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Several lines of evidence pointed to an important role for CGRP in migraine. These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain-producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs. The development of small molecule CGRP receptor antagonists (CGRP-RAs) that showed clinical antimigraine efficacy acutely and prophylactically in randomized placebo-controlled clinical trials subsequently gave definitive pharmacological proof of the importance of CGRP in migraine. More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand [ C]MK-4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of telcagepant, a prototypic CGRP-RA. Taken together, these data indicated that (1) the therapeutic site of action of the CGRP-RAs was peripheral not central; (2) that IV CGRP had most likely evoked migraine through an action at sites outside the blood-brain barrier; and (3) that migraine pain was therefore, at least in part, peripheral in origin. The evolution of CGRP migraine science gave impetus to the development of peripherally acting drugs that could modulate CGRP chronically to prevent frequent episodic and chronic migraine. Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing antibody given IV, shows promise in late stage clinical development. Recently, orally administered next-generation small molecule CGRP-RAs have been shown to have safety and efficacy in acute treatment (ubrogepant and rimegepant) and prevention (atogepant) of migraine, giving additional CGRP-based therapeutic options for migraine patients.
Learn More >The entire field of medicine, not just anesthesiology, has grown comfortable with the risks posed by opioids; but these risks are unacceptably high. It is time for a dramatic paradigm shift. If used at all for acute or chronic pain management, they should be used only after consideration and maximizing the use of nonopioid pharmacologic agents, regional analgesia techniques, and nonpharmacologic methods. Opioids poorly control pain, their intraoperative use may increase the risk of recurrence of some types of cancer, and they have a large number of both minor and serious side effects. Furthermore, there are a myriad of alternative analgesic strategies that provide superior analgesia, decrease recovery time, and have fewer side effects and risks associated with their use. In this article the negative consequences of opioid use for pain, appropriate alternatives to opioids for analgesia, and the available evidence in pediatric populations for both are described.
Learn More >Psychologically Informed Physical Therapy (PIPT) aims to identify individuals at high risk for transitioning to chronicity and merge impairment-focused physical therapy with cognitive behavioral therapy principles. Treatment monitoring is an important part of PIPT and involves identifying changes in clinical measures to inform clinical decision making.
Learn More >To estimate the national burden of school absenteeism associated with pain among 6-17 year old children in the United States.
Learn More >Background and Objectives： Studying the underlying mechanisms of opiate-induced hyperalgesia is fundamental to understanding and treating pain. Our previous study has proved that ephrinB/EphB signaling contributes to opiate-induced hyperagesia, but the manner in which ephrinB/EphB signaling acts on spinal nociceptive information networks to produce hyperalgesia remains unclear. Other studies have suggested that ephrinB/EphB signaling, NMDA receptor and COX-2 act together to participate in the modulation of nociceptive information processes at the spinal level. The objective of this research was to investigate the role of COX-2 in remifentanil-induced hyperalgesia and its relationship with ephrinB/EphB signaling. Methods： We characterized the remifentanil-induced pain behaviours by evaluating thermal hyperalgesia and mechanical allodynia in a mouse hind paw incisional model. Protein expression of COX-2 in spinal cord was assayed by western blotting and mRNA level of COX-2 was assayed by Real-time PCR (RT-PCR). Results： Continuing infusion of remifentanil produced thermal hyperalgesia and mechanical allodynia, which was accompanied by increased expression of spinal COX-2 protein and mRNA. This response was inhibited by pre-treatment with EphB2-Fc, an antagonist of ephrinB/EphB. SC58125 and NS398, inhibitors of COX-2, suppressed pain behaviours induced by remifentanil infusion and reversed the increased pain behaviours induced by intrathecal injection of ephrinB2-Fc, an agonist of ephrinB/EphB. Conclusions: Our findings confirmed that COX-2 is involved in remifentanil-induced hyperalgesia related to ephrinB/EphB signaling. EphrinB/EphB signaling might be the upstream of COX-2.
Learn More >Parental migraine in relation to migraine in offspring: Family linkage analyses from the HUNT Study.
Migraine is known to run in families. While some clinical studies have indicated that migraine is disproportionally transmitted through the maternal line, this has not been examined in a population-based setting.
Learn More >Two guidelines about opioid use in chronic pain management were published in 2017: the and the European Pain Federation position paper on appropriate opioid use in chronic pain management. Though the target populations for the guidelines are the same, their recommendations differ depending on their purpose. The intent of the Canadian guideline is to reduce the incidence of serious adverse effects. Its goal was therefore to set limits on the use of opioids. In contrast, the European Pain Federation position paper is meant to promote safe and appropriate opioid use for chronic pain. The content of the two guidelines could have unintentional consequences on other populations that receive opioid therapy for symptom management, such as patients with cancer. In this article, we present expert opinion about those chronic pain management guidelines and their impact on patients with cancer diagnoses, especially those with histories of substance use disorder and psychiatric conditions. Though some principles of chronic pain management can be extrapolated, we recommend that guidelines for cancer pain management should be developed using empirical data primarily from patients with cancer who are receiving opioid therapy.
Learn More >Intervertebral disc degeneration is a major cause of chronic low back pain, and excessive loading contributes to intervertebral disc degeneration. However, the lack of an effective bipedal in vivo animal model limits research about this condition.
Learn More >Calcitonin gene-related peptide (CGRP), is a peptide neurotransmitter with potent vasodilating properties. CGRP is believed to play a primary role in the pathogenesis of migraine. As such, CGRP and its receptors are obvious druggable targets for novel anti-migraine agents. While the development of small-molecule CGRP receptor antagonists started first, none of these agents is yet available in clinical practice. Conversely, both anti-CGRP and anti-CGRP receptor monoclonal antibodies (mABs) completed clinical development, and the first representatives of these 2 classes are available on the market. MABs are approved for prevention of migraine attacks in chronic or episodic migraine, involving long-term treatments. In light of the physiological role exerted by CGRP in the regulation of vascular tone, the potential risks of a long-term inhibition of CGRP functions raised diffuse concerns. These concerns were correctly addressed by the anti-CGRP receptor mABs erenumab with a 5-year open-label clinical trial; however, this study is currently ongoing and results are not yet available, leaving some uncertainty on the profile of erenumab long-term safety. Similar concerns can be raised with direct anti-CGRP mABs, which entrap the peptide preventing receptor activation. However, evidence exists that plasma CGRP is detectable in patients chronically treated with anti-CGRP mABs. Assuming that plasma CGRP is an indirect marker of peptide levels at the vascular receptor sites, such residual CGRP would maintain a physiological level of receptor stimulation, in spite of a well-established anti-migraine activity of the mABs. This might represent a potential advantage in the safety profile of anti-CGRP mABs, but it needs to be confirmed and expanded with data on free plasma CGRP.
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