Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis

Balanaser, Marielle; Carley, Meg; Baron, Ralf; Finnerup, Nanna Brix; Moore, R Andrew; Chaparro, Luis Enrique; Gilron, Ian

doi:10.1097/j.pain.0000000000002688

Cited by 29 publications

(21 citation statements)

References 70 publications

(735 reference statements)

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“…Although this trial provides no evidence to support the use of a pregabalin-ALA combination for neuropathic pain, the results do help inform the development of future combination therapy strategies. Previous trials involving combinations of first-line neuropathic pain drugs, such as anticonvulsants and antidepressants, have shown that-in flexible dose-titration trialsmaximally tolerated drug doses during combination therapy lower than during monotherapy 2,14 or-in fixed dose-titration trials-treatment-related adverse effects are more frequent or severe during combination therapy. 2 In this trial, we have demonstrated that, in a combination of drugs with differing adverse effect profiles, doses can be titrated to similarly tolerated levels as with monotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…4 However, current combination prescribing is based on little evidence, some combinations may be harmful, and authorities have demanded more research to develop rational combination strategies. 12 Although previous trials support the merits of some drug combinations, 2 several neuropathic pain drugs (eg, anticonvulsants and antidepressants) cause similar adverse effects such that patients can only tolerate lower drug doses during combination therapy (vs monotherapy), thus limiting the magnitude of additive analgesia. 2,17 Therefore, we have postulated that combining agents with differing adverse effect profiles (eg, 1 sedating plus 1 nonsedating drug) to treat neuropathic pain will result in even greater additive analgesia because maximal doses of each drug can be tolerated during combination therapy.…”

Section: Introductionmentioning

confidence: 99%

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Randomized, double-blind, controlled trial of a combination of alpha-lipoic acid and pregabalin for neuropathic pain: the PAIN-CARE trial

Gilron,

Robb,

et al. 2023

Pain

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We compared a combination of the nonsedating antioxidant, alpha-lipoic acid (ALA), with the sedating anticonvulsant, pregabalin, vs each monotherapy to treat neuropathic pain due to peripheral neuropathies. In this randomized, double-blind, 3-period crossover trial, participants received oral ALA, pregabalin, and their combination—each for 6 weeks. The primary outcome was mean daily pain intensity at maximal tolerated doses (MTD); secondary outcomes included quality of life (SF-36), sleep (Medical Outcomes Study-Sleep Scale), adverse effects, drug doses, and other measures. Of 55 participants randomized (20—diabetic neuropathy, 19—small fiber neuropathy, and 16—other neuropathies), 46 completed 2 periods, and 44 completed 3. At MTD, the primary outcome of mean pain intensity (0-10) was 5.32 (standard error, SE = 0.18), 3.96 (0.25), 3.25 (0.25), and 3.16 (0.25) at baseline, ALA, pregabalin, and combination, respectively (P < 0.01 for ALA vs combination and pregabalin). Treatment differences were similar in subgroups with diabetic neuropathy and with other neuropathies. SF-36 total scores (higher number indicates better quality of life) were 66.6 (1.88), 70.1 (1.88), and 69.4 (1.87) with ALA, pregabalin, and combination (P < 0.05 for ALA vs combination and pregabalin). At MTD, there were no statistically significant treatment differences in adverse effects or drug doses. This trial demonstrates superiority of pregabalin vs ALA but provides no evidence to suggest added benefit of combining ALA with pregabalin to treat neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Randomized, double-blind, controlled trial of a combination of alpha-lipoic acid and pregabalin for neuropathic pain: the PAIN-CARE trial

Gilron,

Robb,

et al. 2023

Pain

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“…NP remains a challenging condition to treat, with current recommended pharmacological therapies providing only partial relief from pain, sometimes exacerbating other symptoms [ 41 ]. To the best of our knowledge, this proposed RCT is the first to investigate the safety and efficacy of melatonin for the treatment of NP.…”

Section: Discussionmentioning

confidence: 99%

Melatonin for Neuropathic Pain: Protocol for a Double-blind, Randomized Controlled Trial

