Philip J Wiffen

Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: A quantitative systematic review

To determine the relative efficacy and adverse effects of antidepressants and anticonvulsants in the treatment of diabetic neuroapathy and postherpetic neuralgia, published reports were identified from a variety of electronic databases, including Medline, EMBASE, the Cochrane Library and the Oxford Pain Relief Database, and from two previously published reviews. Additional studies were identified from the reference lists of retrieved reports. The relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50 % pain relief was calculated from available dichotomous data, as was the relative risk (RR) and number-needed-to-harm (NH) for minor adverse effects and drug related study withdrawal. In diabetic neuropathy, 16 reports compared antidepressants with placebo (491 patient episodes) and three compared anticonvulsants with placebo (321). The NNT for at least 50 % pain relief with antidepressants was 3.4 (95 % confidence interval 2.6-4. 7) and with anticonvulsants 2. 7 (2. 2-3. 8). In postherpetic neuralgia, three reports compared antidepressants with placebo (145 patient episodes) and one compared anticonvulsants with placebo (225), giving an NNT with antidepressants of 2.1 (1. 7-3) and with anticonvulsants 3.2 (2.4-5). There was little difference in the incidence of minor adverse effects with either antidepressants or anticonvulsants compared with placebo, with 1VH (minor) values of about 3. For drug-related study withdrawal, antidepressants had an NNH (major) of 17 (11-43) compared with placebo, whereas with anticonvulsants there was no significant difference from placebo. Antidepressants and anticonvulsants had the same efficacy and incidence of minor adverse effects in these tzoo neuropathic pain conditions. There was no evidence that selective serotonin reuptake inhibitors (SSRIs) were better than older antidepressants, and no evidence that gabapentin was better than older anticonvulsants. In these trials patients were more likely to stop taking antidepressants than anticonvulsants because of adverse effects.

Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain

Abstract Objective To determine the efficacy and safety of topical rubefacients containing salicylates in acute and chronic pain. Data sources Electronic databases and manufacturers of salicylates. Study selection Randomised double blind trials comparing topical rubefacients with placebo or another active treatment, in adults with acute or chronic pain, and reporting dichotomous information, around a 50% reduction in pain, and analyses at one week for acute conditions and two weeks for chronic conditions. Data extraction Relative benefit and number needed to treat, analysis of adverse events, and withdrawals. Data synthesis Three double blind placebo controlled trials had information on 182 patients with acute conditions. Topical salicylate was significantly better than placebo (relative benefit 3.6, 95% confidence interval 2.4 to 5.6; number needed to treat 2.1, 1.7 to 2.8). Six double blind placebo controlled trials had information on 429 patients with chronic conditions. Topical salicylate was significantly better than placebo (relative benefit 1.5, 1.3 to 1.9; number needed to treat 5.3, 3.6 to 10.2), but larger, more valid studies were without significant effect. Local adverse events and withdrawals were generally rare in trials that reported them. Conclusions Based on limited information, topically applied rubefacients containing salicylates may be efficacious in the treatment of acute pain. Trials of musculoskeletal and arthritic pain suggested moderate to poor efficacy. Adverse events were rare in studies of acute pain and poorly reported in those of chronic pain. Efficacy estimates for rubefacients are unreliable owing to a lack of good clinical trials.

Oral aspirin in postoperative pain: a quantitative systematic review

OBJECTIVES A systematic review of the analgesic efficacy and adverse effects of single-dose aspirin compared with placebo in postoperative pain. DESIGN Published studies were identified from systematic searching of bibliographic databases and reference lists of retrieved reports. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat for one patient to achieve at least 50% pain relief. For adverse effects, relative risk and number-needed-to-harm were calculated. Sensitivity analyses were planned to test the impact of different pain models, pain measurements, sample sizes, quality of study design, and study duration on the results. RESULTS Seventy-two randomized single-dose trials met our inclusion criteria, with 3253 patients given aspirin, and 3297 placebo. Significant benefit of aspirin over placebo was shown for aspirin 600/650 mg, 1000 mg and 1200 mg, with numbers-needed-to-treat for at least 50% pain relief of 4.4 (4.0-4.9), 4.0 (3.2-5.4) and 2.4 (1.9-3.2) respectively. Single-dose aspirin 600/650 mg produced significantly more drowsiness and gastric irritation than placebo, with numbers-needed-to-harm of 28 (19-52) and 38 (22-174) respectively. Type of pain model, pain measurement, sample size, quality of study design, and study duration had no significant impact on the results. CONCLUSIONS There was a clear dose-response for pain relief with aspirin, even though these were single dose studies. Adverse effects, drowsiness and gastric irritation were also evident in the single dose studies. The pain relief achieved with aspirin was very similar milligram for milligram to that seen with paracetamol.

