A Systematic Review and Meta-analysis of Non-pharmacological Methods to Manipulate Experimentally Induced Secondary Hypersensitivity.

This systematic review and meta-analysis investigated the effects of non-pharmacological manipulations on experimentally induced secondary hypersensitivity in pain-free humans. We investigated the magnitude (change/difference in follow-up ratings from pre-manipulation ratings) of secondary hypersensitivity (primary outcome), and surface area of secondary hypersensitivity (secondary outcome), in 27 studies representing 847 participants. Risk of bias assessment concluded most studies (23 of 27) had an unclear or high risk of performance and detection bias. Further, 2 (of 27) studies had a high risk of measurement bias. Datasets were pooled by the method of manipulation and outcome. The magnitude of secondary hypersensitivity was decreased by diverting attention, anodal transcranial direct current stimulation, or emotional disclosure; increased by directing attention toward the induction site, nicotine deprivation, or negative suggestion; and unaffected by cathodal transcranial direct current stimulation or thermal change. Area of secondary hypersensitivity was decreased by anodal transcranial direct current stimulation, emotional disclosure, cognitive behavioral therapy, hyperbaric oxygen therapy, placebo analgesia, or spinal manipulation; increased by directing attention to the induction site, nicotine deprivation, or sleep disruption (in males only); and unaffected by cathodal transcranial direct current stimulation, thermal change, acupuncture, or electroacupuncture. Meta-analytical pooling was only appropriate for studies that used transcranial direct current stimulation or hyperbaric oxygen therapy, given the high clinical heterogeneity among the studies and unavailability of data. The evidence base for this question remains small. We discuss opportunities to improve methodological rigor including manipulation checks, structured blinding strategies, control conditions or time points, and public sharing of raw data. PERSPECTIVE: We described the effects of several non-pharmacological manipulations on experimentally induced secondary hypersensitivity in humans. By shedding light on the potential for non-pharmacological therapies to influence secondary hypersensitivity, it provides a foundation for the development and testing of targeted therapies for secondary hypersensitivity.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Risks of harm with cannabinoids, cannabis, and cannabis-based medicine for pain management relevant to patients receiving pain treatment: protocol for an overview of systematic reviews.

INTRODUCTION: With the increasing availability of cannabis and cannabinoids and their potential utility for pain treatment, there is a growing need to evaluate the risk-benefit considerations of cannabinoids for the management of pain. As part of the IASP Cannabis and Cannabinoids Task Force, this protocol describes a planned overview of systematic reviews summarizing the risks of harm with cannabinoids that are relevant to patients receiving pain treatment. METHODS: This overview will involve literature searches of several databases and a defined search strategy that will target systematic reviews or meta-analyses of cannabinoids where harms are the primary focus. Data extraction will include various features of the cannabinoid(s) and the harm(s) being studied as well as other methodological features of each included systematic review. Methodological quality of each included review will be assessed using AMSTAR-2 as well as compliance with the PRISMA harms checklist. Prospero registration pending. DISCUSSION: The broad overview of reviews defined by this protocol is expected to synthesize available good quality evidence of harms that will help inform risk-benefit considerations about the use of cannabinoids for pain management.

Up-date on Clinical Management of Postherpetic Neuralgia and Mechanism-Based Treatment: New Options in Therapy.

Patients with postherpetic neuralgia may experience various sensory signs and symptoms of pain. Despite this, the recommendations for medicinal treatment do not differ accordingly. In order to find the appropriate treatment options for postherpetic neuralgia, several attempts have been made in the past. The crucial obstacle to these attempts was insufficient or no subgrouping of patients according to their sensory phenotype, mostly resulting in an unsatisfactory treatment response. Recently, a new concept of retrospective stratification according to the patients' sensory phenotype has been made in a large cohort of pain patients. This new stratification tool allows a predictive validity for treatment response in subgroups of patients and might be of potential value in determining the optimal treatment in postherpetic neuralgia patients.

Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain: preclinical and clinical studies.

Neuropathic pain affects up to 10% of the general population, but drug treatments recommended for the treatment of neuropathic pain are associated with modest efficacy and/or produce dose-limiting side effects. Hence, neuropathic pain is an unmet medical need. In the past 2 decades, research on the pathobiology of neuropathic pain has revealed many novel pain targets for use in analgesic drug discovery programs. However, these efforts have been largely unsuccessful as molecules that showed promising pain relief in rodent models of neuropathic pain generally failed to produce analgesia in early phase clinical trials in patients with neuropathic pain. One notable exception is the angiotensin II type 2 (AT2) receptor that has clinical validity on the basis of a successful double-blind, randomized, placebo-controlled, clinical trial of EMA401, a highly selective, orally active, peripherally restricted AT2 receptor antagonist in patients with postherpetic neuralgia. In this study, we review research to date on target validation, efficacy, and mode of action of small molecule AT2 receptor antagonists in rodent models of peripheral neuropathic pain and in cultured human sensory neurons, the preclinical pharmacokinetics of these compounds, and the outcome of the above clinical trial.

Novel, nonreflex tests detect analgesic action in rodents at clinically relevant concentrations.

