ACD856, a novel positive allosteric modulator of Trk receptors, single ascending doses in healthy subjects: Safety and pharmacokinetics.

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 Cmax 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).

Inhibition of P2X7 receptors by Lu AF27139 diminishes colonic hypersensitivity and CNS prostanoid levels in a rat model of visceral pain.

Visceral pain is a prominent feature of various gastrointestinal diseases. The P2X7 receptor is expressed by multiple cell types including dorsal root ganglion satellite glial cells, macrophages, and spinal microglia, all of which have been implicated in nociceptive sensitization. We have used the selective and CNS penetrant P2X7 receptor antagonist Lu AF27139 to explore this receptor's role in distinct rat models of inflammatory and visceral hypersensitivity. Rats injected with CFA in the hindpaw displayed a marked reduction in hindpaw mechanical threshold, which was dose-dependently reversed by Lu AF27139 (3-30 mg/kg, p.o.). In rats injected with TNBS in the proximal colon, the colorectal distension threshold measured distally was significantly lower than sham treated rats at 7 days post-injection (P < 0.001), indicative of a marked central sensitization. Colonic hypersensitivity was also reversed by Lu AF27139 (10-100 mg/kg) and by the κ-opioid receptor agonist U-50,488H (3 mg/kg, s.c.). Moreover, both Lu AF27139 and U-50,488H prevented a TNBS-induced increase in spinal and brain levels of PGE2 and LTB4, as well as an increase in brain levels of PGF2α and TXB2. Lu AF27139 was well tolerated as revealed by a lack of significant effect on rotarod motor function and coordination at all doses tested up to 300 mg/kg. Thus, P2X7 receptor antagonism is efficacious in a rat model of visceral pain, via a mechanism which potentially involves attenuation of microglial function within spinal and/or supraspinal pain circuits, albeit a peripheral site of action cannot be excluded.

Risk factors for persistent pain and its influence on maternal wellbeing after cesarean section.

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.

Prediction of H3 receptor occupancy diurnal fluctuations using population modeling and simulation with focus on guiding dose selection in a Phase IIa study.

PURPOSE: 4-[(1S,2S)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzamide ("AZ1") is a histamine 3 (H3) autoreceptor in vivo antagonist. Sleep disturbance is a well-known class-effect for H3 antagonists and associated with high H3 receptor occupancy (RO) at night. The objective of the present work was to investigate if it was possible to obtain large diurnal fluctuations in RO for AZ1 and to suggest suitable doses for a Phase IIa study. METHODS: Four Phase I studies were pooled and used to build a population pharmacokinetic model in NONMEM. Based on simulations of the PK model and the reported Ki-value for H3 RO from a human PET-study, RO vs. time profiles were simulated. RESULTS: The model well described the AZ1 pharmacokinetics. Simulations predicting plasma concentration and RO vs. time profiles for several doses were explored and doses with a wide range of fluctuation in RO over the dosing interval could be identified. CONCLUSIONS: By using population modeling and simulations of PK data and the Ki-value from a human PET study, predictions of RO vs. time for unstudied doses of AZ1 was made. Using this methodology it was possible to suggest doses with expected large diurnal fluctuations in RO.

Paradoxical heat sensation as a manifestation of thermal hypesthesia: a study of 1090 patients with lesions of the somatosensory system.

ABSTRACT: Paradoxical heat sensation (PHS) is the perception of warmth when the skin is cooled. Paradoxical heat sensation rarely occurs in healthy individuals but more frequently in patients suffering from lesions or disease of the peripheral or central nervous system. To further understand mechanisms and epidemiology of PHS, we evaluated the occurrence of PHS in relation to disease aetiology, pain levels, quantitative sensory testing parameters, and Neuropathic Pain Symptom Inventory (NPSI) items in patients with nervous system lesions. Data of 1090 patients, including NPSI scores from 404 patients, were included in the analysis. We tested 11 quantitative sensory testing parameters for thermal and mechanical detection and pain thresholds, and 10 NPSI items in a multivariate generalised linear model with PHS, aetiology, and pain (yes or no) as fixed effects. In total, 30% of the neuropathic patients reported PHS in contrast to 2% of healthy individuals. The frequency of PHS was not linked to the presence or intensity of pain. Paradoxical heat sensation was more frequent in patients living with polyneuropathy compared with central or unilateral peripheral nerve lesions. Patients who reported PHS demonstrated significantly lower sensitivity to thermal perception, with lower sensitivity to normally painful heat and cold stimuli. Neuropathic Pain Symptom Inventory scores were lower for burning and electric shock-like pain quality for patients with PHS. Our findings suggest that PHS is associated with loss of small thermosensory fibre function normally involved in cold and warm perception. Clinically, presence of PHS could help screening for loss of small fibre function as it is straightforward to measure or self-reported by patients.

