Thoughtfully Integrating Cannabis Products Into Chronic Pain Treatment.

Cannabis products (CPs) and cannabis-based medicines (CBMs) are becoming increasingly available and are commonly used for pain management. The growing societal acceptance of cannabis and liberalization of cannabis laws allows patients to access CPs with minimal clinical oversight. While there is mechanistic plausibility that CPs and CBMs may be useful for pain management, the clinical trial literature is limited and does not refute or support the use of CBMs for pain management. Complicating matters, a large and growing body of observational literature shows that many people use CPs for pain management and in place of other medications. However, products and dosing regimens in existing trials are not generalizable to the current cannabis market, making it difficult to compare and reconcile these 2 bodies of literature. Given this complexity, clinicians need clear, pragmatic guidance on how to appropriately educate and work with patients who are using CBMs for pain management. In this review, we narratively synthesize the evidence to enable a clear view of current landscape and provide pragmatic advice for clinicians to use when working with patients. This advice revolves around 3 principles: (1) maintaining the therapeutic alliance; (2) harm reduction and benefit maximization; and (3) pragmatism, principles of patient-centered care, and use of best clinical judgment in the face of uncertainty. Despite the lack of certainty CPs and chronic pain management use, we believe that following these principles can make most of the clinical opportunity presented by discussions around CPs and also enhance the likelihood of clinical benefit from CPs.

Rescue of dendritic cells from glycolysis inhibition improves cancer immunotherapy in mice.

Inhibition of glycolysis in immune cells and cancer cells diminishes their activity, and thus combining immunotherapies with glycolytic inhibitors is challenging. Herein, a strategy is presented where glycolysis is inhibited in cancer cells using PFK15 (inhibitor of PFKFB3, rate-limiting step in glycolysis), while simultaneously glycolysis and function is rescued in DCs by delivery of fructose-1,6-biphosphate (F16BP, one-step downstream of PFKFB3). To demonstrate the feasibility of this strategy, vaccine formulations are generated using calcium-phosphate chemistry, that incorporate F16BP, poly(IC) as adjuvant, and phosphorylated-TRP2 peptide antigen and tested in challenging and established YUMM1.1 tumours in immunocompetent female mice. Furthermore, to test the versatility of this strategy, adoptive DC therapy is developed with formulations that incorporate F16BP, poly(IC) as adjuvant and mRNA derived from B16F10 cells as antigens in established B16F10 tumours in immunocompetent female mice. F16BP vaccine formulations rescue DCs in vitro and in vivo, significantly improve the survival of mice, and generate cytotoxic T cell (Tc) responses by elevating Tc1 and Tc17 cells within the tumour. Overall, these results demonstrate that rescuing glycolysis of DCs using metabolite-based formulations can be utilized to generate immunotherapy even in the presence of glycolytic inhibitor.

Integrating complementary medicine in the perioperative period: a simple, opioid-sparing addition to your multimodal analgesia strategy?

The current US opioid health-related crisis underscores the importance for perioperative physicians to optimize various approaches to pain management. Multimodal techniques and enhanced recovery after surgery (ERAS) protocols are frequently cited as the most effective strategies for improving the experience of pain and reducing opioid exposure. Complementary medicine (CM) techniques, while frequently shown to be effective at reducing opioid and other pharmacologic agent use, are rarely discussed as part of these multimodal strategies. In general, CM therapies are low-cost with minimal associated risk, making them an ideal choice for incorporation into ERAS and other opioid-sparing protocols. In this Daring Discourse, we discuss the benefits and challenges of incorporating CM therapy into anesthetic practice. We hope that anesthesiologists can become more familiar with the current evidence regarding perioperative CM therapy, and begin incorporating these therapies as part of their comprehensive multimodal approach to perioperative pain management.

Models for erectile dysfunction and their importance to novel drug discovery.

