Prioritizing progressive MS rehabilitation research: A call from the International Progressive MS Alliance.

BACKGROUND: People with multiple sclerosis (MS) experience myriad symptoms that negatively affect their quality of life. Despite significant progress in rehabilitation strategies for people living with relapsing-remitting MS (RRMS), the development of similar strategies for people with progressive MS has received little attention. OBJECTIVE: To highlight key symptoms of importance to people with progressive MS and stimulate the design and implementation of high-quality studies focused on symptom management and rehabilitation. METHODS: A group of international research experts, representatives from industry, and people affected by progressive MS was convened by the International Progressive MS Alliance to devise research priorities for addressing symptoms in progressive MS. RESULTS: Based on information from the MS community, we outline a rationale for highlighting four symptoms of particular interest: fatigue, mobility and upper extremity impairment, pain, and cognitive impairment. Factors such as depression, resilience, comorbidities, and psychosocial support are described, as they affect treatment efficacy. CONCLUSIONS: This coordinated call to action-to the research community to prioritize investigation of effective symptom management strategies, and to funders to support them-is an important step in addressing gaps in rehabilitation research for people affected by progressive MS.

Gene therapy for diabetic peripheral neuropathy: A randomized, placebo-controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor.

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.

Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities.

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.

A Chronology for the Identification and Disclosure of Adverse Effects of Succinylcholine.

BACKGROUND: New therapies are created to address specific problems and enjoy popularity as they enter widespread clinical use. Broader use can reveal unknown adverse effects and impact the life cycle significantly. Succinylcholine, a depolarizing neuromuscular blocker, was the product of decades of research surrounding the ancient compound, curare. It was introduced into practice in the 1950s by Burroughs Wellcome and Company (BW Co) and was welcomed due to its rapidly acting muscle relaxation effects. Global clinical use revealed adverse effects, both minor and major, in particular, hyperkalemia and malignant hyperthermia. We investigated when practitioners and the manufacturer became aware of these adverse effects, how information about these side effects was disseminated, and whether the manufacturer met the regulatory requirements of the time, specifically regarding the timely reporting of adverse effects. SOURCES: Primary literature search using online and archived documents was conducted at the Wood Library-Museum of Anesthesiology, Schaumburg, IL. We consulted documents submitted by BW Co to federal authorities, through the Freedom of Information Act (FOIA), Food and Drug Administration (FDA) reports, promotional advertisements, package inserts, published articles, and textbooks. RESULTS: Initial clinical testing in humans in 1952 found no adverse effects on cardiovascular or respiratory systems. Fasciculations and myalgia were early side effects described in case reports in 1952. Large-scale clinical trials in 1953 found abnormally long recovery times among some patients; the discovery of abnormal pseudocholinesterase enzyme activity was not fully demonstrated until the early 1960s. Bradycardia was first reported in 1957 in children, and in 1959 in adults. In 1960, animal studies reported a transient increase in plasma potassium; further experiments in 1969 clearly demonstrated succinylcholine-induced hyperkalemia in burn patients. Malignant hyperthermia was first described in 1966. Similar cases of elevated temperatures and muscle rigidity were described globally but the underlying mechanism was not elucidated until the 1990s. Standard anesthesia textbooks did not report major side effects of succinylcholine until 1960 and included newly documented side effects with each edition. BW Co's packaging contained warnings as early as the 1950s but were later updated in 1962 and beyond to reflect the newly discovered hyperkalemia and malignant hyperthermia. CONCLUSION: Particularly given the regulatory environment of the time, BW Co appropriately reported the adverse effects of succinylcholine after market entry; it updated promotional and packaging material in a timely manner to reflect newly discovered adverse effects. The toxicity, though alarming and put clinicians on alert, did not seem to heavily impact succinylcholine's use, given its various desirable properties. It is still a choice muscle relaxant used today, although there are efforts to develop superior agents to replace succinylcholine.

Beyond Ether and Chloroform-A Major Breakthrough With Halothane.