Cortical responses to amphetamine exposure studied by pCASL MRI and pharmacokinetic/pharmacodynamic dose modeling.

INTRODUCTION: Perfusion measurement by arterial spin labeling (ASL) techniques is well suited for pharmaceutical magnetic resonance imaging (phMRI) studies to investigate how drugs change the cerebral perfusion status and further, neuronal activity. MATERIALS AND METHOD: Twelve healthy normal male volunteers participated in the study which was based on a double blinded design. Six subjects were randomly selected to receive a single oral dose of 20mg d-amphetamine and six were given placebo. Perfusion measurements by pseudo-continuous ASL (pCASL) technique were repeatedly performed at 10 different time points with a 3T clinical MRI scanner during a 10 hour period after dose together with physiologic data and blood sample collections. The dynamic changes in cerebral perfusion in response to the plasma concentration variations of d-amphetamine were analyzed at voxel-level and for regions of interest. RESULTS: Compared to the placebo group a 20% reduction in cerebral blood flow (CBF) was observed in gray matter for the subjects that received d-amphetamine. The most significant reduction of regional CBF (rCBF) was detected in the basal ganglia, frontal region and insular cortex using voxel based analysis. A relation between d-amphetamine exposure and CBF response was found using PK/PD modeling, which predicted on average a 15% decrease of the CBF in gray matter at a plasma concentration of 30 ng/ml. CONCLUSION: In this study we have demonstrated that repeated perfusion measurements by pCASL technique was sufficiently robust to differentiate the neurological response between the groups that received d-amphetamine and placebo. Quantitative and repetitive CBF measurements can be used for PK/PD modeling of CNS drug responses in humans.

AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects.

The histamine H3 receptor represents an appealing central nervous system drug target due to its important role in the neurobiology of cognition and wake-sleep regulation. The therapeutic benefit of H3 antagonists/inverse agonists may be hampered by disruption of sleep that has been observed in humans with prolonged high H3 receptor occupancy (H3RO), extending into night-time. AZD5213 is a highly selective H3 antagonist (in vitro inverse agonist) developed to achieve a pharmacokinetic profile permitting circadian fluctuations of H3RO. Its efficacy has been demonstrated in rodent behavioural models of cognition. In human subjects, AZD5213 was safe and well tolerated following repeated doses (1-14 mg/d) and demonstrated a short (∼5 h) half-life. In this PET study H3RO was measured using the radioligand [11C]GSK189254 ([11C]AZ12807110) in seven young male volunteers following single doses of AZD5213 (0.05-30 mg). H3RO was calculated using the Lassen plot method. The plasma concentrations and the affinity constant (K i,pl 1.14 nmol/l, corresponding to the plasma concentration required to occupy 50% of available receptors) were used to estimate the H3RO time-course. AZD5213 showed dose and concentration dependent H3RO ranging from 16 to 90%. These binding characteristics and the pharmacokinetic profile of AZD5213 indicate that high daytime and low night-time H3RO could be achieved following once daily oral dosing of AZD5213. Fluctuations of H3RO following circadian rhythm of the histamine system may be expected to reduce the risk of sleep disruption while maintaining daytime efficacy. AZD5213 may thus be an optimal compound to evaluate the clinical benefit of selective H3 antagonism in cognitive disorders.

Evaluation of the analgesic efficacy and psychoactive effects of AZD1940, a novel peripherally acting cannabinoid agonist, in human capsaicin-induced pain and hyperalgesia.

