Amyotrophic Lateral Sclerosis (ALS)

Clinical Snapshot

Amyotrophic lateral sclerosis (ALS) — also called motor neuron disease — is a progressive neurodegenerative disease that destroys both upper motor neurons (in the motor cortex and corticospinal tracts) and lower motor neurons (in the brainstem and spinal cord), producing a combination of spasticity, hyperreflexia, and pseudobulbar features alongside muscle weakness, wasting, fasciculations, and hyporeflexia — often in the same body region.^[1] No currently available therapy in Canada reverses or halts the underlying neurodegeneration. Care combines disease-modifying pharmacotherapy that has a modest effect on the pace of decline with comprehensive multidisciplinary symptomatic, respiratory, and nutritional support, together with early and ongoing goals-of-care planning — ALS is ultimately a terminal illness, and most patients die of respiratory failure.^[2] The single most consistent finding across Canadian and international guidance is that regular follow-up in a multidisciplinary ALS clinic — not any one drug — is the intervention most closely linked to better outcomes.^[1]

Recognize the Condition

Upper motor neuron (UMN) signs

Spasticity and increased muscle tone.
Hyperreflexia, including spread of reflexes to adjacent segments and clonus.
Extensor plantar response (Babinski sign).
Pseudobulbar affect — involuntary, exaggerated laughing or crying episodes that are out of proportion to, or incongruent with, the patient's actual mood.
Slowed, effortful (spastic) speech and swallowing when the corticobulbar tracts are involved.

Lower motor neuron (LMN) signs

Progressive, often asymmetric muscle weakness.
Muscle atrophy and wasting.
Fasciculations (visible muscle twitching) — common but, on their own without weakness or wasting, not diagnostic of ALS.
Muscle cramps, frequently an early and bothersome symptom.
Hyporeflexia or areflexia in the affected region.
Flaccid dysarthria and dysphagia when the lower brainstem (bulbar) motor neurons are involved.

The diagnostic hallmark of ALS is the combination of UMN and LMN signs together, in the same body region and progressively spreading to other regions — a pattern not explained by a single focal lesion, and different from a disease that stays purely UMN- or purely LMN-limited.

Onset patterns

Limb onset (most common): asymmetric distal weakness — a foot drop, or hand clumsiness affecting fine motor tasks such as buttoning or writing — that progressively spreads to other limbs and regions.
Bulbar onset: dysarthria (slurred or slowed speech) and/or dysphagia as the presenting symptoms.
Respiratory onset (uncommon): dyspnea or orthopnea as the presenting symptom, with minimal limb involvement initially — easily missed or misattributed to a primary respiratory or cardiac cause at first presentation.

Cognitive and behavioural change occurs along a spectrum in ALS, from isolated executive dysfunction to frank frontotemporal dementia (ALS-FTD). Screen for this specifically — it affects decision-making capacity, medication adherence, and the timing of advance-care-planning conversations, so it should not be assumed absent just because a patient's language is fluent and their limb weakness is the dominant visible problem.

Risk Factors

Increasing age, with peak onset generally in the 6th and 7th decades of life.
Male sex — a modest male predominance is consistently reported, particularly for limb-onset disease.
Family history of ALS or frontotemporal dementia, or a known pathogenic gene variant — most familial ALS is linked to a C9orf72 hexanucleotide repeat expansion, with SOD1, FUS, and TARDBP among the other recognized causative genes.
Military service — an association between military service and ALS risk is consistently reported across studies, though the underlying mechanism is not established.
Cigarette smoking.
No reliably modifiable environmental risk factor has been established for sporadic ALS; proposed associations with specific occupational or toxin exposures remain inconsistent across studies and should not be presented to patients as an established cause.

