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Supplements A Managed Care Perspective on Scientific Advances in Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis: Disease State Overview
Darrell Hulisz, PharmD, RPh
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Disease-Modifying Treatment of Amyotrophic Lateral Sclerosis
Jordan Schultz, PharmD, MSCS, BCACP
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Disease-Modifying Treatment of Amyotrophic Lateral Sclerosis

Jordan Schultz, PharmD, MSCS, BCACP
There is no cure for ALS. Symptom management remains the foundation of care, and all efforts should be made to maintain quality of life.1,34 Patients should try to maintain normalcy in their lives, for instance, employment, social activities, and standard and preventive medical care (eg, dental care, vaccinations). Patients with ALS and their caregivers are at risk for depression, feelings of hopelessness, and anxiety as the disease progresses.1 Patients should prepare advanced directives for their care, including respiration and nutritional management, and end-of-life care.

Patients with ALS suffer from a wide range of symptoms that progressively worsen and eventually lead to ventilatory and nutritional compromise.1,34 Neither riluzole nor edaravone was shown to improve symptomology. Some of the common symptoms of ALS include:
  • Cramps
  • Fatigue
  • Spasticity
  • Sialorrhea
  • Pseudobulbar affect
  • Persistent saliva and bronchial secretions
  • Excessive or violent yawning
  • Laryngospasm
  • Pain
  • Emotional lability
  • Communication difficulties
  • Constipation
  • Depression
  • Insomnia
  • Anxiety
Muscle Cramps

Muscle cramps are a common problem for patients with ALS.35 Physical and massage therapies can reduce cramping.36 Exercise and stretching aid in cramp prevention. Pharmacologic therapies include levetiracetam, phenytoin, carbamazepine, baclofen, tizanidine, mexiletine, and others.34,37 However, despite some studies suggestive of efficacy, a Cochrane review did not find sufficient evidence to support the use of any intervention for muscle cramps in patients with ALS, although, in many cases, the studies were underpowered.38 Quinine has been removed as an agent for treating cramps because of a concern for significant and life-threatening AEs. Cinchonism is a cluster of symptoms of varying severity associated with quinine toxicity that includes tinnitus, dizziness, disorientation, nausea, visual changes, and auditory deficits. Quinine may cause QT prolongation and serious cardiac arrhythmias, including torsades de pointes.35

Fatigue

There are many causes of fatigue in patients with ALS, including muscle dysfunction, depression, poor sleep, immobility, or respiratory dysfunction.34 Resistance and respiratory exercises may improve endurance and reduce motor deterioration.39 Fatigue and asthenia may be AEs of riluzole therapy. These patients should weigh the modest survival benefit of riluzole therapy versus reduced quality of life because of fatigue. Modafinil has demonstrated improved endurance in ALS with 1 study showing that 76% of patients with ALS responded to therapy versus 14% of patients who received a placebo.40

Spasticity

Spasticity is characterized by tight or stiff muscles, a reduced ability to control spastic muscles, and hyperactive reflexes.41 For example, a muscle that is stretched responds with a contraction (stretch reflex) to try to maintain the muscle at a constant length. A hyperactive stretch reflex will cause the muscle to contract sooner and more vigorously. Moderate exercise and physical and occupational therapies can improve spasticity. 

Baclofen is considered the first-line therapy for spasticity and acts pre- and postsynaptically as a gamma aminobutyric acid (GABA) B agonist at the spinal level.41 AEs include systemic muscle relaxation, sedation, fatigue, and hepatotoxicity. Due to the potential for excessive drowsiness, oral baclofen should be used with caution in elderly patients. Terminating baclofen therapy should be done gradually. Intrathecal baclofen may be delivered by an implanted pump in select individuals.

Tizanidine is an alpha-2 agonist that can be used as a substitute for baclofen or can be added to other oral therapies.41 Tizanidine requires 3 or 4 doses per day, due to a short half-life. Tizanidine does not cause as much muscle weakness as other antispasmodic therapies, but is associated with sedation, moderate hypotension, xerostomia, muscle weakness, and hallucinations, and may prolong the QT interval. Other agents are less commonly used and include benzodiazepines, gabapentin, dantrolene, and botulinum toxin.

Sialorrhea

Excessive sialorrhea (drooling), seen in more than half of patients with ALS, results from a reduced ability to swallow and not increased saliva production.34,42 Anticholinergic medications are generally first-line therapies for patients with sialorrhea, although there are few clinical studies on the use of these agents in patients with ALS. These agents include:
  • Amitriptyline
  • Atropine
  • Diphenhydramine
  • Glycopyrrolate
  • Hyoscyamine
  • Oxitropium
  • Scopolamine
AEs of anticholinergic medications include sedation, constipation, and cognitive issues. Ultrasound-guided botulinum toxin injections into the parotid and submandibular glands reduced sialorrhea 3 to 7 days after the injections.42 Maximum saliva reduction occurs 2 to 4 weeks after treatment and lasts about 3.5 months, but may last up to 6 months.

