessment of risk of bias in included studies statistical heterogeneity (see Assessment of heterogeneity). We
planned not to use continuous data in analyses, and intended to
We used the Oxford Quality Score as the basis for inclusion (Jadad
extract and use continuous data, which probably reflect efficacy
1996), limiting inclusion to studies that were randomised and
and utility poorly, only if useful for illustrative purposes.
double-blind as a minimum.
Unit of analysis issues
Two review authors independently assessed the risk of bias for
each study, using the criteria outlined in the Cochrane Handbook We accepted randomisation to the individual participant only.
for Systematic Reviews of Interventions (Chapter 8, Higgins 2011), We planned to split the control treatment arm between active
and adapted from those used by the Cochrane Pregnancy and treatment arms in a single study if the active treatment arms were
Childbirth Group, with any disagreements resolved by discussion. not combined for analysis.
We assessed the following for each study.
Dealing with missing data
1. Random sequence generation (checking for possible selection
We planned to use intention-to-treat (ITT) analysis where the
bias). We assessed the method used to generate the allocation
ITT population consisted of participants who were randomised,
sequence as: low risk of bias (any truly random process, random
took at least one dose of the assigned study medication, and
number table, computer random number generator); unclear
provided at least one post-baseline assessment. We would assign
risk of bias (when the method used to generate the sequence is
zero improvement to missing participants wherever possible.
not clearly stated). We excluded studies at a high risk of bias that
used a non-random process (odd or even date of birth, hospital Assessment of heterogeneity
or clinic record number).
2. Allocation concealment (checking for possible selection bias). We planned to deal with clinical heterogeneity by combining
The method used to conceal allocation to interventions prior to studies that examined similar conditions, and to assess statistical
assignment determines whether intervention allocation could heterogeneity visually (L'Abbé 1987) and with the use of the I2
have been foreseen in advance of, or during, recruitment, or statistic. When the I2 value was greater than 50%, we would
changed after assignment. We assessed the methods as: low consider possible reasons for this.
risk of bias (telephone or central randomisation, consecutively
numbered, sealed, opaque envelopes); unclear risk of bias Assessment of reporting biases
(when method was not clearly stated). We excluded studies that The aim of this review was to use dichotomous outcomes of known
did not conceal allocation and were, therefore, at a high risk of utility and of value to patients with pain (Hoffman 2010; Moore
bias (open list). 2010c; Moore 2010d; Moore 2010e; Moore 2013a). The review would
3. Blinding of outcome assessment (checking for possible not depend on what the authors of the original studies chose to
detection bias). We planned to assess the methods used to report or not, though clearly difficulties would arise in studies that
blind study participants and outcome assessors from knowledge did not report any dichotomous results.
of which intervention a participant received. We assessed the
methods as: low risk of bias (study stated that it was blinded We planned to assess publication bias using a method designed to
and described the method used to achieve blinding, identical detect the amount of unpublished data with a null effect required
tablets, matched in appearance and smell); unclear risk of bias to make any result clinically irrelevant (usually taken to mean an
(study stated that it was blinded but did not provide an adequate NNT of 10 or higher; Moore 2008).
description of how it was achieved). We excluded studies at a
Data synthesis
high risk of bias that were not double-blind.
4. Incomplete outcome data (checking for possible attrition bias We planned to use a fixed-effect model for meta-analysis. We would
due to the amount, nature, and handling of incomplete outcome have used a random-effects model for meta-analysis if there was
data). We assessed the methods used to deal with incomplete significant clinical heterogeneity and it was considered appropriate
data as: low risk of bias (fewer than 10% of participants did to combine studies. We planned to analyse data for each painful
not complete the study, or used 'baseline observation carried condition separately.
forward' analysis (BOCF), or both); unclear risk of bias (used
LOCF analysis); or high risk of bias (used 'completer' analysis). Quality of the evidence
5. Size of study (checking for possible biases confounded by small We used the GRADE system to assess the quality of the evidence
size). We assessed studies as being at low risk of bias (200 related to the key outcomes listed in Types of outcome measures,
participants or more per treatment arm); unclear risk of bias (50 as appropriate (Appendix 5; Chapter 12.2, Higgins 2011). Two

