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This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.

Endometriosis is a common clinical condition and its treatment will often lead to an estrogen deficiency status. As most of these patients are young, they will need to consider hormone replacement therapy. Endometriosis is a hormone-dependent disease and estrogen replacement can be associated with a risk of recurrence or malignant transformation. Only a few studies have addressed this problem. With the use of hormone replacement therapy (HRT), there is an increased, although undefined, risk of recurrence of endometriosis, especially in known severe cases and in obese patients. Unopposed estrogen appears to carry a higher risk than combined preparations. Delay in starting HRT after pelvic clearance is not of any benefit. After radical surgery for severe endometriosis, women often have much to gain from HRT, particularly in the early years. Benefits of HRT in terms of control of menopausal symptoms, prevention of urogenital atrophy and loss of libido and bone protection are of particular importance. HRT may still have a role in prevention of cardiovascular disease in early menopause, but this remains unproven. Although there is no firm evidence, continuous combined preparations or tibolone would appear to be the optimum choice.

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Preclinical research is a vital step in the drug discovery pipeline and more generally in helping to better understand human disease aetiology and its management. Systematic reviews (SRs) can be powerful in summarising and appraising this evidence concerning a specific research question, to highlight areas of improvements, areas for further research and areas where evidence may be sufficient to take forward to other research domains, for instance clinical trial. Guidance and tools for preclinical research synthesis remain limited despite their clear utility. We aimed to create an online end-to-end platform primarily for conducting SRs of preclinical studies, that was flexible enough to support a wide variety of experimental designs, was adaptable to different research questions, would allow users to adopt emerging automated tools and support them during their review process using best practice. In this article, we introduce the Systematic Review Facility (https://syrf.org.uk), which was launched in 2016 and designed to support primarily preclinical SRs from small independent projects to large, crowdsourced projects. We discuss the architecture of the app and its features, including the opportunity to collaborate easily, to efficiently manage projects, to screen and annotate studies for important features (metadata), to extract outcome data into a secure database, and tailor these steps to each project. We introduce how we are working to leverage the use of automation tools and allow the integration of these services to accelerate and automate steps in the systematic review workflow.

The President of the International Association for the Study of Pain established a task force on cannabis and cannabinoid analgesia to systematically examine the evidence on (1) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain; (2) the clinical efficacy of cannabis, cannabinoids, and cannabis-based medicines for pain; (3) harms related to long-term use of cannabinoids; as well as (4) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the task force outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high-quality clinical trials with cannabinoids are needed. Remaining important questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal, and policy challenges associated with medicinal and nonmedicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management.

Introduction: The International Association for the Study of Pain has established a global task force to comprehensively investigate the use of cannabinoids and cannabis-based medicines for pain management. This systematic review, the first in this field, will assess the preclinical literature that investigates the antinociceptive effects of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators in animal models of tissue damage, inflammation, or neuropathy. Methods: A systematic electronic search of 3 online databases will identify relevant studies in which cannabinoids, cannabis-based medicines, and endocannabinoid system modulators have been tested in animal models of injury-related or pathological persistent pain. Data will be extracted for pain-associated behavioural outcomes, study design, and the reporting of measures to avoid bias. Standardised mean difference meta-analysis will be used to provide summary estimates of efficacy, with the effects of study quality and study design explored using stratified meta-analysis. Perspective: The evaluation of the preclinical evidence will quantify the antinociceptive effects of cannabinoids on pain behaviour in animal models of pathological pain in an effort to quantify the presence and prevalence of analgesic efficacy. It will also provide an understanding of the strengths and weaknesses of the preclinical field and inform an agenda for future research.

Two women with adenocarcinoma of the endometrium and a past history of disseminated pelvic endometriosis presented with vaginal bleeding. One also had obstructive uropathy. The two patients had undergone total abdominal hysterectomy with removal of one or both ovaries three and 13 years previously and subsequently were treated with unopposed oestrogen replacement therapy. Adenocarcinoma of the endometrium following endometriosis is a rare condition and few cases are reported in the literature. A summary of the cases and related literature are presented.