The aim of the present study was to investigate the effects of AZD1940, a novel peripherally acting cannabinoid CB(1) /CB(2) 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 CB(1)/CB(2) 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.

Intraoperative injection of bupivacaine-adrenaline close to the fascia reduces morphine requirements after cesarean section: a randomized controlled trial.

OBJECTIVE: The purpose of this study was to investigate whether a single injection of bupivacaine with adrenaline close to the fascia could decrease opiate consumption and pain in patients undergoing cesarean section in spinal anesthesia. DESIGN: Randomized double-blind controlled study. SETTINGS: Karolinska University Hospital, Huddinge, Sweden. POPULATION: 260 women scheduled for elective cesarean section were enrolled in the study. METHODS: The treatment group (n= 130) received 40 mL bupivacaine (2.5 mg/mL) with adrenaline (5 µg/mL) (Marcain® adrenalin) and the control group (n= 130) received 40 mL saline solution (0.9%), which was, in both groups, injected close to the fascia before closure of the wound. MAIN OUTCOME MEASURES: Morphine consumption and mean resting pain intensity numerical rating scale at 12 and 24 hours were the primary outcome variables. Other assessments for pain as well as mobilization parameters were considered secondary. RESULTS: Morphine requirements were significantly less in the bupivacaine group, 19.0 mg/woman, compared with 24.0 mg/woman in the placebo group, during the first 12 postoperative hours. During this time period there was also a trend towards a difference between groups in mean pain intensity, but significant only during the first six hours. Over the whole first postoperative 24 hours, there were no differences in either morphine requirement or pain intensity between groups. CONCLUSIONS: A single injection of bupivacaine with adrenaline in the surgical wound decreases the need for morphine requirements for the first 12 postoperative hours and contributes to safe and effective pain management in women undergoing cesarean section.

Lack of effect of central nervous system-active doses of nabilone on capsaicin-induced pain and hyperalgesia.

The aim of the present study was to investigate the effects of nabilone on capsaicin-induced pain and hyperalgesia, as well as on biomarkers of cannabinoid central nervous system (CNS) effects. A randomized, double-blind, placebo-controlled, crossover study was conducted in 30 healthy male volunteers receiving single doses of nabilone (1, 2 or 3 mg). Pain intensity after intradermal capsaicin injections in the forearm was assessed by continuous visual analogue scale (0-100 mm). Capsaicin cream was applied to the calf to induce hyperalgesia. Primary hyperalgesia was assessed by measuring heat pain thresholds, whereas secondary hyperalgesia was assessed by measuring the area where light tactile stimulation was felt to be painful. Pain and hyperalgesia were measured at baseline and 2-3.5 h after dosing. The CNS effects were assessed at baseline and up to 24 h after dosing using visual analogue mood scales for feeling 'stimulated', 'anxious', 'sedated' and 'down'. Plasma samples for pharmacokinetic analysis were obtained up to 24 h after drug administration. Nabilone did not significantly attenuate either ongoing pain or primary or secondary hyperalgesia, whereas dose-dependent CNS effects were observed from 1.5 to 6 h after dosing, being maximal at 4-6 h. Plasma concentrations of nabilone and its metabolite carbinol were maximal 1-2 h after dosing. Adverse events (AE) were common on nabilone treatment. Four subjects withdrew due to pronounced CNS AE (anxiety, agitation, altered perception, impaired consciousness). Although nabilone had marked CNS effects, no analgesic or antihyperalgesic effects were observed.

Management of alcohol use disorders in patients with chronic pancreatitis.

