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Medication

Medication Summary

Four mechanism-based medications are approved in the United States.

The glutamate pathway antagonist riluzole is the first medication that has shown efficacy in extending life in amyotrophic lateral sclerosis (ALS). The American Academy of Neurology (AAN) guideline recommends that riluzole be offered to patients with ALS.^[2]

The pyrazolone free radical scavenger, edaravone (Radicava), was approved to slow the functional decline in patients with ALS.^[182] This medication was not approved by the European Drug Agency, as the efficacy was demonstrated in a small sub-population of carefully-selected patients, and could not be generalized.

The FDA approved sodium phenylbutyrate/taurursodiol (Relyvrio) in September 2022.^{[183, 184, 185]}

Tofersen, the first treatment to target ALS with a mutation in the SOD1 gene, was approved in April 2023.^[186]

Other medications may be useful for relief of symptoms associated with ALS. These include the following:

Muscle relaxants to relieve spasticity
The combination of dextromethorphan and quinidine to decrease emotional lability of pseudobulbar affect
Anticholinergics and sympathomimetics for sialorrhea
Mucolytics for thickened secretions
Lorazepam for anxiety
Selective serotonin reuptake inhibitors (SSRIs) for depression
Nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol (Ultram), ketorolac (Toradol), morphine (immediate or extended release), or transdermal fentanyl, for pain

Class Summary

Riluzole is thought to counteract excitatory amino acid (glutaminergic) pathways, noncompetitively block N-methyl-D-aspartate (NMDA)–mediated responses, and inactivate voltage-dependent sodium channels. Its exact mechanism of action in ALS is unknown.

Riluzole (Exservan, Rilutek, Tiglutik)

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Riluzole (Rilutek)

Benzothiazole agent that is well absorbed, with average oral bioavailability of 60% and mean elimination half-life of 12 hours; steady state is reached within 5 days with multiple dose administration. Metabolism occurs in the liver (P450-dependent glucuronidation and hydroxylation), with 6 major and a few minor metabolites produced. It is available as a tablet, oral suspension, or oral film that dissolves on the tongue. The recommended dosage for riluzole is 50 mg twice daily. Riluzole is used for extension of time to death or tracheostomy.

Class Summary

Tofersen is an antisense oligonucleotide that causes degradation of superoxide dismutase 1 (SOD1), which is the second most common and best understood genetic cause of ALS. Tofersen binds to SOD1 mRNA, allowing for its degradation by RNase-H in an effort to reduce synthesis of SOD1 protein production.

Tofersen (Qalsody)

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Tofersen is an antisense oligonucleotide that blocks production of mSOD1 in patients with SOD1 ALS. It has been approved by the FDA for patients with SOD1 ALS. It is administered intrathecally into the spinal fluid, via a lumbar puncture. Initially, three doses are given 14 days apart, and then maintenance injections are given every 28 days.

Class Summary

Several drugs that decrease oxidative stress have been approved by the FDA for treatment of ALS. The precise mechanism by which by which these drugs exerts therapteutic effects in patients with ALS is unknown.

Edaravone (Radicava, Radicava ORS)

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Edaravone is a pyrazolone free radical scavenger; mechanism by which the drug exerts its therapeutic effects in ALS is unknown. It is theorized to decrease effects of oxidative stress, a likely factor in the onset and progression of ALS. Administration is by IV infusion, requiring it to be given by a healthcare professional and monitoring for infusion-related reactions. An oral formulation is also available.

Sodium phenylbutyrate/taurursodiol (Relyvrio)

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The precise mechanism of action in patients with ALS is unknown. Sodium phenylbutyrate is a histone deacetylase inhibitor shown to upregulate heat shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress. Taurursodiol recovers mitochondrial bioenergetics deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the cell’s apoptotic threshold.

Class Summary

These agents relieve spasticity and muscle spasms in patients with symptoms of limb stiffness.

Baclofen (Lioresal, Gablofen, Lyvispah)

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Baclofen is metabolized in the liver and excreted primarily in urine. This agent is not a controlled substance under the Drug Enforcement Administration (DEA).

