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Early identification of people who use opioids in pregnancy may improve health outcomes for pregnant people and infants. However, characterization of diverse circumstances surrounding type of opioid use and indications for opioid use are lacking.
Learn More >There is conflicting evidence on the association between intrapartum epidural analgesia and risk of autism spectrum disorder (ASD) in offspring.
Learn More >Psychologically based interventions aim to improve pain-related functioning by targeting pain-related fears, cognitions and behaviors. Mediation and moderation analyses permit further examination of the effect of treatment on an outcome. This systematic review and meta-analysis aims to synthetize the evidence of specific mediators and moderators (i.e., treatment targets) of psychologically based treatment effects on pain and disability. A total of 28 mediation and 11 moderation analyses were included. Thirteen mediation studies were included in a meta-analysis, and the rest was narratively synthetized. Reductions in pain-related fear (indirect effect [IE]: -0.07; 95% confidence interval [CI]: -0.11, -0.04) and catastrophizing (IE: -0.07; 95%CI: -0.14, -0.00), as well as increases in self-efficacy (IE: -0.07; 95%CI: -0.11, -0.04), mediated effects of cognitive behavioral therapy on disability but not on pain intensity, when compared to control treatments. Enhancing pain acceptance (IE: -0.17; 95%CI: -0.31, -0.03) and psychological flexibility (IE: -0.30; 95%CI: -0.41, -0.18) mediated acceptance and commitment therapy effects on disability. The narrative synthesis showed conflicting evidence, which did not support a robust moderated effect for any of the examined constructs. Overall, the methodological quality regarding mediation was low, and some key pitfalls are highlighted alongside recommendations to provide a platform for future research.
Learn More >Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side-effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50-488H (0.01-0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001-0.001 mg/kg) and triazole 1.1 (0.32-1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01-0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0-56 min), alone and combined with oxycodone (0.1 mg/kg). U50-488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1's behavioral effects was relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias.
Learn More >Patients with pruritus receiving hemodialysis frequently experience oppressive physical and psychiatric symptoms that directly affect their quality of life and increase mortality. However, treatment options are limited.
Learn More >In England, the prevalence of chronic pain is higher in more deprived compared to less deprived areas. Patients in such areas also experience more severe and disabling pain than those in less deprived areas. However, little is known about whether the distribution of services for chronic pain reflect these ranging levels of need. This study examines how the types of services available for chronic pain patients vary between healthcare providers in England, serving areas of differing deprivation.
Learn More >Whiplash injuries typically occur from a motor vehicle collision and lead to chronic whiplash-associated disorders (CWAD) in 20% to 50% of cases. Changes in neurotransmission, metabolism, and networks seem to play a role in the pathogenic mechanism of CWAD.
Learn More >The worsening opioid epidemic has highlighted the need for the development of new, safe, and effective analgesic therapeutics. Opioid therapy currently is associated with the risk of conversion to addiction, diversion from patients for whom use is intended, and the development of analgesic tolerance, or the loss of efficacy with continued treatment. To this end, we have developed a line of non-opioid, agmatine-based compounds and assessed them for their efficacy in reversing behavioral expressions of pain in animal models, as well as evaluated their safety following chronic exposure. We have previously shown that agmatine, decarboxylated L-arginine, is an N-methyl-D-aspartate (NMDA) receptor antagonist that preferentially antagonizes receptors that express NR2B subunits. This preferential antagonism is desirable for NMDA-based therapeutics as it can lead to a widening of the therapeutic window and avoidance of the side effects commonly associated with NMDA antagonism including motor ataxia and psychoactive effects. However, agmatine has shown limited penetration through the blood brain barrier (BBB) and a short systemic half-life, limiting its clinical utility. We have designed strategically-substituted agmatine (SSA) compounds with the goal of improving its penetration through the BBB by increasing the lipophilicity of agmatine, potentially improving distribution across the BBB and increasing its half-life following systemic delivery. To this end, we have evaluated this series of SSAs for safety and efficacy in multiple animal models of pain. Mice (21-30 g, M/F) were assessed for their baseline mechanical sensitivity, and then one of several models of pain was induced: inflammatory pain (Complete Freund's Adjuvant, (CFA) injected into a hindpaw), neuropathic pain (spared nerve injury surgery), or post-surgical pain (hindpaw muscle incision). Mechanical sensitivity was again assessed, then an SSA compound, agmatine (the parent compound), or vehicle control was administered, and mechanical sensitivity was recorded for up to three hours following administration. The SSA compounds effectively reversed pain behaviors in mice following administration in the various pain models. Additionally, side effects characteristic of NMDA receptor antagonists were assessed and not found at the range of doses that produced analgesia, indicating a wide therapeutic window. These data indicate that the strategically-substituted agmatines are anti-hyperalgesic compounds with a wide therapeutic window, avoiding the motor impairment typical of drugs of this class.