CONTEXT: The outcome of treatment for patients with chronic pancreatitis may be improved by multidisciplinary management. OBJECTIVE: To study patients with chronic pancreatitis, especially regarding alcohol use, within a multi disciplinary program. MAIN OUTCOME MEASURES: Prospective assessment at baseline and follow-up of alcohol use disorders using DSM-IV criteria, AUDIT score, interview-based quantification of alcohol intake and the biomarker for alcohol use s-CDT in patients referred because of chronic pancreatitis together with retrospective classification with the M-ANNHEIM risk factor analysis and severity scoring for chronic pancreatitis. RESULTS: Sixty patients (95%) of 63 consecutively included patients were classified as having chronic pancreatitis. Forty-four of these (73%) were available for follow-up evaluation, which took place after a minimum of 1 year (median 3 years). Alcohol consumption decreased at follow-up and no patients had ongoing alcohol dependence (P<0.001) as compared to 10 (23%) at initial evaluation. Patients with harmful alcohol use (AUDIT score ≥8 points) and pathological s-CDT had a reduction in both parameters (P=0.004 and P=0.060, respectively). Pain score according to M-ANNHEIM was unchanged, whereas use of analgesics decreased (P=0.005). CONCLUSIONS: This feasibility study of patients with chronic pancreatitis demonstrated that multidisciplinary management seems to give a positive and sustainable effect on alcohol abuse and may be a useful concept for optimal classification, selection and treatment of patients with chronic pancreatitis.

P2X7 receptor-mediated release of microglial prostanoids and miRNAs correlates with reversal of neuropathic hypersensitivity in rats.

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-1ß, 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.

Association of sensory phenotype with quality of life, functionality, and emotional well-being in patients suffering from neuropathic pain.

ABSTRACT: Neuropathic pain highly affects quality of life, well-being, and function. It has recently been shown based on cluster analysis studies that most patients with neuropathic pain may be categorized into 1 of 3 sensory phenotypes: sensory loss, mechanical hyperalgesia, and thermal hyperalgesia. If these phenotypes reflect underlying pathophysiological mechanisms, they may be more relevant for patient management than underlying neurological diagnosis or pain intensity. The aim of this study was thus to examine the impact of these sensory phenotypes on mental health, functionality, and quality of life. Data of 433 patients from the IMI/EuroPain network database were analyzed, and results of HADS-D/A, Pain Catastrophizing Scale, Euro Quality of Life 5D/-VAS, Brief Pain Inventory, and Graded Chronic Pain Scale between the sensory phenotypes were compared using multiple regression analysis. There was no difference in chronic pain grade, pain intensity, depression, or anxiety scores between phenotypes. Pain interference (Brief Pain Inventory) was higher (P = 0.002); self-reported health state lower (Euro Quality of Life 5D VAS, P = 0.02); and problems regarding mobility (P = 0.008), usual activities (P = 0.004), and self-care (P = 0.039) more prominent (EQ5-D) in the sensory loss compared with the thermal hyperalgesia phenotype. Patients with sensory loss also showed higher pain catastrophizing scores (P = 0.006 and 0.022, respectively) compared with the 2 other groups. Sensory phenotype is associated with the impact of neuropathic pain conditions on well-being, daily functionality, and quality of life but is less associated with pain intensity. These results suggest that the somatosensory phenotype should be considered for personalized pain management.

Contralateral Sensory and Pain Perception Changes in Patients With Unilateral Neuropathy.

OBJECTIVE: To test whether contralateral sensory abnormalities in the clinically unaffected area of patients with unilateral neuropathic pain are due to the neuropathy or pain mechanisms. METHODS: We analyzed the contralateral clinically unaffected side of patients with unilateral painful or painless neuropathy (peripheral nerve injury [PNI], postherpetic neuropathy [PHN], radiculopathy) by standardized quantitative sensory testing following a validated protocol. Primary outcome was the independent contribution of the following variables on the contralateral sensory function using generalized linear regression models: pain intensity, disease duration, etiology, body area, and sensory patterns in the most painful area. RESULTS: Among 424 patients (PNI n = 256, PHN n = 78, radiculopathy n = 90), contralateral sensory abnormalities were frequent in both painful (n = 383) and painless (n = 41) unilateral neuropathy, demonstrating sensory loss for thermal and mechanical nonpainful stimuli and both sensory loss and gain for painful test stimuli. Analysis by etiology revealed contralateral pinprick hyperalgesia in PHN and PNI. Analysis by ipsilateral sensory phenotype demonstrated mirror-image pinprick hyperalgesia in both mechanical and thermal hyperalgesia phenotypes. Pain intensity, etiology, and affected body region predicted changes in only single contralateral somatosensory parameters. Disease duration had no impact on the contralateral sensory function. CONCLUSION: Mechanisms of sensory loss seem to spread to the contralateral side in both painful and painless neuropathies. Contralateral spread of pinprick hyperalgesia was restricted to the 2 ipsilateral phenotypes that suggest sensitization; this suggest a contribution of descending net facilitation from supraspinal areas, which was reported in rodent models of neuropathic pain but not yet in human patients.

