If the Doors of Perception Were Cleansed, Would Chronic Pain be Relieved? Evaluating the Benefits and Risks of Psychedelics.

Psychedelic substances have played important roles in diverse cultures, and ingesting various plant preparations to evoke altered states of consciousness has been described throughout recorded history. Accounts of the subjective effects of psychedelics typically focus on spiritual and mystical-type experiences, including feelings of unity, sacredness, and transcendence. Over the past 2 decades, there has been increasing interest in psychedelics as treatments for various medical disorders, including chronic pain. Although concerns about adverse medical and psychological effects contributed to their controlled status, contemporary knowledge of psychedelics suggests that risks are relatively rare when patients are carefully screened, prepared, and supervised. Clinical trial results have provided support for the effectiveness of psychedelics in different psychiatric conditions. However, there are only a small number of generally uncontrolled studies of psychedelics in patients with chronic pain (eg, cancer pain, phantom limb pain, migraine, and cluster headache). Challenges in evaluating psychedelics as treatments for chronic pain include identifying neurobiologic and psychosocial mechanisms of action and determining which pain conditions to investigate. Truly informative proof-of-concept and confirmatory randomized clinical trials will require careful selection of control groups, efforts to minimize bias from unblinding, and attention to the roles of patient mental set and treatment setting. PERSPECTIVE: There is considerable promise for the use of psychedelic therapy for pain, but evidence-based recommendations for the design of future studies are needed to ensure that the results of this research are truly informative.

Essential statistical principles of clinical trials of pain treatments.

This article presents an overview of fundamental statistical principles of clinical trials of pain treatments. Statistical considerations relevant to phase 2 proof of concept and phase 3 confirmatory randomized trials investigating efficacy and safety are discussed, including (1) research design; (2) endpoints and analyses; (3) sample size determination and statistical power; (4) missing data and trial estimands; (5) data monitoring and interim analyses; and (6) interpretation of results. Although clinical trials of pharmacologic treatments are emphasized, the key issues raised by these trials are also directly applicable to clinical trials of other types of treatments, including biologics, devices, nonpharmacologic therapies (eg, physical therapy and cognitive-behavior therapy), and complementary and integrative health interventions.

Convergent neural representations of experimentally-induced acute pain in healthy volunteers: A large-scale fMRI meta-analysis.

Characterizing a reliable, pain-related neural signature is critical for translational applications. Many prior fMRI studies have examined acute nociceptive pain-related brain activation in healthy participants. However, synthesizing these data to identify convergent patterns of activation can be challenging due to the heterogeneity of experimental designs and samples. To address this challenge, we conducted a comprehensive meta-analysis of fMRI studies of stimulus-induced pain in healthy participants. Following pre-registration, two independent reviewers evaluated 4,927 abstracts returned from a search of 8 databases, with 222 fMRI experiments meeting inclusion criteria. We analyzed these experiments using Activation Likelihood Estimation with rigorous type I error control (voxel height p < 0.001, cluster p < 0.05 FWE-corrected) and found a convergent, largely bilateral pattern of pain-related activation in the secondary somatosensory cortex, insula, midcingulate cortex, and thalamus. Notably, these regions were consistently recruited regardless of stimulation technique, location of induction, and participant sex. These findings suggest a highly-conserved core set of pain-related brain areas, encouraging applications as a biomarker for novel therapeutics targeting acute nociceptive pain.

Systematic review of outcome domains and measures used in psychosocial and pharmacological treatment trials for cannabis use disorder.

Cannabis use disorder (CUD) is prevalent and demand for treatment is increasing, yet few individuals engage in formal treatment and the efficacy of established interventions for CUD is modest. Existing clinical trials evaluating psychosocial and pharmacological treatments for CUD have incorporated a wide variety of measures for assessing cannabis use outcomes, including abstinence, self-reported frequency and quantity used, withdrawal, use/dependence severity, and other psychosocial outcomes. The heterogeneity of measures and outcomes has limited quantitative analyses of the comparative effectiveness of existing interventions. The purpose of this systematic review is to: 1) identify and characterize approaches for measuring cannabis use in existing CUD intervention trials, including abstinence, frequency and quantity of use, and 2) summarize measures used to assess treatment efficacy in other outcome domains (e.g., cannabis use severity, psychosocial functioning, cannabis withdrawal), and provide a platform for future research to evaluate which outcome measures are most likely to reflect treatment efficacy and clinically significant improvement in other outcome domains.

Neuropathic pain.

Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aß, Aδ and C fibres) and central neurons, and affects 7-10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.

How transparent are migraine clinical trials? Repository of Registered Migraine Trials (RReMiT).