Informed decisions.
review authors independently rated the quality of evidence for each registries. After deduplication and reading the titles and abstracts
outcome. we obtained and read the full texts of five published records and
two clinical trial registry reports. We excluded five studies, and
We paid particular attention to: included one (two reports) (Figure 1).
1. inconsistency, where point estimates vary widely across studies, Included studies
or CIs of studies show minimal or no overlap (Guyatt 2011);
We included one study, identified as a registry report
2. potential for publication bias, based on the amount of
(NCT01008553) and in a published pooled analysis (Arai 2015). This
unpublished data required to make the result clinically
study used an enriched enrolment randomised withdrawal (EERW)
irrelevant (Moore 2008).
design in which 258 participants underwent open-label titration
In addition, there may be circumstances where the overall rating over 10 to 29 days with fentanyl one-day patches to determine
for a particular outcome needs to be adjusted as recommended by the maximum tolerated dose. It was not clear whether participants
GRADE guidelines (Guyatt 2013a). For example, if there are so few stopped or continued with previously inadequate medication.
data that the results are highly susceptible to the random play of
Those who had pain intensity below 45/100 in the last three days
chance, or if a study used LOCF imputation in circumstances where
of this open-label titration, an improvement from pre-treatment of
there are substantial differences in adverse event withdrawals,
at least 15/100, achieved a stable dosage of fentanyl, and required
one would have no confidence in the result and would need to
fewer than two doses per day of rescue medication, were classified
downgrade the quality of the evidence by three levels to very
as 'responders' (163 participants; 63% of those entering the open
low quality. In circumstances where no data were reported for an
titration period) and were randomised to double-blind treatment
outcome, we would report the level of evidence as very low quality
with either the same dose of fentanyl or placebo for 12 weeks. Of
(Guyatt 2013b).
84 receiving fentanyl, 47 completed the 12 weeks, compared with
'Summary of findings' table 28/79 receiving placebo (Arai 2015).
We have included a 'Summary of findings' table to present the main Fentanyl was administered as a one-day patch, and all participants
findings in a transparent and simple tabular format. In particular, started with fentanyl 12.5 µg/h, increasing to a maximum of 50 µg/h
we have included key information concerning the quality of over 10 to 29 days. Morphine hydrochloride was available as rescue
evidence, the magnitude of effect of the interventions examined, medication (5 mg per fentanyl 12.5 µg/h).
and the sum of available data on the outcomes of 'moderate' and
'substantial' benefit, withdrawal due to lack of efficacy, withdrawal Participants were opioid-naïve and had pain that was not
due to adverse events, serious adverse events, and death. adequately controlled with non-opioid analgesics. They were
adults (mean age 67 years) with PHN (51%), CRPS (type not
Subgroup analysis and investigation of heterogeneity specified, 20%), or chronic postoperative pain (for a duration of
12 weeks or more, but no further details given; 29%). There were
We planned all analyses to be according to individual neuropathic
approximately equal numbers of men and women. Mean baseline
pain conditions, because placebo response rates for the same
pain intensity was 74/100 before treatment and 40/100 at the end of
outcome can vary between conditions, as can the drug-specific
titration. For those entering the double-blind period, baseline pain
effects (Moore 2009).
was 30/100 in the fentanyl group and 28/100 in the placebo group.
We did not plan subgroup analyses since our experience of previous
Excluded studies
reviews indicates that there would be too few data for any
meaningful subgroup analysis (Gaskell 2014; McNicol 2013). We excluded five studies. Three were open-label studies, two
of which were in mixed pain conditions, one was a single-blind
Sensitivity analysis study (ongoing), and one compared fentanyl with fentanyl plus
We planned no sensitivity analysis because the evidence base was gabapentin (no appropriate control). See the Characteristics of
known to be too small to allow reliable analysis. We planned excluded studies table.
to examine details of dose-escalation schedules in the unlikely
situation that this could provide some basis for a sensitivity
Risk of bias in included studies
analysis, but this was not possible. See Figure 2 for a summary of our assessment of the risk of bias
in the included study. Studies with EERW designs are likely to
RESULTS have additional sources of bias, or may require somewhat different
assessments (Moore 2015), but we have not included those here.
Description of studies
Results of the search
Searches identified 193 potentially relevant records in CENTRAL,
452 in MEDLINE, and 770 in Embase, and two in clinical trial

Informed decisions.
Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation Since we identified only one study for inclusion, we were unable to
carry out any analyses.
The study did not report the methods used to generate the
randomisation sequence or to conceal allocation (unclear risk of Efficacy
bias).
Details of efficacy outcomes are provided in Appendix 6.
Blinding
Participants with at least 30% or at least 50% pain relief
Blinding was achieved by using a placebo patch that was
indistinguishable from the fentanyl patch. There was a period of These outcomes were not reported.
down-titration for the placebo group, which would help to maintain
PGIC much or very much improved
the blinding (low risk of bias).
The study reported the participants' assessment of 'treatment
Incomplete outcome data satisfaction for pain' on a five-point scale (very dissatisfied,
Study did not mention how missing data were handled. The study's dissatisfied, neither satisfied or dissatisfied, satisfied, very
primary outcome (median time to withdrawal) appears robust, but satisfied) after the double-blind phase. We judged that the
other outcomes are unclear. categories of 'satisfied' and 'very satisfied' approximate to our
PGIC outcome of moderate benefit. In the fentanyl group, 49/84
Other potential sources of bias (58%) participants were either satisfied or very satisfied, and
corresponding data in the placebo group were 32/79 (41%). It
We judged the study to be at unclear risk of bias due to its size (84
is not clear how data from participants who withdrew due to
and 79 participants in treatment arms for the randomised phase).
adverse events were analysed for this outcome, but some form of
Effects of interventions imputation must have been used for participants who withdrew
as the numbers are greater than the number who completed the
See: Summary of findings for the main comparison study.

