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.

Michael Chikinda,Cameron S. Metcalf,Misty D. Smith,Tristan Underwood,Grzegorz Bulaj,Eugene Watanabe,Gerry Garcia,Adam K. Kochanski,H. Steve White,Merodean Huntsman,Fabiola Vanegas

doi:10.3389/fneur.2019.00277

Michael Chikinda, Cameron S. Metcalf + Show 9 more

Open Access

https://doi.org/10.3389/fneur.2019.00277

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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 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.

Highlights

Pain and epilepsy are distinct neurological conditions which share unmet needs for innovating treatments
CD-1 mice (N = 5–8 per group) were evaluated for thermal hyperalgesia following carrageenan administration and, as shown Figure 1A and Table 2, there were no significant differences in paw withdrawal latency (PWL) between music-treated and control groups
Mice receiving an acute dose of ibuprofen showed a significant reduction in hyperalgesia when treated in combination with music, as demonstrated by an increase in post-carrageenan PWL in ibuprofen + music-exposed mice, whereas other compounds did not significantly reduce this hyperalgesic response to carrageenan (Figure 1B and Table 2)

Summary

Introduction

Pain and epilepsy are distinct neurological conditions which share unmet needs for innovating treatments. People living with chronic pain have limited options for pain relief. Opioid-based pain management has considerable adverse effects, in addition to abuse potential [e.g., the opioid epidemic in the US resulted in over 47,000 deaths in 2017 due to overdosing opioids [1]]. People with epilepsy face multiple challenges including: [1] seizure control (estimated 30% are refractory to current antiseizure drugs), [2] medication nonadherence, tolerability and adverse effects related to antiseizure drugs, [3] significantly higher mortality, and [4] co-morbidities requiring additional therapies. Novel approaches to chronic pain management and control of epileptic seizures will benefit millions of people living with epilepsy and pain worldwide [2, 3]

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