Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder which can affect the muscles involved in swallowing, speaking, breathing, and ambulation (1). This Fast Facts discusses pharmacologic management strategies for patients with ALS; see Fast Fact #300 for non-pharmacologic management strategies and Fast Fact #299 for management of sialorrhea specifically.

Pseudobulbar Affect (PBA): This term refers to disordered emotional expressions caused by disruption of cortico-pontine-cerebellar tracts. It typically manifests as inappropriate and uncontrollable laughing or crying inconsistent with the patient’s mood and can be socially debilitating.

• The combination drug dextromethorphan/quinidine is the only FDA approved treatment of PBA. Its mechanism of action for pseudobulbar affect seems to be related to its anti-glutamatergic and anti-NMDA actions (2). The recommended dose is 20 mg dextromethorphan/10 mg quinidine twice daily. The rationale for combination therapy is that dextromethorphan is rapidly metabolized by an enzyme that is inhibited by quinidine. While the combination drug reduces pill burden, it is expensive, hence having the patient take both medications separately can be a less costly option (3).
• Tricyclic and SSRI anti-depressants have shown benefit, but clinical trial data is limited by small numbers of patients and poor standardization of PBA diagnostic and severity criteria (4).

Depression      Major depressive disorder is a common in ALS. Selective serotonin reuptake inhibitors are often used; however, there are no randomized controlled trials specific to ALS (5). Although the American Academy of Neurology advocates treatment of depression in ALS, there are insufficient data to recommend any specific pharmacotherapy (6).

Spasticity        Damage to the upper motor neurons in ALS leads to spasticity, which can be associated with cramps and incoordination of movement. There are no high-quality, controlled trials evaluating pharmacologic treatments for spasticity (7) and clinicians should be aware that some degree of spasticity can be useful for maintenance of posture. Although baclofen and tizanidine are both commonly used, experts tend to reserve tizanidine for more severe cases (5).

• Baclofen: initial dosing is 5-10 mg BID-TID; doses up to 120 mg per day may be needed (8).
• The starting dose for tizanidine is 2-4 mg BID with 24 mg as the maximum daily dose (8).
• Intrathecal baclofen pumps are considered only for patients with medically refractory spasticity.
• Mexiletine has demonstrated effectiveness in alleviating muscle cramps in controlled trials (9).

Pain     Spasticity, muscle spasms, joint stiffness and skin breakdown related to immobility are all potential sources of pain in ALS, which occurs in the later stages in up to 80% of patients (11). There is insufficient evidence on which to base specific recommendations for the treatment of pain in ALS. However, as in other conditions, non-opioid analgesics and anti-inflammatory medications are generally considered first-line. When these medications fail, opioids are used commonly.

Dyspnea          Air hunger due to ventilatory failure is common in the later stages of ALS, occurring in up to 85% of patients (11). According to the American Academy of Neurology, there are insufficient data to support specific treatments for dyspnea in ALS (5). In addition to non-invasive ventilation, opioids are used commonly to relieve air hunger. One small, non-randomized prospective study demonstrated that morphine appears to be both safe and effective in this patient population (12).

Disease-modifying agents There currently is no medication to cure, stop, or reverse the progressive disease course in ALS. There are, however, a few FDA approved disease-modifying agents (13). Obtaining insurance coverage and out of pocket cost for these medications may prohibit their use for some or add to their financial and emotional stress (14,15). Persons with ALS may choose not to initiate medications or continue these medications after weighing the potential benefits and burdens associated.

Although there are no published guidelines, it is reasonable to discontinue these medications when a person living with ALS becomes ventilator-dependent, or at the time of hospice enrollment. ●           Riluzole is an oral tablet shown to prolong time to tracheostomy and death by about 2-3 months (13,16). It may not relieve ALS-associated symptoms or improve quality of life and side effects such as fatigue or elevated liver function can warrant discontinuation.

• Edaravone is available in oral and intravenous formulations (17). It has been shown to improve functional scores but does not appear to prolong time to ventilation or death (18,19). Benefits of use may be limited to one year. It appears to be well tolerated except for headaches, dermatitis, bruising, and gait disturbances in some (20).
• Sodium phenylbutyrate/taurusodiol (Relyvrio®) is an oral solution that has been shown to prolong survival by almost 7 months (21,22). Side effects are predominantly gastrointestinal (23).

References

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   doi:10.1001/jama.2018.11439.
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6. American Academy of Neurology. AAN Summary of Evidence-based Guideline for Clinicians. The Care of the Patient with Amyotrophic Lateral Sclerosis: Multidisciplinary Care, Symptom Management, and Cognitive/Behavioral Impairment.
   https://www.aan.com/Guidelines/Home/GetGuidelineContent/377. Updated October 2009. Accessed May 1, 2015
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9. Oskarsson B, Moore D, et al. Mexiletine for muscle cramps in amyotrophic lateral sclerosis: a randomized double-blind crossover trial. Muscle and Nerve 2018; 58:42-48.
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11. Oliver D. The quality of care and symptom control – the effects on the terminal phase of ALS/MND. J Neurol Sci. 1996;139(Suppl.):134-136.
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15. Chen JJ. Overview of current and emerging therapies for amytrophic lateral sclerosis. Am J Manag Care. 2020;26(9 Suppl):S191-S197. doi:10.37765/ajmc.2020.88483
16. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;2012(3):CD001447. doi:10.1002/14651858.CD001447.pub3
17. Hardiman O, van den Berg LH. Edaravone: a new treatment for ALS on the horizon? Lancet Neurol 2017; 16(7):490-491.
18. Witzel S, Maier A, Steinbach R, et al. Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis. JAMA
    Neurol. 2022;79(2):121-130. doi:10.1001/jamaneurol.2021.4893
19. Shefner J, Heiman-Patterson T, Pioro EP, et al. Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19). Muscle Nerve. 2020;61(2):218-221. doi:10.1002/mus.26740
20. Genge A, Pattee GL, Sobue G, et al. Oral edaravone demonstrated a favorable safety profile in patients with amyotrophic lateral sclerosis after 48 weeks of treatment. Muscle Nerve.
    2023;67(2):124-129. doi:10.1002/mus.27768
21. Paganoni S, Macklin EA, Hendrix S, et al. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020;383(10):919-930. doi:10.1056/NEJMoa1916945
22. Paganoni S, Watkins C, Cawson M, et al. Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes. Muscle Nerve. 2022;66(2):136-141. doi:10.1002/mus.27569
23. Johnson SA, Fang T, de Marchi F, et al. Pharmacotherapy for Amyotrophic Lateral Sclerosis: A Review of Approved and Upcoming Agents. Drugs. 2022;82(13):1367-1388.
    doi:10.1007/s40265-022-01769-1

Conflict of Interest: The authors have disclosed no relevant conflicts of interest.

Version History: First electronically published June 2015; updated in June 2021; and again in March 2023 to reflect changes in disease-modifying therapies.