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The PREEMPT Studies established onabotulinumtoxinA as preventive treatment for adults with chronic migraine (CM). The purpose of the REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilisation, and Patient-reported OutcomeS observed in practice (REPOSE) Study was to observe real-life, long-term (24-month) use of onabotulinumtoxinA in adults with CM and report on the utilisation, effectiveness, safety, and tolerability.
Learn More >Loss-of-function mutations in Na1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal approach, we investigated how Na1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous Na1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that Na1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some Na1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade.
Learn More >The use of compounded topical pain creams has increased dramatically, yet their effectiveness has not been well evaluated.
Learn More >Chronic musculoskeletal pain affects a substantial portion of adults visiting the emergency department (ED). Current treatment is limited in scope and does not effectively reduce musculoskeletal pain in patients. The study will evaluate the use of duloxetine, a serotonin-norepinephrine reuptake inhibitor Food and Drug Administration approved for the treatment of chronic pain, as a promising option in its prevention. The proposed study may present a well-tolerated and effective non-opioid treatment for patients with acute musculoskeletal pain that may also be effective in preventing the transition to persistent or chronic musculoskeletal pain.
Learn More >The addictive potential of clinically-used opioids due to their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction. Its interaction with inflammatory cells in arthritic joints was evaluated in vitro using a RAW264.7 cell culture, and subsequent confocal microscopy analysis confirmed that P-HMP could be internalized by the cells via endocytosis. In vivo imaging studies indicated that the prodrug can passively target to the arthritic joint after systemic administration in a rodent model of monoarticular adjuvant-induced arthritis (MAA). The inflammatory pain-alleviating properties of the prodrug were assessed in MAA rats using the incapacitance test, and were observed to be similar to dose-equivalent HMP. Analgesia through mechanisms at the spinal cord level was further measured using the tail flick test and it was determined that the prodrug significantly reduced spinal cord analgesia versus free HMP, further validating the peripheral restriction of the macromolecular prodrug. Immunohistochemical analysis of cellular uptake of the P-HMP within the MAA knee joint proved the internalization of the prodrug by phagocytic synoviocytes, co-localized with HMP's target receptor as well as with pain-modulating ion channels. Therefore, it can be concluded that the novel inflammation-targeting polymeric prodrug of HMP (P-HMP) has the potential to be developed as an effective and safe analgesic agent for musculoskeletal pain.
Learn More >Monoclonal antibodies that target calcitonin gene-related peptide or the canonical calcitonin gene-related peptide receptor have emerged as effective and well tolerated for the preventive treatment of migraine. These large molecules appear ideally suited for migraine prevention. They have an extended biological half-life, are administered either monthly or quarterly either by subcutaneous injection or intravenous infusion, require minimal or no dose-titration and have the potential for a rapid onset of effect compared to conventional oral preventive drugs. There is high selectivity and they target an important mediator in the pathogenesis of migraine.
Learn More >Internationally, use of lidocaine infusions to treat cancer pain varies by center. Existing systematic reviews do not adequately inform use of lidocaine in cancer pain.
Learn More >Postherpetic neuralgia (PHN) is the most common complication of varicella zoster virus (VZV) reactivation and a cause of considerable physical and psychosocial morbidity. No known treatment effectively prevents the development of PHN in patients with VZV reactivation. In this study, our objective was to evaluate the efficacy of premedication with gabapentin for reducing the risk of PHN in patients with diabetic and nondiabetic neuropathy. We retrospectively searched the electronic health records of patients with diabetic and nondiabetic neuropathy treated with gabapentin at Mayo Clinic before diagnosis of VZV reactivation. In total, PHN developed in 7 patients with diabetic neuropathy receiving gabapentin (n=62 [11.3%]) compared with 26 not receiving premedication with gabapentin (n=50 [52.0%]) (odds ratio, 0.12; 95% CI, 0.05-0.31; P<.001); PHN developed in 11 patients with nondiabetic neuropathy receiving gabapentin (n=109 [10.1%]) compared with 108 not receiving premedication with gabapentin (n=217 [49.8%]) (odds ratio, 0.11; 95% CI, 0.06-0.22; P<.001). In this cohort of patients with neuropathy, gabapentin administration before the onset of VZV reactivation significantly reduced the risk of PHN.
Learn More >Molecular basis of abdominal pain in IBD is not fully characterized. Serotonin (5-HT) increases visceral pain severity and contributes to exacerbation of inflammation. Moreover, it is well established that decreased anandamide (AEA) signaling in the gut increases visceral pain severity. The aim of this study was to investigate the interplay between 5-HT and endocannabinoid signaling in colitis.
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