Red Flags & Refer

Refer or escalate promptly for any of the following. In ALS, several of these are not one-time events but findings to actively screen for at every visit, since a proactive multidisciplinary approach — not a reactive one — is what current Canadian guidance recommends:^[1]

Symptoms or signs suggesting respiratory insufficiency — orthopnea, morning headache, unrefreshing sleep, daytime somnolence, use of accessory respiratory muscles, or a weak, ineffective cough — warrant an urgent formal respiratory assessment; do not wait for a scheduled routine spirometry visit.^[3]
Progressive dysphagia with weight loss, recurrent choking, or aspiration pneumonia — needs urgent dietitian/speech-language pathology assessment and a timely gastrostomy discussion (see Non-Pharmacologic Treatment and the Clinical Decision Algorithm) before nutritional status or respiratory reserve deteriorates further.
Acute respiratory distress, marked hypercapnia/hypoxia symptoms, or an inability to clear secretions — a medical emergency; ensure the patient's documented wishes regarding intubation and invasive ventilation are known and immediately accessible before any acute presentation, not discovered for the first time during one.
New jaundice, unexplained nausea or fatigue, or markedly elevated liver enzymes in a patient on riluzole — assess promptly for drug-induced hepatotoxicity (see Monitoring & Follow-Up).
Fever or signs of infection in a patient on riluzole, particularly within the first 2 months of treatment — assess for riluzole-associated neutropenia.
New dry cough or progressive dyspnea in a patient on riluzole without an alternative respiratory explanation — assess for riluzole-associated interstitial lung disease and discontinue the drug if confirmed.
Expressed suicidal ideation, or a significant new decline in mood or hopelessness — ALS carries a real and often underrecognized suicide risk, particularly around the time of diagnosis and at major functional-loss milestones; assess promptly and involve psychiatry or psychosocial support.
Cognitive or behavioural change suggesting frontotemporal involvement, especially if it affects a patient's capacity to participate in treatment or advance-care-planning decisions — refer for formal cognitive assessment.
A presentation that does not fit typical ALS — isolated UMN or isolated LMN signs confined to one region for a prolonged period, sensory loss, early bowel/bladder dysfunction, ophthalmoplegia, or unusually slow or absent progression — reconsider the diagnosis and evaluate for a treatable mimic (see Assessment & Diagnosis) rather than continuing to manage the patient as ALS.

Assessment & Diagnosis

Distinguishing ALS from its key mimics

Feature	ALS	Multifocal motor neuropathy	Cervical spondylotic myelopathy	Kennedy disease (SBMA)
Motor neuron signs	Combined UMN + LMN	Pure LMN, often in individual nerve/motor-unit distributions crossing normal root or nerve boundaries	UMN below the level of compression; can also show LMN signs at the compressed level itself	Pure LMN, slowly progressive over years
Sensory findings	Absent	Absent by definition (a pure motor neuropathy)	Often present (dermatomal or long-tract sensory loss)	Often present (a sensory neuronopathy), plus gynecomastia
Key investigation finding	EMG: widespread active and chronic denervation with normal sensory nerve conduction	Nerve conduction studies: conduction block; anti-GM1 ganglioside antibodies often positive	MRI cervical spine: cord compression correlating with the clinical level	Genetic testing: androgen receptor gene CAG repeat expansion
Why the distinction matters	—	A treatable mimic that responds to IVIG — missing it means withholding an effective, disease-controlling therapy	A surgically treatable mimic when caught before irreversible cord injury	A different, X-linked, much more slowly progressive disease with a distinct genetic-counselling and prognostic conversation

Do not anchor on ALS prematurelyAny of the atypical features listed in Red Flags & Refer — especially sensory loss, early sphincter dysfunction, or disease confined to a single limb or region for a prolonged period — should prompt a mimic workup, particularly for multifocal motor neuropathy, since it is treatable and a missed diagnosis here has real consequences.

