Summary Background New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and E valuation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. Methods Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fi xed-eff ects Mantel-Haenszel method. Findings 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment eff ects. Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009). T rial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2–8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5–9·4) for pregabalin; 7·2 (5·9–9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4–19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, fi nal quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These fi ndings permitted a strong recommendation for use and proposal as fi rst-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. Interpretation Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest effi cacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profi ling probably account for moderate trial outcomes and should be taken into account in future studies. Funding NeuPSIG of the International Association for the Study of Pain.

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Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

In neuropathic pain it has been suggested that pain phenotype based on putative pain mechanisms may predict response to treatment. This was a randomised, double-blind, placebo-controlled, and phenotype-stratified study with 2 6-week treatment periods of oxcarbazepine (1800-2400mg) and placebo. The primary efficacy measure was change in median pain intensity between baseline and the last week of treatment measured on an 11-point numeric rating scale, and the primary objective was to compare the effect of oxcarbazepine in patients with and without the irritable nociceptor phenotype as defined by hypersensitivity and preserved small nerve fibre function determined by detailed quantitative sensory testing. Ninety-seven patients with peripheral neuropathic pain due to polyneuropathy, surgical or traumatic nerve injury, or postherpetic neuralgia were randomised. The intention-to-treat population comprised 83 patients: 31 with the irritable and 52 with the nonirritable nociceptor phenotype. In the total sample, oxcarbazepine relieved pain of 0.7 points (on a numeric rating scale 0-10; 95% confidence interval [CI] 0.4-1.4) more than placebo (P=0.015) and there was a significant interaction between treatment and phenotype of 0.7 (95% CI 0.01-1.4, P=0.047). The number needed to treat to obtain one patient with more than 50% pain relief was 6.9 (95% CI 4.2-22) in the total sample, 3.9 (95% CI 2.3-12) in the irritable, and 13 (95% CI 5.3-∞) in the nonirritable nociceptor phenotype. In conclusion, oxcarbazepine is more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs the nonirritable nociceptor phenotype.

The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study.

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(13)00045-X.pdf

Challenges and opportunities of drug repositioning

Diabetic peripheral neuropathy: current perspective and future directions.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain

/pdf/patient-phenotyping-in-clinical-trials-of-chronic-pain-6zo8gniw9a.pdf

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.

A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α(2)-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n=89) or placebo gel (n=90) applied 3 times a day to their feet for 12weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0-10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P=0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P<0.05). In subjects with a capsaicin pain rating ⩾2 (0-10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P=0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain.

Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy.

Intermetatarsal neuroma or Morton's neuroma is a painful condition of the foot resulting from an entrapment of the common digital nerve typically in the third intermetatarsal space. The pain can be severe and especially problematic with walking. Treatment options are limited and surgery may lead to permanent numbness in the toes. Capsaicin, the pungent ingredient of hot peppers, produces analgesia by inducing retraction of nociceptive afferents from the area of innervation and is effective in treating certain neuropathic pain disorders. A randomized double-blind placebo-controlled study was conducted to test the efficacy, tolerability, and safety of a single 0.1 mg dose of capsaicin vs placebo injected into the region of the neuroma. A total of 58 subjects diagnosed with Morton's neuroma with foot pain ≥4 (0-10 numerical pain rating scale) were injected with 2 mL of lidocaine into the intermetatarsal space proximal to the neuroma to provide local anesthesia. After 5 minutes, 0.1 mg capsaicin or placebo was injected into the intermetatarsal space containing the painful neuroma. Average foot pain was rated for 2 weeks before through 4 weeks after injection. At weeks 1 and 4, the decrease in pain was significantly greater in the subjects treated with capsaicin (P = 0.021 and P = 0.019, respectively). A trend toward significance was noted at weeks 2 and 3. Improvements in functional interference scores and reductions in oral analgesic use were also seen in the capsaicin-treated group. These findings suggest that injection of capsaicin is an efficacious treatment option for patients with painful intermetatarsal neuroma.

A randomized, double-blind, placebo-controlled trial of injected capsaicin for pain in Morton's neuroma.

BACKGROUND AND OBJECTIVES
To evaluate the safety, tolerability, and biological activity of a topical selective integrin inhibitor (OTT166) eyedrop administered BID for diabetic retinopathy (DR) and diabetic macular edema (DME).


STUDY DESIGN/MATERIALS AND METHODS
A prospective, multicenter, randomized, double-masked Phase 1b study. Subjects with nonproliferative DR and DME with central subfield thickness (CST) > 325 microns were randomized to OTT166 eyedrops (2.5% or 5%) BID for 28 days. Subjects were followed for an additional 28 days after treatment cessation.


RESULTS
Forty-four subjects were enrolled. No drug-related serious adverse events (SAEs) and two drug-related adverse events (AEs) were reported. OTT166 was well-tolerated with no evidence of ocular toxicity. Best-corrected visual acuity (BCVA) remained stable. Mean central retinal thickness (CRT) overall was variable: +12.8/+1.8 microns at Day 28 (end of treatment) and -50.3/+5.5 microns at Day 56 (end of study) for the 2.5% and 5% groups, respectively. Median CRT overall demonstrated consistent reduction by end of study: -39.0/-16.5 microns for the 2.5% and 5% groups, respectively. Median responses were greater in the treatment-naïve group (-41.5/-26.0 microns for the 2.5% and 5% groups, respectively). Thirty-seven percent of 'responder' subjects exhibited a mean reduction in CRT of 46.6 microns on optical coherence tomography (OCT) at end of treatment (Day 28) which persisted to end of the study (Day 56) - mean reduction of 67.4 microns, suggesting a durable effect.


CONCLUSION
OTT166 eyedrops were safe, well-tolerated, and demonstrated biological activity in 37% of responders. These results warrant further evaluation of OTT166 eyedrops. [Ophthalmic Surg Lasers Imaging Retina 2022;53:553-560.].

The Safety and Biological Activity of OTT166, a Novel Topical Selective Integrin Inhibitor for the Treatment of Diabetic Eye Disease: A Phase 1b Study.

Kerrie L. Brady

Papers

Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy.

A randomized, double-blind, placebo-controlled trial of injected capsaicin for pain in Morton's neuroma.

The Safety and Biological Activity of OTT166, a Novel Topical Selective Integrin Inhibitor for the Treatment of Diabetic Eye Disease: A Phase 1b Study.