Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia–Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability

Abstract

BACKGROUND: Patients susceptible to malignant hyperthermia (MH) may experience disabling manifestations of an unspecified myopathy outside the context of anesthesia, including myalgia, fatigue, or episodic rhabdomyolysis. Clinical observations suggest that oral dantrolene may relief myopathic symptoms in MH-susceptible (MHS) patients. However, high-dose oral dantrolene has been associated with severe hepatotoxicity. METHODS: In a retrospective database review (1994–2018), we investigated a cohort of patients who were diagnosed as MHS by a positive caffeine-halothane contracture test (CHCT), had myopathic manifestations, and received oral dantrolene. Our aim was to investigate the occurrence of serious adverse effects and the adherence to oral dantrolene therapy. We also explored factors associated with self-reported clinical improvement, considering as nonresponders patients with intolerable adverse effects or who reported no improvement 8 weeks after starting treatment. RESULTS: Among 476 MHS patients with positive CHCT, 193 had muscle symptoms, 164 started oral dantrolene, 27 refused treatment, and 2 were excluded due to abnormal liver function before starting therapy. There were no serious adverse effects reported. Forty-six of 164 patients (28%; 95% confidence interval [CI], 22%–35%) experienced mild to moderate adverse effects. Twenty-two patients (22/164, 13%; 95% CI, 9%–19%) discontinued treatment, among which 16 due to adverse effects and 6 due to lack of improvement. One hundred forty-two patients (87%; 95% CI, 80%–90%) adhered to therapy and reported improvement of myalgia (n = 78), fatigue (n = 32), or rhabdomyolysis/hiperCKemia (n = 32). The proportion of responders was larger among patients with MH history than among those referred due to a clinical myopathy with nonpertinent anesthetic history (97% vs 79%, respectively; 95% CI of the difference, 8.5–28; P < .001). Patients with a sarcoplasmic reticulum Ca2+ release channel ryanodine receptor gene (RYR1) variant had higher odds of responding to dantrolene treatment (OR, 6.4; 95% CI, 1.3–30.9; P = .013). Dantrolene median dose was 50 (25–400) and 200 (25–400) mg·day–1 in responders and nonresponders, respectively. CONCLUSIONS: We found that oral dantrolene produced no serious adverse effects within the reported dose range, and was well tolerated by most MH-susceptible patients presenting myopathic symptoms. Our study provides dosing and adverse effect data as a basis for further randomized controlled clinical trials to determine the efficacy of oral dantrolene for symptomatic relief in MHS-related myopathies.

Oral Dantrolene Reduces Myalgia and Hyperckemia in a Child with RYR1-Related Exertional Myalgia/Rhabdomyolysis

“…Multiple descriptions of oral low-dose dantrolene in adults with both MHS and ERM indicate an improvement in muscle symptoms and good tolerability, without significant adverse events [5][6][7][8]. To the best of our knowledge, this is the first report of the use of dantrolene in a pediatric patient for controlling anesthesia-independent muscle symptoms.…”

“…In individuals with MHS, the use of oral dantrolene has been reported to control anesthesia-independent muscle symptoms, such as awake MH and ERM since the 1980 s [5][6][7]. In 2023, Moreno et al evaluated the use of oral dantrolene for myopathic symptoms in 164 MHS patients with muscle symptoms, showing that the drug was well-tolerated, with no serious adverse effects, and 87% of patients adhered to therapy and reported improvement of myalgia, fatigue, or rhabdomyolysis/hiperCKemia [8].…”

Association of malignant hyperthermia and exertional heat illness in young athletes: An analysis of awareness among clinical and athletic first responders

“…Also, due to inevitable delays in the administration of dantrolene, oral doses may be offered to MH or MHS patients so that they can be administered at the earliest possible time to avert a crisis. [ 23 ]…”