Informed decisions.
Other pain-related outcomes Other withdrawals

The primary outcome chosen in the study was median time During titration 12/258 participants withdrew because of physician
to withdrawal from the double-blind phase, where withdrawal (2) or participant (6) decision, participant was determined
occurred when there was worsening of pain of 15/100 (mean to increase dosage (3), and participant was considered not
increase over three consecutive days) from entry into this phase, appropriate for the study (1). During the double-blind period
use of three or more doses of rescue medication per day for five or 4/84 participants taking fentanyl withdrew due to physician (1)
more days, the participant requested it because of a lack of efficacy, or participant (2) decision, and an inability to perform required
or the participant requested an increase in study drug dosage. The tests (1), and 8/79 taking placebo withdrew due to physician (2) or
median time to withdrawal for the placebo group was 45 days, but participant (2) decision, and excessive use of rescue medication (4).
could not be estimated for the fentanyl group because fewer than
half the participants withdrew over the 12 weeks; the assumption We downgraded the quality of the evidence for withdrawals to
must be that the median time to withdrawal was greater than 42 very low because there was only one study, with a small number
days. of participants per treatment arm in the randomised withdrawal
phase, and low numbers of events.
The study did not report the number of participants who remained
'responders' at the end of the 12-week double-blind treatment Adverse events
period as a treatment outcome. However, Arai 2015 reports Details of adverse events are provided in Appendix 7.
the number of participants completing the study (and therefore
continuing on treatment) without an increase in pain of more Any adverse event
than 15/100. For fentanyl, this was 47/84 (56%) and for placebo it
was 28/79 (35%). The implication, then, is that because only 63% During the titration phase, 231/258 (90%) participants experienced
responded sufficiently to enter the randomised withdrawal phase, at least one adverse event. During the double-blind phase, 72/84
only a maximum of 35% of participants entering the study would (86%) and 56/79 (71%) participants experienced at least one
have useful pain relief and tolerability with transdermal fentanyl, adverse event with fentanyl and placebo, respectively. Generally,
compared with 22% with placebo. participants experienced fewer adverse events during the double-
blind period.
The group mean change (increase) in pain intensity from
randomisation to the end of the double-blind phase (mean of last Most adverse events were of mild or moderate intensity.
three days) was 0.5/100 (from 30.1 to 29.6) in the fentanyl group, Serious adverse events
and 9.6/100 (from 27.5 to 37.1) in the placebo group. This mean
change is unlikely to be of clinical significance, but probably masks During the titration phase, 13/258 participants experienced a
larger changes in some individuals. It is not clear how data from serious adverse event. During the double-blind phase, 8/84 and
participants who withdrew during treatment were analysed for this 4/79 participants experienced a serious adverse event with fentanyl
outcome. and placebo, respectively. No serious adverse event occurred in
more than one participant, and no deaths were reported.
We downgraded the quality of the evidence for efficacy to very
low because there was only one study, with a small number of Specific adverse events
participants, low numbers of events, and there was no information
Constipation (124/258), nausea (103/258), somnolence (118/258),
about how participants who withdrew from the study were
and dizziness (52/258) were the most common adverse events
analysed (see Summary of findings for the main comparison).
reported during the titration period. As would be expected, the
Withdrawals rates of these events were lower in the double-blind period. Among
the 84 participants taking fentanyl in the double-blind phase, 12
Details of withdrawals are provided in Appendix 7. reported constipation, 12 nausea, 12 somnolence, and 6 dizziness,
and among 79 taking placebo, 10 reported constipation, 10 nausea,
Withdrawals due to lack of efficacy 5 somnolence, and 3 dizziness.
Following the titration period, 50/258 participants were classified
as non-responders to fentanyl. During the double-blind period, A small number of participants experienced application-site
one participant taking fentanyl withdrew because of perceived reactions during titration: pruritus (15/258), erythema (8/258),
lack of efficacy, and a further 18/84 were withdrawn because they dermatitis (4/258), rash (3/258). Few participants in either group
experienced a greater than 15/100 increase in pain intensity. With reported these events during the double-blind period.
placebo, 4/79 withdrew because of perceived lack of efficacy, and a We downgraded the quality of the evidence for adverse events to
further 35/79 were withdrawn because they experienced a greater very low because there was only one study, with a small number
than 15/100 increase in pain intensity. of participants per treatment arm in the randomised withdrawal
Withdrawals due to adverse events phase, and low numbers of events.
During titration 39/258 participants withdrew due to adverse DISCUSSION

events. During the double-blind period 14/84 participants taking
fentanyl and 4/79 taking placebo withdrew due to adverse events. Summary of main results
We found only one study to include in this review. The study
assessed the efficacy of fentanyl, using the transdermal route of

