Background
This is an updated version of the original Cochrane review published in Issue 3, 2006, which included 23 trials. The use of opioids for neuropathic pain remains controversial. Studies have been small, have yielded equivocal results, and have not established the long-term profile of benefits and risks for people with neuropathic pain.

Objectives
To reassess the efficacy and safety of opioid agonists for the treatment of neuropathic pain.

Search methods
We searched CENTRAL, on The Cochrane Library (Issue 10 of 12, 2012), MEDLINE (1966 to Oct week 3, 2012), and EMBASE (1980 to 2012, week 42) for articles in any language, and reference lists of reviews and retrieved articles. Searches were originally run in 2005, then again in 2010 and 2012.

Selection criteria
We included randomized controlled trials (RCTs) in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology. Pain was assessed using validated instruments, and adverse events were reported. We excluded studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally.

Data collection and analysis
Two review authors independently extracted data and included demographic variables, diagnoses, interventions, efficacy, and adverse effects.

Main results
Thirty-one trials met our inclusion criteria, studying 10 different opioids: 23 studies from the original 2006 review and eight additional studies from this updated review.

Seventeen studies (392 participants with neuropathic pain, average 22 participants per study) provided efficacy data for acute exposure to opioids over less than 24 hours. Sixteen reported pain outcomes, with contradictory results; 8/16 reported less pain with opioids than placebo, 2/16 reported that some but not all participants benefited, 5/16 reported no difference, and 1/16 reported equivocal results. Six studies with about 170 participants indicated that mean pain scores with opioid were about 15/100 points less than placebo.

Fourteen studies (845 participants, average 60 participants per study) were of intermediate duration lasting 12 weeks or less; most studies lasted less than six weeks. Most studies used imputation methods for participant withdrawal known to be associated with considerable bias; none used a method known not to be associated with bias. The evidence, therefore, derives from studies predominantly with features likely to overestimate treatment effects, i.e. small size, short duration, and potentially inadequate handling of dropouts. All demonstrated opioid efficacy for spontaneous neuropathic pain. Meta-analysis demonstrated at least 33% pain relief in 57% of participants receiving an opioid versus 34% of those receiving placebo. The overall point estimate of risk difference was 0.25 (95% confidence interval (CI) 0.13 to 0.37, P < 0.0001), translating to a number needed to treat for an additional beneficial outcome (NNTB) of 4.0 (95% CI 2.7 to 7.7). When the number of participants achieving at least 50% pain relief was analyzed, the overall point estimate of risk difference between opioids (47%) and placebo (30%) was 0.17 (95% CI 0.02 to 0.33, P = 0.03), translating to an NNTB of 5.9 (3.0 to 50.0). In the updated review, opioids did not demonstrate improvement in many aspects of emotional or physical functioning, as measured by various validated questionnaires. Constipation was the most common adverse event (34% opioid versus 9% placebo: number needed to treat for an additional harmful outcome (NNTH) 4.0; 95% CI 3.0 to 5.6), followed by drowsiness (29% opioid versus 14% placebo: NNTH 7.1; 95% CI 4.0 to 33.3), nausea (27% opioid versus 9% placebo: NNTH 6.3; 95% CI 4.0 to 12.5), dizziness (22% opioid versus 8% placebo: NNTH 7.1; 95% CI 5.6 to 10.0), and vomiting (12% opioid versus 4% placebo: NNTH 12.5; 95% CI 6.7 to 100.0). More participants withdrew from opioid treatment due to adverse events (13%) than from placebo (4%) (NNTH 12.5; 95% CI 8.3 to 25.0). Conversely, more participants receiving placebo withdrew due to lack of efficacy (12%) versus (2%) receiving opioids (NNTH -11.1; 95% CI -20.0 to -8.3).

Authors' conclusions
Since the last version of this review, new studies were found providing additional information. Data were reanalyzed but the results did not alter any of our previously published conclusions. Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies demonstrated significant efficacy of opioids over placebo, but these results are likely to be subject to significant bias because of small size, short duration, and potentially inadequate handling of dropouts. Analgesic efficacy of opioids in chronic neuropathic pain is subject to considerable uncertainty.  Reported adverse events of opioids were common but not life-threatening. Further randomized controlled trials are needed to establish unbiased estimates of long-term efficacy, safety (including addiction potential), and effects on quality of life.