Gilron¹,

Tu²,

Holden³

et al. 2022

JMIR Res Protoc

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Background Neuropathic pain (NP), a complication of several conditions (eg, diabetic neuropathy and varicella zoster), is a common challenging problem, and there is a growing need to develop safe and effective nonopioid treatments. Sleep disturbance is commonly associated with NP because pain intensity in NP conditions is often worse at night. The pineal hormone melatonin has been shown to reduce pain in both preclinical and clinical settings, in addition to multiple trials demonstrating efficacy for primary insomnia and delayed sleep phase syndrome. Objective We propose to conduct a clinical trial to evaluate the efficacy and safety of melatonin for NP. Methods Using a double-blind, placebo-controlled, crossover design, 30 adults with NP will be randomly allocated to one of two sequences of treatment with melatonin and placebo. During each of the two treatment periods, participants will take capsules containing melatonin or placebo for 4 weeks, followed by a 7-day washout period. The primary outcome will be mean daily pain intensity (scored 0-10) at maximally tolerated doses (MTDs) during each period. Secondary outcomes, assessed at MTDs, will include global improvement, adverse events, mood, and quality of life. Results This trial was registered in the International Standard Randomized Controlled Trial registry May 4, 2022 (ISRCTN #16215617), attained conditional ethics approval May 9, 2022 (Queen’s University Health Sciences & Affiliated Teaching Hospitals Research Ethics Board protocol number ANAE-387-22), and recruitment is set to start August 2022. Conclusions This trial will provide rigorous evidence comparing the efficacy of melatonin to that of placebo in the treatment of NP. Trial Registration ISRCTN Registry 16215617; https://www.isrctn.com/ISRCTN16215617 International Registered Report Identifier (IRRID) PRR1-10.2196/40025

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“…Unfortunately, pharmacologic intervention seldom achieves complete resolution of neuropathic pain due to limited efficacy, dose-limiting adverse events, or both [119][120][121]. Therefore, a standardized approach to combining pharmacotherapies is an unmet medical need and remains an area of intense study [122][123][124]. Spinal cord stimulation is an emerging therapeutic adjunct for the management of PDN [125].…”

Section: Principle 3: Individualized Treatment and Scheduled Follow-upmentioning

confidence: 99%

Screening for diabetic peripheral neuropathy in resource-limited settings

Nkonge

2023

Diabetol Metab Syndr

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Background Diabetic neuropathy is the most common microvascular complication of diabetes mellitus and a major risk factor for diabetes-related lower-extremity complications. Diffuse neuropathy is the most frequently encountered pattern of neurological dysfunction and presents clinically as distal symmetrical sensorimotor polyneuropathy. Due to the increasing public health significance of diabetes mellitus and its complications, screening for diabetic peripheral neuropathy is essential. Consequently, a review of the principles that guide screening practices, especially in resource-limited clinical settings, is urgently needed. Main body Numerous evidence-based assessments are used to detect diabetic peripheral neuropathy. In accordance with current guideline recommendations from the American Diabetes Association, International Diabetes Federation, International Working Group on the Diabetic Foot, and National Institute for Health and Care Excellence, a screening algorithm for diabetic peripheral neuropathy based on multiphasic clinical assessment, stratification according to risk of developing diabetic foot syndrome, individualized treatment, and scheduled follow-up is suggested for use in resource-limited settings. Conclusions Screening for diabetic peripheral neuropathy in resource-limited settings requires a practical and comprehensive approach in order to promptly identify affected individuals. The principles of screening for diabetic peripheral neuropathy are: multiphasic approach, risk stratification, individualized treatment, and scheduled follow-up. Regular screening for diabetes-related foot disease using simple clinical assessments may improve patient outcomes.

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Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 29 publications

References 70 publications

Randomized, double-blind, controlled trial of a combination of alpha-lipoic acid and pregabalin for neuropathic pain: the PAIN-CARE trial

Randomized, double-blind, controlled trial of a combination of alpha-lipoic acid and pregabalin for neuropathic pain: the PAIN-CARE trial

Melatonin for Neuropathic Pain: Protocol for a Double-blind, Randomized Controlled Trial

Screening for diabetic peripheral neuropathy in resource-limited settings

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