Plain language summary
Opioids for neuropathic pain
Neuropathic pain is pain caused by nerve damage. It is often difficult to diagnose and treat. The use of opioids (strong pain killers such as morphine) to treat neuropathic pain is controversial owing to concerns about addiction and beliefs that this type of pain does not always respond well to opioids. The review looked at short-term studies lasting less than a day and intermediate-term trials lasting from several days to 12 weeks. The 31 studies found involved 1237 people with neuropathic pain; most studies were small.
Short-term studies produced mixed results, with just over half indicating that opioids might be better than a placebo. While intermediate-term studies all indicated that opioids were better than placebo, most studies were small, most were short, and none used methods known to be unbiased. All these features are likely to make effects of opioids look better in clinical trials than they are in clinical practice. We cannot say whether opioids are better than placebo for neuropathic pain over the long term. Side effects such as constipation, nausea, dizziness, and drowsiness were common, but not life-threatening.
Opioidi za neuropatsku bol
Neuropatska bol nastaje zbog oštećenja živca. Neuropatsku bol je često teško prepoznati i liječiti. Uporaba opioida (jakih lijekova protiv bolova, kao što je morfij) za liječenje neuropatske boli kontroverzno je pitanje zbog mogućeg razvoja ovisnosti, i uvjerenja da ta vrsta boli ne odgovara uvijek dobro na opioide. U ovom Cochrane sustavnom pregledu istražene su kratkoročne kliničke studije koje su trajale kraće od dana i studije koje su trajale od nekoliko dana do 12 tjedana. U medicinskoj je literaturi pronađena 31 studija, s ukupno 1237 uključenih ispitanika s neuropatskom boli; studije su većinom bile malene.
Kratkoročne studije dale su različite zaključke; svega nešto više od polovice tih studija pokazalo je da bi opioidi mogli biti bolji od placeba. Sve studije koje su trajale dulje od jednog dana pokazuju da su opioidi bilo bolji od placeba za liječenje neuropatske boli, ali studije su većinom bile malene, uglavnom su kratko trajale i nijedna nije koristila nepristrane metode. Zbog svega navedenoga, opioidi u kliničkim istraživanjima vjerojatno pokazuju bolji učinak nego u kliničkoj praksi. Temeljem rezultata sustavnog pregleda literature, nije moguće reći jesu li opioidi bolji od placeba za liječenje neuropatske boli tijekom duljeg razdoblja. Zabilježene nuspojave opioida, uključujući zatvor, mučninu, vrtoglavicu i pospanost, bile su česte, ali nisu ugrožavale život sudionika istraživanja.
Prevoditelj:: Croatian Branch of the Italian Cochrane Centre
This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 3, 2006) on 'Opioids for neuropathic pain'.
Description of the condition
The percentage of people suffering from neuropathic pain is unknown, but is estimated to be as high as 7% to 8% (Bouhassira 2008; Torrance 2006) in developed nations. Estimates of the prevalence of chronic pain (of which neuropathic pain is a subset) suggest that around 20% of both developed and undeveloped nations' populations are affected (Breivik 2004; Breivik 2006). Neuropathic pain may result from a large variety of insults to the peripheral or central somatosensory nervous system, including trauma, inflammation, ischemia, and metabolic and neoplastic disorders. Common examples of peripheral neuropathic pain include diabetic neuropathy and postsurgical neuralgia. Central neuropathic pain includes central post-stroke pain, pain in multiple sclerosis, and pain after spinal cord injury. The main clinical characteristics of neuropathic pain are continuous or intermittent spontaneous pain, typically described as burning, aching, or shooting in quality, and abnormal sensitivity of the painful site to normally innocuous stimuli such as light touch by garments, running water, or even wind (allodynia) (Baron 2010; Maier 2010). Neuropathic pain, like many other forms of chronic pain, often has negative effects on quality of life (Jensen 2007; Meyer-Rosberg 2001). Pharmacotherapy for neuropathic pain has generally involved the use of antidepressants or anticonvulsants, but even with the current generation of these drugs, effective analgesia is achieved in less than half of this population (Dworkin 2010; Finnerup 2010; O'Connor 2009; Sindrup 1999).
Description of the intervention
Opioids are the most effective broad-spectrum analgesics available and are considered the cornerstone of therapy for moderate-to-severe acute pain or pain of similar intensity due to life-threatening illnesses, but their long-term use in non-cancer pain, of which neuropathic pain is a component, is controversial. In the United States, the therapeutic use of opioids in general has risen significantly over the last decade (Manchikanti 2008). Despite this, the safety and efficacy of the different opioids in the treatment of neuropathic pain have yet to be established. Clinical trials assessing the efficacy of opioids for reducing neuropathic pain have been reported for more than 25 years, yet great variability in trial design in terms of the type of neuropathic pain syndrome treated, the type of opioid administered, and the duration of treatment has yielded contradictory results. Studies that have suggested efficacy have used small study populations, raising questions about the validity of the results.