Oral ibuprofen and diclofenac in post-operative pain: a quantitative systematic review.

Surveys show consistently that pain is not treated well. Improvement depends on knowing which treatments are the most effective. We used systematic review to compare the relative efficacy of two common analgesics, ibuprofen and diclofenac, in post‐operative pain.

Systematic review of enriched enrolment, randomised withdrawal trial designs in chronic pain: a new framework for design and reporting.

Abstract Enriched enrolment, randomised withdrawal (EERW) pain trials select, before randomisation, patients who respond by demonstrating a predetermined degree of pain relief and acceptance of adverse events. There is uncertainty over the value of this design. We report a systematic review of EERW trials in chronic noncancer pain together with a critical appraisal of methods and potential biases in the methods used and recommendations for the design and reporting of future EERW trials. Electronic and other searches found 25 EERW trials published between 1995 and June 2014, involving 5669 patients in a randomised withdrawal phase comparing drug with placebo; 13 (median, 107 patients) had a randomised withdrawal phase of 6 weeks or less, and 12 (median, 334) lasted 12 to 26 weeks. Risks of bias included short duration, inadequate outcome definition, incomplete outcome data reporting, small size, and inadequate dose tapering on randomisation to placebo. Active treatment was usually better than placebo (22/25 trials). This review reduces the uncertainty around the value of EERW trials in pain. If properly designed, conducted, and reported, they are feasible and useful for making decisions about pain therapies. Shorter, small studies can be explanatory; longer, larger studies can inform practice. Current evidence is inadequate for valid comparisons in outcome between EERW and classical trials, although no gross differences were found. This systematic review provides a framework for assessing potential biases and the value of the EERW trials, and for the design of future studies by making recommendations for the conduct and reporting of EERW trials.

Antiepileptic Drugs for Neuropathic Pain and Fibromyalgia

CLINICAL QUESTION Are antiepileptic drugs associated with reduced pain intensity in patients with neuropathic pain or fibromyalgia? BOTTOM LINE In treating diabetic neuropathy and postherpetic neuralgia compared with placebo, gabapentin and pregabalin are associated with a modest increase in the number of patients experiencing meaningful pain reduction. In treating fibromyalgia, compared with placebo, pregabalin alone is associated with a small increase in the number of patients experiencing meaningful pain reduction. There is insufficient evidence for other antiepileptics.

Evidence for efficacy of acute treatment of episodic tension-type headache: methodological critique of randomised trials for oral treatments.

&NA; A systematic review (55 trials, 12,000 patients) showed deficiencies in reporting International Headache Society outcomes of efficacy in trials for episodic tension‐type headache. &NA; The International Headache Society (IHS) provides guidance on the conduct of trials for acute treatment of episodic tension‐type headache (TTH), a common disorder with considerable disability. Electronic and other searches identified randomised, double‐blind trials of oral drugs treating episodic TTH with moderate or severe pain at baseline, or that tested drugs at first pain onset. The aims were to review methods, quality, and outcomes reported (in particular the IHS‐recommended primary efficacy parameter pain‐free after 2 hours), and to assess efficacy by meta‐analysis. We identified 58 reports: 55 from previous reviews and searches, 2 unpublished reports, and 1 clinical trial report with results. We included 40 reports of 55 randomised trials involving 12,143 patients. Reporting quality was generally good, with potential risk of bias from incomplete outcome reporting and small size; the 23 largest trials involved 82% of patients. Few trials reported IHS outcomes. The number needed to treat values for being pain‐free at 2 hours compared with placebo were 8.7 (95% confidence interval [CI] 6.2 to 15) for paracetamol 1000 mg, 8.9 (95% CI 5.9 to 18) for ibuprofen 400 mg, and 9.8 (95% CI 5.1 to 146) for ketoprofen 25 mg. Lower (better) number needed to treat values were calculated for outcomes of mild or no pain at 2 hours, and patient global assessment. These were similar to values for these drugs in migraine. No other drugs had evaluable results for these patient‐centred outcomes. There was no evidence that any one outcome was better than others. The evidence available for treatment efficacy is small in comparison to the size of the clinical problem.

