Riluzole

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 10.15.2021
Released 07.06.1999
Expires For CME 10.15.2024

Riluzole

Author: K K Jain MD†

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Riluzole

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Introduction

Historical note and terminology

Riluzole is a member of the benzothiazole class and is believed to be a glutamate antagonist. Several other glutamate antagonists (such as dextromethorphan and branched-chain amino acids) have been tried previously for the treatment of amyotrophic lateral sclerosis but without any success. Riluzole is the first drug to be approved for the treatment of amyotrophic lateral sclerosis; it received United States Food and Drug Administration approval in 1995 and was launched in several countries in 1996.

Pharmacology

Pharmacodynamics. The mode of action of riluzole is not known. The following pharmacologic properties may be related to its beneficial effect in amyotrophic lateral sclerosis:

	• An inhibitory effect on glutamate release.
	• Neuroprotective action of riluzole may be partly mediated by its increase of transporter-mediated glutamate uptake.
	• Inactivation of voltage-dependent sodium channels.
	• Ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors. Riluzole has been shown to be neuroprotective in experimental models of neuronal injury involving excitotoxic mechanisms. Transcranial magnetic stimulation has shown that riluzole reduces cortical excitability in patients with amyotrophic lateral sclerosis. This finding supports the view that attenuation of glutamate-related excitotoxicity is an important factor contributing to the beneficial effect. Riluzole has protective effects on dopamine neurons in vitro against neuronal injuries induced by impairment of cellular energy metabolism and oxidative stress. These results provide a basis for exploring the neuroprotective potential of riluzole in Parkinson disease.
	• Riluzole increased the amount and activity of heat shock factor 1 to boost the expression of heat shock proteins and glutamate transporter 1, providing neuroprotection under stress (15).
	• Results of experimental studies on neurons and myotubes indicate that one of the mechanisms of riluzole's therapeutic effect might be increasing the glucose transport rate in cells affected by amyotrophic lateral sclerosis (05).
	• A longitudinal study of the effect of riluzole therapy on cortical hyperexcitability in patients with amyotrophic lateral sclerosis by using transcranial magnetic stimulation combined with peripheral nerve function excitability found transient modulation of cortical and axonal hyperexcitability as compared with healthy controls, which accounted for modest clinical effectiveness (09).

Pharmacokinetics. Important points are as follows:

	• Riluzole is well absorbed following oral administration and has a bioavailability of 60%.
	• Pharmacokinetics are linear over a dose range of 25 to 100 mg given every 12 hours.
	• The mean elimination half-life is 12 hours after repeated doses.
	• Riluzole is 96% bound to plasma proteins.
	• Riluzole is metabolized to six major (and several minor) metabolites, some of which are pharmacologically active. Metabolism is mostly hepatic and consists of cytochrome P450-dependent hydroxylation and glucuronidation.
	• Excretion of riluzole is mainly renal as glucuronides.

Formulations. An oral liquid formulation, 5 mg/mL suspension, is now available and provides an important therapeutic option for patients with amyotrophic lateral sclerosis, as most of them are unable to swallow solid tablets due to disease-related dysphagia (06).

Delivery of riluzole to the brain. Entry of riluzole into the brain across the blood-brain barrier is restricted because it is a substrate of P-glycoprotein. A formulation of riluzole with lipid nanoparticles has been shown to improve delivery to the brain with greater efficacy than free riluzole in rats (03). Results of another animal experimental study indicate that nanoemulsion of riluzole for intranasal administration improves delivery to the brain and has the potential to reduce the dose of riluzole and avoid dose-related adverse events during treatment of amyotrophic lateral sclerosis (19).

Indications

Riluzole is indicated for the treatment of amyotrophic lateral sclerosis.

Off-label uses

	• A randomized, double-blind, placebo-controlled trial has shown some benefit in patients with cerebellar ataxia (21).
	• Riluzole has been reported as useful for the prevention of acute noise-induced hearing loss.
	• Riluzole has been used to treat psychiatric conditions in children, particularly obsessive-compulsive disorder. The dose of riluzole used in children achieved serum concentration levels like those observed in adults (12).
	• Autistic disorder. Riluzole, when used as an adjunctive therapy to risperidone, improved irritability in children with autism, but it also significantly increased appetite and weight gain (11).
	• Even when applied after a transient excitotoxic stimulus, riluzole can provide effective prevention of secondary excitotoxic damage to premotoneurons in spinal cord injury, although not to motoneurons that remain very vulnerable (22). A phase I trial is evaluating the safety and pharmacokinetic profile of riluzole as a neuroprotective agent in patients with spinal cord injury (04; 08).
	• A positive correlation has been observed between cognitive measures and regional cerebral glucose metabolism in a clinical trial, suggesting engagement of the glutamatergic system by riluzole. The findings support the main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole-treated group than in the placebo group and future larger and longer studies should test riluzole as a potential novel therapeutic intervention for Alzheimer disease (17).
	• A double-blind, placebo-controlled randomized trial of riluzole on patients with early cervical myelopathy did not show a significant change in the clinical outcome and diffuse tensor imaging (20).
	• In a systematic review and metaanalysis of placebo-controlled studies of riluzole on patients with neurodegenerative movement disorders, there was motor improvement in hereditary ataxia (16).
	• Exploratory findings of a randomized, double-blind, placebo-controlled, parallel trial offer some evidence that riluzole augmentation of an SSRI or SNRI may selectively improve hyperarousal symptoms without changes in overall posttraumatic stress disorder symptoms, depression, anxiety, or disability (23).
	• A clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures did not show any benefit of riluzole in minimizing neuropathy and suggests that it worsens neuropathy (24).