Transparency in research requires public access to unbiased information prior to trial initiation and openly available results upon study completion. The Repository of Registered Migraine Trials is a global snapshot of registered migraine clinical trials and scorecard of results availability via the peer-reviewed literature, registry databases, and gray literature. The 295 unique clinical trials identified employed 447 investigational agents, with 30% of 154 acute migraine trials and 11% of 141 migraine prophylaxis trials testing combinations of agents. The most frequently studied categories in acute migraine trials were triptans, nonsteroidal anti-inflammatory drugs, antiemetics, calcitonin gene-related peptide antagonists, and acetaminophen. Migraine prophylaxis trials frequently studied anticonvulsants, ß-blockers, complementary/alternative therapies, antidepressants, and botulinum toxin. Overall, 237 trials were eligible for a results search. Of 163 trials completed at least 12 months earlier, 57% had peer-reviewed literature results, and registries/gray literature added another 13%. Using logistic regression analysis, studies with a sample size below the median of 141 subjects were significantly less likely to have results, but the dominant factor associated with availability of results was time since study completion. In unadjusted models, trials registered on ClinicalTrials.gov and trials with industry primary sponsorship were significantly more likely to have results. Recently completed trials rarely have publicly available results; 2 years after completion, the peer-reviewed literature contains results for fewer than 60% of completed migraine trials. To avoid bias, evidence-based therapy algorithms should consider factors affecting results availability. As negative trials are less likely to be published, special caution should be exercised before recommending a therapy with a high proportion of missing trial results.

Adverse event reporting in nonpharmacologic, noninterventional pain clinical trials: ACTTION systematic review.

Assessment of treatment safety is 1 of the primary goals of clinical trials. Organizations and working groups have created reporting guidelines for adverse events (AEs). Previous research examining AE reporting for pharmacologic clinical trials of analgesics in major pain journals found many reporting inadequacies, suggesting that analgesic trials are not adhering to existing AE reporting guidelines. The present systematic review documented AE reporting in 3 main pain journals for nonpharmacologic, noninterventional (NP/NI) trials examining pain treatments. To broaden our pool of nonpharmacologic trials, we also included trials examining acupuncture, leech therapy, and noninvasive stimulation techniques (eg, transcutaneous electrical nerve stimulation). We documented AE reporting at 2 levels of specificity using coding manuals based on the Consolidated Standards of Reporting Trials (CONSORT) harms reporting standards and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) AE reporting checklist. We identified a number of inadequacies in AE reporting across the 3 journals. For example, using the ACTTION coding manual, we found that less than one-half of the trials reported specific AE assessment methods; approximately one-third of the trials reported withdrawals due to AEs for each study arm; and about one-fourth of the trials reported all specific AEs. We also examined differences in AE reporting across several trial characteristics, finding that AE reporting was generally more detailed in trials with patients versus those using healthy volunteers undergoing experimentally evoked pain. These results suggest that investigators conducting and reporting NP/NI clinical trials are not adequately describing the assessment and occurrence of AEs.

Polyunsaturated fatty acids and their potential therapeutic role in multiple sclerosis.

Considerable interest has been shown in the potential anti-inflammatory effects of polyunsaturated fatty acids (PUFAs) in multiple sclerosis (MS) and other autoimmune inflammatory disorders. Studies suggest a modest association between consumption of low levels of unsaturated fat and an increased incidence of MS. Moreover, in vitro and in vivo studies have demonstrated that omega-3 and omega-6 PUFA supplementation can reduce immune-cell activation via a number of complex pathways. Noncontrolled and controlled clinical trials of PUFA supplementation in patients with MS have, however, provided mixed results. These studies had important limitations in design and selection of outcome measures, and these factors might partially explain the inconsistent results. We propose that the potential role of PUFAs as disease-modifying, anti-inflammatory treatments for MS should be revisited in proof-of-concept trials that use accepted MRI outcome measures.

Pharmacotherapy of painful diabetic neuropathy.

The scope of this review is to describe the epidemiology, physiology, symptomatology, and treatment of diabetic painful neuropathy, which is a common complication of diabetes with significant morbidity. This article focuses on treatment options. Various clinical trials of several classes of medications (eg, antidepressants, anticonvulsants, and topical medications) and alternative treatments (eg, acupuncture, electrostimulation, magnets) are reviewed. Physicians have a large panel of medications that can be used effectively solely or in combination at their disposal. However, a number of these treatments have significant side effects, which are noted, that limit their use. As the understanding of the pathophysiologic mechanisms of diabetic neuropathy improves, new medications are under investigation, which are reviewed in this article. There is great hope that the future may hold treatments that would prevent nerve damage.