Pharmacology/Drug Development

Osteoarthritis (OA) is a painful and disabling musculoskeletal disorder, with a large impact on the global population, resulting in several limitations on daily activities. In OA, inflammation is frequent and mainly controlled through inflammatory cytokines released by immune cells. These outbalanced inflammatory cytokines cause cartilage extracellular matrix (ECM) degradation and possible growth of neuronal fibers into subchondral bone triggering pain. Even though pain is the major symptom of musculoskeletal diseases, there are still no effective treatments to counteract it and the mechanisms behind these pathologies are not fully understood. Thus, there is an urgent need to establish reliable models for assessing the molecular mechanisms and consequently new therapeutic targets. Models have been established to support this research field by providing reliable tools to replicate the joint tissue . Studies firstly started with simple 2D culture setups, followed by 3D culture focusing mainly on cell-cell interactions to mimic healthy and inflamed cartilage. Cellular approaches were improved by scaffold-based strategies to enhance cell-matrix interactions as well as contribute to developing mechanically more stable models. The progression of the cartilage tissue engineering would then profit from the integration of 3D bioprinting technologies as these provide 3D constructs with versatile structural arrangements of the 3D constructs. The upgrade of the available tools with dynamic conditions was then achieved using bioreactors and fluid systems. Finally, the organ-on-a-chip encloses all the state of the art on cartilage tissue engineering by incorporation of different microenvironments, cells and stimuli and pave the way to potentially simulate crucial biological, chemical, and mechanical features of arthritic joint. In this review, we describe the several available tools ranging from simple cartilage pellets to complex organ-on-a-chip platforms, including 3D tissue-engineered constructs and bioprinting tools. Moreover, we provide a fruitful discussion on the possible upgrades to enhance the systems making them more robust regarding the physiological and pathological modeling of the joint tissue/OA.

Ketamine is an intravenous anesthetic with analgesic effects that has a rapid onset and short duration of action. Many studies have been conducted on the use of ketamine; however, the quantity and quality of such studies have not been reported. Therefore, we aimed to conduct a bibliometric analysis of research on ketamine from 2001 to 2020.

Medication assisted treatment (MAT) is an evidence-based solution to combatting opioid use disorder (OUD); however, MAT is largely unavailable in rural areas. This study investigated clinician and staff perceptions related to OUD and MAT, in particular, buprenorphine treatment, in rural primary care practices. In this qualitative study, we interviewed staff members from 42 practices and analyzed the data using a grounded hermeneutic editing approach. Four key themes emerged: 1) policies and procedures to reduce opioid prescribing were already in place, 2) there was an emotional toll to treating "those types" of patients, 3) there is a lack of local resources for help with chronic pain and buprenorphine treatment, and 4) there is a strong desire to help local patients and community members but hesitancy to engage in buprenorphine treatment. Although there was almost no provision of MAT, many practices were interested in learning more to help their communities.

Chronic pain increases risk for opioid overdose among individuals with opioid use disorder. The purpose of this study is to evaluate the relationship between recent overdose and whether or not chronic pain is active. 3,577 individuals in treatment for opioid use disorder in 2017 or 2018 were surveyed regarding recent overdoses and chronic pain. Demographics from the 2017 Treatment Episode Data Set, which includes all U.S. facilities licensed or certified to provide substance use care, were used to evaluate the generalizability of the sample. χ2 tests and logistic regression models were used to compare associations between recent overdoses and chronic pain. Specifically, active chronic pain was associated with opioid overdose among people in treatment for opioid use disorder. Individuals with active chronic pain were more likely to have had a past month opioid overdose than those with no history chronic pain (adjusted OR = 1.55, 95% CI 1.16-2.08, p = 0.0003). In contrast, individuals with prior chronic pain, but no symptoms in the past 30 days, had a risk of past month opioid overdose similar to those with no history of chronic pain (adjusted OR = 0.88, 95% CI 0.66-1.17, p = 0.38). This suggests that the incorporation of treatment for chronic pain into treatment for opioid use disorder may reduce opioid overdoses.

Neuropathic pain is a widespread problem with a big impact on quality of life. The currently used drug regimens are often insufficiently effective or cause – sometimes unacceptable – side effects. Intravenous lidocaine could be an alternative treatment, by blocking spontaneous depolarization and hyperexcitability in upregulated sodium channels in nociceptors. Research so far has shown varying results but the treatment protocols differed a lot and follow-up was usually short. In our hospital, lidocaine infusions have been applied for many years in a unique treatment protocol consisting of a relatively high dose of lidocaine (1000 mg) administered over 25 hours. Our aim is to share information on both the efficacy and safety of this treatment schedule.

This study aimed to test for the possible antinociceptive effect of the naturally occurring terpene citral in rodent models of acute and chronic orofacial pain and to test for the possible involvement of transient receptor potential (TRP) channels in this effect. Acute nociceptive behavior was induced in one series of experiments by administering formalin, cinnamaldehyde, menthol or capsaicin to the upper lip. Nociceptive behavior was assessed by orofacial rubbing, and the effects of pre-treatment with citral (0.1, 0.3 or 1.0 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint or mustard oil injected into the masseter muscle, preceded by citral or vehicle (control) treatment. The chronic pain model involved infraorbital nerve transection (IONX) that induced mechanical hypersensitivity which was assessed by von Frey hair stimulation of the upper lip. Motor activity was also evaluated. Docking experiments were performed using TRPV1 and TRPM8 channels. Citral but not vehicle produced significant (p<0.01, ANOVA) antinociception on all the acute nociceptive behaviors, and these effects were attenuated by TRPV1 antagonist capsazepine, TRPM3 antagonist mefenamic acid and by TRPM8 desensitization, but not by ruthenium red and TRPA1 antagonist HC-030031. The IONX animals developed facial mechanical hypersensitivity that was significantly reduced by citral but not by vehicle. The docking experiments revealed that citral may interact with TRPV1 and TRPM8 channels. These results indicate the potential use of citral as an inhibitor of orofacial nociception in both acute and chronic pain states through TRPV1, TRPM3 and TRPM8 channels. See also Figure 1(Fig. 1).