Informed decisions.
administration, for the treatment of neuropathic pain in opioid- The number of participants in the single included study (258
naïve participants; 258 participants entered the dose-titration screened, 163 in the randomised double-blind phase) contrasts
period, and 163 'responders' entered the double-blind phase. The with 1096 who participated in randomised open studies and 1393
results indicated a reduction in pain intensity with open-label in observational studies of various designs (Appendix 8). Despite
fentanyl that was better maintained with fentanyl than placebo in there being 2489 participants in these studies, with chronic pain of
the randomised, double-blind withdrawal period. However, during mostly mixed origins, no useful conclusions can be drawn because
titration, 1 in 3 (101/258) participants withdrew overall, mainly due of problems in design, in outcomes, and in comparators used.
to intolerable adverse events (1 in 7; 39/258) or not achieving a Although some people had useful pain relief with fentanyl, there
sufficiently good level of pain relief to proceed to the double-blind is no additional evidence that the proportion would be any higher
phase (1 in 5; 50/258). Of those who did enter the double-blind than with no treatment.
phase, only about 1 in 2 (37/84) in the fentanyl group and 2 in 3
(51/79) in the placebo group maintained good pain relief and were One study did provide a useful insight into the relative efficacy
able to tolerate adverse events over 12 weeks. of transdermal fentanyl and oral pregabalin in neuropathic cancer
pain (Raptis 2014). The study had a randomised but open parallel
Taking the pool of participants originally recruited, therefore, after design and was conducted over four weeks with initial titration for
12 weeks treatment a maximum of about 3 in 10 would have both drugs; initial pain relief was high, about 7/10 on a numerical
maintained low pain and continued with the treatment, compared rating scale. Of 60 participants given transdermal fentanyl, 22
with 2 in 10 with placebo. (37%) had pain intensity reduction of 30% or more. Of 60
participants given oral pregabalin, 44 (73%) had that degree of pain
Most (90%) participants experienced adverse events during the reduction. All-cause withdrawals were 10/60 for fentanyl and 3/60
titration phase, and the majority continued to do so in the double- for pregabalin. Pregabalin has a well-established evidence base in
blind phase, although most participants experienced fewer events. neuropathic pain (Moore 2009), and the evidence from this open,
Most adverse events were of mild or moderate intensity, and but otherwise well-conducted study, indicates fentanyl to be much
the most common were constipation, nausea, somnolence, and less effective.
dizziness, which are typically associated with opioids.
Quality of the evidence
Overall completeness and applicability of evidence
The methods used in the included study are fundamentally sound,
The amount of evidence we have is small, from a single study. but the study is substantially underpowered, particularly for the
Although participants had three different types of neuropathic randomised, double-blind, withdrawal phase, and does not specify
pain, the study was underpowered to demonstrate a differential the imputation method(s) used for withdrawals (Moore 2015). It
response. Participants were opioid-naïve at screening, so high does not report the most useful outcome from the double-blind
numbers of adverse events and withdrawals are to be expected; phase, the number of participants who maintained therapeutic
lower levels might be seen in an unselected or opioid-tolerant efficacy and were able to continue taking the medication (with
population. Fentanyl patches are generally not recommended for tolerable adverse events), although we were able to estimate this.
opioid-naïve patients.
These factors downgrade the evidence for all outcomes to very low
About half of participants had PHN, 20% had CRPS, and 29% had quality, which means that further research is very likely to have an
chronic postoperative pain at enrolment. The study did not specify important impact on our confidence in our understanding of the
CRPS type II as an inclusion criterion, and provided no further effect.
details about the nature of the surgery leading to postoperative
pain. We have no information about the efficacy of fentanyl in other Potential biases in the review process
types of neuropathic pain, such as diabetic neuropathy, or about
routes of administration other than transdermal, or comparisons We know of no potential biases in the review process. It is unlikely
with other active treatments. The particular formulation used in that there is a large body of unpublished evidence showing a large
this study is not commonly used; in most countries a 72-hour (three- effect from fentanyl in neuropathic pain.
day) patch is available.
Agreements and disagreements with other studies or
As best we know, there is insufficient evidence to support or reviews
refute the use of fentanyl for treating neuropathic pain. This is This review agrees with previous reviews and Cochrane reviews
despite the fact that a UK survey found that weak and strong that there appears to be no body of good clinical studies
opioids were used frequently for treating neuropathic pain, either assessing the efficacy of fentanyl, at any dose or in formulation,
alone or in combination with other drugs (Hall 2013). The lack for neuropathic pain (McNicol 2013). The one study in this
of evidence for long-term benefit with fentanyl reflects similar review was published after McNicol 2013. A recent review of all
findings for oxycodone, buprenorphine, and other opioids (Gaskell pharmacotherapy for neuropathic pain in adults did not mention
2014; McNicol 2013; Wiffen 2015). This lack of evidence of efficacy fentanyl (Finnerup 2015).
combined with substantial evidence of harm has led to calls for
referral to a pain management specialist (ideally with expertise
in opioid use) if daily dosing exceeds 80 to 100 mg morphine
equivalents, particularly if pain and function are not substantially
improved (Franklin 2014).

Informed decisions.
AUTHORS' CONCLUSIONS Implications for research
Implications for practice Large, robust, randomised trials with patient-centred outcomes
would be required to produce evidence to support or refute the
For people with neuropathic pain efficacy of fentanyl in neuropathic pain. The necessary design of
such trials is well established, but, for opioids in neuropathic pain,
There is insufficient evidence to support or refute the suggestion
the main outcomes should be those of at least a 30% and at least
that fentanyl has any efficacy in any neuropathic pain condition.
a 50% reduction in pain intensity over baseline at the end of a
For clinicians trial of 12 weeks' duration in participants continuing on treatment.
Withdrawal for any reason should be regarded as treatment failure,
There is insufficient evidence to support or refute the suggestion and LOCF analysis should not be used. The reason for this is that,
that fentanyl has any efficacy in any neuropathic pain condition. in chronic pain, opioids frequently produce withdrawal rates of
50% or more, meaning that LOCF analysis can overstate treatment
For policy makers
efficacy to a large extent. BOCF should be used in preference to
There is insufficient evidence to support or refute the suggestion LOCF as it provides a more relevant estimate of efficacy for the real
that fentanyl has any efficacy in any neuropathic pain condition. world.
In the absence of any supporting evidence, it should probably not
be recommended, except at the discretion of a pain specialist with ACKNOWLEDGEMENTS
particular expertise in opioid use.
Institutional support was provided by the Oxford Pain Relief Trust.
For funders
The National Institute for Health Research (NIHR) is the largest
There is insufficient evidence to support or refute the suggestion single funder of the Cochrane Pain, Palliative and Supportive
that fentanyl has any efficacy in any neuropathic pain condition. Care Review Group (PaPaS). Disclaimer: the views and opinions
In the absence of any supporting evidence, it should probably not expressed herein are those of the review authors and do not
be recommended, except at the discretion of a pain specialist with necessarily reflect those of the NIHR, National Health Service (NHS),
particular expertise in opioid use. or the Department of Health.
The protocol was based on a template developed in collaboration

with the Cochrane Neuromuscular Diseases and Musculoskeletal
Review Groups. The editorial process was managed by PaPaS.