How the intervention might work
Opioids provide analgesia by binding to opioid receptors of the mu and kappa class and blocking the release of neurotransmitters such as substance P. Opioid receptors are expressed both centrally and peripherally during the inflammatory response in injured tissue.
Why it is important to do this review
There is a lack of definitive evidence regarding the efficacy of opioids in reducing neuropathic pain in general, and central neuropathic pain in particular. Equally, there are concerns about tolerability of opioids and the potential for abuse, addiction, hormonal abnormalities, dysfunction of the immune system, and, in some cases, paradoxical hyperalgesia with long-term use (Rhodin 2010; Seghal 2012; Tompkin 2011; Vallejo 2004). Therefore, we conducted a systematic review of published randomized controlled trials (RCTs).
Summary of main results
The results of this review can be divided into two categories according to the duration of included trials.
Short-term trials demonstrated mixed results with respect to the analgesic efficacy of opioids. Our updated search did not yield any new studies suitable for statistical analysis. Although our meta-analysis showed an overall mean difference in the last measured pain intensity for short-term active treatment versus placebo of -16 points (on a 0 - 100 visual analog scale (VAS)), the result should be interpreted with caution because it is based on only six of 17 studies (and only 90 of 392 participants). Thus, our conclusion regarding this category of studies has not changed from our previous meta-analyses.
In contrast, intermediate-term trials demonstrated consistent opioid analgesic efficacy in reducing spontaneous neuropathic pain that was almost entirely statistically significant when results were pooled, although studies were small, mostly short, and potentially dealt inadequately with data once participants withdrew from treatment. Our updated review added data to our original analyses, increasing confidence in their findings, but also introduced new outcome analyses, i.e. number of participants with at least 33% and 50% reduction and assessments of functioning, which are considered clinically important in chronic pain (Dworkin 2008). Intermediate-term studies are more clinically relevant than short-term studies because they assess the benefits and risks associated with opioid treatments for weeks to months, i.e. they reflect how opioids are administered for neuropathic pain in clinical practice. This part of the meta-analysis was based on most of the available trials and included the majority of participants. Hence, we conclude that intermediate-term opioid treatment has a beneficial effect over placebo for spontaneous neuropathic pain as measured by both number of participants with at least 33% and at least 50% pain relief and in mean differences in post-intervention pain intensity. Opioids did not demonstrate improvement in many aspects of emotional or physical functioning, as measured by various validated questionnaires. This raises the concern that improvements in pain relief are not accompanied by similar improvements in activities of daily living or quality of life. It should be noted, however, that our meta-analyses of functioning included few studies, with low overall numbers of participants.
When comparing opioids with active controls, only the comparison of morphine with the rarely used antiarrythmic mexiletine demonstrated superiority of opioid (Wu 2008), with other comparisons not showing statistically significant differences between treatments. This may be due to opioids genuinely having similar efficacy to other interventions, or it may simply be a result of low participant numbers. Indirect comparisons with meta-analyses of other treatments for neuropathic pain offer limited clarification. For example, Moore 2011 compared gabapentin with placebo for several similar efficacy outcomes. While the numbers needed to treat for an additional beneficial outcome (NNTBs) are similar for at least 50% pain relief and 33% pain relief (defined as 'moderate' relief in Moore 2011), placebo rates are much higher in the opioid analyses. Equally, participants in the gabapentin analyses often required the maximum daily dose (3600 mg), whereas in the opioid studies a larger effect was achieved by a low to moderate dose of opioid. Moreover, the dose-dependent analgesic effects shown in two of the opioid studies (Morley 2003; Rowbotham 2003) have not been confirmed by further trials; it is therefore unclear if high doses of opioids produce a greater magnitude of pain reduction in people with neuropathic pain. Thus, we are unable to confirm the commonly held belief that opioids have no ceiling effect in this population. This may be particularly important in light of recent concerns regarding mortality risk associated with high opioid dose regimens (Gomes 2011).
