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) technologies offer a means to deliver behavioral, psychosocial, disease self-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 difference in ibuprofen-treated mice and reduced paw edema in combination with CBD or NAX 5055. 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 Metcalf et al. Music-Enhanced Analgesic and Antiseizure Activities model of how musical elements such as rhythm, sequences, phrases and punctuation found in K.448 and K.545 may exert responses via parasympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Based on our findings, we discuss: (1) how enriched environment (EE) can serve as a preclinical surrogate for testing combinations of non-pharmacological modalities and drugs for the treatment of pain and other chronic 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.

Non-pharmacological Interventions for Intractable Epilepsy

“…This music therapy is effective in following epileptic syndromes and conditions ( Liao et al, 2015 ); Lennox-Gastaut Syndrome, Intractable or drug-resistant epilepsy in children, benign epilepsy, refractory status epilepticus, refractory gelastic seizures; For the prevention of sudden death due to epilepsy, due to its effect on the cardiovascular system and respiration rate ( Koelsch and Jäncke, 2015 , Metcalf et al, 2019 , Scorza et al, 2008 ); …”

“…For the prevention of sudden death due to epilepsy, due to its effect on the cardiovascular system and respiration rate ( Koelsch and Jäncke, 2015 , Metcalf et al, 2019 , Scorza et al, 2008 );…”

Digital therapeutics in the clinic

“…The benefit of DTx is typically best observed when it is used in conjunction with another type of conventional therapy 25 . As a digital software, DTx allow for patients to access the application from the comfort of their homes outside of a hospital setting, which may improve patient outcomes and adherence 26 .…”

From Precision Metapharmacology to Patient Empowerment: Delivery of Self-Care Practices for Epilepsy, Pain, Depression and Cancer Using Digital Health Technologies

“…For health care insurance companies and health care systems, digital interventions offer cost savings ( Jiang et al, 2019 ; Richards et al, 2020 ). For research communities, precision metapharmacology encourages preclinical and clinical discoveries on improving pharmacotherapies by combining them with non-pharmacological interventions ( Metcalf et al, 2019 ). For governments and funding agencies, developing and delivery of lifestyle interventions offer means to reduce burden of chronic diseases and to improve public health.…”