Gabapentin for the management of vismodegib-induced muscle cramps
2 Department of Internal Medicine, Gülhane Education and Research Hospital, Ankara, Turkey
3 Department of Neurology, Başkent University Adana Medical and Research Center, Adana, Turkey
Department of Dermatology, Gülhane Education and Research Hospital, Ankara
|How to cite this article:
Çaliskan E, Taşçı &, Bek S. Gabapentin for the management of vismodegib-induced muscle cramps. Indian J Dermatol Venereol Leprol 2017;83:505-506
Muscle cramps due to vismodegib treatment may be challenging and can cause treatment discontinuation in patients with basal cell carcinoma. Therefore, symptomatic approaches to relieve muscle cramps are necessary. With this regard, we report our findings from an incidental case with intractable cramps who presented to thedepartment of dermatology.
The patient was an 83-year-old man with a history of radiation exposure to scalp for tinea capitis in his childhood. He was treated many times with surgical excisions and twice with radiotherapy for multiple basal cell carcinomas on the scalp previously. On admission, we performed dermoscopy and detected 11 distinct lesions of obviousbasal cell carcinoma on scalp region. A crusted ulcerwas seenon the vertex. After confirming the diagnosis of basal cell carcinoma with biopsy for this lesion, vismodegib treatment was started [Figure - 1]. One month after the initiation of treatment, the patient reported severe disturbing cramps in his hands, legs and flanks, 2–4 times a day, mostly in the night, leading to sleep disturbance. He did not report any aggravating or relieving factor associated with the cramps. We intended to use amlodipine for his cramps, but the drug was contraindicated due to co-existing heart failure. Hence, magnesium was initiated at a dose of 365 mg/day. However, magnesium supplementation did not improve the symptoms even after 3 weeks. Approximately after 10 weeks of treatment with vismodegib, he presented with herpes zoster on his trunk. In addition to his antiviral treatment with valacyclovir, gabapentin 600 mg thrice a day was prescribed due to severe pain. One week after the treatment, he noticed aremarkable improvement in muscle cramps. To test any causal relationship between gabapentin use and cramp relief, we interrupted and re-initiated the treatment twice and observed cessation and alleviation of the cramps. Consequently, gabapentin was reduced to 600 mg once a day as the adequate dose and cramp frequency decreased to once or twice a week. Pigmented basal cell carcinomas disappeared clinically and dermoscopically nearly by the 6th month of treatment. Dermoscopic improvement of the lesions during the treatment course revealed the efficasy of vismodegib. However, we continued this treatment for the ulcerated lesion on vertex. Clinical improvement was confirmed with the absence of basal cell carcinoma histologically and vismodegibwas terminated by the 9th month of treatment. After the cessation of vismodegib treatment, the patient required gabapentin less frequently for another month and he was free of cramps for the next 5 months in the follow-up period.
|Figure 1: Pretreatment image of the patient with pigmented and ulcerated basal cell carcinomas|
Pathophysiology of muscle cramps caused by vismodegib has not been defined clearly. Cell membrane calcium channel activation by the drug was proposed  and some benefits from amlodipine treatment were reported in a vismodegib-treated case series.
Muscle cramps arise from discharges of motor nerves rather than within the muscle itself. High-frequencydischarges leading to cramps can be driven by the central nervous system or generated spontaneously within the peripheral nervous system. Despite the facts that support the involvement of both central and peripheral nervous systems, evidence favors a peripheral origin. Previously, regulation of myelin formation in the peripheral nervous system by hedgehog signaling has been shown. Recently, theimportance of sonic hedgehog and its receptor complex has been documented in adult peripheral nerve regeneration. Moreover, sonic hedgehog and smoothened transcript levels were found increased after injury and the knockdown of sonic hedgehog resulted in impaired regeneration. Considering the importance of hedgehog signaling in nerve regeneration and myelination, inhibition of this pathway might be associated with the onset of crampsand/or neuropathy.
Indeed, drug-related peripheral neuropathies were recordedin more than 5% ofpatients receiving vismodegib. However, neuropathy may not be evident in all cases. In another study, it was concluded that 60% of patients reporting muscle cramps without manifesting neuropathic complaints have smallfiber neuropathy.
Mechanism of action of gabapentin for muscle cramps has not been clearly defined, but it probably has effects on both central and peripheral nervous systems. In an open-label trial, 2-week gabapentin treatment reduced the number of cramps by more than a half in 85.7% of patients. Moreover, after 3 months, cramps disappeared in 100% of the patients. Although such a benefit from gabapentin was not specifically tested in randomized controlled trials, it is commonly prescribed for muscle cramps by neurologists. In addition, disabling cramps were reported in up to two-thirds of the patients with some sort of neuropathy which is the primary clinical indication for gabapentin.
In conclusion, central and peripheral nervous system injury might be involved in the mechanism of vismodegib-induced muscle cramps, suggesting the need for clinical research with the available options for neuropathies. In the meantime, we believe that gabapentin can be considered an option for the patients with intractable cramps so that treatment discontinuation could be prevented. However, further randomized trials are needed to prove this theory.
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Conflicts of interest
There are no conflicts of interest.
Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012;366:2180-8.[Google Scholar]
Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Connor T, et al. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 2012;151:414-26.[Google Scholar]
Ally MS, Tang JY, Lindgren J, Acosta-Raphael M, Rezaee M, Chanana AM, et al. Effect of calcium channel blockade on vismodegib-ınduced muscle cramps. JAMA Dermatol 2015;151:1132-4.[Google Scholar]
Miller TM, Layzer RB. Muscle cramps. Muscle Nerve 2005;32:431-42.[Google Scholar]
Yoshimura K, Takeda S. Hedgehog signaling regulates myelination in the peripheral nervous system through primary cilia. Differentiation 2012;83:S78-85.[Google Scholar]
Martinez JA, Kobayashi M, Krishnan A, Webber C, Christie K, Guo G, et al. Intrinsic facilitation of adult peripheral nerve regeneration by the Sonic hedgehog morphogen. Exp Neurol 2015;271:493-505.[Google Scholar]
Berlin J, Bendell JC, Hart LL, Firdaus I, Gore I, Hermann RC, et al. A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin Cancer Res 2013;19:258-67.[Google Scholar]
Lopate G, Streif E, Harms M, Weihl C, Pestronk A. Cramps and small-fiber neuropathy. Muscle Nerve 2013;48:252-5.[Google Scholar]
Serrao M, Rossi P, Cardinali P, Valente G, Parisi L, Pierelli F. Gabapentin treatment for muscle cramps: An open-label trial. Clin Neuropharmacol 2000;23:45-9.[Google Scholar]
Maxwell SK, Kokokyi S, Breiner A, Ebadi H, Bril V, Katzberg HD. Characteristics of muscle cramps in patients with polyneuropathy. Neuromuscul Disord 2014;24:671-6.[Google Scholar]