Browse by Audience
The delta opioid receptor (DOPr) is an emerging target for the management of chronic pain and depression. Studies have highlighted the potential of biased signaling, the preferential activation of one signaling pathway over another downstream of DOPr, to generate a better therapeutic profile. BMS 986187 is a recently discovered positive allosteric modulator (PAM) of the DOPr. Here we ask if BMS 986187 can directly activate the receptor from an allosteric site in the absence of orthosteric ligand and if a signaling bias is generated.
Learn More >Neuropathic pain is a major incurable clinical problem resulting from peripheral nerve trauma or disease. A central mechanism is the reduced expression of the potassium chloride cotransporter 2 (KCC2) in dorsal horn neurons induced by brain-derived neurotrophic factor (BDNF), causing neuronal disinhibition within spinal nociceptive pathways. Here, we demonstrate how neurotensin receptor 2 (NTSR2) signaling impairs BDNF-induced spinal KCC2 down-regulation, showing how these two pathways converge to control the abnormal sensory response following peripheral nerve injury. We establish how sortilin regulates this convergence by scavenging neurotensin from binding to NTSR2, thus modulating its inhibitory effect on BDNF-mediated mechanical allodynia. Using sortilin-deficient mice or receptor inhibition by antibodies or a small-molecule antagonist, we lastly demonstrate that we are able to fully block BDNF-induced pain and alleviate injury-induced neuropathic pain, validating sortilin as a clinically relevant target.
Learn More >Although biomechanics play a role in the development of low back pain (LBP), and perhaps in the persistent and/or recurrent nature of LBP, there is debate regarding whether biomechanics alone can provide the basis for intervention. Biomechanics, which refers to the mechanics of the body including its neuromuscular control, has been extensively studied in LBP. But, can gains be made in understanding LBP by research focused on this component of the biology in the multifactorial bio-psycho-social problem of LBP? This commentary considers whether biomechanics research has the potential to advance treatment of LBP, and how likely it is that this research will lead to better treatment strategies for LBP. A viewpoint-counterpoint format is taken to present both sides of the argument. This is considered first from the perspective of the challenges faced by an approach that considers biomechanics in isolation. Second, 3 models are described that place substantial emphasis on biomechanical factors. Third, reactions to each viewpoint are presented as a foundation for further research and clinical practice to progress understanding of the place for biomechanics in guiding treatment for LBP. .
Learn More >The 2016 CDC guidelines for opioid prescribing by primary care physicians have exposed some shortfalls in our thinking about opioid use and stranded many chronic pain patients with inadequate analgesia. Opioid prescribing rates started to decline in 2012, but still remain high. The response from providers to the 2016 guidelines have led to unintended consequences. Some of the CDC guidance seems arbitrary and not supported by evidence (the 90 MME per day cutoff). Patient and prescriber education, the role of buprenorphine (an atypical Schedule III opioid), and abuse-deterrent opioids are not mentioned at all but could play crucial roles in reducing abuse. Opioid use disorder (OUD) is not defined by the guidance which calls on primary care physicians to recognize and treat it. Opioid withdrawal syndrome is not mentioned and tapering plans, although advised, are not described in a practical way. While the morbidity and mortality associated with OUD are public health crises, so is untreated pain. Chronic pain patients deserve consideration, yet emerge as the silent epidemic within the opioid crisis. To be sure, there is much good in the CDC guidance or any guidelines that urge caution and care in opioid prescribing. Pain specialists must speak out to advocate for patients dealing with pain, to educate patients and prescribers about analgesic options, and to make sure that pain is adequately treated particularly in vulnerable populations.
Learn More >Erenumab was effective and well tolerated in a pivotal clinical trial of episodic migraine that included subjects both naïve to, and those who had failed, previous preventives. Here we evaluated the efficacy and safety of erenumab (70 mg or 140 mg) versus placebo in the subgroup of patients who had previously failed preventive treatment(s): ≥1 or ≥2 prior failed migraine preventive categories, and in patients who had never failed.
Learn More >To use a mouse model of imiquimod-induced psoriasis to investigate the relationship between pruritus and mast cells, nerve growth factor (NGF) and endogenous pruritogenic peptides, which are highly expressed in the skin of psoriasis patients.