Diagnostic approach

ALS remains a clinical diagnosis, supported by electrophysiologic and imaging findings that establish the extent of lower motor neuron involvement and exclude alternative explanations. The revised El Escorial/Awaji framework is the tool most commonly used to categorize diagnostic certainty (definite, probable, or possible ALS) based on how many body regions — bulbar, cervical, thoracic, and lumbosacral — show combined UMN/LMN involvement.^[1]

Investigations

Electromyography (EMG) and nerve conduction studies — to confirm widespread lower motor neuron involvement (active and chronic denervation) across multiple regions, and to exclude multifocal motor neuropathy and other neuropathic or myopathic mimics.
MRI of the brain and spinal cord — primarily to exclude structural mimics, especially cervical spondylotic myelopathy.
Baseline bloodwork: creatine kinase (mild-to-moderate elevation is common in ALS itself and should not be mistaken for a primary myopathy), TSH, vitamin B12, HIV serology, and serum protein electrophoresis.
Anti-GM1 ganglioside antibodies when multifocal motor neuropathy is a genuine clinical consideration.
Genetic counselling and testing (e.g., C9orf72, SOD1, FUS, TARDBP) for a patient with a family history of ALS or frontotemporal dementia, or notably young age at onset — arrange pre- and post-test genetic counselling given the implications for the patient's relatives.

Functional status is tracked longitudinally with the Revised ALS Functional Rating Scale (ALSFRS-R), a 12-item questionnaire scored out of 48 and repeated at every multidisciplinary visit — the standard tool for tracking disease trajectory in both practice and clinical trials. It is not reproduced here as an interactive calculator: correct scoring depends on the full standardized item wording and clinician judgment on each item, not an independently verifiable point-sum a pharmacist could safely reimplement.

Treatment Targets

Slow the rate of functional decline using disease-modifying pharmacotherapy, understanding that no currently available therapy in Canada halts or reverses disease progression.
Achieve and maintain the best possible control of every individual symptom domain — spasticity, sialorrhea, pseudobulbar affect, pain, mood, sleep, and cramps — since these accumulate and interact as the disease progresses.
Anticipate and proactively manage respiratory decline, rather than reacting only once respiratory failure is already symptomatic.
Maintain nutritional status and safe swallowing for as long as possible, escalating to enteral feeding before a nutritional or respiratory crisis forces the decision.
Preserve the patient's ability to communicate for as long as possible, introducing augmentative and alternative communication tools before speech is severely impaired.
Support the patient and family through a multidisciplinary ALS clinic model, with palliative care integrated early rather than reserved for the end of life.
Elicit and regularly revisit the patient's goals of care — regarding ventilatory support, enteral feeding, and end-of-life preferences — while the patient still retains full decision-making capacity and communication ability.

Choose Initial Treatment

Direct treatment rule

Every patient with confirmed ALS should be offered riluzole 50 mg PO twice daily, taken at least 1 hour before or 2 hours after a meal — food significantly reduces absorption. Riluzole has a modest effect on slowing functional decline; that modesty is a reason to combine it with comprehensive symptomatic and multidisciplinary care, not a reason to withhold it.^[1]^[2]

Obtain baseline liver enzymes (ALT, AST, bilirubin) and a baseline complete blood count before starting riluzole, and monitor transaminases monthly for the first 3 months, then periodically thereafter (see Monitoring & Follow-Up).

Early-stage disease with preserved respiratory function and independence in most activities of daily living — discuss edaravone as an additional disease-modifying option. Edaravone was studied specifically in patients within 2 years of symptom onset, with forced vital capacity (FVC) at least 80% predicted, a score of at least 2 on every individual ALSFRS-R item, and no requirement for invasive ventilation — this population is a reasonable guide to who is most likely to derive benefit, though Health Canada's approval and provincial formulary coverage are not restricted to this exact profile.^[4] Edaravone is given as an IV infusion or an oral suspension in 28-day cycles: an initial cycle of daily dosing for 14 days followed by a 14-day drug-free interval, then subsequent cycles of dosing on 10 of every 14 days followed by a 14-day drug-free interval.

