US Pharm. 2009;34(8):HS10-HS12.
“Today, I consider myself the luckiest man on the face of the earth.”1 These were the famous words of Lou Gehrig, one of the greatest baseball players of all time. Less than two years later, he was laid to rest because of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. ALS is a progressive motor neuron disease that leads to respiratory distress, muscle deterioration, eating difficulties, and death. Other notable people with ALS include Henry A. Wallace (vice president under Franklin D. Roosevelt) and Jon Stone (co-creator of Sesame Street).
Etiology
The worldwide prevalence of ALS is 6 to 8 per 100,000 people.2 It is estimated that 22,600 to 30,000 Americans were diagnosed with ALS in 2000.2 Since there is no mandatory reporting of ALS, these numbers may not accurately reflect its incidence in the U.S. population. Death usually occurs within 3 to 5 years.3 However, approximately 10% of patients will live more than 10 years, as in the case of Stephen Hawking, the British theoretical physicist. Approximately 5 of every 100,000 deaths of people over the age of 20 years in the United States results from ALS.4
Epidemiology
Although ALS is thought to have a uniform distribution across the world, recent data suggest a higher incidence in Europeans and North Americans. This same data also suggest a lower incidence among Africans, Asians, and Hispanics.2,5 Between 40 to 70 years of age, ALS is more frequently diagnosed in men than in women (1.6:1). As age increases above 70 years, that ratio approaches 1:1. Age of onset is typically between 55 to 65 years of age, and the only known risk factors are gender and an increase in age.2,4 Interestingly, hyperlipidemia may have neuroprotective properties and prolong survival in patients with ALS.6
Types of ALS
There are two types of ALS, sporadic and familial. Both have the same signs, symptoms, and prognosis, with the primary difference being the underlying cause.
Sporadic ALS: Sporadic ALS accounts for 90% to 95% of all cases. Four main causes have been hypothesized to cause sporadic ALS: oxidative damage, apoptosis (programmed cell death), glutamate-mediated excitotoxicity, and protein aggregation. Other possible causes include chronic inflammation and autoimmune processes. While the cause of sporadic ALS is still unknown, it may not be due to any single factor.7
Familial ALS: The remaining 5% to 10% of ALS cases are familial, where genetics plays an important role. Of these, 20% are caused by a mutation on the gene encoding superoxide dismutase 1 (SOD1). The remaining 80% are caused by unknown genetic mutations.8
Diagnosis
Signs and Symptoms: Patients present with signs and symptoms of upper motor neuron (UMN) and lower motor neuron (LMN) degradation, which are consistent with the different neurologic regions affected: the bulbar, cervical, lumbar, and thoracic regions. These include difficulties in speech and swallowing, uncontrollable laughing or crying at inappropriate times, respiratory failure, and weakness/wasting of the arms and legs.3,9 Respiratory depression and hypercapnia (higher than normal levels of CO2 in the blood) are typically the cause of death.3
El Escorial Criteria for Diagnosis: A detailed history and physical examination must show clinical signs and symptoms of both UMN and LMN degeneration. A complete list of inclusion and exclusion criteria is shown in TABLE 1.10
Rating Scales: The most commonly used is the ALS Functional Rating Scale (ALSFRS). The ALSFRS evaluates 10 areas of functioning in patients, including speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bedclothes, walking, climbing stairs, and breathing.11
Treatment
Riluzole: Riluzole (Rilutek) is the only FDA-approved medication for the treatment of ALS. It is available as a 50-mg tablet that is taken twice daily.12 It is proposed that excess glutamate (an excitatory neurotransmitter) reaches toxic concentrations in the synapses, causing the neurons in the central nervous system to die. Riluzole is an antiglutamate agent that is thought to exhibit its action through direct blocking of glutamate release, noncompetitive blocking of the N-methyl-d-aspartate acid receptor, and direct action on voltage-dependent sodium channels.13,14
Two trials confirm that taking riluzole prolongs survival and slows disease progression.14,15 At the end of 12 and 21 months, riluzole showed a 38.6% and 19.4% reduction in mortality, respectively, when compared to placebo in the first trial.15 The second trial compared placebo to 50 mg, 100 mg, and 200 mg daily in divided doses. Comparing the risk-to-benefit ratio, the 100 mg daily dose (50 mg twice daily) had an acceptable safety profile and showed a 35% decrease in death or tracheostomy (a surgical airway made in the trachea) at 18 months as compared to placebo.14