Our assessment of safety did not find data related to serious adverse events, including mortality, most likely because of the relative rarity of such events, especially with low-to-moderate doses of opioids. Instead, we were able to analyze data related to relatively common, widely identified opioid-induced adverse events. Not surprisingly, and in agreement with our earlier review, many of the most commonly recognized opioid side effects occurred more frequently in those treated with opioid than with placebo. Conversely, there were few statistically significant differences between opioids and active controls, which may be due to controls having similar side-effect profiles, or to the small participant numbers for each comparison. However, constipation and drowsiness did appear to occur more commonly. In placebo-controlled studies, 13% of participants withdrew from opioid therapy due to adverse events, and 2% due to lack of efficacy. While these percentages are not particularly high, most of the study durations were less than eight weeks; therefore numbers may increase over longer periods. Additionally, the available randomized controlled trials (RCTs) do not clearly address the issues of addiction and abuse. The absence of any report of addictive behavior or abuse in any of the intermediate-term trials may have several explanations. It is possible that the prevalence of these behaviors is indeed low (Sullivan 2005). Alternatively, the duration of treatment in these studies may have been too short to allow such behaviors to develop. Furthermore, although not mentioned specifically as an exclusion criterion in all studies, it is reasonable to assume that the recruitment of people with active or potential abuse disorders (Dunbar 1996) into such studies would routinely be avoided. The need to further assess the risk of abuse and addiction continues to be important.
Overall completeness and applicability of evidence
The included articles studied participants with a wide range of neuropathies, but predominately postherpetic neuralgia (PHN) and diabetic neuropathy. This reflects the distribution of neuropathic pain in the general population, with the exception that few studies included participants with back pain of neuropathic origin, which is thought to be the most common type of neuropathic pain (Torrance 2006). This may be due to the fact that it is often difficult to diagnose back pain as being purely neuropathic, with it frequently also having features of nociceptive pain. There were insufficient numbers of participants with individual neuropathies to perform a subanalysis of efficacy or safety. While our updated review added a substantial amount of data for each meta-analysis, the overall numbers are still low for most comparisons. In particular, the inconsistency of reporting of outcomes related to functioning precludes our making firm conclusions. Many of the studies reported outcomes only on those participants completing the trial; therefore efficacy may have been over-estimated. In those that performed an intention-to-treat (ITT) or modified ITT analysis, the most commonly used method of imputation was last observation carried forward (LOCF), which again may overestimate efficacy (Moore 2012). None of the studies used baseline observation carried forward (BOCF). The short duration of many intermediate-term studies is also a potential source of bias (Moore 2010a).
Several points deserve consideration in terms of applicability of the evidence.
First, the fact that short-term trials, in contrast to the intermediate-term trials, yielded inconsistent efficacy results suggests that short-term opioid administration is unlikely to serve as a useful predictive tool when initiating a trial of opioid therapy in people with neuropathic pain.
Second, the NNTB results further confirm that opioids reduce various forms of neuropathic pain and are relatively safe, and therefore indicate that opioids at low-to-moderate doses are suitable for use over periods of weeks to months in the treatment of neuropathic pain. However, despite the common use of NNTB values to compare relative efficacy of different treatments, especially when head-to-head comparative trials are relatively scarce, their validity has been questioned for reasons such as differences in trial designs, exclusion of non-placebo-controlled trials, dichotomization of data, and strict and not necessarily clinically relevant cut-off points (i.e. 50% pain relief) (Finnerup 2010).
Third, the use of a single dimension for assessment of efficacy of analgesic treatments is problematic in any form of chronic pain, which is a multi-dimensional phenomenon. This becomes even more problematic in neuropathic pain, where even a single etiological syndrome (e.g. PHN) typically differs considerably from one patient to another in term of its clinical representation. For that reason the use of additional outcome measures rather than a single pain intensity or pain relief method have been recommended (Wittink 2005). Unfortunately, consistent improvement in specific features of neuropathic pain (e.g. evoked pain), in emotional or physical aspects of functioning, or in health-related quality of life could not be demonstrated in the present review.
Fourth, the debate regarding the differential efficacy of opioids for central versus peripheral neuropathic pain (Ballantyne 2003; Canavero 2003; Dellemijn 1999; McQuay 1997; Nicholson 2004) has not been resolved by our study. Results of the included studies varied considerably and the meta-analyses could not include all relevant studies. Despite limited data, the meta-analyses showed similar opioid responsiveness for pain of central and peripheral etiologies.
Fifth, although a dose-dependent analgesic effect was found in two studies, the dose ranges tested are still in the low-intermediate range and do not necessarily reflect clinical practice in some countries (e.g. the USA). This, along with increasing concerns about opioid toxicity, especially at higher dose ranges (greater than the daily equivalent of 200 mg of oral morphine), does not support the use of high doses of opioids for the relief of neuropathic pain.
Lastly, this review also included a quantitative analysis of common opioid-related adverse effects. Although the analysis is based on a relatively large number of participants with neuropathic pain, those enrolled in clinical trials may not be representative of the broader patient population seen in clinical practice. Enrolled participants have met inclusion criteria, and their willingness to enter a clinical trial suggests that they may have a higher adherence profile compared with those who are not enrolled.