BACKGROUND: The use of equipment powered by electricity in the operating room increased the risk of fires in the presence of flammable agents such as ether and cyclopropane. Chloroform was associated with cardiac arrhythmias and liver damage. The introduction of halothane in the late 1950s was heralded as a solution to many problems facing the specialty of anesthesia. We explore whether the manufacturer promptly reported halothane's adverse effects to regulatory agencies and practitioners. SOURCES: We consulted documents submitted by Ayerst Laboratories to federal authorities through the Freedom of Information Act, promotional advertisements, package inserts, published articles, and textbooks. RESULTS: Two major complications associated with the use of halothane, cardiac arrhythmias and the risk of hepatotoxicity, were disclosed by the manufacturer when the drug was first introduced to the US market. Reports appeared timely and complete; there was no apparent attempt to conceal or otherwise downplay these risks. CONCLUSION: The process of drug discovery and approval for clinical use has always been a lengthy, complex, and extremely expensive undertaking, with only a small minority of compounds receiving approval. The risk of adverse effects or drug interaction directly impacts commercial viability. In the case of halothane, the manufacturer disclosed major adverse effects, and the drug enjoyed decades of popularity until it was replaced by agents with a better drug profile.

Indications for Opioid Antagonists.

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. 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.

Phase IA Clinical Trial Evaluating the Tolerability, Pharmacokinetics, and Analgesic Efficacy of an Intrathecally Administered Neurotensin A Analogue in Central Neuropathic Pain Following Spinal Cord Injury.

We evaluated CGX-1160 in a Phase Ia clinical trial to determine the safety of escalating doses in patients with central neuropathic pain following spinal cord injury (SCI). Our secondary objective was to detect a trend toward analgesic efficacy. Four subjects received 3 consecutive escalating doses of CGX-1160 starting at 25 µg/h over 6 hours until 2 consecutive subjects experienced any adverse effect; 2 of the 4 subjects received 2 sequences of 3 consecutive dose escalations. Maximum tolerated dose was defined by the development of diarrhea (900 µg/h over 6 hours). Cerebrospinal fluid (CSF) and blood were collected for pharmacokinetic (PK) evaluation. The CSF concentration-versus-time data fit to a biexponential PK model, showing a rapid redistribution phase followed by a significantly slower terminal elimination phase. Incorporating an effect site delay into the model improved the fit to the data (concentration producing 50% of the maximum effect [C50 ], 58.7 ug/mL at the site of drug effect). Maximal reduction from the baseline pain intensity was 63%. In summary, CGX-1160 was generally well tolerated when administered intrathecally at doses up to 1000 µg/h. Peak analgesic effect occurred after the peak intrathecal concentration, indicating the presence of an effect site compartment to the PK model to represent the concentration and effect profiles for this unique compound.

Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN).

OBJECTIVE: To evaluate the safety and efficacy of a once-daily gastroretentive formulation of gabapentin (G-GR; 1800 mg). METHODS: This was an 11-week, double-blind, randomized, placebo-controlled Phase 3 clinical trial in patients with postherpetic neuralgia. Patients underwent a 2-week dose titration, 8 weeks of stable dosing, and 1 week of dose tapering. The primary endpoint was the change in average daily pain intensity score from Baseline to Week 10 using Baseline Observation Carried Forward (BOCF) imputation. RESULTS: Four-hundred and fifty-two patients (mean age 65.6 y, BMI 29 Kg/m) were randomized. Baseline average daily pain intensity score during the week prior to randomization was 6.6 and 6.5 for the G-GR and placebo treatment groups, respectively. Three hundred and seventy-seven patients completed the study (84% G-GR, 83% placebo). G-GR significantly reduced BOCF change in average daily pain intensity compared with placebo (-2.1 vs. -1.6; G-GR vs. placebo, P=0.013). Compared with placebo, more G-GR-treated patients reported "much" or "very much" improvement (patient global impression of change, 43% vs. 34%; P<0.0434), and G-GR reduced sleep interference (-2.3 vs. -1.59; P<0.0001), although neither endpoint was considered statistically significant based on a stringent hierarchical statistical paradigm. Other secondary endpoints showed similar trends. The most common adverse events were dizziness (G-GR, 11.3% vs. placebo, 1.7 %) and somnolence (G-GR, 5.4% vs. placebo, 3.0%). CONCLUSION: Once-daily G-GR 1800 mg was effective and well tolerated for the relief of pain in patients with postherpetic neuralgia.

Use of sensory methods for detecting target engagement in clinical trials of new analgesics.

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.

Duloxetine for the management of diabetic peripheral neuropathic pain: evidence-based findings from post hoc analysis of three multicenter, randomized, double-blind, placebo-controlled, parallel-group studies.

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 >or=30% and >or=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.

Advances and limitations in the evaluation of analgesic combination therapy.

