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 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.

Keywords: arthritis; cancer pain; epileptic seizures; inflammation; mobile medical apps; neuropathic pain; opioids; refractory epilepsy.

Figure 1

Analgesic effects of music-based intervention in the carrageenan model of inflammatory pain in CD-1 mice. (A)—effects of 21-day exposure to the Mozart playlist (MUSIC–blue; CONTROL–white) on paw withdrawal latency. Carrageenan-injected (ipsilateral paws) show thermal hyperalgesia (reduced withdrawal latency) in comparison to non-injected (contralateral) paws. (B)—effects of music (MUSIC–blue; CONTROL–white) on activity of ibuprofen following i.p. administration. Ibuprofen was administered at a dose of 25 mg/kg, 30 min prior to testing. Hyperalgesia was observed in animals exposed to control conditions whereas music-exposed and ibuprofen-treated animals show a normalized response to thermal stimulation (reduction of hyperalgesia). N = 5–8 per group. ^*P < 0.05, ^**P < 0.01, ^***P < 0.001. Data were analyzed using a two-way ANOVA followed by a Bonferroni post-hoc test.

Figure 2

Effects of music-based intervention on paw thickness (edema) following carrageenan administration in CD-1 mice. (A)—Carrageenan-injected (ipsilateral paws) show increased thickness (caliper measurement across the dorso-ventral aspect of the paw) compared to non-injected (contralateral) paws (MUSIC–blue; CONTROL–white). (B)—effects of music (MUSIC–blue; CONTROL–white) on activity of Cannabidiol (CBD, 100 mg/kg) following i.p. administration. CBD was administered 120 min prior to testing. Edema was observed following carrageenan in animals exposed to control conditions whereas music-exposed and CBD-treated animals show a diminished edema. N = 6–8 per group. ^***P < 0.001. Data were analyzed using a two-way ANOVA followed by a Bonferroni post-hoc test.

Figure 3

Analgesic effects of music-based intervention in the carrageenan model of inflammatory pain in CF-1 mice. (A)—effects of 21-day exposure to the Mozart playlist (MUSIC–blue; CONTROL–white) on paw withdrawal latency difference. Latency differences (contralateral PWL–ipsilateral PWL) show that hyperalgesia was observed in animals exposed to control conditions and music-exposed mice show a reduced latency difference.^*P < 0.05. (B)—Effects of music-based intervention on paw thickness (edema) following carrageenan administration in CF-1 mice. Edema was observed following carrageenan in animals exposed to control conditions whereas music-exposed animals show a diminished edema (MUSIC–blue; CONTROL–white). ^**P < 0.01, ^***P < 0.001. N = 5–8 per group. Data were analyzed using either a t-test (A) or a two-way ANOVA followed by a Bonferroni post-hoc test (B).

Figure 4

Effects of music intervention in plantar incision model of surgical pain in CD-1 mice. (A)—Paw withdrawal latency (PWL; sec) following thermal stimulation in mice following plantar incision. Incised paws (ipsilateral) show a greatly diminished PWL as compared to non-incised (contralateral) paws. ^****P < 0.0001. (B)—Paw withdrawal threshold to mechanical stimulation following plantar incision. Thresholds in ipsilateral paws are shown as a percentage (%) of the contralateral paw withdrawal threshold. ^*P < 0.05. N = 13–15. Data were analyzed using a two-way ANOVA followed by a Bonferroni post-hoc test (A) or a t-test (B).

Figure 5

Antiseizure effects of music-based intervention in the corneal kindling model of epilepsy in CF-1 mice. (A)—The percentage of fully kindled animals, as well as the number of fully kindled animals (number reaching fully kindled status / N; e.g., 7/11 and 5/15 for CONTROL- (white) and MUSIC (blue)-treated groups, respectively), is shown for each treatment group. (B)—The cumulative seizure burden (sum of all Racine scores for each stimulation) for all animals following achievement of fully kindled status. Mice exposed to music showed a lower post-kindling seizure burden. ^*P < 0.05 compared to control kindled. Data were compared by a Fisher's exact test (A) or a t-test (B).

Figure 6

Reduced mortality in animals exposed to daily music during kindling development. A survival analysis was conducted for all animals (N = 20 per group at study start) during kindling acquisition in CF-1 mice. While nearly 50% of control kindled animals die by the end of kindling acquisition, a significantly lower portion of mice in the music (music + kindling) died during this period. Groups were compared by Log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests.

Figure 7

Evaluation of the effects of music treatment on handling-induced seizures in the TMEV model of acquired epilepsy. Groups of mice (N = 10) were exposed to either control conditions or music for a 3-week period prior to inoculation with TMEV. Daily handling sessions occurred during day 3—day 7 post-inoculation wherein seizures were scored (Racine scale). The cumulative seizure burden during this time is shown in (A). The final cumulative seizure burden, expressed as a percentage of control-treated animals, is shown in (B). Groups were compared by a Mann-Whitney U-test.

Figure 8

Working model of mechanisms by which musical compositions can exert their analgesic and anticonvulsant activities. This model serves as a platform for testing a number of specific hypotheses; not addressed in the present investigation. The auditory system processes acoustic waves with specific rhythm, sequences, phrases and punctuation which generate action potentials in the nervous system. The role of specific musical structures (rhythm and pitch) in K.448 was studied in rodents and humans (85), whereas high periodicity was proposed to account for the antiseizure effects (73). Musical tempo modulate emotions (113) which can in turn affect pain processing (114, 115). Exposure to K.448 was shown to activate the parasympathetic nervous system (33). Music was shown to modulate the hypothalamic-pituitary-adrenal (HPA) axis, decrease stress hormone cortisol and increase expression of BDNF in the hippocampus (44, 57, 85, 94, 95, 103). The roles of prefrontal cortex (PFC) in pain processing (116) and music processing (97) have been studied. Further studies are required to test mechanism(s) of action of music-enhanced analgesia and antiseizure activities.

Figure 9

Developing music-based and behavioral interventions and their combinations with pharmaceutical drugs using digital therapeutics strategy. Streaming of patient-preferred music can be combined with disease self-management and behavioral therapy yielding a mobile app for non-pharmacological interventions. Step 1: Once the mobile app is clinically tested for efficacy in pivotal randomized controlled trial (RCT) and receives the regulatory approval or clearance, it becomes a mobile medical app (software as a medical device). Step 2: testing clinical efficacy of combining a pharmaceutical drug (ibuprofen structure is shown as an example of an analgesic drug) with the mobile medical app can lead to premarket application for the regulatory approval of drug-device combination product in which the mobile medical app is a medical device.