Informed decisions.
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* Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Informed decisions.
Arai 2015
Methods Study N02. Multicentre, EERW, open-label titration phase (10 to 29 days), and parallel group, dou-
ble-blind withdrawal phase (12 weeks)
Participants PHN, CRPS, postoperative pain syndrome > 12 weeks, mean PI > 50/100, opioid-naïve, inadequate PR
with non-opioid analgesics
Excluded: pain from other causes, asthma, bradyarrythmia, severe respiratory function disorders, he-
patic dysfunction, renal impairment, hypersensitivity to fentanyl or other opioids
N = 258 (titration phase)
M 134, F 124
Mean age 67 years (SD 14)
Mean baseline PI 74/100 (SD 13)
N = 163 (double-blind phase)
M 83, F 80
Mean age 67 years (SD 14)
Mean baseline PI 29/100 (SD 11)
Interventions Titration phase: fentanyl 1-day adhesive patch 12.5 µg/h for minimum 2 days. Increased by 12.5 µg/h
based on VAS PI and use of rescue medication to maximum 50 µg/h, over 10 to 29 days
Double-blind phase:
Fentanyl 1-day adhesive patch 12.5 to 50 µg/h, n = 84
Placebo patch, n = 79
Patches applied to chest abdomen, upper arm or thigh, replaced every day for 12 weeks
Rescue medication: morphine hydrochloride (5 mg per fentanyl 12.5 µg/h)
Outcomes Participants responding during titration period
Median time to withdrawal due to loss of analgesic efficacy
Median change in PI from randomisation to last 3 days of double-blind period (VAS)
Satisfaction scores
Notes Oxford Quality Score: R1, DB2, W1
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Unclear risk Method of sequence generation not described
tion (selection bias)
Allocation concealment Unclear risk Not described

(selection bias)
Blinding of participants Low risk "Placebo patch indistinguishable from one-day adhesive transdermal patch
and personnel (perfor- containing fentanyl"
mance bias)
All outcomes

Informed decisions.
Arai 2015 (Continued)
Blinding of outcome as- Low risk "Placebo patch indistinguishable from one-day adhesive transdermal patch
sessment (detection bias) containing fentanyl"
All outcomes
Incomplete outcome data Unclear risk Analyses used full analysis set, but no mention of imputation methods. Study's
(attrition bias) primary outcome seems robust, but other outcomes unclear
All outcomes
Size Unclear risk 50 to 199 participants per treatment arm
CRPS: complex regional pain syndrome; DB: double-blind; EERW: enriched enrolment randomised withdrawal; F: female; M: male; N:
number of participants in study; n: number of participants in treatment arm; PHN: postherpetic neuralgia; PI: pain intensity; PR: pain relief;
R: randomised; SD: standard deviation; VAS: visual analogue scale; W: withdrawals.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Canneti 2013 Open-label study
Ding 2014 Compares fentanyl with fentanyl + gabapentin
Kalso 2007 Open-label, mixed conditions, secondary analysis of Allan 2005
NCT01127100 Single-blind (outcomes assessor), ongoing study
Park 2010 Open-label cohort, mixed conditions
APPENDICES
Appendix 1. Methodological considerations for chronic pain

There have been several changes in how the efficacy of conventional and unconventional treatments is assessed in chronic painful
conditions. The outcomes are now better defined, particularly with new criteria for what constitutes moderate or substantial benefit
(Dworkin 2008); older trials may report only participants with 'any improvement'. Newer trials tend to be larger, avoiding problems from
the random play of chance. Newer trials also tend to be of longer duration, up to 12 weeks, and longer trials provide a more rigorous and
valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are now
applying stricter criteria for the inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall
assessment. To summarise some of the recent insights that must be considered in this new review.
1. Pain results tend to have a U-shaped distribution rather than a bell-shaped distribution. This is true in acute pain (Moore 2011a; Moore
2011b), back pain (Moore 2010d), and arthritis (Moore 2010e), as well as in fibromyalgia (Straube 2010); in all cases average results
usually describe the experience of almost no-one in the trial. Data expressed as averages are potentially misleading, unless they can
be proven to be suitable.
2. As a consequence, we have to depend on dichotomous results (the individual either has or does not have the outcome) usually from
pain changes or patient global assessments. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)
group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials of less
than 12 weeks' duration, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore 2010d); the effect
is particularly strong for less-effective analgesics, and this may also be relevant in neuropathic-type pain.
3. The proportion of people with at least moderate benefit can be small, even with an effective medicine, falling from 60% with an effective
medicine in arthritis to 30% in fibromyalgia (Moore 2009; Moore 2010d; Moore 2010e; Moore 2013b; Moore 2014c; Straube 2008; Sultan
2008). One Cochrane review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different
types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore

Informed decisions.
2009). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling should
not be done unless there are good reasons for doing so.
4. Individual patient analyses indicate that people who get good pain relief (moderate or better) have major benefits in many other
outcomes, affecting quality of life in a significant way (Moore 2010c; Moore 2014a).
5. Imputation methods such as last observation carried forward (LOCF), used when participants withdraw from clinical trials, can overstate
drug efficacy, especially when adverse event withdrawals with drug are greater than those with placebo (Moore 2012b).
Appendix 2. Search strategy for CENTRAL via CRSO

1. MESH DESCRIPTOR Neuralgia EXPLODE ALL TREES (610)
2. MESH DESCRIPTOR Peripheral Nervous System Diseases EXPLODE ALL TREES (2590)
3. MESH DESCRIPTOR Somatosensory Disorders EXPLODE ALL TREES (710)
4. ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)):TI,AB,KY (3306)
5. ((neur* or nerv*) adj6 (compress* or damag*)):TI,AB,KY (635)
6. 1 OR 2 OR 3 OR 4 OR 5 (6357)
7. MESH DESCRIPTOR Fentanyl EXPLODE ALL TREES (3897)
8. (fentanyl or fentanil* or Abstral or Actiq or DTrans or Durogesic or Fentalis or Matrifen or Mezolar or Osmanil or Sublimaze or Tilofyl or
Victanyl):TI,AB,KY (9907)
9. 6 AND 9 (193)
Appendix 3. Search strategy for MEDLINE via Ovid