Effects of food on pharmacokinetics of immediate release oral formulations of aspirin, dipyrone, paracetamol and NSAIDs – a systematic review

It is common to advise that analgesics, and especially non‐steroidal anti‐inflammatory drugs (NSAIDs), be taken with food to reduce unwanted gastrointestinal adverse effects. The efficacy of single dose analgesics depends on producing high, early, plasma concentrations; food may interfere with this. This review sought evidence from single dose pharmacokinetic studies on the extent and timing of peak plasma concentrations of analgesic drugs in the fed and fasting states.

World Health Organization essential medicines lists: where are the drugs to treat neuropathic pain?

Neuropathic pain is a priority health issue [5], which currently is the topic of the 2014–2015 Global Year Against Neuropathic Pain campaign of the International Association for the Study of Pain (http://www.iasp-pain.org/GlobalYear/NeuropathicPain). Between 6% and 10% of adults are affected by chronic pain with neuropathic features [6,14,25], and this prevalence is significantly greater among individuals with specific conditions. For example, neuropathic pain is a common comorbidity in infectious diseases such as HIV, leprosy, and herpes zoster, and in non-infectious conditions such as diabetes mellitus, stroke, multiple sclerosis, and traumatic limb and spinal cord injury [7,13,16,19,21]. The pain is associated with significant decreases in quality of life and socioeconomic well-being, even more so than non-neuropathic chronic pain [9,20,22]. Developing and emerging countries share the greatest burden of conditions that predispose to development of neuropathic pain [5,10], and can ill afford the negative consequences of this pain. There are medicines with proven efficacy in the treatment of neuropathic pain [11,12]. Nevertheless, the pain can be difficult to treat, with significant inter-individual variation in efficacy within and between drug classes, independent of the presumed aetiology of the neuropathy [2,4]. Effective management of neuropathic pain within a population therefore requires access to a small, but crucial group of drug classes with proven efficacy. The World Health Organization’s (WHO) model list of essential medicines (http://www.who.int/selection_medicines/list/en/) presents those medicines deemed necessary to meet priority health needs, and local implementation of essential medicines policies is associated with improved quality use of medicines [15,18]. But, none of the analgesic medicines included in the WHO model list are recommended as first-line treatments for neuropathic pain [11]. Thus the WHO model list is not a good framework from which national policies on managing neuropathic pain can be structured and countries routinely adapt the model list according to local needs and resources [18]. To estimate the nominal availability of medicines recommended for the treatment of neuropathic pain in developing and emerging countries, we assessed national essential medicines lists (NEMLs) for the inclusion of recommended treatments. We also assessed whether the coverage of recommended drugs classes on these NEMLs was dependent on countries’ economic status.

Ethical issues in preparing and publishing systematic reviews

The medical evidence base, or ‘literature’, forms the basis for clinical and policy decisions, so those who contribute to it have a responsibility to ensure that it is as accurate and unbiased as possible. Since publications are also used to judge the productivity of individuals and departments, and to select candidates for academic positions, it is important that those who did the work receive fair credit. Preparing a systematic review is a form of research, and should therefore be undertaken in a responsible manner to ensure integrity and avoid misconduct. This paper sets out practical and ethical issues to be considered when preparing and publishing a systematic review. It is written primarily for authors involved in The Cochrane Collaboration, but has broader relevance. Cochrane Review Groups, which are responsible for the quality of reviews that they publish, have highlighted concerns about unclear or inappropriate authorship, copying of material from other sources, and dual or duplicate publication. Various journals and editors’ organizations have produced publication guidelines and instructions for potential authors. One of the best known is the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, produced by the International Committee of Medical Journal Editors (1). Guidance is also available in the Cochrane Handbook (2). However, many of the requirements and conventions are scattered, so it may be hard for researchers to get a complete picture of best practices. Another problem facing those preparing systematic reviews is that general guidance, designed mainly for preparing primary reports of research, may not be applicable or may not cover the special issues that arise with systematic reviews. This paper therefore aims to help review authors avoid ethical problems by providing an introduction and overview of good practice in preparing and publishing systematic reviews.