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 a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are ...mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic-ie, a patient can be sorted to more than one phenotype-and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5.
Purpose
AlzeCure Pharma AB is developing novel positive allosteric modulators of Trk-receptors for treatment of Alzheimer’s disease, depression, other psychiatric conditions and other disorders where ...cognition is impaired. The preceding candidate drug ACD855 was shown to have a too long half-life in humans to allow further development. To de-risk the development of the follow-up compound ACD856, the oral single ascending dose study of ACD856 in humans was preceded by an intravenous microdose study, assessing the elimination half-life in plasma.
Methods
A phase 0 study with a microdose of ACD856 (0.100 mg), was conducted in six healthy male subjects all receiving ACD856. Sequentially, a randomized, placebo-controlled, double-blind Phase I single ascending oral dose study (1 – 150 mg) was conducted, including 56 healthy subjects. Both studies assessed the safety and tolerability, as well as the PK properties of ACD856 after single dose intravenous and oral administration.
Results
ACD856 was well tolerated with no treatment emergent, or dose related adverse events or other safety assessments. In the microdose study, ACD856 exhibited a bi-exponential plasma decline, low distribution volume, low plasma clearance with a half-life of approximately 20 hours. Orally, ACD856 exhibited rapid absorption, an almost complete bioavailability and a dose proportional increase in exposure. While the C
max
was lowered and delayed by food intake, the effect on plasma half-life and the overall bioavailability was low. No renal elimination of ACD856 was detected.
Conclusion
The prediction proved accurate demonstrating the value of conducting a microdose study prior to ascending dose studies.
Trial registration
NCT05783830 March 24, 2023 (microdose study, retrospectively registered) and NCT05077631 October 14, 2021 (single ascending dose study).
Objectives
To investigate the overall incidence and risk factors for persistent pain and its interference with daily life after cesarean section.
Design
Prospective long‐term follow‐up study.
Setting
...Karolinska University Hospital, Stockholm, Sweden.
Population
260 healthy women who underwent elective cesarean section.
Methods
Information on demographics, medical history, postoperative pain and analgesic requirements was collected. A questionnaire consisting of the Brief Pain Inventory was posted at 3, 6 and 12 months after surgery. Women rated pain intensity as well as interference with factors related to general function and quality of life.
Main outcome measures
The overall incidence and risk factors for persistent postoperative pain at three time points. Persistent pain was considered a secondary outcome.
Results
At 3, 6 and 12 months respectively 40, 27 and 22% of patients reported pain in one or more locations, in the surgical site as well as in other areas. A psychological indication, as well as a first cesarean section, increased the risk for pain at 3 months. Severe postoperative pain in the immediate postoperative period or undergoing a first cesarean section were significant independent risk factors for the development of persistent pain up to 6 months after cesarean section. Parameters related to quality of life were significantly impaired in women with persistent pain.
Conclusion
Several factors, including severe postoperative pain, were shown to influence the risk for persistent pain after cesarean section. Long‐term pain markedly affected women's wellbeing.
Tourette syndrome (TS) is a neuropsychiatric disorder characterised by multiple, persistent tics. These semi‐voluntary motor and phonic manifestations are typically aggravated by exposure to acute ...stress, yet the mechanisms underlying this exacerbation remain unclear. Using a well‐characterised animal model of TS, the D1CT‐7 mouse, we recently showed that acute stress increases tic‐like responses and causes sensorimotor gating deficits, as measured by the prepulse inhibition of the startle. We showed that these effects are promoted by the brain synthesis of the neurosteroid allopregnanolone (AP). In line with this idea, inhibition of AP synthesis by finasteride was found to suppress the tic‐exacerbating effects of stress; conversely, AP administration resulted in a marked enhancement of the number of tic‐like motor bursts. Given that the primary mechanism of AP is based on the positive allosteric modulation of GABAA receptors, in the present study, we hypothesised that the enhancement in tic‐like behaviours induced by either stress or AP may be countered by isoallopregnanolone (isoAP), the natural 3β‐epimer of AP that acts as an antagonist to the AP‐binding site within GABAA receptors. In agreement with our hypothesis, isoAP (5‐10 mg kg‐1, s.c.) dose‐dependently reduced the number of tic‐like behaviours induced by stress in D1CT‐7 mice. These effects were comparable to those elicited by both the benchmark TS therapy haloperidol (0.3 mg kg‐1, i.p.), as well as finasteride (25 mg kg‐1, i.p.). IsoAP also countered the prepulse inhibition deficits secondary to stress in D1CT‐7 mice. Finally, isoAP opposed the enhancement of tic‐like behaviours induced by AP (15 mg kg‐1, i.p.). Given that isoAP is well‐tolerated and has an optimal safety profile, these data suggest that this steroid may have therapeutic properties in TS.
A large number of analgesics have failed to prove superiority over placebo in randomized controlled trials (RCTs), and as this has been related to increasing placebo responses, there is currently an ...interest in specifying predictors of the placebo response. The literature on placebo mechanisms suggests that factors related to patients' expectations of treatment efficacy are pivotal for the placebo response. Also, general characteristics of RCTs have been suggested to influence the placebo response. Yet, only few meta-analyses have directly tested these hypotheses. Placebo data from 9 industrially sponsored, randomized, double-blind, placebo-controlled, multicenter phase III trials in 2017 adult patients suffering from chronic painful osteoarthritis (hip or knee) or low back pain were included. The primary outcome was pain intensity. Based on previous studies, we chose 3 expectancy-related primary predictors: type of active medication, randomization ratio, and number of planned face-to-face visits. In addition, explorative analyses tested whether RCT and patients' characteristics predicted the placebo response. Opioid trials, a high number of planned face-to-face visits, and randomization ratio predicted the magnitude of the placebo response, thereby supporting the expectancy hypothesis. Exploratory models with baseline pain intensity, age, washout length, and discontinuation because of adverse events accounted for approximately 10% of the variability in the placebo response. Based on these results and previous mechanisms studies, we think that patients' perception of treatment allocation and expectations toward treatment efficacy could potently predict outcomes of RCTs.