The most common adverse events include asthenia (loss of strength without associated muscle loss; 14%-26%), nausea (12%-21%), dizziness (4%-11%), and an elevation of liver enzymes (8%). The rise in liver enzymes can surpass three times the upper normal limit (>105 units/L), but levels return to normal once riluzole is discontinued.14,16 It is recommended that alanine aminotransferase (ALT) be monitored at baseline, monthly for 3 months, every 3 months for the next 9 months, and then periodically thereafter.12 Patients may also experience dizziness, vertigo, and somnolence.12
Currently there are no clinical trials studying drug–drug interactions with riluzole. However, there is an increased potential of hepatotoxicity when it is given with other hepatotoxic medications.16
Symptom Management
Many patients fear the loss of control. It is important for the caregiving team to reassure the patient that symptoms can be managed through medication and nonmedication therapies.9,17,18
Nutrition and Difficulty Swallowing: As ALS progresses, patients experience greater difficulty in swallowing. A few tips to help with swallowing include changing food consistency, tilting the chin towards the chest when swallowing, and swallowing a few times per bite. As swallowing becomes increasingly difficult, the concern shifts to the patient’s nutritional status. Good nutritional status will help the patient maintain a higher quality of life. A percutaneous endoscopic gastrostomy (PEG) tube may be offered to patients who are experiencing weight loss. (It involves placing a tube into the stomach through the abdominal wall.)9,17,18
Muscle Cramps: Patients may experience muscle cramps ranging in severity from mild to severe. Adequate hydration and stretching exercises are the best preventive measures for cramps. If cramps are severe, quinine sulfate, baclofen, dantrolene, gabapentin, benzodiazepines, or carbamazepine may be prescribed. Vitamin E 400 IU twice daily and magnesium supplement 5 mmol 3 times daily may also be recommended.9,17,18
Respiratory Management: Respiratory depression is an indicator of disease progression and should be handled aggressively. The patient and caregiver need to discuss respiratory management with the physician every 3 months since the patient’s desire for life-sustaining treatment may change over time. Treatment options range from noninvasive positive pressure ventilation (NIPPV) for symptomatic relief to tracheostomy for long-term survival.9,17,18 If the patient is experiencing an increase in shortness of breath due to a decline in lung function, breaks throughout the day or NIPPV may be beneficial.9
Sialorrhea and Secretions: Sialorrhea (excessive salivation or drooling) due to a decrease in facial muscle tone and involuntary swallowing of saliva are common. This can be very frustrating and embarrassing. If drooling becomes bothersome, a trial of amitriptyline, hyoscyamine, atropine, diphenhydramine, glycopyrrolate, or scopolamine may be tried.9,17,18 If these fail, botulinum toxin injected directly into the salivary gland may be useful.19 If the saliva is thick and phlegmlike, an increase in fluid intake, humidified air, or beta-blocker therapy (propranolol or metoprolol) may be beneficial.9,17,18
Pseudobulbar Affect: At times, patients may find that they cannot control their emotions and may start laughing or crying uncontrollably at inappropriate times. Treatment includes amitriptyline and fluvoxamine (a selective serotonin reuptake inhibitor [SSRI]).9,17,18 A new combination agent consisting of dextromethorphan and quinidine has shown promise in a phase II/III clinical trial for decreasing pseudobulbar symptoms.20
Pain: Patients may experience pain from joint immobilization, skin breakdown, and muscle spasms. Frequent changing of position can help decrease skin breakdown and improve joint immobilization. If pain still occurs, nonsteroidal anti-inflammatory drugs (NSAIDs) should be the first option. Opioids should be reserved for pain that is nonresponsive to NSAID therapy. There are no specific recommendations for the choice of NSAID or opioid therapy.17,18
Fatigue: Fatigue may be due to general muscle wasting or a decrease in respiratory function. Additionally, as nerves die, the remaining nerves must take their place, increasing the burden placed on these remaining nerves. Taking life easy, with naps and breaks throughout the day, can be an effective treatment.9 Methylphenidate, pyridostigmine, amantadine, and pemoline may provide short-term relief.9 A recent study of modafinil showed promising results. Patients experienced a decrease in daytime sleepiness and fatigue and an increase in attention, alertness, and focus.21
