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VM202 is a plasmid DNA encoding two isoforms of hepatocyte growth factor (HGF). A previous phase II study in subjects with painful diabetic peripheral neuropathy (DPN) showed significant reductions in pain. A phase III study was conducted to evaluate the safety and efficacy of VM202 in DPN. The trial was conducted in two parts, one for 9 months (DPN 3‐1) with 500 subjects (VM202: 336 subjects; and placebo: 164) and a preplanned subset of 101 subjects (VM202: 65 subjects; and placebo: 36) with a noninterventional extension to 12 months (DPN 3‐1b). VM202 or placebo was administered to calf muscles on days 0 and 14, and on days 90 and 104. The primary end point in DPN 3‐1 was change from baseline in the mean 24‐h Numerical Rating Scale (NRS) pain score. In DPN 3‐1b, the primary end point was safety, whereas the secondary efficacy end point was change in the mean pain score. VM202 was well‐tolerated in both studies without significant adverse events. VM202 failed to meet its efficacy end points in DPN 3‐1. In DPN 3‐1b, however, VM202 showed significant and clinically meaningful pain reduction versus placebo. Pain reduction in DPN 3‐1b was even greater in subjects not receiving gabapentin or pregabalin, confirming an observation noted in the phase II study. In DPN 3‐1b, symptomatic relief was maintained for 8 months after the last injection suggesting that VM202 treatment might change disease progression. Despite the perplexing discrepancy between the two studies, the safety and long‐lasting pain‐relieving effects of VM202 observed in DPN 3‐1b warrant another rigorous phase III study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Current therapies for painful diabetic peripheral neuropathy (DPN) are palliative and do not target the underlying mechanisms. Moreover, symptomatic relief is often limited with existing neuropathic pain drugs. Thus, there is a great medical need for safer and effective treatments for DPN. WHAT QUESTION DID THIS STUDY ADDRESS? Can nonviral gene delivery of hepatocyte growth factor reduce pain in patients with DPN and potentially modify progression of the disorder? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Nonviral gene therapy can be used safely and practically to treat DPN. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? As the first gene medicine to enter advanced clinical trials for the treatment of DPN, this study provides the proof of concept of an entirely new potential approach to the disorder.

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.In 2018, the Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened to discuss strategies to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Objective: This post hoc analysis was aimed to summarize the efficacy and tolerability of duloxetine as represented by number needed to treat (NNT) and number needed to harm (NNH) to provide a clinically useful assessment of the position of duloxetine among current agents used to treat diabetic peripheral neuropathic pain (DPNP). Methods: Data were pooled from three 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in which patients received 60 mg duloxetine either QD or BID or placebo. NNT was calculated based on rates of response (defined as ≥30% and ≥50% reductions from baseline in the weekly mean of the 24-hour average pain severity scores); NNH was calculated based on rates of discontinuation due to adverse events (AEs). Results: Patients receiving duloxetine 60 mg QD and 60 mg BID had NNTs (95% CI) of 5.2 (3.8-8.3) and 4.9 (3.6-7.6), respectively, based on last observation carried forward; NNTs of 5.3 (3.8-8.3) for 60 mg QD and 5.7 (4.1-9.7) for 60 mg BID were obtained based on baseline observations carried forward. The NNHs (95% CI) based on discontinuation due to AEs were 17.5 (10.2-58.8) in the duloxetine 60-mg QD group and 8.8 (6.3-14.7) in the 60-mg BID group. Conclusion: These post hoc results suggest that duloxetine was effective and well tolerated for the management of DPNP and further support the importance of duloxetine as a treatment option for clinicians and patients to assist with the management of DPNP.

Purpose of Review As opioids have become more common in clinical practice for the treatment of both acute and chronic pain, so too has the need for a deeper understanding of the clinical applications of opioid antagonists. The purpose of this review is to present both the longstanding and potential new indications for the use of drugs that block the effects of opioid receptors. Recent Findings There is a growing body of data demonstrating the modulation of pain by opioid antagonists. Additional clinical studies that show their direct antinociceptive effects and/or enhancement of the analgesic potency of opioid agonists are warranted. Summary We briefly discuss the well-established role that these agents play in the reversal of life-threatening opioid toxicity and explore both existing and expanding clinical applications, including their apparent paradox that they may themselves be associated with analgesia.

The translation of analgesic efficacy seen in preclinical pain models into the clinic is problematic and is associated with a number of factors that may result in the failure of clinical trials to detect the effect of investigational therapeutic agents. The use of translational pain biomarkers in phase I trials can potentially reduce some of these risks by measuring the interaction between the drug and its target (termed target engagement) in humans. To serve this purpose, sensory tests and other measures of pharmacological activity in nociceptive pathways need to be identified, based on the preclinical profile of the drug being tested and the feasibility of human assessments. Here we discuss some examples to assess the utility of sensory and related pain biomarkers in the early phase of evaluation of novel analgesics for confirmation of target engagement in humans. The emphasis is on the TRPV1 antagonists, but some other target mechanisms are also discussed in examining the validity of this approach.

Issue Title: Development of Analgesics for the Control and Prevention of Neuropathic Pain

A 41-year-old woman had a three-year history of multiple painful subcutaneous nodules on the head, neck, and trunk. The pain was present at rest and increased on palpation of the nodules and with activity. The patient described intermittent fever and swelling of the arms and legs. Examination disclosed subcutaneous nodules on the neck and trunk that were tender on palpation. A diagnostic procedure was performed. A 41-year-old woman had a three-year history of multiple painful subcutaneous nodules on the head, neck, and trunk. The pain was present at rest and increased on palpation of the nodules and with activity. Presentation of Case A 41-year-old woman was referred to the dermatology clinic of this hospital for evaluation of painful subcutaneous nodules. She had been well until three years earlier, when several painful nodules developed on her posterior neck and scalp. She saw her physician, who noted enlarged left retroauricular and posterior occipital lymph nodes. A biopsy of an occipital lymph node performed at another hospital disclosed reactive lymphoid hyperplasia, and a biopsy of a scalp lesion showed normal fibroadipose tissue. Radiography of the skull and chest and computed tomography (CT) of the chest, abdomen, and pelvis disclosed no abnormalities. During . . .