Class Summary

Alpha2 adrenergic agonists decrease excitatory input to alpha motor neurons (which are a type of lower motor neuron [LMN]). Common alpha2 adrenergic effects include decrease release of acetylcholine and norepinephrine, contraction of sphincters in the gastrointestinal tract, and inhibition of lipolysis.

Tizanidine (Zanaflex)

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Tizanidine is a centrally acting muscle relaxant metabolized in the liver and excreted in urine and feces. It is used in patients with predominantly upper motor neuron (UMN) involvement. It is not a DEA-controlled substance.

Class Summary

The combination of dextromethorphan and quinidine is shown to decrease emotional lability of pseudobulbar affect (PBA).

Dextromethorphan and quinidine (Nuedexta)

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Dextromethorphan is a sigma-1 receptor agonist and an uncompetitive NMDA receptor antagonist. Quinidine increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P4502D6, which catalyzes a major biotransformation pathway for dextromethorphan. The mechanism by which dextromethorphan exerts therapeutic effects in patients with PBA is unknown.

This combination is indicated for PBA and symptoms associated with ALS (and multiple sclerosis) that result in involuntary, sudden, and frequent episodes of laughing and/or crying. It is available as a capsule containing dextromethorphan 20 mg and quinidine 10 mg.

Questions

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Media Gallery

The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities).
The genetic/environmental/age- and time-dependent interactions hypothesis for amyotrophic lateral sclerosis (ALS). Risk factors operate upstream to a putative biochemical transformation (likely an acquired nucleic acid or protein change), which causes the appearance of altered proteins or nucleic acids or abnormal quantities of normal proteins or nucleid acids. These agents spread within the motor system and cause the downstream disintegration of the motor system and the downstream biochemical, histologic, and clinical consequences of ALS. (Adapted from Armon C. What is ALS? In: Amyotrophic Lateral Sclerosis: A Patient Care Guide for Clinicians. Bedlack RS, Mitsumoto H, Eds. Demos Medical Publishing, New York, 2012:1-23)
Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.

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Table 1. Familial Forms of ALS^[77, 78, 79]

Table 1. Familial Forms of ALS ^{[77, 78, 79]}

Gene	Locus	Protein	Inheritance
SOD1 (ALS1)	21q22.11	Superoxide dismutase 1 (SOD1)	AD*
ALS2	2q33	Alsin (ALS2)	Juvenile/AR**
ALS3	18q21	Unknown	AD
ALS4	9q34	SETX	Juvenile/AD
ALSS	15q15	SPG11	Juvenile/AR
FUS (ALS6)	16p11.2	FUS	AD
ALS7	20ptel-p13	Unknown	AD
ALS8	20q13.3	VABP	AD
ALS9	14q11.2	Angiogenin (ANG)	AD
TARDBP (ALS10)	1p36.2	TAR DNA-binding protein (TARDBP)	AD
ALS11	6q21	FIG4	AD
ALS12	10p13	OPTN	AD; AR
ALS13	12q24	ATXN2	AD
ALSX	Xp11	UBQLN2	X-linked
C9orf72 (ALS-FTD)	9q21-22	C9ORF72	AD
ALS-FTD	9p13.3	SIGMAR1	AD; Juvenile/AR
PFL1	17p13.2	Profilin 1	AD
AD–autosomal dominant; *AR—autosomal recessive

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Author

Carmel Armon, MD, MSc, MHS Chair, Department of Neurology, Assaf Harofeh Medical Center, Tel Aviv University Sackler Faculty of Medicine, Israel

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Sigma Xi, The Scientific Research Honor Society

Disclosure: Received research grant from: Neuronix Ltd, Yoqnea'm, Israel<br/>Received income in an amount equal to or greater than $250 from: JNS - Associate Editor. UpToDate - Author Royalties.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Nicholas Lorenzo, MD, CPE, MHCM, FAAPL Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Former Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, CPE, MHCM, FAAPL is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association for Physician Leadership

Disclosure: Nothing to disclose.

Acknowledgements

Neil A Busis, MD Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Amyotrophic Lateral Sclerosis Medication

Medication Summary

Glutamate Inhibitors