Pharmacology/Drug Development

The impact of opioid analgesic use before cancer diagnosis on survival in patients with chronic pain is unclear. Therefore, we designed a propensity score-matched population-based cohort study to compare overall and cancer-related survival of patients with chronic pain who received long-term opioid analgesic treatment with that of those who did not receive such treatment.

Burn injury-induced pain (BIP) is an extremely complicated condition usually resistant to analgesic drugs, while its pathogenesis remains unknown. Considerable attention has been attracted to elucidate the glial mechanisms in chronic pain. In this study, we initiatively used a mouse model of second-degree BIP to investigate the underlying non-neuronal mechanisms at the spinal cord level. Our behavioral results showed that hind-paw burn injury caused persistent allodynia and hyperalgesia for 2 weeks in mice. Further studies revealed that both microglia and astrocytes activated in a spatially- and temporally-dependent manner in spinal cord after burn injury. In addition, the phosphorylated p38 mitogen-activated protein kinase (MAPK)-mediated tumor necrosis factor (TNF) release in spinal microglia is essentially attributed to the early stage of BIP, while the c-Jun N-terminal kinase (JNK) MAPK-dependent chemokine CXCL1 expression is mainly involved in the maintenance of pain hypersensitivity. Most strikingly, burn injury-induced pain symptoms and the activation of astrocytes were significantly suppressed by TNF inhibitor Thalidomide. On the contrary, intrathecal injection of TNF caused apparent pain hypersensitivity, accompanied by the activation of astrocytes and the upregulation of CXCL1 via the JNK MAPK signaling pathway, indicating that TNF is the key cytokine in the interaction between microglia and astrocytes at the spinal level. Moreover, treatment with the CXCR2 receptor antagonist SB225002 to block the biological activities of CXCL1 significantly attenuated the mechanical allodynia and thermal hyperalgesia in this BIP model. Taken together, this study indicates that intervention of glial pathways provides a new perspective in the management of BIP.

Opioids, and numerous centrally active drugs, are metabolized by cytochrome P450 2D (CYP2D). There are sex and estrous cycle differences in brain oxycodone analgesia. Here we investigated the mechanism examining the selective role of CYP2D in the brain on sex, estrous cycle, and hormonal regulation. Propranolol, CYP2D-specific mechanism-based inhibitor, or vehicle was delivered into cerebral ventricles 24 hours before administering oxycodone (or oxymorphone, negative control) orally to male and female (in estrus and diestrus) rats. Ovariectomized and sham-operated females received no treatment, estradiol, progesterone or vehicle. Analgesia was measured using tail-flick latency, and brain drug and metabolite concentrations were measured by microdialysis. Data were analyzed by two-way or mixed ANOVA. Following propranolol (versus vehicle) inhibition and oral oxycodone, there were greater increases in brain oxycodone concentrations and analgesia, and greater decreases in brain oxymorphone/oxycodone ratios (an in vivo phenotype of CYP2D in brain) in males and females in estrus, compared to females in diestrus; with no impact on plasma drug concentrations. There was no impact of propranolol pre-treatment, sex, or cycle after oral oxymorphone (non-CYP2D substrate) on brain oxymorphone concentrations or analgesia. There was no impact of propranolol pre-treatment following ovariectomy on brain oxycodone concentrations or analgesia, which was restored in ovariectomized females following estradiol, but not progesterone, treatment. Sex, cycle, and estradiol regulation of CYP2D in brain in turn altered brain oxycodone concentration and response, which may contribute to the large inter-individual variation in response to the numerous centrally acting CYP2D substrate drugs, including opioids.

Chronic pain is associated with insomnia. The objective of this clinical study is to compare the efficacy and safety of different prescribed doses of zopiclone and clonidine; for the management of insomnia in patients with chronic pain.

To investigate the effect of chronic caffeine use and caffeine cessation on vasodilatory function in the posterior circulation in patients with migraine.

This study was aimed at evaluating the efficacy of glucosamine and potential mechanisms of actions in a neuropathic pain model in rats.

Arthritic injuries happen frequently during a lifetime due to accidents, sports, aging, diseases, etc. Such injuries can be cartilage/bone injuries, tendon injuries, ligament injuries, inflammation, pain, and/or synovitis. Oral and injective administration of therapeutics are typically used but cause many side effects. Transdermal administration is an alternative route for safe and efficient delivery. Transdermal formulations of non-steroidal anti-inflammatory drugs have been available on market for years and show promising efficacy in pain relieving, inflammation alleviation, infection control, and so on. Innovative transdermal patches, gels/films, and microneedles have also been widely explored as formulations to deliver therapeutics to combat arthritic injuries. However, transdermal formulations that halt disease progression and promote damage repair are translated slowly from lab bench to clinical applications. One major reason is that the skin barrier and synovial capsule barrier limit the efficacy of transdermal delivery. Recently, many nanocarriers, such as nanoparticles, nanolipids, nanoemulsions, nanocrystals, exosomes, etc., have been incorporated into transdermal formulations to advance drug delivery. The combined transdermal formulations show promising safety and efficacy. Therefore, this review will focus on stating the current development of nanomedicine-based transdermal formulations for the treatment of arthritic injuries. The advances, limitations, and future perspectives in this field will also be provided to inspire future studies and accelerate clinical translational studies. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Biology-Inspired Nanomaterials > Lipid-Based Structures.

Describe population pharmacokinetics of intravenous (IV) and subcutaneous (SC) tanezumab across Phase 2b/3 studies of osteoarthritis (OA) and chronic low back pain (CLBP). Methods Data from 10 studies of IV or SC tanezumab (2.5-20 mg every 8 weeks for up to 56 weeks) were included in a multi-step analysis. In Step 1, a two-compartment model with linear and non-linear elimination (based on prior analysis of pre-2015 IV osteoarthritis studies) was expanded to include other pre-2015 studies. In Step 2, post-2015 SC studies were combined into the model. Steps 3 and 4 evaluated impact of baseline nerve growth factor (NGF) and treatment-emergent anti-drug antibodies (TE ADA).