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The increase in opioid-related deaths in the United States (and other countries) has prompted a national debate in medicine about the appropriateness of opioids for the treatment of acute and chronic pain, and specifically in children, if medical opioid use causes or increases the risk of opioid use disorder (OUD) later in life. Some in the medical community and in government advocate withholding opioids from children after an arbitrary number of days of treatment, regardless of diagnosis. Here, I argue that opioid experimentation and misuse is no more common in children and adolescents today than 2 or 3 decades ago, that there is no compelling evidence that appropriate medical use of opioids leads to OUD, and that the epidemic of inadequately treated pain in children remains the more compelling issue.
Learn More >Chronic itch is the most common skin-related condition, associated with a high psychosocial and economic burden. In recent years, increasing evidence of sex differences in the perception, clinical presentation and treatment requirements of itch points towards potential benefits when using sex-adapted therapies. It is well-known that body composition, absorption, metabolism, elimination and adverse drug reactions (ADRs) differ between sexes, but only little is known about the impact of sex in the pharmacology of itch treatments, which could help to rationalise sex-adapted treatment strategies.
Learn More >Cluster headache is by many regarded as a males' disorder that is often accompanied by an unhealthy lifestyle. We aimed to study the influence of sex and lifestyle factors on clinical presentation, the diagnostic process and management.
Learn More >Inflammation or injuries of the trigeminal nerve are often associated with persistent facial pain and its sequelae. A number of models have been described to study trigeminal pain in rodents, but the long-lasting behavioral consequences are unknown. The present study characterizes the impact of a distal infraorbital nerve injury, called DIONI, which consists of ligature and transection of distal fibers of the infraorbital nerve. We assessed nociception using a conflict paradigm and optogenetics, and a set of reward, aversion, spatial, temporal and competition tasks in the IntelliCage to study multiple aspects of cognition, circadian rhythms and social interactions in groups of mice in home cage environments. Mice with DIONI developed cold and mechanical allodynia, and hypersensitivity towards blue light stimulation. They maintained a long lasting memory of aversive stimuli (airpuff from above), but had no difficulty in learning appetitive tasks, which consisted of preference for a rewarding corner in the IntelliCage. Indeed, they were more strongly 'addicted' to sugar than sham mice but temporarily failed to re-learn the location of rewarding sites after corner switching (Reversal learning). They were mildly overactive in some tasks but without disruptions of circadian rhythms, or impact on social structure. They adopted a strategy to maintain licking with fewer nosepokes, presumably trying to avoid mechanical stimulation of the snout. The results suggest that mice with distal infraorbital nerve injury develop strong aversive memories and some cognitive inflexibility, but create adaptive strategies to cope with the persistent trigeminal hypersensitivity.
Learn More >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.
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