Opioids for neuropathic pain

Background
Pharmacotherapy remains an important modality for the treatment of neuropathic pain. However, as monotherapy current drugs are associated with limited efficacy and dose-related side effects. Combining two or more different drugs may improve analgesic efficacy and, in some situations, reduce overall side effects (e.g. if synergistic interactions allow for dose reductions of combined drugs).

Objectives
This review evaluated the efficacy, tolerability and safety of various drug combinations for the treatment of neuropathic pain.

Search methods
We identified randomised controlled trials (RCTs) of various drug combinations for neuropathic pain from CENTRAL, MEDLINE, EMBASE and handsearches of other reviews and trial registries. The most recent search was performed on 9 April 2012.

Selection criteria
Double-blind, randomised studies comparing combinations of two or more drugs (systemic or topical) to placebo and/or at least one other comparator for the treatment of neuropathic pain.

Data collection and analysis
Data extracted from each study included: proportion of participants a) reporting ≥ 30% pain reduction from baseline OR ≥ moderate pain relief OR ≥ moderate global improvement; b) dropping out of the trial due to treatment-emergent adverse effects; c) reporting each specific adverse effect (e.g. sedation, dizziness) of ≥ moderate severity. The primary comparison of interest was between study drug(s) and one or both single-agent comparators. We combined studies if they evaluated the same drug class combination at roughly similar doses and durations of treatment. We used RevMan 5 to analyse data for binary outcomes.

Main results
We identified 21 eligible studies: four (578 participants) evaluated the combination of an opioid with gabapentin or pregabalin; two (77 participants) evaluated an opioid with a tricyclic antidepressant; one (56 participants) of gabapentin and nortriptyline; one (120 participants) of gabapentin and alpha-lipoic acid, three (90 participants) of fluphenazine with a tricyclic antidepressant; three (90 participants) of an N-methyl-D-aspartate (NMDA) blocker with an agent from a different drug class; five (604 participants) of various topical medications; one (313 participants) of tramadol with acetaminophen; and another one (44 participants) of a cholecystokinin blocker (L-365,260) with morphine. The majority of combinations evaluated to date involve drugs, each of which share some element of central nervous system (CNS) depression (e.g. sedation, cognitive dysfunction). This aspect of side effect overlap between the combined agents was often reflected in similar or higher dropout rates for the combination and may thus substantially limit the utility of such drug combinations. Meta-analysis was possible for only one comparison of only one combination, i.e. gabapentin + opioid versus gabapentin alone. This meta-analysis involving 386 participants from two studies demonstrated modest, yet statistically significant, superiority of a gabapentin + opioid combination over gabapentin alone. However, this combination also produced significantly more frequent side effect-related trial dropouts compared to gabapentin alone.

Authors' conclusions
Multiple, good-quality studies demonstrate superior efficacy of two-drug combinations. However, the number of available studies for any one specific combination, as well as other study factors (e.g. limited trial size and duration), preclude the recommendation of any one specific drug combination for neuropathic pain. Demonstration of combination benefits by several studies together with reports of widespread clinical polypharmacy for neuropathic pain surely provide a rationale for additional future rigorous evaluations. In order to properly identify specific drug combinations which provide superior efficacy and/or safety, we recommend that future neuropathic pain studies of two-drug combinations include comparisons with placebo and both single-agent components. Given the apparent adverse impact of combining agents with similar adverse effect profiles (e.g. CNS depression), the anticipated development and availability of non-sedating neuropathic pain agents could lead to the identification of more favourable analgesic drug combinations in which side effects are not compounded.