Electron beam radiation to the submandibular gland and the lower part of the parotid gland provided benefit for 4 to 6 months.42 Electron beam radiation appears to be better tolerated than photon-based therapy.

Pseudobulbar Affect

Pseudobulbar affect (PBA) is excessive laughing or crying, or involuntary emotional expression. It affects 20% to 50% of patients with ALS.34 Antidepressants are frequently used, although it is not a mood disorder, and may include:
  • Tricyclic antidepressants (eg, amitriptyline)
  • Fluvoxamine
  • Nortriptyline
  • Fluoxetine
  • Sertraline
Another option for PBA includes the combination of dextromethorphan (DM) and quinidine (Q). This treatment has been studied and found to reduce the frequency and severity of laughing and crying behaviors in patients with ALS.43 DM likely exerts its effect on PBA via uncompetitive NMDA glutamate receptor antagonism and a sigma-1 receptor agonism. Q is added to the formulation at a relatively low dose simply to block hepatic metabolism of DM. The dose of Q is well below that used to treat cardiac arrhythmia. DM may also protect neurons from glutamatergic excitotoxicity. The AEs of DM/Q include dizziness, diarrhea, nausea, and urinary tract infection.

Emerging Therapies

Masitinib is an oral tyrosine kinase inhibitor that downregulates activated spinal cord glia cells and skeletal muscle mast cells through inhibition of c-Kit and CSF-1R. In the AB10015 study, masitinib administered as an add-on to riluzole to patients with ALS, having a baseline ALSFRS-R progression rate of less than 1.1 points/month, delayed progression-free survival by 25% and slowed decline of function (ALSFRS-R) by 27%, quality of life (ALSAQ-40) 34%, and FVC by 17%.44 A post hoc analysis suggested that earlier treatment of patients, whether progressing slowly or quickly, could stave off functional decline more effectively.45 However, in April 2018, the National Institute for Health and Care Excellence (NICE) in the United Kingdom adopted a negative opinion of masitinib and decline to authorize the agent for the treatment of ALS.46 In their view, the reliability of the data was not robust enough to support a registration (based on an inspection carried out on two of the main clinical investigation centers of the study). They felt the clinical relevance of the distinction made between patients with “normal” progression (85% of patients in the study) and those with “rapid” progression (15% of the patients) was not demonstrated. Furthermore, there was a suspicion of bias regarding the primary analysis of the ALSFRS score for patients who stopped the study prematurely. ALSFRS-R measures abilities such as walking, speech, hand control, and respiration. The company sponsoring this agent in trials was expected to address this decision and ask for reconsideration in July 2018.47

Other agents continue to be explored, including antisense oligonucleotides, although just for carriers of mutated SOD1 gene.18 However, as can be seen in Table 3, many disease-modifying therapies have been investigated over the years, but with little success.6 Fortunately, prospects for new therapies are improving, as new information is obtained on the molecular pathology of ALS.

Conclusions

ALS is a spectrum of motor system diseases for which adequate therapies are lacking. Riluzole has been the mainstay of active therapy for 2 decades. Recently, edaravone was approved in the United States and European Union based on improved functional score. It is unclear at this time if these improvements will translate to longer survival. Until the time that a truly remarkable drug for ALS is identified, people with ALS, and their caregivers, will be challenged by the wide array of symptoms facing these patients. It is incumbent on all members of the care team to provide appropriate support and counseling as the patient transitions through stages of their disease. 

Author affiliations: Clinical Pharmacy Specialist, Department of Pharmaceutical Care, University of Iowa Hospitals and Clinics; Adjunct Assistant Professor, Department of Neurology, Carver College of Medicine at University of Iowa; Adjunct Assistant Professor, Department of Pharmacy Practice and Sciences, University of Iowa College of Pharmacy, Iowa City, IA.
Funding source: This activity is supported by an educational grant from Mitsubishi Tanabe Pharma America, Inc.
Author disclosure: Dr Schultz has no relevant financial relationships with commerical interests to disclose.
Authorship information: Concept and design, drafting of the manuscript, and critical revision of the manuscript for intellectual content.
Address correspondence to: jordan-schultz@uiowa.edu.
Dr Schultz gratefully acknowledges David Modrak, PhD, for his contributions to the development of this article.
 
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