Browse by Audience
This randomized, double-blind, Phase 3 study (56-week treatment; 24-week follow-up) assessed tanezumab in patients with chronic low back pain (CLBP) and history of inadequate response to standard-of-care analgesics (NCT02528253). Patients received placebo, subcutaneous tanezumab (5mg or 10mg every 8 weeks), or oral tramadol prolonged-release (100-300mg/day). Primary endpoint was change in Low Back Pain Intensity (LBPI) at week 16 for tanezumab versus placebo. Key secondary endpoints were proportion of patients with ≥50% decrease in LBPI at week 16, change in Roland Morris Disability Questionnaire (RMDQ) at week 16, and change in LBPI at week 2 for tanezumab versus placebo. Adverse events and joint safety were assessed through weeks 56 and 80, respectively. Tanezumab 10mg met the primary endpoint by significantly improving LBPI at week 16 versus placebo; least squares (LS) mean (95% CI) difference = -0.40 (-0.76, -0.04; P=0.0281). Tanezumab 10mg significantly improved all key secondary endpoints. Tanezumab 5mg did not meet the primary endpoint (LS mean [95% CI] treatment difference versus placebo = -0.30 [-0.66, 0.07; P=0.1117]), preventing formal testing of key secondary endpoints for this dose. The proportion of patients with ≥50% improvement in LBPI at week 16 was 37.4% in the placebo group, 43.3% in the tanezumab 5mg group (Odds ratio [95% CI] vs placebo = 1.28 [0.97, 1.70; P=0.0846]) and 46.3% in the tanezumab 10mg group (Odds ratio [95% CI] vs placebo = 1.45 [1.09, 1.91; P=0.0101]). Prespecified joint safety events were more frequent with tanezumab 10mg (2.6%) than tanezumab 5mg (1.0%), tramadol (0.2%), or placebo (0%). Seven patients, all in the tanezumab 10mg group (1.4%), underwent total joint replacement. In conclusion, tanezumab 10mg significantly improved pain and function versus placebo in patients with difficult-to-treat CLBP. Tanezumab was associated with a low rate of joint safety events, some requiring joint replacement. Sponsored by Pfizer Inc. and Eli Lilly & Company.
Learn More >Rheumatoid arthritis (RA) is an autoimmune disorder. It causes inflammation, swelling, and pain in the joints of the human body. Overexpressed matrix metalloproteinases (MMPs) at the inflammatory sites of RA are a target in the construction of inflammation-responsive drug delivery vehicles for enhancing the therapeutic effect of anti-inflammatory drugs in the treatment of RA. In this paper, we report MMP-responsive PEGylated lipid nanoparticles through the co-assembly of triglycerol monostearate (TGMS) and 1,2-distearoyl–glycero-3-phospho-ethanolamine-poly(ethyleneglycol) (DSPE-PEG) in which the ester bond of TGMS is cleavable by MMPs and the PEG chain provides a stealth layer. The lipid nanoparticles show high biocompatibility, extended blood circulation, and preferential distribution in the inflammatory joints of RA. The loaded dexamethasone (Dex) can be rapidly released from the lipid nanoparticles in response to MMPs. After being intravenously administered to arthritic rats, Dex-loaded MMP-responsive PEGylated lipid nanoparticles significantly reduce the degree of joint swelling and inhibit the production of TNF-α and IL-1β in joint tissues. These results demonstrate that MMP-responsive PEGylated lipid nanoparticles are a smart drug vehicle for the treatment of RA with improved therapeutic efficacy.
Learn More >There is ample evidence for the role of the immune system in developing chronic pain following peripheral nerve injury. Especially Toll-like receptors (TLRs) and their associated signaling components and pro-inflammatory cytokines such as IL-1β, induced after injury, are involved in nociceptive processes and believed to contribute to the manifestation of chronic neuropathic pain states. Whereas the inhibition of the kinase function of IRAK-4, a central kinase downstream of TLRs and IL-1 receptors (IL-1Rs), seems efficacious in various chronic inflammatory and autoimmune models, it's role in regulating chronic neuropathic pain remained elusive to date. Here, we examined whether pharmacological inhibition of IRAK-4 kinase activity using PF-06650833 and BMS-986147, two clinical-stage kinase inhibitors, is effective for controlling persistent pain following nerve injury. Both inhibitors potently inhibited TLR-triggered cytokine release in human peripheral blood mononuclear cell (PBMC) as well as human and rat whole blood cultures. BMS-986147 showing favorable pharmacokinetic (PK) properties, significantly inhibited R848-triggered plasma TNF levels in a rat in vivo cytokine release model after single oral dosing. However, BMS-986147 dose dependently reversed cold allodynia in a rat chronic constriction injury (CCI) model following intrathecal administration only, supporting the notion that central neuro-immune modulation is beneficial for treating chronic neuropathic pain. Although both inhibitors were efficacious in inhibiting IL-1β- or TLR-triggered cytokine release in rat dorsal root ganglion cultures, only partial efficacy was reached in IL-1β-stimulated human glial cultures indicating that inhibiting IRAK-4́s kinase function might be partially dispensable for human IL-1β driven neuroinflammation. Overall, our data demonstrate that IRAK-4 inhibitors could provide therapeutic benefit in chronic pain following nerve injury, and the central driver for efficacy in the neuropathic pain model as well as potential side effects of centrally available IRAK-4 inhibitors warrant further investigation to develop effective analgesia for patients in high unmet medical need.
