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BACKGROUND AND PURPOSE: Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable. EXPERIMENTAL APPROACH: After 14 consecutive days of intraperitoneal CBDA-ME administration at 0.01, 0.1 and 1 µg·kg-1 , commencing 1 day after surgically implanting a sciatic nerve-constricting cuff to induce NEP, the anti-nociceptive efficacy of this cannabinoid was assessed in male and female Sprague-Dawley rats relative to vehicle-treated counterparts. In females, 2 and 4 µg·kg-1 daily doses of CBDA-ME were also evaluated. Behavioural tests were performed for hind paw mechanical and thermal withdrawal thresholds once a week for 8 weeks. At endpoint, in vivo electrophysiological recordings were obtained to characterize soma threshold changes in primary sensory neurons. KEY RESULTS: In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested. CONCLUSION AND IMPLICATIONS: Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.

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Background: Cancer pain involves nervous system damage and pathological neurogenesis. Neuropathic pain arises from damage to the nervous system and is driven by ectopic signaling. Both progesterone and pregabalin are neuroprotective in animal models, and there is evidence that both drugs bind to and inhibit voltage-gated calcium channels. Aims: This study was designed to characterize the effects of progesterone and pregabalin in preclinical models of cancer and neuropathic pain in both sexes. Methods: We measured peripheral sensory signaling by intracellular in vivo electrophysiology and behavioral indicators of pain in rat models of cancer-induced bone pain and neuropathic pain. Results: Female but not male models of cancer pain showed a behavioral response to treatment and pregabalin reduced excitability in C and A high-threshold but not low-threshold sensory neurons of both sexes. Male models of neuropathic pain treated with pregabalin demonstrated higher signaling thresholds only in A high-threshold neurons, and behavioral data indicated a clear recovery to baseline mechanical withdrawal thresholds in all treatment groups. Female rat treatment groups did not show excitability changes in sensory neurons, but all demonstrated higher mechanical withdrawal thresholds than vehicle-treated females, although not to baseline levels. Athymic female rat models of neuropathic pain showed no behavioral or electrophysiological responses to treatment. Conclusions: Both pregabalin and progesterone showed evidence of efficacy in male models of neuropathic pain. These results add to the evidence demonstrating differential effects of treatments for pain in male and female animals and widely differing responses in models of cancer and neuropathic pain.

Contexte: La douleur cancéreuse implique des lésions du système nerveux et une neurogenèse pathologique. La douleur neuropathique résulte d'une lésion du système nerveux et est provoquée par une signalisation ectopique. La progestérone et la prégabaline sont toutes deux neuroprotectrices dans les modèles animaux et il est prouvé que ces deux médicaments se lient aux canaux calciques à tension contrôlée et les inhibent.Objectifs: Cette étude visait à caractériser les effets de la progestérone et de la prégabaline dans des modèles précliniques de cancer et de douleur neuropathique chez les deux sexes.Méthodes: Nous avons mesuré la signalisation sensorielle périphérique par électrophysiologie intracellulaire in vivo, ainsi que les indicateurs comportementaux de la douleur dans des modèles de rats atteints de douleurs osseuses et de douleurs neuropathiques induites par le cancer.Résultats: Contrairement aux modèles masculins, les modèles féminins atteints de douleur cancéreuse ont montré une réponse comportementale au traitement, tandis que la prégabaline a réduit l'excitabilité des neurones sensoriels C et A à seuil élevé mais non à seuil bas chez les deux sexes. Les modèles masculins atteints de douleur neuropathique traités à la prégabaline ont montré des seuils de signalisation plus élevés uniquement dans les neurones A à seuil élevé, tandis que les données comportementales ont indiqué un net retour aux seuils de retrait mécanique de départ dans tous les groupes de traitement. Les groupes de rats femelles traités n'ont pas montré de changements d'excitabilité dans les neurones sensoriels, mais tous ont montré des seuils de retrait mécanique plus élevés que les femelles traitées avec le vecteur, sans toutefois atteindre les niveaux de départ. Les modèles atteints de douleur neuropathique parmi les rats femelles athymiques n'ont montré aucune réponse comportementale ou électrophysiologique au traitement.Conclusions: La prégabaline et la progestérone ont toutes deux démontré leur efficacité dans les modèles masculins atteints de douleur neuropathique. Ces résultats s'ajoutent aux données probantes démontrant les effets différentiels des traitements de la douleur chez les animaux mâles et femelles, et les réponses très différentes dans les modèles atteints de cancer et de douleur neuropathique.

