Music-enhanced analgesia and antiseizure activities in animal models of pain and epilepsy: Toward preclinical studies supporting development of digital therapeutics and their combinations with pharmaceutical drugs

Abstract

Digital therapeutics (software as a medical device) and mobile health (mHealth) technologiesofferameanstodeliverbehavioral,psychosocial,diseaseself-management and music-based interventions to improve therapy outcomes for chronic diseases, including pain and epilepsy. To explore new translational opportunities in developing digital therapeutics for neurological disorders, and their integration with pharmacotherapies, we examined analgesic and antiseizure effects of specific musical compositions in mouse models of pain and epilepsy. The music playlist was created based on the modular progression of Mozart compositions for which reduction of seizures and epileptiform discharges were previously reported in people with epilepsy. Our results indicated that music-treated mice exhibited significant analgesia and reduction of paw edema in the carrageenan model of inflammatory pain. Among analgesic drugs tested (ibuprofen, cannabidiol (CBD), levetiracetam, and the galanin analog NAX 5055), music intervention significantly decreased paw withdrawal latency differenceinibuprofen-treatedmiceandreducedpawedemaincombinationwithCBDor NAX5055.To the best of our knowledge,this is the first animal study on music-enhanced antinociceptive activity of analgesic drugs. In the plantar incision model of surgical pain, music-pretreated mice had significant reduction of mechanical allodynia. In the corneal kindling model of epilepsy, the cumulative seizure burden following kindling acquisition was lower in animals exposed to music. The music-treated group also exhibited significantly improved survival, warranting further research on music interventions for preventing Sudden Unexpected Death in Epilepsy (SUDEP). We propose a working model of how musical elements such as rhythm, sequences, phrases and punctuation foundinK.448andK.545mayexertresponsesviaparasympatheticnervoussystemand thehypothalamic-pituitary-adrenal(HPA)axis.Basedonourfindings,wediscuss:(1)how enriched environment (EE) can serve as a preclinical surrogate for testing combinations ofnon-pharmacologicalmodalitiesanddrugsforthetreatmentofpainandotherchronic diseases, and (2) a new paradigm for preclinical and clinical development of therapies leading to drug-device combination products for neurological disorders, depression and cancer. In summary, our present results encourage translational research on integrating non-pharmacological and pharmacological interventions for pain and epilepsy using digital therapeutics.