Constipation: Constipation can significantly decrease a patient’s quality of life. Constipation can be caused by a decrease in fluid intake, decreased physical activity, diet, and numerous medications. Increases in fluid and fiber intake, along with an increase in activity, if appropriate, are the first steps in prevention. For acute constipation, nonprescription laxatives, suppositories, and Fleet enemas may be helpful. No specific product recommendations have been made for the treatment of acute constipation. Stool softeners and osmotic laxatives can be effective for long-term therapy.9,17
Depression: Depression, which affects up to 44% of patients, can significantly impact a patient’s quality of life and decision making toward life-sustaining treatment in the terminal phase of the disease.22 There are currently no clinical trials assessing the effectiveness of different antidepressants, but treatment in clinical practice is fairly consistent.17,18 By taking advantage of the common side effects of drowsiness and dry mouth, amitriptyline should be first-line therapy in patients who are experiencing insomnia and/or sialorrhea. If treatment fails or if the patient does not need to take advantage of amitriptyline’s side effects, SSRIs such as sertraline, fluoxetine, and paroxetine may be used. Psychotherapy is an essential part of any treatment for depression and can help improve a patient’s quality of life.9,17,18,22
Anxiety: Anxiety can affect up to 30% of patients with ALS.22 While there are no trials assessing the effectiveness of different treatments, clinical practice includes the use of benzodiazepines such as lorazepam, diazepam or alprazolam, and buspirone.9,17,18,22
Dysarthria: Almost all patients will experience dysarthria (speech difficulties) at some point during the course of the disease. Since there are no medications available for this, speech therapists may help maintain verbal communication. Slow speaking and overexaggeration of words may be helpful. Writing boards and electronic communication devices may be useful tools if verbal communication becomes too difficult.9,17,18
Sleep Disturbances: Sleep disturbances are typically a secondary problem. Causes include sleep apnea, restless legs syndrome, depression, anxiety, pain, drooling, and not being able to turn in bed. A sleep study may be necessary. If all secondary causes are ruled out, short-acting sedatives such as chloral hydrate 250 to 500 mg, diphenhydramine 50 to 100 mg, or flurazepam 15 to 30 mg may be used sparingly.17,18 In addition, zolpidem or temazepam may be used.9
Clinical Trials
Many medications have shown promise in clinical trials performed on genetically altered mice with ALS symptoms. However, only riluzole has shown benefit in human clinical trials. All other medications have either shown no significant difference or were harmful to patients by accelerating their decline when compared to placebo. Although not a comprehensive list, verapamil, lamotrigine, high-dose vitamin E, gabapentin, topiramate, celecoxib, minocycline, TCH346 (a tricyclic selegiline analogue), and subcutaneous insulin-like growth factor type 1 (IGF-1) have all failed in clinical trials.23-31
Role of the Pharmacist
Patients taking riluzole should be counseled to take 50 mg twice daily on an empty stomach (1 hour before or 2 hours after meals). The tablet may be crushed and mixed with one-half cup of applesauce or pudding for patients who have difficulty swallowing. Since patients may experience dizziness, vertigo, or somnolence, they should be advised not to drive or operate machinery until the effects are evident.12
The patient and caregiver need to be reassured that symptoms can be managed. There is a point in treatment where the pharmacist’s primary focus will change from the patient to the caregiver. As the disease progresses, ALS places an increasing burden on the caregiver, which can lead to burnout and depression. For more information about support groups, caregivers should contact the National Alliance for Caregiving (www.caregiving.org).
Many medications and devices for symptom management, such as humidifiers, can be purchased in community pharmacies without a prescription. Counseling on the use of constipation products such as stool softeners, fiber supplements, osmotic laxatives, rectal suppositories, and enemas can be helpful. Recommendations for products such as vitamin E and magnesium supplements for cramps, NSAIDs for pain control, diphenhydramine for sialorrhea, and humidifiers for thick secretions can help patients with symptom management.
Conclusion
Amyotrophic lateral sclerosis is a progressive, fatal neurologic disease. Riluzole is currently the only medication available to treat patients with ALS. However, with over a dozen different signs and symptoms, patients may require more drug therapy for symptom management than most other diseases. Patients may very well be on multiple prescription and nonprescription medications over the course of the disease. While there is currently no cure for this disease, improvements in symptom management and treatment continue to be made.
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