1. exp NEURALGIA/ (15118)
2. exp PERIPHERAL NERVOUS SYSTEM DISEASES/ (124585)
3. exp SOMATOSENSORY DISORDERS/ (17961)
4. ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)).mp. (43123)
5. ((neur* or nerv*) adj6 (compress* or damag*)).mp. (52215)
6. 1 or 2 or 3 or 4 or 5 (200106)
7. Fentanyl/ (11986)
Victanyl).mp. (17707)
9. 7 or 8 (17707)
10.randomized controlled trial.pt. (417624)
11.randomized.ab. (309508)
12.placebo.ab. (159698)
13.drug therapy.fs. (1862631)
14.randomly.ab. (219030)
15.trial.ab. (322047)
16.groups.ab. (1378466)
17.10 or 11 or 12 or 13 or 14 or 15 or 16 (3483323)
18.6 and 9 and 17 (452)
Appendix 4. Search strategy for Embase via Ovid

1. exp NEURALGIA/ (81076)
2. exp PERIPHERAL NERVOUS SYSTEM DISEASES/ (55241)
3. exp SOMATOSENSORY DISORDERS/ (72226)
4. ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)).mp. (80613)
5. ((neur* or nerv*) adj6 (compress* or damag*)).mp. (73746)
6. 1 or 2 or 3 or 4 or 5 (294021)
7. Fentanyl/ (50046)
Victanyl).mp. (54103)
9. 7 or 8 (54103)
10.random*.ti,ab. (1042778)
11.factorial*.ti,ab. (26694)

Informed decisions.
12.(crossover* or cross over* or cross-over*).ti,ab. (79506)

13.placebo*.ti,ab. (230284)
14.(doubl* adj blind*).ti,ab. (163796)
15.assign*.ti,ab. (276944)
16.allocat*.ti,ab. (99797)
17.RANDOMIZED CONTROLLED TRIAL.sh. (390913)
18.DOUBLE-BLIND PROCEDURE.sh. (127382)
19.CROSSOVER PROCEDURE.sh. (45369)
20.10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 (1482600)
21.6 and 9 and 20 (770)
Appendix 5. GRADE: criteria for assigning grade of evidence

The GRADE system uses the following criteria for assigning a quality level to a body of evidence (Chapter 12, Higgins 2011).
• High: randomised trials; or double-upgraded observational studies.

• Moderate: downgraded randomised trials; or upgraded observational studies.
• Low: double-downgraded randomised trials; or observational studies.
• Very low: triple-downgraded randomised trials; or downgraded observational studies; or case series/case reports.
Factors that may decrease the quality level of a body of evidence are:
1. limitations in the design and implementation of available studies suggesting high likelihood of bias;
2. indirectness of evidence (indirect population, intervention, control, outcomes);
3. unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses);
4. imprecision of results (wide confidence intervals);
5. high probability of publication bias.
Factors that may increase the quality level of a body of evidence are:
1. large magnitude of effect;

2. all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results show no effect;
3. dose-response gradient.
Appendix 6. Summary of outcomes: efficacy
Study Treatment Pain outcome Other efficacy outcome
Arai 2015 Titration: Fentanyl Titration: Randomised withdrawal:

1-day patch, 12.5 to
50 µg/h 163/258 completed Median time to withdrawal due to
insufficient analgesic efficacy
Randomised with- Mean PI reduced from 73.5 (SD 12.8) to 39.5 (1) not estimated
drawal: (20.0) (mean of last 3 days) (scale 0 to 100) (2) 45 days
(1) Fentanyl patch Randomised withdrawal: Use of rescue medication (mean

(titrated dose) doses/day)
Mean change in PI from randomisation to last 3
(2) Placebo (down- days of double-blind period (scale 0 to 100) (1) 0.4 (SD 0.68)
titration) (1) 0.5 (30.1, SD 11.5 to 29.6, SD 21.7) (2) 0.7 (SD 0.86)
(2) 9.6 (27.5, SD 11.2 to 37.1, SD 20.2)
Measures of health disability using
PGIC (satisfied, very satisfied with pain treat- SF-36 did not change substantially
ment; 5-point scale) during treatment
(1) 49/84
(2) 32/79

Informed decisions.
(Continued)
PGIC: Patient Global Impression of Change; PI: pain intensity; SD: standard deviation; SF-36: Short-Form 36-Item Health Survey
Appendix 7. Summary of outcomes: adverse events and withdrawals
Study Treatment Adverse events Serious AEs Withdrawals
Arai 2015 Titration: Fen- Titration: No deaths re- Titration:

tanyl 1-day Any AE 231/258 ported AE: 39/258
patch, 12.5 to 50 Participant decision: 6/258
µg/h (most mild or moderate) Titration: Physician decision: 2/258
13/258 Participant determined to in-
Randomised Most common were:
crease dose: 3/258
withdrawal: Randomised Participant not appropriate
constipation (124/258), nausea
withdrawal: for study: 1/258
(1) Fentanyl (103/258), somnolence (118/258), and
(1) 8/84 Non-responders: 50/258
patch (titrated dizziness (52/258)
(2) 4/79
dose)
Application-site reactions during Randomised withdrawal:
(2) Placebo titration: pruritus (15/258), erythe- Fentanyl: 37/84
(down titration) ma (8/258), dermatitis (4/258), rash AE: 14/84
(3/258) LoE: 1/84
> 15/100 increase in PI: 18/84
Randomised withdrawal: Physician or participant deci-
(1) 72/84 sion: 3/84
(2) 56/79 Other: 1/84
Most mild or moderate Placebo: 51/79

