Pharmacology/Drug Development

Fibromyalgia is a complex disease process that is as prevalent as it is poorly understood. Research into the pathophysiology is ongoing, and findings will likely assist in identifying new therapeutic options to augment those in existence today that are still insufficient for the care of a large population of patients. Recent evidence describes the use of cannabinoids in the treatment of fibromyalgia. This study provides a systematic, thorough review of the evidence alongside a review of the seminal data regarding the pathophysiology, diagnosis, and current treatment options. Fibromyalgia is characterized by widespread chronic pain, fatigue, and depressive episodes without an organic diagnosis, which may be prevalent in up to 10% of the population and carries a significant cost in healthcare utilization, morbidity, a reduced quality of life, and productivity. It is frequently associated with psychiatric comorbidities. The diagnosis is clinical and usually prolonged, and diagnostic criteria continue to evolve. Some therapies have been previously described, including neuropathic medications, milnacipran, and antidepressants. Despite some level of efficacy, only physical exercise has strong evidence to support it. Cannabis has been used historically to treat different pain conditions since ancient times. Recent advances allowed for the isolation of the active substances in cannabis and the production of cannabinoid products that are nearly devoid of psychoactive influence and provide pain relief and alleviation of other symptoms. Many of these, as well as cannabis itself, are approved for use in chronic pain conditions. Evidence supporting cannabis in chronic pain conditions is plentiful; however, in fibromyalgia, they are mostly limited. Only a handful of randomized trials exists, and their objectivity has been questioned. However, many retrospective trials and patient surveys suggest the significant alleviation of pain, improvement in sleep, and abatement of associated symptoms. Evidence supporting the use of cannabis in chronic pain and specifically in fibromyalgia is being gathered as the use of cannabis increases with current global trends. While the current evidence is still limited, emerging data do suggest a positive effect of cannabis in fibromyalgia. Cannabis use is not without risks, including psychiatric, cognitive, and developmental as well as the risks of addiction. As such, clinical judgment is warranted to weigh these risks and prescribe to patients who are more likely to benefit from this treatment. Further research is required to define appropriate patient selection and treatment regimens.

Chronic pain is a distressing yet poorly-treated condition that can arise as a result of diseases and injuries to the nervous system. The development of more efficacious therapies for chronic pain is essential and requires advances in our understanding of its underlying mechanisms. Clinical and preclinical evidence has demonstrated that immune responses play a crucial role in chronic pain. The lysosomal cysteine protease cathepsin S (CatS) plays a key role in such immune response. Here we discuss the preclinical evidence for the mechanistic importance of extracellular CatS in chronic pain focussing on studies utilising drugs and other pharmacological tools that target CatS activity. We also consider the use of CatS inhibitors as potential novel antihyperalgesics, highlighting that the route and timing of delivery would need to be tailored to the initial cause of pain in order to ensure the most effective use of such drugs.

Opioid abuse has rapidly developed into an epidemic across the United States. Patients are often introduced to opioids following surgical procedures-this is particularly relevant following spinal surgery. Surgeons can help reduce this opioid burden by finding alternatives to narcotic analgesia in the postoperative period. One such medication that has shown potential in this role is ketamine, which has been studied in various surgical specialties. A review was performed of current literature regarding ketamine use in the perioperative period specific to spinal surgery. This review focused on prospective randomized control trials; the primary endpoint was opioid consumption in the postoperative period, monitored through patient-controlled analgesia (PCA) use. Both pediatric and adult spinal surgery patients were included; cervical, thoracic, and lumbar procedures were also all included. 10 studies were selected for this reviewed based on inclusion criteria, published between 2004 and 2017. 7 of these studies demonstrated a significant decrease in postoperative opioid use with the integration of ketamine in the perioperative period, while 3 trials showed no significant difference in opioid consumption. There is inherent difficulty in standardizing studies of this nature-dosing protocols, medication timing, and supplemental analgesia were variable throughout the included studies. However, this review of the most up-to-date prospective studies indicate ketamine has potential to play a significant role in reducing opioid requirements following spinal surgery, and further study is warranted in this field.

The role of lipids in pain signaling is well established and built on decades of knowledge about the pain and inflammation produced by prostaglandin and leukotriene metabolites of cyclooxygenase and lipoxygenase metabolism, respectively. The analgesic properties of other lipid metabolites are more recently coming to light. Lipid metabolites have been observed to act directly at ion channels and G protein-coupled receptors on nociceptive neurons as well as act indirectly at cellular membranes. Cytochrome P450 metabolism of specifically long-chain fatty acids forms epoxide metabolites, the epoxy-fatty acids (EpFA). The biological role of these metabolites has been found to mediate analgesia in several types of pain pathology. EpFA act through a variety of direct and indirect mechanisms to limit pain and inflammation including nuclear receptor agonism, limiting endoplasmic reticulum stress and blocking mitochondrial dysfunction. Small molecule inhibitors of the soluble epoxide hydrolase can stabilize the EpFA in vivo, and this approach has demonstrated relief in preclinical modeled pain pathology. Moreover, the ability to block neuroinflammation extends the potential benefit of targeting soluble epoxide hydrolase to maintain EpFA for neuroprotection in neurodegenerative disease.