Do not start sodium phenylbutyrate-taurursodiol (Albrioza/AMX0035) in a new patient — the manufacturer voluntarily withdrew Albrioza from the Canadian market by the end of 2024 after its confirmatory Phase 3 trial (PHOENIX) failed to meet its primary or secondary endpoints. It is no longer to be initiated in new patients; patients already established on the drug may be eligible for a manufacturer-run patient support program, arranged through the prescriber.^[5]

Refer promptly

Refer every newly confirmed ALS diagnosis to a multidisciplinary ALS clinic without delay — regular multidisciplinary follow-up, not any single drug, is the intervention most consistently linked to better outcomes in current Canadian guidance.^[1]

Non-Pharmacologic Treatment

The multidisciplinary ALS clinic model

Care coordinated through a dedicated multidisciplinary ALS clinic — bringing neurology, respirology, physiatry/physiotherapy/occupational therapy, speech-language pathology, dietitian, social work, and palliative care together, ideally within the same visit — is the central organizing recommendation of current Canadian guidance, and pharmacists are an integral part of this team for medication review, symptom-management optimization, drug-access navigation, and adherence support.^[1]

Physiotherapy and occupational therapy: maintain range of motion, prevent contractures, provide mobility aids and adaptive equipment, and complete a home safety assessment before falls or injuries occur.
Speech-language pathology: introduce augmentative and alternative communication (AAC) strategies and devices proactively, while speech is still functional — waiting until speech is severely impaired makes learning new communication technology much harder.
Respiratory therapy: teach airway clearance techniques, and introduce a mechanical insufflation-exsufflation ("cough assist") device once cough becomes weak or ineffective, to reduce aspiration and pneumonia risk.^[3]
Dietitian: recommend texture-modified diets and calorie-dense oral supplementation as dysphagia progresses, and support the nutrition-related decision points below.
Social work and palliative care: integrate palliative care early in the disease course as a partner in symptom management and advance-care planning, not only once the patient is imminently dying — this is an explicit recommendation of current Canadian guidance.^[1]
Caregiver support: assess caregiver burden at every visit and connect families to respite and support resources; ALS places a substantial and progressively increasing caregiving demand on family members.

Respiratory support

Non-invasive ventilation (NIV) is the respiratory intervention with the clearest benefit in ALS and should be discussed proactively as respiratory function declines, rather than only once a patient is symptomatic in a respiratory crisis (see Clinical Decision Algorithm).^[3] Invasive ventilation (tracheostomy) is an option some patients choose for longer-term survival, but this decision — like NIV — should be discussed well in advance as part of ongoing goals-of-care conversations, not decided under emergency conditions.

Nutrition support

Percutaneous endoscopic gastrostomy (PEG) placement should be discussed proactively once dysphagia or weight loss develops, while pulmonary reserve is still adequate to tolerate the procedure safely (see Clinical Decision Algorithm) — deferring the conversation until oral intake has already failed closes the safest window for the procedure.^[2]

Pharmacologic Treatment Options

Two therapeutic categories

Disease-modifying therapy

Riluzole (essentially every patient) and edaravone (an additional option, particularly in early-stage disease) both have a modest effect on slowing functional decline. Albrioza (AMX0035) is no longer available to new patients in Canada — see Choose Initial Treatment.

Symptomatic and supportive therapy

Every other drug in this table treats a specific symptom rather than the underlying disease — spasticity, sialorrhea, pseudobulbar affect, cramps, pain, mood, and sleep each need their own selection, and most patients eventually need several of these at the same time.