Combination pharmacotherapy for the treatment of neuropathic pain in adults

Herpes zoster (HZ) is a prevalent viral disease that inflicts substantial morbidity and associated healthcare and socioeconomic burdens. Current treatments are not fully effective, especially among the most vulnerable patients. Although widely recommended, vaccination against HZ is not routine; barriers in Asia-Pacific include long-standing neglect of adult immunisation and sparse local data. To address knowledge gaps, raise awareness, and disseminate best practice, we reviewed recent data and guidelines on HZ from the Asia-Pacific region. We searched PubMed, Scopus, and World Health Organization databases for articles about HZ published from 1994 to 2014 by authors from Australia, China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, New Zealand, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. We selected articles about epidemiology, burden, complications, comorbidities, management, prevention, and recommendations/guidelines. Internet searches retrieved additional HZ immunisation guidelines. From 4007 retrieved articles, we screened-out 1501 duplicates and excluded 1264 extraneous articles, leaving 1242 unique articles. We found guidelines on adult immunisation from Australia, India, Indonesia, Malaysia, New Zealand, the Philippines, South Korea, and Thailand. HZ epidemiology in Asia-Pacific is similar to elsewhere; incidence rises with age and peaks at around 70 years – lifetime risk is approximately one-third. Average incidence of 3–10/1000 person-years is rising at around 5% per year. The principal risk factors are immunosenescence and immunosuppression. HZ almost always causes pain, and post-herpetic neuralgia is its most common complication. Half or more of hospitalised HZ patients have post-herpetic neuralgia, secondary infections, or inflammatory sequelae that are occasionally fatal. These disease burdens severely diminish patients’ quality of life and incur heavy healthcare utilisation. Several countries have abundant data on HZ, but others, especially in South-East Asia, very few. However, Asia-Pacific countries generally lack data on HZ vaccine safety, efficacy and cost-effectiveness. Physicians treating HZ and its complications in Asia-Pacific face familiar challenges but, with a vast aged population, Asia bears a unique and growing burden of disease. Given the strong rationale for prevention, most adult immunisation guidelines include HZ vaccine, yet it remains underused. We urge all stakeholders to give higher priority to adult immunisation in general and HZ in particular.

/pdf/looking-back-to-move-forward-a-twenty-year-audit-of-herpes-tobv3mrzo7.pdf

Looking back to move forward: a twenty-year audit of herpes zoster in Asia-Pacific.

Background Postherpetic neuralgia (PHN) is a neuropathic pain that causes a reduction in patients' quality of life. There are many topical drugs for PHN, including topical lidocaine patch, topical application of capsaicin, and others. Objectives This study aims to compare the efficacy and safety of topical drugs for PHN. Study design Relevant studies were found by systemically searching for terms including "topical" and "Postherpetic neuralgia" in PubMed, Cochrane library, MEDLINE, and EMBASE databases (inception through June 12, 2019). The primary outcome was the percentage of change in the Numeric Rating Scale or the Visual Analog Scale scores from baseline. The secondary outcome was the number of adverse events. Methods The efficacy and safety of topical drugs for PHN was investigated by the pairwise meta-analysis and Bayesian network meta-analysis, applying Revman 5.3, the Stata 14.0 software, and GeMTC 0.14.3. Results Twelve studies met the inclusion criteria, and eligible studies were selected for the ultimate meta-analysis. Our meta-analysis displayed 6 topical drugs for PHN. Lidocaine, high-concentration capsaicin, and aspirin/diethyl ether (ADE) had a higher possibility of bringing pain relief than placebo. Among them, lidocaine had the highest possibility of being the most effective drug for PHN and had the statistical significances compared with diclofenac, high-concentration capsaicin, indomethacin, low-concentration capsaicin, and placebo, and lidocaine was significantly preferable than other effective drugs in the aspect of safety. Limitations (1) The small number of included studies; (2) a small number of patients and short-term trials in progress, including lidocaine and ADE; (3) both randomized controlled trial and crossover randomized trial were included in our network meta-analysis; (4) only studies published in English were evaluated; (5) lack of head-to-head comparisons of some treatments; (6) different measurement methods were used in different trial, which may cause deviation; and (7) with the lack of cycles in the included trials, the inconsistency factors cannot be calculated, and node-splitting method cannot be performed in our network meta-analysis to check the inconsistency. Conclusions Compared with other topical drugs, lidocaine was the most effective and most tolerable drug to be recommended for PHN.