INTRODUCTION: Erectile dysfunction (ED) affects quality of life and is a barometer for vascular health. The pathophysiology is complex and multifactorial. Animal models have been critical in elucidating an improved comprehension of erectile function. They provide experimental platforms where desired physiologic, and non-physiologic perturbations can be performed. Results have led to the development of novel therapeutic targets. AREAS COVERED: The current article provides an overview of history of animal models in ED research as well as a review of the current roles in the study of ED. The authors highlight the advantages and disadvantages of each model while illustrating the similarities to the human condition and summarizing the major preclinical studies investigating novel therapeutic targets in the treatment of ED. EXPERT OPINION: Animal models have been instrumental in the discovery of the current therapeutic agents. Advances in molecular biology and proteomics have uncovered many novel potential targets including tissue regeneration and stem cell applications. Rodent models are the current animal model of choice for ED research due to lower cost, well-established modeling protocol, and the ability to manipulate genetically. Future clinical trials should directly assess the translatability of these animal models to humans as well as the safety risks and long-term efficacy that the results generate.

Analgesic efficacy of continuous intravenous magnesium infusion as an adjuvant to morphine for postoperative analgesia: a systematic review and meta-analysis.

BACKGROUND: The efficacy of perioperative intravenous magnesium administration on postoperative opioid use, opioid-related side effects (e.g., nausea and vomiting) and pain are uncertain, as randomized controlled trials on this topic have reported disparate results. The objective of this systematic review is to determine if perioperative magnesium reduces opioid use, opioid-related side effects, and postoperative pain. METHODS: An electronic search was conducted using the Library of Medicine's PubMed and EMBASE databases. Included studies consisted of randomized controlled trials in an adult population with a clearly defined comparison of perioperative intravenous magnesium administration to a control with a documented assessment of opioid usage and postoperative pain. Relevant data was abstracted from included studies. Pooled estimates for weighted mean difference (WMD) with 95% confidence intervals (CI) were obtained for our primary outcome (opioid usage) using the Cochrane Collaboration's RevMan version 4.2.7 (Cochrane Collaboration; Oxford, United Kingdom). WMD and odds ratios (OR) were calculated using a random effects model. RESULTS: The literature search ultimately yielded 22 trials, enrolling 1177 (599 magnesium, 578 control) patients, who were included in the analysis. A significant decrease in morphine usage by those patients who received magnesium was noted (WMD = -7.40; 95% CI: -9.40 to -5.41, p < 0.00001). Perioperative magnesium administration was not associated with a difference in postoperative nausea or vomiting (RR = 0.76; 95% CI: 0.52 to 1.09, p = 0.14). The pooled visual analog scores for pain at 4-6 hours after surgery were significantly less in those patients who received magnesium surgery (WMD = -0.67; 95% CI: -1.12 to -0.23, p = 0.003); however, there was no difference in pain scores at 20-24 hours after surgery (WMD = -0.25; 95% CI: -0.62 to 0.71, p = 0.17). CONCLUSION: Based on the results of this systematic review, perioperative intravenous magnesium may be a useful adjuvant for the management of postoperative pain providing analgesia through a different mechanism of action than that of opioids and would make a potential addition to a multimodal anlgesic treatment plan; however, the decrease in opioid use with perioperative magnesium infusion does not appear to be associated with a decresea in opioid-related side effects.

Analgesic efficacy of ultrasound-guided regional anesthesia: a meta-analysis.