Quality of the evidence
The quality of evidence improved somewhat with those articles included in our updated search. Many more of the newer studies reported outcomes considered to be clinically relevant, such as numbers of participants with at least 50% pain relief, and in a format that allowed us to perform meta-analysis (Dworkin 2008). Additionally, the risk of bias for each domain, while low overall, was generally lower in newer studies.
Potential biases in the review process
We believe the search methodology used here to be unbiased, and the selection criteria relevant to the nature of neuropathic pain. However, two aspects of our review methodology have the potential to introduce bias to our analyses. First, we included studies of less than 12 weeks duration. While we included 'short-term' studies purely for 'proof of concept', even amongst our 'intermediate-term' studies only one (Hanna 2008) was conducted over 12 weeks. Studies of less than 12 weeks duration may overestimate treatment efficacy (Moore 2010a). Given the dearth of long-term studies, we adopted a 'best available evidence' approach, and anticipate that future studies will have longer durations, allowing us to better assess the efficacy and safety of opioids administered over clinically relevant time periods.
Second, we analyzed data from cross-over studies in the same manner as that from parallel studies. This approach may give rise to a unit-of-analysis error (Higgins 2011). However, as discussed (Effects of interventions) we performed a sensitivity analysis where cross-over studies were removed from meta-analyses and found negligible differences in estimates of effect for either efficacy or safety.
Agreements and disagreements with other studies or reviews
Most recent guidelines on the pharmacotherapy of neuropathic pain are in agreement with the results of the present review and recommend the use of opioids, typically as second- or third-line treatment options (Attal 2010; Dworkin 2010; Moulin 2007; Pergolizzi 2008).
A systematic review of the evidence for pharmacological treatment of neuropathic pain (Finnerup 2010) also found that opioids have a consistent efficacy in neuropathic pain. Notably, the NNTBs for achieving meaningful pain relief in several neuropathic pain conditions (i.e. painful polyneuropathy, postherpetic neuralgia, peripheral nerve injury and mixed neuropathic pain) varied from 2.1 to 5.1 and were slightly lower than the NNTBs found in the present review. The differences in findings occurred for several reasons. First, we excluded studies with tramadol. Second, we had two additional studies in our NNTB analysis (Khoromi 2007; Zin 2010). Third, Finnerup 2010 combined results for participants with at least 33% and at least 50% pain relief, whereas we analyzed these outcomes separately. Last, and perhaps most importantly, they performed meta-analysis separately for each neuropathic pain syndrome. We combined data as we considered numbers of participants for each syndrome to be insufficient for subanalysis.
Appendix 1. CENTRAL search strategy (pre-2012)
|#1|| MeSH descriptor Pain, this term only|
|#2|| MeSH descriptor Neuralgia, this term only|
|#3|| MeSH descriptor Pain, Intractable, this term only|
|#4|| MeSH descriptor Complex Regional Pain Syndromes explode all trees|
|#5|| MeSH descriptor Diabetic Neuropathies, this term only|
|#6|| MeSH descriptor Trigeminal Neuralgia, this term only|
|#7|| MeSH descriptor Somatosensory Disorders explode all trees|
|#8|| (neuropathic near/2 pain*):ti|
|#10|| (complex regional pain syndrome):ti|
|#11|| (reflex sympathetic dystrophy):ti|
|#13|| (post-herpetic neuralgia):ti|
|#14|| (phantom limb pain):ti|
|#16|| (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15)|
|#17|| MeSH descriptor Narcotics, this term only|
|#18|| MeSH descriptor Analgesics, Opioid, this term only|
|#19|| (morphine or buprenorphine or codeine or dextromoramide or diphenoxylate or dipipanone or dextropropoxyphene or propoxyphene or diamorphine or dihydrocodeine or alfentanil or fentanyl or remifentanil or meptazinol or methadone or nalbuphine or oxycodone or papaveretum or pentazocine or meperidine or pethidine or phenazocine or hydrocodone or hydromorphone or levorphanol or oxymorphone or butorphanol or dezocine or sufentanil or ketobemidone):ti,ab,kw|
|#20|| (#17 OR #18 OR #19)|
|#21|| (#16 AND #20)|
|#22|| (#21)Cochrane Reviews|
|#23|| (#21)Other reviews|
Appendix 2. MEDLINE search strategy (pre-2012)
3. pain, intractable.sh.
4. exp Complex Regional Pain Syndromes/
5. diabetic neuropathies.sh.
6. trigeminal neuralgia.sh.
7. exp somatosensory disorders/
8. (neuropathic adj2 pain).tw.
10. complex regional pain syndrome.tw.
11. reflex sympathetic dystrophy.tw.
13. post-herpetic neuralgia.tw.
14. phantom limb pain.tw.
16. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15
18. *"Analgesics, Opioid"/
19. (morphine or buprenorphine or codeine or dextromoramide or diphenoxylate or dipipanone or dextropropoxyphene or propoxyphene or diamorphine or dihydrocodeine or alfentanil or fentanyl or remifentanil or meptazinol or methadone or nalbuphine or oxycodone or papaveretum or pentazocine or meperidine or pethidine or phenazocine or hydrocodone or hydromorphone or levorphanol or oxymorphone or butorphanol or dezocine or sufentanil or ketobemidone).mp.
20. 17 or 18 or 19
21. randomized controlled trial.pt.
26. (meta-anal: or metaanaly: or meta analy:).ti,ab,sh.
27. ((doubl: or singl:) and blind:).ti,ab,sh.
28. exp clinical trials/
30. 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29
32. 16 and 20 and 30
33. 32 not 31
[mp=title, original title, abstract, name of substance, mesh subject heading].
Appendix 3. EMBASE search strategy (pre-2012)
3 Neuropathic Pain/
4 exp Complex Regional Pain Syndrome/
5 (diabetic adj neuropath$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
6 Trigeminus Neuralgia/
7 Somatosensory Disorder/
8 (neuropathic adj pain$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
9 "complex regional pain syndrome$".mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
10 neuralgi$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
11 "reflex sympathetic dystroph$".mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
12 causalgi$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
13 Postherpetic Neuralgia/
14 ("post herpetic neuralgi$" or "post-herpetic neuralgi$").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
15 Phantom Pain/
16 (phantom adj pain$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
17 Intractable Pain/
18 (intractable adj pain$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
20 allodynia.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
22 Narcotic Agent/
23 (narcotic adj agent$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
24 (analgesic$ adj3 opioid$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]
25 (morphine or buprenorphine or codeine or dextromoramide or diphenoxylate or dipipanone or dextropropoxyphene or propoxyphene or diamorphine or dihydrocodeine or alfentanil or fentanyl or remifentanil or meptazinol or methadone or nalbuphine or oxycodone or papaveretum or pentazocine or meperidine or pethidine or phenazocine or hydrocodone or hydromorphone or levorphanol or oxymorphone or butorphanol or dezocine or sufentanil or ketobemidone).mp.
26 22 or 23 or 24 or 25
27 21 and 26
30 (crossover* or cross over* or cross-over*).ti,ab.
32 (doubl* adj blind*).ti,ab.
33 (singl* adj blind*).ti,ab.
37 CROSSOVER PROCEDURE.sh.
38 DOUBLE-BLIND PROCEDURE.sh.
39 RANDOMIZED CONTROLLED TRIAL.sh.
40 SINGLE BLIND PROCEDURE.sh.
42 ANIMAL/ or NONHUMAN/ or ANIMAL EXPERIMENT/
44 42 and 43
45 42 not 44
46 41 not 45
47 27 and 46
Appendix 4. CENTRAL search strategy 2012
#1 MeSH descriptor: [Pain] this term only
#2 MeSH descriptor: [Neuralgia] this term only
#3 MeSH descriptor: [Pain, Intractable] this term only
#4 MeSH descriptor: [Complex Regional Pain Syndromes] explode all trees
#5 MeSH descriptor: [Diabetic Neuropathies] explode all trees
#6 MeSH descriptor: [Trigeminal Neuralgia] explode all trees
#7 MeSH descriptor: [Somatosensory Disorders] explode all trees
#8 (neuropathic near/2 pain*):ti,ab,kw (Word variations have been searched)
#9 (neuralgia):ti,ab,kw (Word variations have been searched)
#10 (complex regional pain syndrome):ti,ab,kw (Word variations have been searched)
#11 (reflex sympathetic dystrophy):ti,ab,kw (Word variations have been searched)
#12 (causalgia):ti,ab,kw (Word variations have been searched)
#13 (post-herpetic neuralgia):ti,ab,kw (Word variations have been searched)
#14 (phantom limb pain):ti,ab,kw (Word variations have been searched)
#15 (allodynia):ti,ab,kw (Word variations have been searched)
#16 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15)
#17 MeSH descriptor: [Narcotics] this term only
#18 MeSH descriptor: [Analgesics, Opioid] this term only
