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To investigate the distribution of nociceptive nerve fibers in the cervical intervertebral discs of patients with chronic neck pain and determine whether these nociceptive nerve fibers are related to discogenic neck pain.
Learn More >Nociceptive signals conveyed to the dorsal horn of the spinal cord by primary nociceptors are subject to extensive modulation by local neurons and by supraspinal descending pathways to the spinal cord before being relayed to higher brain centers. Descending modulatory pathways to the spinal cord comprise, among others, noradrenergic, serotonergic, γ-aminobutyric acid (GABA)ergic, and dopaminergic fibers. The contributions of noradrenaline, serotonin, and GABA to pain modulation have been extensively investigated. In contrast, the contributions of dopamine to pain modulation remain poorly understood. The focus of this review is to summarize the current knowledge of the contributions of dopamine to pain modulation. Hypothalamic A11 dopaminergic neurons project to all levels of the spinal cord and provide the main source of spinal dopamine. Dopamine receptors are expressed in primary nociceptors as well as in spinal neurons located in different laminae in the dorsal horn of the spinal cord, suggesting that dopamine can modulate pain signals by acting at both presynaptic and postsynaptic targets. Here, I will review the literature on the effects of dopamine and dopamine receptor agonists/antagonists on the excitability of primary nociceptors, the effects of dopamine on the synaptic transmission between primary nociceptors and dorsal horn neurons, and the effects of dopamine on pain in rodents. Published data support both anti-nociceptive effects of dopamine mediated by D2-like receptors and pro-nociceptive effects mediated by D1-like receptors.
Learn More >Although recent scientific advances have improved our understanding of basic biological mechanisms underlying chemotherapy-induced peripheral neuropathy (CIPN), few interventions are available to prevent or treat CIPN. While some biological targets from preclinical studies show promise in non-human animal models, few targets have been translated to successful clinical trials. To address this problem, the National Cancer Institute's (NCI's) Symptom Management and Health-Related Quality of Life Steering Committee convened a meeting of experts in the CIPN and oncology symptom management fields to participate in a Clinical Trials Planning Meeting (CTPM). Investigators presented data from preclinical and translational studies for possible CIPN interventions; these were evaluated for readiness of randomized clinical trial testing by experts, and recommendations were provided. Breakout sessions were convened to discuss and develop future studies. The CTPM experts concluded that there is compelling evidence to move forward with selected pharmacological and non-pharmacological clinical trials for the prevention and treatment of CIPN. Several key feasibility issues need to be addressed, however. These include: identification of optimal outcome measures to define the CIPN phenotype, establishment of parameters that guide the evaluation of clinically meaningful effects, and adoption of approaches for inclusion of translational and biomarker/genetic measures. The results of the CTPM provide support for conducting clinical trials that include both pharmacological and non-pharmacological approaches, alone or in combination, with biomarkers, genetics or other measures designed to inform underlying CIPN mechanisms. Several working groups were formed to design rigorous CIPN clinical trials, the results of which are ongoing.
Learn More >Opioid use in chronic non cancer pain (CNCP) is still controversial regarding their effectiveness and safety. We conducted a 2-year prospective cohort study in 4 multidisciplinary chronic pain clinics to assess long-term opioid effectiveness in CNCP patients. All adult CNCP patients consecutively admitted to their first consultation were recruited. Demographic and clinical data were collected, and propensity score matching was used to adjust for differences between opioid users and nonusers. The Brief Pain Inventory and the Short version of Treatment Outcomes in Pain Survey were used to measure pain outcomes and quality of life. A total of 529 subjects were matched and included in our analysis. Rate of prescription opioid use was 59.7% at baseline, which increased to 70.3% over 2 years, of which 42.7% of the prescriptions were for strong opioids. Opioid users reported no improvement regarding pain symptoms, physical function, emotional function, and social/familiar disability. Opioid users reported higher satisfaction with care and outcomes at 1 year of follow-up, but at 2 years, they only reported improvement in satisfaction with outcomes. Opioids have shown limited effectiveness in long-term CNCP management, as opioid users presented no improvements regarding functional outcomes and quality of life. These findings emphasize the need for proper selection and outcome assessment of CNCP patients prescribed opioids. PERSPECTIVE: This study adds important additional evidence concerning the controversial use of opioids in CNCP management. Opioid users presented no improvement regarding pain relief, functional outcomes and quality of life over 2 years of follow-up. Therefore, our results support and highlight the limited effectiveness of opioids in long-term CNCP management.
Learn More >Recent findings from a phase II clinical trial showed analgesic effects of an angiotensin II type-2 receptor (AT2R) antagonist in postherpetic neuralgia patients. This study aimed to investigate whether AT2R antagonism could provide effective analgesia in voluntary measures of unevoked/ongoing pain-like behaviors in mice with experimental neuropathy. Mice were subjected to spared nerve injury to induce neuropathy and tested in 2 operant behavioral tests to measure ongoing mechanical and cold pain hypersensitivities. Systemic administration of an AT2R antagonist provided effective analgesia in these behavioral measures of mechanical and cold pain in spared nerve injury mice, suggesting its effectiveness in neuropathic pain.
Learn More >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.
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