No pain, still gain (of function): the relation between sensory profiles and the presence or absence of self-reported pain in a large multicenter cohort of patients with neuropathy.

ABSTRACT: The pathophysiology of pain in neuropathy is complex and may be linked to sensory phenotypes. Quantitative sensory testing, a standardized method to evaluate sensory profiles in response to defined stimuli, assesses functional integrity of small and large nerve fiber afferents and central somatosensory pathways. It has revealed detailed insights into mechanisms of neuropathy, yet it remains unclear if pain directly affects sensory profiles. The main objective of this study was to investigate sensory profiles in patients with various neuropathic conditions, including polyneuropathy, mononeuropathy, and lesions to the central nervous system, in relation to self-reported presence or absence of pain and pain sensitivity using the Pain Sensitivity Questionnaire. A total of 443 patients (332 painful and 111 painless) and 112 healthy participants were investigated. Overall, loss of sensation was equally prevalent in patients with and without spontaneous pain. Pain thresholds were equally lowered in both patient groups, demonstrating that hyperalgesia and allodynia are just as present in patients not reporting any pain. Remarkably, this was similar for dynamic mechanical allodynia. Hypoalgesia was more pronounced in painful polyneuropathy, whereas hyperalgesia was more frequent in painful mononeuropathy (compared with painless conditions). Self-reported pain sensitivity was significantly higher in painful than in painless neuropathic conditions. Our results reveal the presence of hyperalgesia and allodynia in patients with central and peripheral lesions of the somatosensory system not reporting spontaneous pain. This shows that symptoms and signs of hypersensitivity may not necessarily coincide and that painful and painless neuropathic conditions may mechanistically blend into one another.

Isoallopregnanolone reduces tic-like behaviours in the D1CT-7 mouse model of Tourette syndrome.

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 3ß-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.

Pain thresholds and intensities of CRPS type I and neuropathic pain in respect to sex.

BACKGROUND AND AIMS: Healthy women have generally been found to have increased experimental pain perception and chronic pain has a higher prevalence in female as compared to male patients. However, no study has investigated whether pain intensity and pain perception thresholds are distinct or similar between sexes within various chronic pain entities. We investigated whether average pain intensities and pain thresholds assessed using quantitative sensory testing (QST) differed between women and men suffering from three distinct chronic pain conditions: Complex Regional Pain Syndrome (CRPS type I), peripheral nerve injury (PNI) or polyneuropathy (PNP), as compared to paired healthy volunteers. METHODS: QST data of 1,252 patients (669 female, 583 male) with PNI (n = 342), PNP (n = 571) or CRPS (n = 339), and average pain intensity reports from previously published studies were included. Absolute and z-values (adjusted for age and body region) of cold, heat, pressure (PPT) and pinprick pain thresholds were compared in generalized linear models with aetiology, duration of underlying pain disease and average pain intensity as fixed effects. RESULTS: Average pain intensity during the past four weeks did not differ between women and men, in both mean and range. In women absolute pain thresholds for cold, heat and pinprick were lower than in males across all diagnoses (p < .05). However, after z-transformation these differences disappeared except for PPT in CRPS (p = .001). DISCUSSION: Pain thresholds in patients show only minor sex differences. However, these differences mimic those observed in healthy subjects and do not seem to be linked to specific pathophysiological processes. SIGNIFICANCE: Female healthy participants and female patients with neuropathic pain conditions or CRPS I report lower pain thresholds compared to males, but pain intensity is similar and there is no sex difference in the extent to which the thresholds are altered in neuropathic pain or CRPS. Thus, the sex differences observed in various chronic pain conditions mimic those obtained in healthy participants, indicating that these differences are not linked to specific pathophysiological processes and are of minor clinical relevance.

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.

Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations.

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.