Pharmacology/Drug Development

Preclinical pain research has applied state-of-the-art methods over the past 40 years to describe, characterize, and image molecules, cells, and circuits in rodents to understand the pathophysiology of chronic pain. Despite generating a plethora of novel analgesic targets, pharmaceuticals for chronic pain treatment remain largely limited to the same 6 drug classes as present 40 years ago. It is possible that 40 years of effort has brought us to the verge of a paradigm shift and an explosion of novel analgesic drug classes with remarkable safety, efficacy, and tolerability. We think it more likely that advances will not occur until we follow the description of exciting discoveries with hypothesis testing using clinically relevant preclinical animal models and ethologically relevant outcome measures, which better reflect the clinical characteristics of chronic pain syndromes. Furthermore, to be valuable, experiments using such models must be conducted to the highest levels of internal validity, rigor, and reproducibility. Efforts by funders, most recently the Helping End Addiction Long-Term by the National Institutes of Health, aim to address some of these challenges and enhance communication and collaboration between preclinical and clinical investigators. However, the greater problem is a culture that emphasizes novelty and number of publications over scientific rigor and robust replication leading to a high likelihood of false-positive results. A path forward is provided by the evolution of clinical research beginning 50 years ago that resulted in methods to reduce bias and enhance transparency and ethics of reporting, moving from case reports to randomized controlled trials to innovative study designs with a focus on rigor, generalizability, and reproducibility. We argue that culture changed in clinical science in part because powerful forces outside the peer review system, especially from federal regulators that approve new drugs and human studies committees that addressed ethical failures of earlier research, mandated change in studies within their purview. Whether an external force will affect change in peclinical pain research is unclear.

Mitragynine (MG) is an alkaloid found in (kratom) that is used as an herbal remedy for pain relief and opioid withdrawal. MG acts at μ-opioid and α-adrenergic receptors in vitro but the physiological relevance of this activity in the context of neuropathic pain remains unknown. The purpose of the present study was to characterize the effects of MG in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN), and to investigate the potential impact of sex on MG's therapeutic efficacy. Inhibition of oxaliplatin-induced mechanical hypersensitivity was measured following intraperitoneal administration of MG. Both male and female C57BL/6J mice were used to characterize potential sex-differences in MG's therapeutic efficacy. Pharmacological mechanisms of MG were characterized through pretreatment with the opioid and adrenergic antagonists naltrexone, prazosin, yohimbine, and propranolol (1, 2.5, 5 mg/kg). Oxaliplatin produced significant mechanical allodynia of equal magnitude in both male and females, which was dose-dependently attenuated by repeated MG exposure. MG was more potent in males vs females, and the highest dose of MG (10 mg/kg) exhibited greater anti-allodynic efficacy in males. Mechanistically, activity at µ-opioid, α- and α-adrenergic receptors, but not β-adrenergic receptors contributed to the effects of MG against oxaliplatin-induced mechanical hypersensitivity. Repeated MG exposure significantly attenuated oxaliplatin-induced mechanical hypersensitivity with greater potency and efficacy in males, which has crucial implications in the context of individualized pain management. The opioid and adrenergic components of MG indicate that it shares pharmacological properties with clinical neuropathic pain treatments.

Transdermal fentanyl patches are an effective alternative to the sustained release of oral morphine for chronic pain management. Due to the narrow therapeutic range of fentanyl, the concentration of fentanyl in the blood needs to be carefully monitored. Only then can effective pain relief be achieved while avoiding adverse effects such as respiratory depression. This study developed a physics-based digital twin of a patient by implementing drug uptake, pharmacokinetics, and pharmacodynamics models. The twin was employed to predict the effect of conventional fentanyl transdermal in a 20-80-year-old virtual patient. The results show that, with increasing age, the maximum transdermal fentanyl flux and maximum concentration of fentanyl in the blood decreased by 11.4% and 7.0%, respectively. However, the results also show that as the patient's age increases, the pain relief increases by 45.2%. Furthermore, the digital twin was used to propose a tailored therapy based on the patient's age. This predesigned therapy customized the duration of applying the commercialized fentanyl patches. According to this therapy, a 20-year-old patient needs to change the patch 2.1 times more frequently than conventional therapy, which leads to 30% more pain relief and 315% more time without pain. In addition, the digital twin was updated by the patient's pain intensity feedback. Such therapy increased the patient's breathing rate while providing effective pain relief, so a safer treatment. We quantified the added value of a patient's physics-based digital twin and sketched the future roadmap for implementing such twin-assisted treatment into the clinics.

Chronic-pain is a debilitating illness that has become exceedingly widespread with currently limited treatments. Differences in the molecular signature of nociceptors, have been demonstrated between human and the commonly-used mouse model, suggesting functional differences in detection and transmission of noxious-stimuli. Therefore, direct understanding of pain-physiology in humans is required for pain treatment. This could be facilitated by studying humans carrying deleterious genetic mutations affecting pain sensation. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with several body-functions, in particular, noxious-heat detection and inflammatory-pain. Reports of adverse effects in human trials have hinder the clinical development of TRPV1 antagonists as novel pain relievers. Hence, studies on the functional roles of TRPV1, which currently rely mainly on evidences obtained from rodents, should be extended to humans. Here, we examined humans carrying a unique missense mutation in TRPV1, rendering the channel non-functional. The affected individual demonstrated lack of aversion towards capsaicin and elevated heat-pain threshold. Surprisingly, he showed elevated cold-pain threshold and extensive neurogenic inflammatory flare and pain-responses following application of the TRPA1 channel-activator, mustard-oil. Our study provides the first direct evidence for pain-related functional-changes linked to TRPV1 in humans, which is a prime target in the development of novel pain-relievers.

The treatment of chronic neuropathic pain remains one of the most challenging of all neurological diseases and very much an art. There exists no consensus for the optimal management of this condition at the moment. Gaining inspiration from recent studies which pointed out the involvement of brain-associated carbonic anhydrase (CA, EC 4.2.1.1) isoform VII in the pathology of various neurodegenerative diseases, which highlighted the relationship between selective inhibition of this isozyme and relieve of neuropathic pain, herein we report the synthesis and CA VII inhibitory activity of novel 4-(3-alkyl/benzyl-guanidino)benzenesulfonamides. Ten benzyl-substituted and five alkyl-substituted 4-guanidinobenzenesulfonamide derivatives were obtained, some of which (, , and ) exhibited satisfactory selectivity towards CA VII over CA I and II, with K-s in the subnanomolar range and good selectivity indexes for inhibiting the target versus the off-target isoforms.

Pharmaceutical opioid consumption has been increasing worldwide, but disparities in access to these medications exist. Few countries of the WHO Eastern Mediterranean Region have well defined pain management policies.

This study aimed to explore the incidence of adverse events (AEs) reported by patients when initiating medicinal cannabis treatment for chronic pain, and the association of cannabis constituents, dose and concomitant medicines with AE incidence.

We aimed to examine the risk of cardiovascular adverse events by tricyclic antidepressant (TCA) dosage among patients with chronic pain.