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BACKGROUND: Evidence with regard to antibiotic prophylaxis for patients with open fractures of the extremities is limited. We therefore conducted a systematic survey addressing current practice and recommendations. METHODS: We included publications from January 2007 to June 2017. We searched Embase, MEDLINE, CINAHL, the Cochrane Central Registry of Controlled Trials (CENTRAL), and the Cochrane Database of Systematic Reviews for clinical studies and surveys of surgeons; WorldCat for textbooks; and web sites for guidelines and institutional protocols. RESULTS: We identified 223 eligible publications that reported 100 clinical practice patterns and 276 recommendations with regard to systemic antibiotic administration, and 3 recommendations regarding local antibiotic administration alone. Most publications of clinical practice patterns used regimens with both gram-positive and gram-negative coverage and continued the administration for 2 to 3 days. Most publications recommended prophylactic systemic antibiotics. Most recommendations suggested gram-positive coverage for less severe injuries and administration duration of 3 days or less. For more severe injuries, most recommendations suggested broad antimicrobial coverage continued for 2 to 3 days. Most publications reported intravenous administration of antibiotics immediately. CONCLUSIONS: Current practice and recommendations strongly support early systemic antibiotic prophylaxis for patients with open fractures of the extremities. Differences in antibiotic regimens, doses, and durations of administration remain in both practice and recommendations. Consensus with regard to optimal practice will likely require well-designed randomized controlled trials. CLINICAL RELEVANCE: The current survey of literature systematically provides surgeons' practice and the available expert recommendations from 2007 to 2017 on the use of prophylactic antibiotics in the management of open fractures of extremities.

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Evidence suggests that there are both nociceptive and neuropathic components of cancer-induced pain. We have observed that changes in intrinsic membrane properties and excitability of normally non-nociceptive Aß sensory neurons are consistent in rat models of peripheral neuropathic pain and cancer-induced pain. This has prompted a comparative investigation of the intracellular electrophysiological characteristics of sensory neurons and of the ultrastructural morphology of the dorsal horn in rat models of neuropathic pain and cancer-induced pain. Neuropathic pain model rats were induced with a polyethylene cuff implanted around a sciatic nerve. Cancer-induced pain model rats were induced with mammary rat metastasis tumour-1 rat breast cancer or MATLyLu rat prostate cancer cells implanted into the distal epiphysis of a femur. Behavioural evidence of nociception was detected using von Frey tactile assessment. Aß-fibre low threshold mechanoreceptor neurons in both cancer-induced pain and neuropathic pain models exhibited slower dynamics of action potential genesis, including a wider action potential duration and lower action potential amplitude compared to those in control animals. Enhanced excitability of Aß-fibre low threshold mechanoreceptor neurons was also observed in cancer-induced pain and neuropathic pain models. Furthermore, both cancer-induced pain and neuropathic pain models showed abundant abnormal axonal sprouting in bundles of myelinated axons in the ipsilateral spinal laminae IV and V. The patterns of changes show consistency between rat models of cancer-induced pain and neuropathic pain. These findings add to the body of evidence that animal models of cancer-induced pain and neuropathic pain share features that may contribute to the peripheral and central sensitization and tactile hypersensitivity in both pain states.

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BACKGROUND: Chronic noncancer pain (CNCP) refers to all pain disorders, not due to cancer, that persist for ≥3 months. The point prevalence of CNCP in the general population of Western countries is between 19 and 33 percent. Opioids are commonly prescribed for CNCP and are associated with both benefits and harms. The Canadian Guideline for Safe and Effective Use of Opioids for CNCP was published in 2010 to provide guidance for optimal opioid prescribing in patients with CNCP. OBJECTIVES: To investigate the attitudes toward, and use of, the Canadian Opioids Guideline among pain physicians. DESIGN: A qualitative study using one-on-one, semistructured interviews with 12 pain physicians in Ontario, Canada, and thematic analysis of verbatim transcripts. RESULTS: Major themes that emerged from interviews included: (1) generally positive attitudes toward the 2010 Canadian Opioids Guideline, but limited use-half (six of 12) reported they did not use the guideline in practice; (2) strongly contrasting views regarding the 200 mg/d morphine equivalent watchful dose; (3) recognition of gaps in the guideline, especially recommendations for urine drug screening and pain severity-specific therapy; (4) the guideline is excessively long and the format suboptimal; and (5) improved dissemination and education are needed to enhance guideline uptake. CONCLUSIONS: Despite its merits, the Canadian Opioids Guideline suffers from information gaps and from limited uptake, at least in part due to suboptimal format and suboptimal dissemination.

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