The Treatment of Topical Drugs for Postherpetic Neuralgia: A Network Meta-Analysis.

Background Postherpetic neuralgia (PHN) is the most common and refractory complication of herpes zoster (HZ). Aggressive treatment of acute pain in HZ has the potential to prevent the development of PHN, but the preventive efficacy of supplemental therapy commonly used in clinical practice is controversial. Objectives Our aim is to examine the efficacy of supplemental therapy in preventing PHN. Study design A meta-analysis. Setting All of the selected studies are randomized controlled trials (RCTs). Methods A systematic and comprehensive database search was performed in CENTRAL (1976 to March 2016), MEDLINE (1977 to January 2016), and EMBASE (May 1980 to December 2016). According to the selection criteria, data of the included studies were extracted by 2 independent reviewers. RevMan 5.3 (The Nordic Cochrane Centre for The Cochrane Collaboration, Copenhagen, Denmark) was used to perform this meta-analysis. Results Nine trials, with a total of 1,757 participants (888 in the treatment group and 867 in the control group), were included in the final analysis. Of the 9 trials, 3 compared systemic adjunct therapies with the control, and 6 trials compared interventional procedures with the control. The early use of supplemental therapy was associated with a significantly less incidence of PHN in 3 months after acute rash presence (RR 0.53, 95%CI 0.34 to 0.81, P = 0.004). The systemic adjunct treatments subgroup was not found with any benefit (RR 0.76, 95%CI 0.46 to 1.26, P = 0.29). A significant decrease in visual analog scale (VAS) score was reported in all of the 9 trials when compared with baseline, but the decrease slopes of the pain scores between the treatment group and the control group were similar in 5 trials. The most common adverse events in systemic adjunct treatments group were dizziness, nausea, dyspepsia, and dry mouth. The interventional procedures group was associated with procedure-related complications such as mild hypotension, voice change, dysphagia, drowsiness, and headache. Limitations There were only a few RCTs and most of them lacked adequate allocation concealment and blinding. Further, the English-only approach might have omitted trials published in non-English journals. Finally, some of the secondary outcomes of data were insufficient for meta-analysis, and future studies are warranted. Conclusion This meta-analysis demonstrates that the early use of supplemental therapy can significantly reduce the incidence of PHN. The subgroup analysis shows that supplemental interventional procedures have a beneficial effect on preventing PHN, while supplemental systemic adjunct treatments do not. The early use of interventional procedures for acute pain may be a preferred choice for patients without contraindication, but evidence is moderate. More data from high-quality RCTs will be needed to confirm these results.Key words: Postherpetic neuralgia, systemic treatment, local anesthesia, analgesia, meta-analysis.

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The Effect of Early Use of Supplemental Therapy on Preventing Postherpetic Neuralgia: A Systematic Review and Meta-analysis.

[Objective] To observe the therapeutic effect of transdermal fentanyl in patients with acute Herpes Zoster and the incidence of Postherpetic Neuralgia(PHN).[Methods] Sixty patients were devided randomly into transdermal fentanyl group(F group,n=31) and transdermal fentanyl combined with Clodine group(C group,n=29),both groups were treated with transdermal fentanyl initially(25 μg/ h),a higher dose(50 μg/ h) was given only when the pain of patients was not cont rolled well.Clodine(20 mg,bid,po) was given beside fentanyl patch in C group.The analgesic effect,and the side effects and incidence of PHN were observed.[Results] Compared with F group,highly effective,total effective rate of C group is significantly higher(P0.05);complications and incidence of PHN significantly decreased in C group.[Conclusion] Transdermal fentanyl combined with Clodine could provide excellent pain relief for the patients with acute herpes zoster and decrease the incidence of complications and PHN.

Yang Yi-xin

Papers

Effectiveness of transdermal fentanyl combined with clodine for pain control of acute herpes zoster

Polymer-modified bentonites with low hydraulic conductivity and improved chemical compatibility as barriers for Cu2+ containment