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Riluzole Preferred	Disease-modifying therapy, every patient with confirmed ALS	50 mg PO BID, on an empty stomach	Hepatotoxicity, rare severe neutropenia, rare interstitial lung disease, nausea, asthenia, dizziness	Modest effect on functional decline. Monitor LFTs monthly x3 months then periodically. Discontinue for ALT/AST over 5x ULN or interstitial lung disease.
Edaravone Preferred	Disease-modifying therapy, especially early-stage disease with preserved respiratory function	60 mg IV daily, or 105 mg PO suspension daily, in 28-day cycles (14 days on/14 off initially, then 10 of 14 days on/14 off)	Bruising/gait disturbance at the IV site, headache, dermatitis; oral suspension contains sodium benzoate — caution in significant hepatic/renal impairment	Oral suspension is taken fasting in the morning, water only for 1 hour afterward. Given alongside, not instead of, riluzole.
Baclofen Preferred	Spasticity, first line	Initial 5 mg PO TID, titrated to a usual 20-30 mg TID-QID	Sedation, weakness (can reduce functional strength — titrate cautiously in ALS), confusion	Never stop abruptly — risk of withdrawal seizures/hallucinations. Consider intrathecal baclofen via a specialist for severe refractory spasticity.
Tizanidine Alternative	Spasticity	Initial 2 mg PO at bedtime, titrated to a usual 4-8 mg TID-QID	Sedation, hypotension, dry mouth, hepatotoxicity	Monitor LFTs. Additive sedation/hypotension with other CNS depressants — a real concern given reduced respiratory reserve in ALS.
Glycopyrrolate Preferred	Sialorrhea, first line	1-2 mg PO BID-TID, or via a compounded/parenteral protocol	Dry mouth, constipation, urinary retention; over-drying can thicken secretions and worsen aspiration risk	Limited CNS penetration — preferred first choice when cognitive change is also a concern.
Atropine sulfate 1% ophthalmic drops (sublingual use) Alternative	Sialorrhea	1-2 drops sublingually, up to QID as needed	Readily crosses the blood-brain barrier — higher confusion/delirium risk than glycopyrrolate	An off-label, low-cost option using the ophthalmic formulation given sublingually; avoid in a patient with significant cognitive impairment.
Botulinum toxin type A, salivary gland injection Special situation	Sialorrhea refractory to oral anticholinergics	Injected into the parotid and/or submandibular glands by a specialist	Can worsen dysphagia if toxin diffuses to swallowing muscles; injection-site discomfort	Use an experienced injector given baseline ALS dysphagia risk. Effect generally lasts approximately 3 months.
Amitriptyline Preferred	Pseudobulbar affect, and/or sialorrhea, and/or comorbid depression/insomnia	Initial 10-25 mg PO at bedtime, titrated as tolerated	Anticholinergic effects (helps sialorrhea, worsens constipation/urinary retention), sedation, QTc prolongation	A practical multi-purpose choice — the dextromethorphan-quinidine product used for pseudobulbar affect elsewhere is not marketed in Canada.
Mexiletine Alternative	Muscle cramps refractory to non-pharmacologic measures	300 mg PO daily in divided doses, guided by tolerability	GI upset, tremor, dizziness, cardiac conduction effects	Obtain a baseline ECG. Reduces cramp frequency/severity without affecting overall disease progression.
Gabapentin Preferred	Neuropathic-type pain; alternative for cramps	Initial 100-300 mg PO at bedtime, titrated to a usual 300-900 mg TID	Sedation, dizziness, peripheral edema	Titrate slowly given reduced respiratory reserve; sedation is additive with other CNS depressants.
Opioids (e.g., morphine) Preferred	Pain not controlled by non-opioid measures; dyspnea/air hunger in advanced disease	Individualized — start low and titrate to effect per a stepwise palliative approach	Sedation, constipation, respiratory depression at high or rapidly escalated doses	Used deliberately for pain and for dyspnea/air hunger as part of goals-of-care-aligned palliative care, not withheld out of respiratory-depression concern alone once comfort is the agreed goal.
Mirtazapine Alternative	Depression, insomnia, and/or poor appetite	Initial 15 mg PO at bedtime, titrated to 15-45 mg at bedtime	Sedation (more pronounced at lower doses), increased appetite/weight gain, dizziness	The appetite-stimulating and sedating properties are a genuine advantage in ALS-related weight loss and insomnia.
Trazodone Alternative	Insomnia, and/or comorbid depression	25-100 mg PO at bedtime	Sedation, orthostatic hypotension, rare priapism	A reasonable option when insomnia is the dominant symptom. Avoid benzodiazepines and diphenhydramine where possible given reduced respiratory reserve.

Mexiletine's cramp-reduction benefit is supported by randomized, placebo-controlled trial evidence in ALS specifically — it does not slow disease progression, but it is a real option for a genuinely bothersome symptom that hydration and stretching alone don't adequately control.^[6]

Special Populations

Pregnancy and lactation: ALS is uncommon in patients of reproductive age; data on riluzole and edaravone in pregnancy and lactation are limited. Use either only if the anticipated benefit is judged to outweigh the largely unknown risk, and involve the prescriber and, where feasible, a maternal-fetal medicine or teratogen-information resource in the decision.