STUDY OBJECTIVE: To determine if the use of ultrasound guidance (vs non-ultrasound techniques) improves the success rate of nerve blocks. DESIGN: Meta-analysis of randomized controlled trials (RCTs) in the published literature. SETTING: University medical center. MEASUREMENTS: 16 RCTs of patients undergoing elective surgical procedures were studied. Patients underwent ultrasound-guided or non-ultrasound techniques (nerve stimulation, surface landmark) for peripheral nerve blocks. Success rates were measured. MAIN RESULTS: Ultrasound guidance (vs all non-ultrasound techniques) was associated with a significant increase in the success rate of nerve blocks [relative risk (RR) = 1.11 (95% confidence interval [CI]: 1.06 to 1.17, P < 0.0001]). When compared with nerve stimulator techniques only, ultrasound guidance was still associated with an increase in the success rate (RR = 1.11 [95% CI: 1.05 to 1.17, P = 0.0001]). For specific blocks, ultrasound guidance (vs all non-ultrasound) was associated with a significant increase in successful brachial plexus (all) nerve blocks (RR = 1.11 [95% CI: 1.05 to 1.20, P = 0.0001]), sciatic popliteal nerve block (RR = 1.22 [95% CI: 1.08 to 1.39, P = 0.002]) and brachial plexus axillary nerve block (RR = 1.13 [95% CI: 1.00 to 1.26, P = 0.05]) but not brachial plexus infraclavicular nerve block (RR = 1.25 [95% CI: 0.88 to 1.76, P = 0.22]). CONCLUSIONS: Ultrasound-guided peripheral nerve block is associated with an increased overall success rate when compared with nerve stimulation or other methods. Ultrasound-guided techniques also increase the success rate of some specific blocks.

New developments in osteoarthritis.

Osteoarthritis (OA) has been a frustrating disease for both the patient and the physician. Its current impact on society is tremendous and rivals that of ischemic heart disease in many regards. As the baby boomers reach late adulthood and the obesity epidemic rages on, OA will assume an even greater impact on society. The current OA armamentarium only reduces pain and perhaps improves function, but has no impact on the disease incidence or progression. Thus, the challenge for researchers to develop disease-modifying OA drugs becomes an issue of paramount importance. Several advances in the understanding of OA pathophysiology have provided a glimpse of optimism that disease modification is a real possibility.

Efficacy of periprostatic local anesthetic for prostate biopsy analgesia: a meta-analysis.

OBJECTIVES: To perform a meta-analysis of available randomized trials investigating the analgesic efficacy of periprostatic block with local anesthetic. METHODS: The National Library of Medicine's PubMed database was searched for the time period 1966 to August 16, 2005 for all relevant articles. Inclusion criteria included subjects undergoing prostate biopsy, trials that were randomized with one arm of the randomization using local anesthetic for periprostatic block before prostate biopsy, and where the assessment of biopsy pain was measured and available in a form compatible for statistical analysis in our meta-analysis. RESULTS: Our search resulted in 107 abstracts, of which a total of 16 articles met all inclusion criteria. There were 660 subjects who received local anesthetics for a periprostatic block and 616 subjects who did not. The weighted mean difference between the groups indicates that subjects receiving local anesthetic periprostatic block would have a statistically lower pain score compared with those who did not (weighted mean difference in visual analogue pain of -1.66 [95% confidence interval -2.03 to -1.29]). CONCLUSIONS: Our meta-analysis suggests that periprostatic block with local anesthetic for prostate biopsy might result in significantly lower levels of pain during the biopsy procedure. Because periprostatic block with local anesthetic is relatively easy to administer and does not seem to be associated with increased morbidity, clinicians performing prostate biopsies should consider using this technique on a routine basis.

New developments in osteoarthritis.

Osteoarthritis (OA) has been a frustrating disease for both the patient and the physician. Its current impact on society is tremendous, and rivals that of ischemic heart disease in many regards. As the baby boomers reach late adulthood and the obesity epidemic rages on, OA will assume an even greater impact on society. The current OA armamentarium only reduces pain and perhaps improves function, and has no impact on the disease incidence or progression. Thus, the challenge for researchers to develop disease-modifying OA drugs becomes an issue of paramount importance. Several advances in our understanding of OA pathophysiology have provided a glimpse of optimism that disease modification is a real possibility. Appreciation of the local factors involved in OA progression as well as the inflammatory nature in a subset of patients has led to different treatment strategies based on predominant phenotype. Further understanding of the initiating events in cartilage destruction, the relationship between the different pathologic influences, and the role of the chondrocyte in maintaining extracellular matrix homeostasis will be necessary to reveal potential targets of therapy.