Summary
The aim of the present study was to investigate the effects of AZD1940, a novel peripherally acting cannabinoid CB1/CB2 receptor agonist, on capsaicin‐induced pain and hyperalgesia, as well ...as on biomarkers of cannabinoid central nervous system (CNS) effects.
The present study was a randomized, double‐blind, placebo‐controlled, four‐sequence, two‐period, cross‐over study in 44 male healthy volunteers aged 20–45 years. The effects of two single oral doses of AZD1940 (400 and 800 μg) were compared with placebo. Pain intensity after intradermal capsaicin injections in the forearm was assessed on a continuous visual analogue scale (VAS; 0–100 mm). Primary and secondary hyperalgesia induced by application of capsaicin cream on the calf were assessed by measuring heat pain thresholds and the area of mechanical allodynia, respectively. The CNS effects were assessed at baseline and up to 24 h after dosing using a visual analogue mood scales (VAMS) for feeling ‘stimulated’, ‘high’, ‘anxious’, ‘sedated’ or ‘down’.
AZD1940 did not significantly attenuate ongoing pain or primary or secondary hyperalgesia compared with placebo. Mild CNS effects for AZD1940were observed on the VAMS for ‘high’ and ‘sedated’. Dose‐dependent mild‐to‐moderate CNS‐related and gastrointestinal adverse events were reported following treatment with AZD1940.
No evidence of analgesic efficacy was found for a peripherally acting CB1/CB2 receptor agonist in the human capsaicin pain model. The emergence of mild dose‐dependent CNS effects suggests that the dose range predicted from preclinical data had been attained.
Clinical and human experimental pain studies often include so-called "healthy" controls in investigations of sensory abnormalities, using quantitative sensory testing (QST) as an outcome measure. ...However, the criteria for what is considered "healthy" vary among the different studies and between study centers and investigators, partly explaining the high variability of the results. Therefore, several aspects should be considered during inclusion of healthy volunteers in QST-based trials to have homogenous groups of healthy controls with less variability between human experimental studies, so that results are less likely to be false negative or false positive because of subject-related factors. The EUROPAIN and NEUROPAIN consortia aimed to define factors influencing the variability in selection of healthy subjects in QST-based studies before the start of both projects and to give recommendations how to minimize it based on the current literature and expertise of the participants. The present suggestions for inclusion criteria of healthy volunteers into QST-based trials describe a 2-level approach including standardized questionnaires enabling the collection of relevant information on sociodemographic data, medical history, current health status, coping strategies in dealing with pain, and the motivation of the volunteer to participate in the study. These suggestions are believed to help researchers interpret their results in comparison with others and improve the quality of clinical studies including healthy volunteers as controls or in human experimental pain studies. They aim to reduce any confounding factors. Furthermore, the acquired information will allow post hoc analyses of variance for different potential influencing factors.
Background
P2X7 receptor antagonists have potential for treating various central nervous system (CNS) diseases, including neuropathic pain, although none have been approved for clinical use. Reasons ...may include insufficient understanding of P2X7 receptor signalling in pain, and the lack of a corresponding preclinical mechanistic biomarker.
Methods
Lu AF27139 is a highly selective and potent small molecule antagonist at rat, mouse and human forms of the P2X7 receptor, with excellent pharmacokinetic and CNS permeability properties. In the current experiments, we probed the utility of previously characterized and novel signalling cascades exposed to Lu AF27139 using cultured microglia combined with release assays. Subsequently, we assessed the biomarker potential of identified candidate molecules in the rat chronic constriction injury (CCI) model of neuropathic pain; study design limitations precluded their assessment in spared nerve injury (SNI) rats.
Results
Lu AF27139 blocked several pain‐relevant pathways downstream of P2X7 receptors in vitro. At brain and spinal cord receptor occupancy levels capable of functionally blocking P2X7 receptors, it diminished neuropathic hypersensitivity in SNI rats, and less potently in CCI rats. Although tissue levels of numerous molecules previously linked to neuropathic pain and P2X7 receptor function (e.g. IL‐6, IL‐1β, cathepsin‐S, 2‐AG) were unaffected by CCI, Lu AF27139‐mediated regulation of spinal PGE2 and miRNA (e.g. rno‐miR‐93‐5p) levels increased by CCI aligned with its ability to diminish neuropathic hypersensitivity.
Conclusions
We have identified a pain‐relevant P2X7 receptor‐regulated mechanism in neuropathic rats, which could hold promise as a translatable biomarker and by association enhance the clinical progression of P2X7 receptor antagonists in neuropathic pain.
Significance
Sub‐optimal translation of preclinical molecules has hindered the clinical development of novel mechanism of action analgesics. We have undertaken a comprehensive in vitro analysis of migroglial signalling mechanisms recruited upon P2X7 receptor activation, a number of which were shown to be modulated by a selective P2X7 receptor antagonist in a well characterized animal model of neuropathic pain. Subject to further confirmation in other neuropathic models, this opens up the possibility to investigate their clinical utility as potential pain biomarkers in patients.
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