Combination therapy using multiple drugs or modalities that target multiple mechanisms is common practice in the treatment of chronic pain. The benefit of combination therapy is purported to lie in its ability to provide improved efficacy with reduced toxicity. However, there are few published trials evaluating combination analgesics. Therefore, clinical choices regarding treatments, doses, and schedules tend to be determined empirically from innumerable drug combinations and permutations. Synergism is in part dependent on the pain condition, drug-drug interactions, and dose responses of the individual treatment components (among known and unknown factors), and a quantification of synergistic interactions would enable a rational approach to the use of combination analgesic therapy. Traditionally, drug interactions were evaluated by first establishing dose-response relationships of the individual component drugs and the combination in fixed dose ratios, followed by constructing isobolograms that would then allow a detailed statistical analysis. This strategy is at best challenging to perform in chronic analgesic trials. This article discusses the gold standard analytic approach to evaluating combination therapies (isobolograms), various permutations of this approach in human subjects, and the challenges of designing randomized controlled clinical trials that assess synergism between two therapies.

Stability and reliability of detection thresholds for human A-Beta and A-delta sensory afferents determined by cutaneous electrical stimulation.

Activity in primary afferent fibers that usually mediate fine touch can evoke sensations of pain in conditions in which there is sensitization of central neurons. Input from these large diameter Abeta afferents may also sustain and exacerbate these central mechanisms. The role of these fibers in clinical pain syndromes can be evaluated by applications of electrical stimuli that preferentially activate Abeta axons. This study assessed the stability and reliability of a method of electrical stimulation (ES) useful for clinical evaluation. Monopolar constant-current rectangular pulses were delivered to 5 equi-spaced sites on the volar aspect of the left forearm along a transverse line 5 cm distal to the antecubital crease. Current intensity was gradually increased to determine detection threshold and pain detection threshold. This study determined: 1) Effect of pulse duration (1, 2, and 5 msec); 2) the variation of detection threshold and pain threshold over repeated stimulation; 3) the effect of electrode position with respect to distance from the trunk of underlying ulnar or median nerves; and 4) the effect of re-positioning the electrode on variability of detection threshold and pain threshold. There was no significant variability over time for either detection threshold (DT) or pain threshold (PT) at any of the 3 pulse durations tested. There was also no significant effect on variability of shifting the electrode between sites, nor was there a significant difference in variability between sites when placed either over or adjacent to peripheral nerves. Under simulated clinical conditions of electrode re-positioning, the mean detection threshold in 300 trials and ten subjects was 0.30 mA with an overall standard error of 0.007, standard errors of 0.014 over the 10 subjects, 0.003 over the 6 trials, and 0.012 over the 5 locations. Similarly, mean pain threshold in these 300 trials was 3.24 +/- 0.093, with standard errors of 0.12 over the 10 subjects, 0.023 over the 6 trials, and 0.13 over the 5 locations. Mean ratio of pain threshold divided by detection threshold ratio was 10.9 +/- 0.25 with a range of 2.0-28.3. Single pulse, constant current electrical stimulation of the skin at threshold levels is a quantifiable and reliable sensory method that is repeatable within and between testing sessions. Our results suggest that in skin unaffected by allodynia, a ratio of the two sensory thresholds (pain threshold and detection threshold) of less than 2.0 is uncommon. We propose that, in the presence of mechanical allodynia, a pain threshold/detection threshold of less than 2.0 suggests that altered central nervous system processing of Abeta input may contribute to allodynia.

The technical aspects of epidural steroid injections: a national survey.

UNLABELLED: Although epidural steroid injections (ESIs) are a common treatment for chronic pain conditions, it is not clear whether there is consensus on their technical aspects. The current literature suggests that variations in technical aspects may affect ESI outcomes. The goal of the survey was to help establish a standard frame of reference for the performance of ESIs. We analyzed survey results from 68 academic anesthesia programs and 28 private practices in the United States. The main finding in this survey is that there is no clear-cut consensus as to the ideal method to perform ESI. There is a wide variation among individual practices in almost every technical aspect of ESI. Private practices use significantly more fluoroscopy than academic centers. The large difference was found in the cervical region where 73% of private practices and only 39% of academic institutions polled perform the ESIs with fluoroscopic guidance (P = 0.005). A similar discrepancy was found in approaches to the epidural space after laminectomy where 61% of private practices, but only 15% of academic centers, use the transforaminal approach. The study results indicate that there is no consensus, and that there is a wide variation in current practices. IMPLICATIONS: A national survey of practices performing epidural steroid injections was conducted. The purpose was to establish whether consensus exists on technical aspects of this procedure. The study results indicate that there is no consensus, and that there is a wide variation in current practices.