Fentanyl: 12 reported constipation, AE: 4/79
12 nausea, 12 somnolence, and 6 LoE: 4/79
dizziness > 15/100 increase in PI: 35/79
Physician or participant deci-
Placebo: 10 reported constipation, sion: 4/79
10 nausea, 5 somnolence, and 3 dizzi- Other: 4/79
ness
Few participants in either group re-

ported application site reactions dur-
ing the double-blind period
AE: adverse event; LoE: lack of efficacy; PI: pain intensity
Appendix 8. Details of studies of fentanyl not included in this review
Study Partici- Design and Number Intervention Efficacy data Adverse event data
pants duration
Randomised open studies
Allan 2001 CNCP re- Ran- N = 256 TD fentanyl 212/251 assessed for More withdrawals (38 vs 22)
quiring domised, compared preference: and AE withdrawals (27 vs 10)
strong opi- open, with CR mor- with fentanyl
oids Moder- cross-over phine fentanyl 65% More nausea, less constipa-
ate control tion with fentanyl

Informed decisions.
(Continued)
with oral 2 x 4 weeks morphine 28%
opioids
no preference 7%
Mean pain score lower

with fentanyl (58/100
vs 63/100)
Better satisfaction
with fentanyl
Allan 2005 CLBP naïve Ran- N = 680 TD fentanyl Similar pain relief, less Similar numbers completed
to strong domised, compared constipation with fen- (48% vs 53%)
opioid open, par- with CR mor- tanyl AE withdrawals: 125 fen-
allel phine tanyl, 104 morphine
LoE withdrawals: 18 fen-
13 months tanyl, 15 morphine
Canneti Peripheral Ran- N = 40 TD fentanyl Mean PI reduced sig- Both well tolerated
2013 neuropath- domised, compared nificantly in both
ic pain with open, par- with TD groups Buprenorpine
advanced allel buprenor- slightly better
AIDS phine
12 months
Raptis 2014 Neuropath- Ran- N = 120 TD fentanyl ≥ 30% PI reduction: AEs more frequent with fen-
ic cancer domised, compared pregabalin 73%, fentanyl (34 vs 16)
pain open, par- with prega- tanyl 37%
allel balin % mean change from Most common: nausea, som-
Increasing baseline: nolence, dizziness with fen-
4 weeks doses over 4 pregabalin 46%, fentanyl, nausea, somnolence
weeks tanyl 22% with pregabalin
Participant satisfac-
tion more frequent AE withdrawals: fentanyl
with pregabalin 10/60, pregabalin 3/60
Observational studies
Agarwal Peripheral Open, co- N = 53 TD fentanyl (3- > 30% pain reduction: Drowsiness (47%)
2007 neuropath- hort 51 entered day) 30/53 Nausea/vomiting (28%)
ic pain, CR- titration 6-week titra- > 50% pain reduction: Constipation (9%)
PS type I, 16 weeks 44 entered tion 21/53 Skin reactions (9%)
postampu- mainte- 25-150 μg/h Mean reduction in PI Withdrawals due to AEs
tation pain nance 8-week main- (0 to 10): 2.94 ± 0.27
40 com- tenance % pain relief: 34 ±
PI ≥ 3/10 pleted 14% (48% in com-
Stable, non- pleters)
opioid medi- Increase in average
cines contin- daytime activity: 37%
ued, opioid
wash out
Dellemijn Neuropath- Open-label N = 48 TD fentanyl - 12-week dose escalation pe-

1998 ic pain - extension titrated over riod: 16 withdrawals due to
mixed 12 weeks to LoE, AEs
24 months max 100 μg/h 17/30 who completed chose
or max toler- not to continue with exten-
ated sion (AEs not justified by ben-
Then tapered efit (13), pain relief persisted
by 25 μg/h (4))
weekly, and

Informed decisions.
(Continued)
substituted 3 discontinued in first year, 1
with mor- in second year
phine SR 60
mg/d, taper- Sedation, nausea, constipa-
ing over 10 tion most frequent AEs
days
2 weeks with
no opioid,
then offered
2-year exten-
sion
Franco CNCP Open-label, N = 236 TD fentanyl 34% participants Somnolence, vomiting, dizzi-
2002 observa- (120 neu- had PI < 3/10 after 6 ness most common AEs
tional ropathic months. Greatest re-
pain) duction in PI in first 3
6 months months
Milligan CNCP mod- Open-label, N = 532 TD fentanyl 67% had ≥ moderate 231 withdrew: 130 due to
2001 erate or se- observa- *103 par- pain control on treat- AEs, 39 LoE (most in first few
vere tional ticipated in ment months)
Allan 2001 Global satisfaction Nausea, constipation, som-
12 months 42% nolence most common
Mitra 2011 Persis- Open-label, N = 46 TD fentanyl vs Equivalent for efficacy More AE withdrawals with
tent pain - observa- TD buprenor- Tolerance after 6 fentanyl early on, buprenor-
mixed tional phine months phine later
12 months
Mystakidou CNCP Open-label, N = 529 TD fentanyl Improvements in pain 55 withdrew, all but one
2003 observa- and QoL within 4 weeks. 24 AE with-
tional Median duration of ef- drawals, 24 LoE withdrawals
fective pain manage- Constipation, nausea, sleepi-
Long-term ment 10 months ness most common
- up to 4 No difference be-
years for a tween NP and noci-
few partici- ceptive
pants
Park 2011 CNCP (most Open-label, N = 65 TD fentanyl Mean PI decreased by 24 withdrawals: 1 LoE, 18 AE
NP), requir- observa- 41 evaluat- titrated 62% (6.7/10 to 2.6/10) Nausea, dizziness, drowsi-
ing opioids tional ed 12 weeks ness, constipation, vomiting
PI moder- most common
ate or se-
vere
AE: adverse event; CLBP: chronic low back pain; CNCP: chronic non-cancer pain; CR: controlled release; CRPS: complex regional pain
syndrome; LoE: lack of efficacy; N: number of participants in study; NP: neuropathic pain; PI: pain intensity; QoL: quality of life; SR:
sustained release TD: transdermal
WHAT'S NEW