Learn More >OnabotulinumtoxinA is an effective preventive treatment for chronic migraine. In chronic migraine, besides a reduction in headache frequency, a decreased reliance on oral prophylactics is also indicative of treatment effectiveness. This study aimed to quantify the change in the use of oral prophylactics after treatment with onabotulinumtoxinA in patients with chronic migraine.
Learn More >General anesthesia (GA) can produce analgesia (loss of pain) independent of inducing loss of consciousness, but the underlying mechanisms remain unclear. We hypothesized that GA suppresses pain in part by activating supraspinal analgesic circuits. We discovered a distinct population of GABAergic neurons activated by GA in the mouse central amygdala (CeA neurons). In vivo calcium imaging revealed that different GA drugs activate a shared ensemble of CeA neurons. CeA neurons also possess basal activity that mostly reflects animals' internal state rather than external stimuli. Optogenetic activation of CeA potently suppressed both pain-elicited reflexive and self-recuperating behaviors across sensory modalities and abolished neuropathic pain-induced mechanical (hyper-)sensitivity. Conversely, inhibition of CeA activity exacerbated pain, produced strong aversion and canceled the analgesic effect of low-dose ketamine. CeA neurons have widespread inhibitory projections to many affective pain-processing centers. Our study points to CeA as a potential powerful therapeutic target for alleviating chronic pain.
Learn More >Recently, the adenosine triphosphate (ATP) sensitive potassium channel opener levcromakalim was shown to induce migraine attacks with a far higher incidence than any previous provoking agent such as calcitonin gene-related peptide. Here, we show efficacy of ATP sensitive potassium channel inhibitors in two validated rodent models of migraine.
Learn More >Chronic low back pain (CLBP) is a highly prevalent and disabling condition in the elderly, and yet it is undertreated and understudied in this patient population. Tapentadol is a central analgesic with an improved tolerability profile that may be particularly beneficial to the elderly CLBP.
Learn More >The opioid epidemic has led to a serious examination of the use of opioids for the treatment of pain. Opioid drugs are effective due to the expression of opioid receptors throughout the body. These receptors respond to endogenous opioid peptides that are expressed as polypeptide hormones that are processed by proteolytic cleavage. Endogenous opioids are expressed throughout the peripheral and central nervous system and regulate many different neuronal circuits and functions. One of the key functions of endogenous opioid peptides are to modulate our responses to pain. This review will focus on the descending pain modulatory circuit which consists of the ventrolateral periaqueductal gray (PAG) projections to the rostral ventromedial medulla (RVM). RVM projections modulate incoming nociceptive afferents at the level of the spinal cord. Stimulation within either the PAG or RVM results in analgesia and this circuit has been studied in detail in terms of the actions of exogenous opioids, such as morphine and fentanyl. Further emphasis on understanding the complex regulation of endogenous opioids will help to make rational decisions with regard to the use of opioids for pain. We also include a discussion of the actions of endogenous opioids in the amygdala, an upstream brain structure that has reciprocal connections to the PAG that contribute to the brain's response to pain.
Learn More >Develop a translational assay of Transient Receptor Potential Ankyrin 1 (TRPA1) activity for use as a preclinical and clinical biomarker.
Learn More >Among patients with cervical myelopathy who were diagnosed with neuropathic pain (NP) by the LANSS test, the study participants were randomly assigned to one of the two study groups. The participants in one study group received opioids only, while those in the other group received opioids and pregabalin. Thirty-nine patients were analyzed in the study (20 patients in the opioid-only group and 19 in the pregabalin add-on group). The LANSS, neck pain, and arm pain scores in the pregabalin add-on group improved significantly compared with those in the opioid-only group after the first 4 weeks (p = 0.005, 0.001 and 0.035, respectively), but there was no significant difference between the two groups during the next 4 weeks (p = 0.615, 0.377 and 0.716, respectively). There was no significant difference in the neck disability index and EuroQol-5Dimension scores after four weeks and eight weeks of follow-up. Adverse events were reported by four patients (20.0%) in the opioid-only group and five patients (26.3%) in the pregabalin add-on group (p = 0.716). However, over time, the occurrence of side effects and dropouts increased in the pregabalin add-on group. This exploratory pilot study suggests that pregabalin add-on treatment is more efficient than the use of opioids alone at the beginning of NP treatment in cervical myelopathy patients. However, prescribing pregabalin add-on treatment for more than four weeks should be done cautiously.
Learn More >