#19 (morphine or buprenorphine or codeine or dextromoramide or diphenoxylate or dipipanone or dextropropoxyphene or propoxyphene or diamorphine or dihydrocodeine or alfentanil or fentanyl or remifentanil or meptazinol or methadone or nalbuphine or oxycodone or papaveretum or pentazocine or meperidine or pethidine or phenazocine or hydrocodone or hydromorphone or levorphanol or oxymorphone or butorphanol or dezocine or sufentanil or ketobemidone):ti,ab,kw (Word variations have been searched)
#20 (#17 or #18 or #19)
#21 #16 and #20 from 2010 to 2012
Appendix 5. MEDLINE search strategy 2012
1 Pain/ (103631)
2 neuralgia/ (6938)
3 pain, intractable/ (5344)
4 exp Complex Regional Pain Syndromes/ (4141)
5 diabetic neuropathies/ (11390)
6 trigeminal neuralgia/ (5361)
7 exp somatosensory disorders/ (14530)
8 (neuropathic adj2 pain).tw. (8560)
9 neuralgia.tw. (7586)
10 complex regional pain syndrome.tw. (1303)
11 reflex sympathetic dystrophy.tw. (1481)
12 causalgia.tw. (426)
13 post-herpetic neuralgia.tw. (486)
14 phantom limb pain.tw. (539)
15 allodynia.tw. (4255)
16 or/1-15 (148967)
17 Narcotics/ (14099)
18 *"Analgesics, Opioid"/ (17512)
19 (morphine or buprenorphine or codeine or dextromoramide or diphenoxylate or dipipanone or dextropropoxyphene or propoxyphene or diamorphine or dihydrocodeine or alfentanil or fentanyl or remifentanil or meptazinol or methadone or nalbuphine or oxycodone or papaveretum or pentazocine or meperidine or pethidine or phenazocine or hydrocodone or hydromorphone or levorphanol or oxymorphone or butorphanol or dezocine or sufentanil or ketobemidone).tw. (72647)
20 or/17-19 (87255)
21 randomized controlled trial.pt. (339247)
22 controlled clinical trial.pt. (85403)
23 randomized.ab. (242011)
24 placebo.ab. (135530)
25 drug therapy.fs. (1577150)
26 randomly.ab. (173651)
27 trial.ab. (250716)
28 groups.ab. (1135692)
29 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 (2936803)
30 exp animals/ not humans.sh. (3795620)
31 29 not 30 (2494786)
32 16 and 20 and 31 (8133)
33 (201008* or 201009* or 201010* or 201011* or 201012* or 2011* or 2012*).ed. (1814643)
34 32 and 33 (1213)
Appendix 6. EMBASE search strategy 2012
1 Pain/ (174379)
2 neuralgia/ (6265)
3 pain, intractable/ (3738)
4 exp Complex Regional Pain Syndromes/ (7151)
5 diabetic neuropathies/ (16484)
6 trigeminal neuralgia/ (8199)
7 exp somatosensory disorders/ (55288)
8 (neuropathic adj2 pain).tw. (13683)
9 neuralgia.tw. (10683)
10 complex regional pain syndrome.tw. (1981)
11 reflex sympathetic dystrophy.tw. (1952)
12 causalgia.tw. (538)
13 post-herpetic neuralgia.tw. (825)
14 phantom limb pain.tw. (807)
15 allodynia.tw. (6059)
16 or/1-15 (268307)
17 Narcotics/ (10729)
18 *"Analgesics, Opioid"/ (6948)
19 (morphine or buprenorphine or codeine or dextromoramide or diphenoxylate or dipipanone or dextropropoxyphene or propoxyphene or diamorphine or dihydrocodeine or alfentanil or fentanyl or remifentanil or meptazinol or methadone or nalbuphine or oxycodone or papaveretum or pentazocine or meperidine or pethidine or phenazocine or hydrocodone or hydromorphone or levorphanol or oxymorphone or butorphanol or dezocine or sufentanil or ketobemidone).tw. (98508)
20 or/17-19 (111821)
21 16 and 20 (17023)
22 random$.tw. (773434)
23 factorial$.tw. (20181)
24 crossover$.tw. (45540)
25 cross over$.tw. (20720)
26 cross-over$.tw. (20720)
27 placebo$.tw. (186291)
28 (doubl$ adj blind$).tw. (138167)
29 (singl$ adj blind$).tw. (12952)
30 assign$.tw. (215292)
31 allocat$.tw. (72818)
32 volunteer$.tw. (167332)
33 Crossover Procedure/ (35309)
34 double-blind procedure.tw. (223)
35 Randomized Controlled Trial/ (333591)
36 Single Blind Procedure/ (16539)
37 or/22-36 (1272131)
38 (animal/ or nonhuman/) not human/ (4520391)
39 37 not 38 (1121112)
40 21 and 39 (3305)
41 (201008* or 201009* or 211010* or 211011* or 201012* or 2011* or 2012*).dd. (2723769)
42 40 and 41 (926)
Appendix 7. Intermediate-term studies: outcome of treatment
| Study|| Diagnosis|| Interventions|
| Frank 2008||Mixed neuropathic|
1. BL 58.6 ± 24.1, endpoint not reported
2. BL 59.9 ± 24.4, endpoint not reported
SF36 – significant differences in some subscales
| Gilron 2005||Diabetic neuropathy|
1. LA morphine
4. Placebo (lorazepam)
Pain intensity (0 - 10 scale ± SE) at maximum tolerated dose:
3.70 ± 0.34 vs. 4.15 ± 0.33 gabapentin arm vs. 3.06 ± 0.33 combination arm vs. 4.49 ± 0.34 placebo arm (combination lower than morphine arm, P = 0.04, gabapentin arm, p < 0.001, or placebo, P < 0.001. All other comparisons NS).