Learn More >Alcohol use disorder (AUD) and chronic pain are complex and debilitating conditions that are difficult to treat, lead to enormous economic costs, and excessive suffering. The difficulty in developing new treatments for AUD is partially due to the lack of consideration given to the wide array of factors that drive alcohol intake. Clinical data suggest that both men and women with chronic pain are more likely to develop alcohol use disorder and report using alcohol to deal with chronic pain. Additionally, it has been shown that self-report of chronic pain correlates with alcohol relapse after a period of abstinence. These data led to the hypothesis that neural mechanisms that contribute to alcohol related behaviors are different in individuals that are also experiencing chronic pain. To test this hypothesis, we used a conditioned place preference (CPP) paradigm to model ethanol seeking in male and female rodents that had undergone either a spared nerve injury (SNI) model of chronic pain or a sham surgery. To determine a dose of ethanol that may be selectively rewarding to injured animals, we first tested the analgesic effects of multiple doses of ethanol on pain-related behaviors in SNI and Sham mice. The higher doses of 1.0g/kg and 2.0g/kg (i.p.) of ethanol were anti-allodynic in SNI mice and analgesic in sham mice. However, we found that the lower dose 0.5 g/kg of ethanol was able to fully reverse mechanical hypersensitivity in SNI animals, while not influencing mechanical thresholds in sham mice. Thus, we conditioned mice using 0.5g/kg of ethanol. We found this dose induced a modest conditioned place preference for the ethanol-paired chamber in both SNI and Sham male mice. Mice then underwent extinction training for 1 week, during which time animals were exposed to the CPP apparatus without receiving any ethanol. To investigate relapse-related behavior, we then tested whether painful stimulation would reinstate ethanol seeking behavior. We found that threshold hindpaw stimulation was able to reinstate ethanol seeking behavior in SNI, but not sham animals. This suggests that animals in chronic pain may associate alcohol with pain relief or that chronic pain animals may be more sensitive to stress induced reinstatement when pain is the stressor. We also tested the effect of drug induced reinstatement and found no differences between SNI and Sham mice, leading us to believe that differences found in pain induced reinstatement were selective to that modality. Ongoing work is aimed at determining the effect of ethanol on weight bearing behavior as well as the effect of chronic pain on ethanol seeking and relapse-related behavior in female mice.
Learn More >Opioids have been increasingly prescribed to treat chronic pain since the 1980s, despite evidence that long-term use of opioids may lead to tolerance and pain sensitization called opioid-induced hyperalgesia (OIH). OIH has been demonstrated in both preclinical models and healthy human volunteers, but is understudied and there is need for novel analgesics capable of mitigating OIH. α /α -selective GABA receptor positive allosteric modulators (PAMs) act specifically at subunits of the GABA receptor found to mediate analgesia, and have demonstrated antinociceptive effects in models of chronic inflammatory and neuropathic pain. However, the efficacy of these compounds at relieving opioid-induced pain hypersensitivity have not yet been investigated. This study systematically examined the antinociceptive effects of α /α -selective GABA receptor PAMs alone and in combination with acetaminophen in an OIH rat model wherein repeated treatment with the opioid fentanyl induces mechanical hyperalgesia. The von Frey test was used to measure mechanical nociception. Duration of actions of α /α -selective GABA receptor PAMs (KRM-II-81, NS16085, HZ-166) alone were studied, and combinations of KRM-II-81 and acetaminophen were also studied at fixed ratios (1:1, 1:3, 3:1). Dose-addition analysis was used to assess the antinociceptive interactions between KRM-II-81 and acetaminophen. α /α -selective GABA receptor PAMs were able to fully reverse mechanical sensitivity caused by OIH. Furthermore, KRM-II-81/acetaminophen combinations produced additive to supra-additive interactions depending on the drug mixture ratios. These findings support the idea that α /α -selective GABA receptor PAMs could serve as novel analgesics for treating OIH, and may interact favorably with other non-opioid analgesics.
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