We propose that predictive validity of tests for analgesia may be improved by looking to reinstate specific, innate behaviors suppressed by pain, e.g., burrowing, because effective plasma concentrations in the rat are closer to effective clinical plasma concentrations than those generally used in rodent reflex withdrawal assays.

Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Significant pain from HIV-associated sensory neuropathy (HIV-SN) affects ∼40% of HIV infected individuals treated with antiretroviral therapy (ART). The prevalence of HIV-SN has increased despite the more widespread use of ART. With the global HIV prevalence estimated at 33 million, and with infected individuals gaining increased access to ART, painful HIV-SN represents a large and expanding world health problem. There is an urgent need to develop effective pain management strategies for this condition. OBJECTIVE: To evaluate the clinical effectiveness of analgesics in treating painful HIV-SN. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Cochrane central register of controlled trials, www.clinicaltrials.gov, www.controlled-trials.com and the reference lists of retrieved articles. SELECTION CRITERIA: Prospective, double-blinded, randomised controlled trials (RCTs) investigating the pharmacological treatment of painful HIV-SN with sufficient quality assessed using a modified Jadad scoring method. REVIEW METHODS: Four authors assessed the eligibility of articles for inclusion. Agreement of inclusion was reached by consensus and arbitration. Two authors conducted data extraction and analysis. Dichotomous outcome measures (≥ 30% and ≥ 50% pain reduction) were sought from RCTs reporting interventions with statistically significant efficacies greater than placebo. These data were used to calculate RR and NNT values. RESULTS: Of 44 studies identified, 19 were RCTs. Of these, 14 fulfilled the inclusion criteria. Interventions demonstrating greater efficacy than placebo were smoked cannabis NNT 3.38 95%CI(1.38 to 4.10), topical capsaicin 8%, and recombinant human nerve growth factor (rhNGF). No superiority over placebo was reported in RCTs that examined amitriptyline (100mg/day), gabapentin (2.4 g/day), pregabalin (1200 mg/day), prosaptide (16 mg/day), peptide-T (6 mg/day), acetyl-L-carnitine (1g/day), mexilitine (600 mg/day), lamotrigine (600 mg/day) and topical capsaicin (0.075% q.d.s.). CONCLUSIONS: Evidence of efficacy exists only for capsaicin 8%, smoked cannabis and rhNGF. However,rhNGF is clinically unavailable and smoked cannabis cannot be recommended as routine therapy. Evaluation of novel management strategies for painful HIV-SN is urgently needed.

Assessment of neuropathic pain in primary care.

Management of patients presenting with chronic pain is a common problem in primary care. Essentially, the classification of chronic pain falls into 3 broad categories: (1) pain owing to tissue disease or damage (nociceptive pain), (2) pain caused by somatosensory system disease or damage (neuropathic pain), and (3) pain without a known somatic background. Key challenges in developing a targeted holistic approach to treatment include appropriate diagnosis of the cause or causes of pain; identifying the type of pain and assessing the relative importance of its various components; and determining appropriate treatment. In clinical examination, sensory abnormalities are the crucial findings leading to a diagnosis of neuropathic pain, for which pharmacotherapy with antidepressants and anticonvulsants represents the cornerstone of medical treatment. Chronic neuropathic pain is underrecognized and undertreated, yet primary care physicians are uniquely placed on the frontlines of patient management, where they can play a pivotal role in treatment and prevention through diagnosis, therapy, follow-up, and referral. This review provides guidance in understanding and identifying the neuropathic contribution to pain presenting in primary care; assessing its severity through patient history, physical examination, and appropriate diagnostic tests; and establishing a rational treatment plan.

Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB(1)/CB(2) receptors.

Activation of cannabinoid receptors causes inhibition of spasticity, in a mouse model of multiple sclerosis, and of persistent pain, in the rat formalin test. The endocannabinoid anandamide inhibits spasticity and persistent pain. It not only binds to cannabinoid receptors but is also a full agonist at vanilloid receptors of type 1 (VR1). We found here that vanilloid VR1 receptor agonists (capsaicin and N-N'-(3-methoxy-4-aminoethoxy-benzyl)-(4-tert-butyl-benzyl)-urea [SDZ-249-665]) exhibit a small, albeit significant, inhibition of spasticity that can be attenuated by the vanilloid VR1 receptor antagonist, capsazepine. Arvanil, a structural "hybrid" between capsaicin and anandamide, was a potent inhibitor of spasticity at doses (e.g. 0.01 mg/kg i.v.) where capsaicin and cannabinoid CB(1) receptor agonists were ineffective. The anti-spastic effect of arvanil was unchanged in cannabinoid CB(1) receptor gene-deficient mice or in wildtype mice in the presence of both cannabinoid and vanilloid receptor antagonists. Likewise, arvanil (0.1-0.25 mg/kg) exhibited a potent analgesic effect in the formalin test, which was not reversed by cannabinoid and vanilloid receptor antagonists. These findings suggest that activation by arvanil of sites of action different from cannabinoid CB(1)/CB(2) receptors and vanilloid VR1 receptors leads to anti-spastic/analgesic effects that might be exploited therapeutically.