% change in pain intensity greater in combination arm vs. placebo: 20.4%, P = 0.03.
All other comparisons NS
| || |
| Gimbel 2003||Diabetic neuropathy|
1. LA oxycodone
VAS: 4.1 ± 0.3 vs 5.3 ± 0.3
NRS (0 - 10) BL - end of treatment
1. 7.9 ± 1.7 – 4.7 ± 2.9
2. 7.8 ± 1.6 - 5.8 ± 2.6
| ≥ 33% reduction in intensity item in NPS: oxycodone 37/82, placebo 20/77.|
Satisfaction with medication, sleep quality & 9/14 BPI parameters oxycodone > placebo;
Median time to pain < 4: 6 vs. 17 days;
% days with mild pain: 47 ± 39 vs 29 ± 37;
no difference in RMHI, SIP, SF-36
| Hanna 2008||Diabetic neuropathy|
1. LA oxycodone + gabapentin
2. Placebo+ gabapentin
Box scale-11 pain scores ; PID (BL to end of treatment)
1. 2.1 ± 2.61
2. 1.5 ± 2.38
Categorical pain relief scale –
% good + very good
56% vs. 41%
Sleep Disturbances, SF BPI, MPQ, EuroQol 5D Questionnaire – SSD in favor of oxycodone group. NND
Sleep Quality –NSD .NND
| Harke 2001||Mixed peripheral|
1. LA morphine
No sig differences between morphine & placebo
carbamazepine superior to placebo in NPS and in time without spinal cord stimulator
| || |
| Huse 2001||Phantom limb|
1. LA morphine
VAS (0 - 10): 3.3 ± 1.6 vs 4.0 ± 1.2
50% ΔVAS: 42% vs 8%
PES sensory: 0.7 ± 0.8 vs 1.7 ± 0.8
PES affective: 0.8 ± 0.6 vs 1.6 ± 0.7
No correlation between ΔVAS and PRSS, Brief Stress Scale or WHYMPI;
‘d2-test’: 101 ± 19 vs. 106 ± 18
| Khoromi 2007|
3. Morphine + nortriptyline
NRS-average leg pain (0 - 10): BL to end of treatment
1. 4.9 ± 2.4 to 3.4 ±2.8
2. 4.9 ± 2.4 to 3 ± 2.7
3. 4.9 ± 2.4 to 3.4 ± 2.5
4. 4.9 ± 2.4 to 3.7 ± 2.7
NRS-worst leg pain (0-10): BL to end of treatment
1. 5.7 ± 2.4 to 4.5 ± 3.1
2. 5.7 ± 2.4 to 3.8 ± 3
3. 5.7 ± 2.4 to 3.8 ± 2.4
4. 5.7 ± 2.4 to 4.6 ± 2.8
CGPRS (0 - 5)
Mod or more pain relief N (%)
1. 13/32 (4%)
2. 12/31 (40%)
3. 18/28 (67%)
4. 11/33 (37%)
BDI: BL to end of treatment
1. 8 ± 6.7 to 9.6 ± 8.5
2. 8 ± 6.7 to 7.3 ± 7.1
3. 8 ± 6.7 to 6 ± 5
4. 8 ± 6.7 to 9 ± 8.5
ODI - NSD
BDI: BL to end of treatment
1. 30 ± 15 to 25.7 ± 16.5
2. 30 ± 15 to 27.5 ± 16.7
3. 30 ± 15 to 27.4 ± 15.4
4. 30 ± 15 to 30.5 ± 15.9
| Morley 2003||Mixed|
1. Methadone low-dose
3. Methadone high-dose
Low-dose vs placebo:
VAS max : 69 ± 17 vs 74 ± 13 ns
VAS ave: 60 ± 20 vs 64 ± 19 ns
High dose vs placebo:
VAS max : 64 ± 23 vs 64 ± 27
VAS ave : 58 ± 25 vs 64 ± 22
Low-dose vs placebo:
VAS : 23 ± 19 vs 15 ± 16 ns
High dose vs placebo:
VAS: 32 ± 27 vs 23 ± 21
| Raja 2002||Postherpetic neuralgia|
1. Morphine or methadone
2. Nortriptyline or desipramine
1. 4.4 ± 2.4
2. 5.1 ± 2.3
3. 6.0 ± 2.0
Both active treatments superior to placebo
1. 38.2 ± 32.2
2. 31.9 ± 30.4
3. 11.2 ± 19.8
Both active treatments superior to placebo
Wechsler Adult Intelligence Scale–Revised slightly worsened with TCA;
Sleep improved from baseline with active treatments;
All other outcomes unchanged
| Rowbotham 2003||Mixed neuropathic|
1. Levorphanol high dose
2. Levorphanol low dose
1. 42.1 ± 26.5 (-36%)
2. 53.4 ± 24.7 (-21%)
|Categorical pain relief scale - NSD|
SDMT & MPI improved in both groups
| Watson 1998||Postherpetic neuralgia|
1. LA oxycodone
Daily VAS: 35 ± 25 vs 54 ± 25
Daily CPS: 1.7 ± 0.7 vs 2.3 ± 0.7
|Daily categorical pain relief scale: 2.9 ± 1.1 vs. 1.9 ± 1.0|