Learn More >The emergence of several fentanyl-related substances in the recreational drug marketplace has resulted in a surge of opioid overdose deaths in the United States. Many of these substances have never been examined in living organisms under controlled conditions. In the present study, seven fentanyl-related substances were tested in adult male Swiss Webster mice for their effects on locomotion and antinociception and compared to those of fentanyl and morphine. In locomotor activity tests, fentanyl (1, 10 mg/kg), morphine (100, 180 mg/kg), isobutyrylfentanyl (10 mg/kg), crotonylfentanyl (10 mg/kg), para-fluorobutyrylfentanyl (10, 100 mg/kg), para-methoxybutyrylfentanyl (10 mg/kg), thiophenefentanyl (100 mg/kg), and benzodioxolefentanyl (0.1 mg/kg) produced significant (p ≤ 0.05) dose-dependent increases in locomotion. Valerylfentanyl, however, was without effects on locomotion up to 100 mg/kg. In warm-water tail-withdrawal tests, all substances produced significant (p ≤ 0.05) dose-dependent increases in antinociception with increasing ED values (CI) of isobutyrylfentanyl [0.0768 mg/kg (0.044-0.128)] > fentanyl [0.0800 mg/kg (0.0403-0.164)] > para-methoxybutyrylfentanyl [0.106 mg/kg (0.0516-0.195)] > crotonylfentanyl [0.226 mg/kg (0.176-0.292)] > para-fluorobutyrylfentanyl [0.908 mg/kg (0.459-1.58)] > thiophenefentanyl [4.66 mg/kg (3.65-5.95)] > valerylfentanyl [6.43 mg/kg (3.91-10.5)] > morphine [7.82 mg/kg (5.42-11.0)] > benzodioxolefentanyl [46.3 mg/kg (25.8-83.4)]. Naltrexone (1 mg/kg) increased antinociceptive ED values several fold in decreasing magnitudes of isobutyrylfentanyl (233x) > para-methoxybutyrylfentanyl (37.7x) > thiophenefentanyl (34.6x) > valerylfentanyl (11.9x) > para-fluorobutyrylfentanyl (10.9x) > benzodioxolefentanyl (8.42x) > crotonylfentanyl (6.27x) > fentanyl (3.95x) > morphine (1.48x). These findings establish that locomotor and antinociceptive effects of several fentanyl-related substances are similar to those of morphine and fentanyl and are mediated by opioid receptors.
Learn More >To investigate the functional connectivity of the hypothalamus in chronic migraine compared to interictal episodic migraine in order to improve our understanding of migraine chronification.
Learn More >NKTR-181, a new molecular entity, full mu-opioid receptor agonist with an inherently slow rate of CNS entry, was designed to provide analgesia while reducing abuse potential. The objective of this phase 3, enriched-enrollment, randomized-withdrawal trial was to evaluate the analgesic efficacy, safety, and tolerability of NKTR-181 in patients with chronic low-back pain (CLBP). Adults with moderate-to-severe CLBP refractory to non-opioid analgesics achieving an analgesic NKTR-181 dosage (100-400 mg twice daily) during the open-label titration period were randomized to continued NKTR-181 treatment, double-blind, or switched to placebo. The study was conducted at 55 sites in the United States. Of 1189 patients exposed to NKTR-181 during the titration period, 610 were randomized to NKTR-181 100-400 mg every 12 hours or placebo for 12-weeks. The primary outcome measure was the change in weekly pain score (scale, 0-10) at 12-weeks from randomization baseline. Secondary outcome measures included responder rates defined by ≥30% and ≥50% improvement in pain score from screening to 12 weeks. Among 610 randomized patients, the mean pain score decreased from 6.73 to 2.32 during open-label titration. After randomization, the least-squares mean change in pain score was +0.92 for NKTR-181 vs. +1.46 for placebo (P=0.002). The ≥30%-improvement responder rate of NKTR-181 vs. Placebo was 71.2% vs. 57.1% (P<0.001), and the ≥50%-improvement responder rate was 51.1% vs. 37.9% (P=0.001). NKTR-181 was well tolerated with a low incidence (<3%) of CNS-related AEs during the randomized treatment phase. In patients with moderate-to-severe CLBP, NKTR-181 demonstrated significant analgesic efficacy and a favorable safety/tolerability profile, with a low incidence of CNS AEs.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Learn More >Complex Regional Pain Syndrome (CRPS) develops after fracture. The acute CRPS phenotype resembles exaggerated inflammation which is explained by local and systemic activation of a pro-inflammatory network including peptides and cytokines. Epidemiologic data suggest that inactivation of the peptidase angiotensin converting enzyme (ACE) in patients treated for hypertension increases the odds to develop CRPS. This hint lead us to investigate the serum protease network activity in CRPS patients vs. respective controls. For this purpose, we developed a dabsyl-bradykinin (DBK)-based assay and used it to investigate CRPS patients, as well as healthy (HC) and pain (painful diabetic neuropathy; dPNP) controls. The major result is that the degradation of DBK to fragments 1-8 and 1-5 in HC and dPNP is shifted to higher values for DBK1-8 and lower values for DBK 1-5 at one hour of incubation in CRPS patients. Using this novel reporter peptide assay, we have been able to show that the resolving protease network for mediators like BK might be different in CRPS patients; having a look at the the clinical signs, which resemble inflammation, this resolving protease network is probably less effective in CRPS.
Learn More >