Informed decisions.
Date Event Description
29 May 2019 Amended Contact details updated.
11 October 2017 Review declared as stable See Published notes.
CONTRIBUTIONS OF AUTHORS
SD and RAM wrote the protocol.
SD and PC searched for and selected studies for inclusion and carried out data extraction.
All review authors were involved in the analysis and in writing the full review.
DECLARATIONS OF INTEREST
SD: none known.
CS: none known. She is a specialist pain physician and manages patients with chronic pain.
PC received support from Boston Scientific (2014) for travel and accommodation at a scientific meeting; Boston Scientific does not market
drugs. PC is a specialist pain physician and manages patients with chronic pain.
PW: none known.
RK has consulted for Grunenthal Ltd (2014-15) and MundiPharma Research (2015), and received lecture fees from Grunenthal Ltd (2013-14)
and Pfizer Ltd (2013-14). He is an Associate Professor in Clinical Pharmacy Practice and Advanced Pharmacy Practitioner.
DA has received lecture fees from Grünenthal (2013, 2014, 2015) and Pfizer (2013, 2016). He is a specialist pain physician and manages
patients with chronic pain.
RAM has received grant support from RB relating to individual patient-level analyses of trial data on ibuprofen in acute pain and the
effects of food on drug absorption of analgesics (2013), and from Grünenthal relating to individual patient-level analyses of trial data
regarding tapentadol in osteoarthritis and back pain (2015). He has received honoraria for attending boards with Menarini concerning
methods of analgesic trial design (2014), with Novartis about the design of network meta-analyses (2014), and RB on understanding the
pharmacokinetics of drug uptake (2015).
SOURCES OF SUPPORT
Internal sources
• Oxford Pain Relief Trust, UK.
General institutional support
External sources
• The National Institute for Health Research (NIHR), UK.
NIHR Cochrane Programme Grant: 13/89/29 - Addressing the unmet need of chronic pain: providing the evidence for treatments of pain
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

In the protocol the inclusion criteria included both CRPS types I and II as a diagnosis of neuropathic pain. We have now removed CRPS type
I because it is no longer considered to be neuropathic pain. We identified no studies in CRPS type I.
NOTES
No new studies likely to change the conclusions are expected. Therefore, this review has now been stabilised following discussion with the
authors and editors. If appropriate, we will update the review if new evidence likely to change the conclusions is published, or if standards
change substantially which necessitate major revisions.

Informed decisions.
INDEX TERMS
Medical Subject Headings (MeSH)

Analgesics, Opioid [*therapeutic use]; Fentanyl [*therapeutic use]; Neuralgia [*drug therapy]; Pain Measurement; Randomized
Controlled Trials as Topic
MeSH check words

Aged; Female; Humans; Male


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Cochrane

Fentanyl for neuropathic pain in adults (Review)

Derry S, Stannard C, Cole P, Wiffen PJ, Knaggs R, Aldington D, Moore RA

Derry S, Stannard C, Cole P, Wiffen PJ, Knaggs R, Aldington D, Moore RA.

Fentanyl for neuropathic pain in adults (Review)

Fentanyl for neuropathic pain in adults (Review) i

Fentanyl for neuropathic pain in adults

Contact address: Sheena Derry, Oxford, Oxfordshire, UK. sheena.derry@retired.ox.ac.uk.

Editorial group: Cochrane Pain, Palliative and Supportive Care Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Fentanyl for neuropathic pain in adults

Quality of the evidence

Fentanyl for neuropathic pain in adults (Review) 2

Summary of findings for the main comparison.

Patient or population: Adults with chronic neuropathic pain

Comparison: Placebo patch

Substantial benefit: No data No data - - - -

at least 50% reduction in

PGIC much improved

Cochrane Database of Systematic Reviews

Cochrane Database of Systematic Reviews

BACKGROUND combining pharmacological interventions with physical or

Fentanyl for neuropathic pain in adults (Review) 5

Fentanyl for neuropathic pain in adults (Review) 8

Figure 1. Study flow diagram.

Fentanyl for neuropathic pain in adults (Review) 9

Fentanyl for neuropathic pain in adults (Review) 10

Fentanyl for neuropathic pain in adults (Review) 11

Fentanyl for neuropathic pain in adults (Review) 12

Other pain-related outcomes Other withdrawals

During titration 39/258 participants withdrew due to adverse DISCUSSION

Fentanyl for neuropathic pain in adults (Review) 13

Fentanyl for neuropathic pain in adults (Review) 14

AUTHORS' CONCLUSIONS Implications for research

The protocol was based on a template developed in collaboration

Fentanyl for neuropathic pain in adults (Review) 15

References to studies included in this review Allan 2001

Fentanyl for neuropathic pain in adults (Review) 16

Franco 2002 Higgins 2011

Franklin 2014 Hoffman 2010

Guyatt 2011 Kalso 2013

Fentanyl for neuropathic pain in adults (Review) 17

and differences, Rochester, Minnesota,1945-1984. Mitra 2011

Fentanyl for neuropathic pain in adults (Review) 18

Fentanyl for neuropathic pain in adults (Review) 19

Raptis 2014 Trescot 2008

Characteristics of included studies [ordered by study ID]

Fentanyl for neuropathic pain in adults (Review) 20

N = 258 (titration phase)

Mean age 67 years (SD 14)

Mean baseline PI 74/100 (SD 13)

N = 163 (double-blind phase)

Mean age 67 years (SD 14)

Mean baseline PI 29/100 (SD 11)

Fentanyl 1-day adhesive patch 12.5 to 50 µg/h, n = 84

Rescue medication: morphine hydrochloride (5 mg per fentanyl 12.5 µg/h)

Outcomes Participants responding during titration period

Median time to withdrawal due to loss of analgesic efficacy