Categorical Disability Scale: 0.3 ± 0.8 vs. 0.7 ± 1.0
Effectiveness scale: 1.8 ± 1.1 vs. 0.7 ± 1.0
POMS & BDI no difference
| Watson 2003||Diabetic neuropathy|
1. LA oxycodone
Daily VAS: 26.3 ± 24.7 vs 46.7 ± 26.9
Daily CPS: 1.3 ± 0.9 vs 1.9 ± 0.9
|Categorical pain relief scale: 1.8 ± 1.4 vs. 2.79 ± 1.2|
Overall Pain and Sleep Questionnaire, PDI, SF36 oxycodone superior vs. placebo;
NNTB for moderate relief = 2.6
| Wu 2008||Post-amputation Pain|
Change in overall pain intensity BL - end of treatment; NRS (0 - 10), (95% confidence interval)
1. -2.8 (-3.4 to -2.3)
2. -1.5 (-2.2 to -0.9)
3. -1.4 (-2.2 to -0.6)
1. 1. 53%
2. 2. 53%
3. 3. 19%
> 33% PR, N (%)
2. 16/42 (38%)
> 50% PR, N (%)
1. 23/50 (46%)
2. 11/42 (26%)
3. 13/43 (30%)
|WHYMPI – no differences between groups|
| Zin 2010|
1. Pregabalin + oxycodone
2. Pregabalin + placebo
VAS (0 - 10) BL- end of treatment
1. 6.85 ± 0.3 – 3.59 ± 2.35
2. 6.73 ± 0.29 – 4.03 ± 2.33
> 50% PR from BL to end of treatment
1. 15/26 (58%)
2. 19/29 (66%)
Sleep Interference Score – NSD;
NPS - most subscales NSD;
SF36 – most subscales NSD;
POMS – NSD;
COGNITIVE PERFORMANCE-TMTB – NSD;
PGIC – NSD;
Data are presented as mean ± standard deviation unless specified
ΔVAS = change in VAS from baseline; ‘d2-test’ = test for attention performance; BDI = Beck Depression Inventory; BL= baseline; BPI = Brief Pain Inventory; CGIC = Clinician global impression of change; CGPRS = Categorical Global Pain Relief Scale; CPS = Categorical Pain Scale; HADS = Hospital Anxiety and Depression Score LA = long-acting; MPI = Multidimensional Pain Inventory; NND = no numerical data; NPS = Neuropathic Pain scale; ODI = Oswestry Disability Index; PDI = Pain Disability Index; PES = Pain Experience Scale; PGIC = Patient global impression of change; POMS = Profile of Mood States; PR = pain reduction; PRSS = Pain-Related Self-Treatment Scale; RMHI = Rand Mental Health Inventory; SA = short acting; SDMT = Symbol-Digit Modalities Test; SF = Short Form; SF36 = Short Form 36; SIP = Sickness Impact Profile; TCA = tricyclic antidepressants; VAS = visual analog scale; WHYMPI = West Haven-Yale Multidimensional Pain Inventory
Contributions of authors
AM: screened retrieved papers against inclusion criteria, appraised risk of bias and extracted data from papers and wrote parts of the Background in the updated review.
EE: conceived the review and provided clinical perspective. Designed and coordinated review, participated in retrieval of papers, screened retrieved papers against inclusion criteria, appraised quality of papers, extracted data from papers, wrote parts of the updated review (Abstract, Applicability of evidence, Agreements and disagreements with other studies or reviews).
EM: developed the search strategy, organized retrieval of and screened retrieved papers against inclusion criteria in original review, appraised risk of bias of papers, extracted data from papers, meta-analyzed data, compiled Characteristics of included studies; Characteristics of excluded studies tables. Wrote Methods and Results Section and parts of Discussion (Summary of main results, Overall completeness of evidence, Quality of the evidence; Potential biases in the review process).