References

01: Andrews JA, Jackson CE, Heiman-Patterson TD, Bettica P, Brooks BR, Pioro EP. Real-world evidence of riluzole effectiveness in treating amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2020;21(7-8):509-18.** PMID 32573277
02: Bensimon G, Lacomblez L, Meininger V. A controlled clinical trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 1994;330:585-91. PMID 8302340
03: Bondi ML, Craparo EF, Giammona G, Drago F. Brain-targeted solid lipid nanoparticles containing riluzole: preparation, characterization and biodistribution. Nanomedicine (Lond) 2010;5(1):25-32. PMID 20025461
04: Chow DS, Teng Y, Toups EG. Pharmacology of riluzole in acute spinal cord injury. J Neurosurg Spine 2012;17(1 Suppl):129-40. PMID 22985379
05: Daniel B, Green O, Viskind O, Gruzman A. Riluzole increases the rate of glucose transport in L6 myotubes and NSC-34 motor neuron-like cells via AMPK pathway activation. Amyotroph Lateral Scler Frontotemporal Degener 2013;14(5-6):434-43. PMID 23834207
06: Dyer AM, Smith A. Riluzole 5 mg/mL oral suspension: for optimized drug delivery in amyotrophic lateral sclerosis. Drug Des Devel Ther 2016;11:59-64. PMID 28053507
07: Falcao de Campos C, de Carvalho M. Riluzole-induced recurrent pancreatitis. J Clin Neurosci 2017;45:153-4. PMID 28867362
08: Fehlings MG, Wilson JR, Frankowski RF, et al. Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial. J Neurosurg Spine 2012;17(1 Suppl):151-6. PMID 22985381
09: Geevasinga N, Menon P, Ng K, et al. Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS. Amyotroph Lateral Scler Frontotemporal Degener 2016:1-9. PMID 27249331
10: Georgoulopoulou E, Fini N, Vinceti M, et al. The impact of clinical factors, riluzole and therapeutic interventions on ALS survival: a population based study in Modena, Italy. Amyotroph Lateral Scler Frontotemporal Degener 2013;14(5-6):338-45. PMID 23373475
11: Ghaleiha A, Mohammadi E, Mohammadi MR, et al. Riluzole as an adjunctive therapy to risperidone for the treatment of irritability in children with autistic disorder: a double-blind, placebo-controlled, randomized trial. Paediatr Drugs 2013;15(6):505-14. PMID 23821414
12: Grant P, Farmer C, Song J, Kish T, Swedo S. Riluzole serum concentration in pediatric patients treated for obsessive-compulsive disorder. J Clin Psychopharmacol 2017;37(6):713-6. PMID 29045303
13: Ianiro G, Cammarota G, Milani A, Mettimano M, Gasbarrini A. Moderately severe acute pancreatitis associated with riluzole. J Clin Gastroenterol 2014;48(6):563. PMID 24356456
14: Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 1996;347(9013):1425-31. PMID 8676624
15: Liu AY, Mathur R, Mei N, Langhammer CG, Babiarz B, Firestein BL. Neuroprotective drug riluzole amplifies the heat shock factor 1 (HSF1)- and glutamate transporter 1 (GLT1)-dependent cytoprotective mechanisms for neuronal survival. J Biol Chem 2011;286(4):2785-94. PMID 21098017
16: Liu J, Wang LN. The efficacy and safety of riluzole for neurodegenerative movement disorders: a systematic review with meta-analysis. Drug Deliv 2018;25(1):43-8. PMID 29226728
17: Matthews DC, Mao X, Dowd K, et al. Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease. Brain 2021.** PMID 34145880
18: Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2012;3:CD001447. PMID 22419278
19: Parikh RH, Patel RJ. Nanoemulsions for intranasal delivery of riluzole to improve brain bioavailability: formulation development and pharmacokinetic studies. Curr Drug Deliv 2016;13(7):1130-43. PMID 26638977
20: Rajasekaran S, Aiyer SN, Shetty AP, Kanna RM, Maheswaran A, Shetty JY. Effectiveness of riluzole as a pharmacotherapeutic treatment option for early cervical myelopathy: a double-blinded, placebo-controlled randomised controlled trial. Eur Spine J 2016;25(6):1830-5. PMID 26596730
21: Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2015;14(10):985-91. PMID 26321318
22: Samano C, Nistri A. Mechanism of neuroprotection against experimental spinal cord injury by riluzole or methylprednisolone. Neurochem Res 2019;44(1):200-13. PMID 29290040
23: Spangler PT, West JC, Dempsey CL, et al. Randomized controlled trial of riluzole augmentation for posttraumatic stress disorder: efficacy of a glutamatergic modulator for antidepressant-resistant symptoms. J Clin Psychiatry 2020;81(6):20m13233.** PMID 33113596
24: Trinh T, Park SB, Murray J, et al. Neu-horizons: neuroprotection and therapeutic use of riluzole for the prevention of oxaliplatin-induced neuropathy-a randomised controlled trial. Support Care Cancer 2021;29(2):1103-10. PMID 32607598

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Riluzole

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Riluzole

Riluzole

Riluzole

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
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to access the full version.

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Also in This Category

Neurogenetics and genetic and genomic testing

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Chronic progressive external ophthalmoplegia

Serotonin syndrome

Drug-induced myasthenic syndromes

Distal myopathies

Acupuncture

Riluzole

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Chronic progressive external ophthalmoplegia

Serotonin syndrome

Drug-induced myasthenic syndromes

Distal myopathies

Acupuncture

This is an article preview.
Start a Free Account
to access the full version.