Hepatic impairment: riluzole undergoes substantial hepatic metabolism — avoid starting it in a patient with baseline transaminases already significantly elevated, and use tizanidine cautiously given its own hepatotoxicity signal.

Renal impairment: the edaravone oral suspension contains sodium benzoate, which can accumulate in significant renal or hepatic impairment — use caution and involve the prescriber before starting in this situation. Reduce gabapentin dosing for reduced renal function.

Cognitive impairment / ALS-FTD overlap: a patient with significant cognitive or behavioural involvement may lose the capacity to participate in complex treatment or advance-care-planning decisions as the disease progresses — complete these conversations, and confirm a substitute decision-maker, as early as possible rather than waiting until capacity is already in question.

Bulbar-predominant disease / dysphagia: confirm a patient can safely and reliably swallow oral tablets before relying on an oral regimen for a symptom that itself needs urgent control (e.g., significant sialorrhea or pain) — discuss alternative formulations or routes with the prescriber and pharmacy as dysphagia progresses, and revisit every regimen once a feeding tube is placed.

Older adults: use particular caution with any sedating symptomatic drug (opioids, gabapentin, tricyclic antidepressants, benzodiazepines) given the combination of reduced respiratory reserve and age-related pharmacokinetic change — start low and titrate slowly.

Monitoring & Follow-Up

Riluzole-specific monitoring

Baseline ALT, AST, bilirubin, and CBC before starting.
Repeat transaminases monthly for the first 3 months of treatment, then periodically thereafter for the duration of therapy.
Discontinue riluzole if ALT/AST rises above 5 times the upper limit of normal, if bilirubin rises, or if there are other signs of clinically significant liver injury.
Assess promptly for neutropenia if fever develops, particularly within the first 2 months of treatment.
Ask about new dry cough or breathlessness at every visit — a possible sign of riluzole-associated interstitial lung disease.

Respiratory monitoring

Perform a symptom review and spirometry (FVC or SVC) at every multidisciplinary visit. FVC alone is not a sufficient basis for NIV timing decisions — pair it with a structured symptom review (orthopnea, morning headache, daytime somnolence) and, where available, additional measures such as maximal inspiratory pressure, sniff nasal inspiratory pressure, or overnight oximetry.^[3]

Functional and nutritional monitoring

Track the ALSFRS-R score at every multidisciplinary visit to follow the trajectory of decline.
Track weight and swallowing function at every visit; involve the dietitian and speech-language pathologist proactively rather than only once a problem is already advanced.
Reassess communication needs and augmentative/alternative communication device requirements regularly as speech changes.
Screen for depression, anxiety, suicidal ideation, and caregiver burden at routine intervals — these are common, often underrecognized, and undertreated in ALS.^[7]
Reassess goals of care regularly, not as a single conversation held only at diagnosis — preferences can and do evolve as the disease progresses.

Treatment Failure / Next Step

Recognize that continued functional decline on riluzole and/or edaravone is expected — these drugs slow, not stop, disease progression. A falling ALSFRS-R score is not, by itself, evidence that the drug has "failed" or should be stopped.
Confirm adherence and rule out a correctable cause of accelerated decline (an intercurrent illness, a new medication interaction, or a new but treatable symptom driving apparent functional loss) before attributing everything to underlying disease progression.
Reassess respiratory status, nutritional status, and communication needs at every visit as clinical thresholds are crossed (see Clinical Decision Algorithm) — proactively raise NIV, PEG, or AAC rather than waiting for the patient or family to bring it up.
Escalate symptomatic therapy stepwise as new symptoms emerge or existing ones become refractory (for example, adding botulinum toxin for sialorrhea unresponsive to oral anticholinergics, or referring for intrathecal baclofen for refractory spasticity) — see Pharmacologic Treatment Options and Drug Tables.
Discuss eligibility for ALS clinical trials with the patient's neurologist if the patient is interested — trial availability changes over time, and referral to a comprehensive ALS clinic is the most reliable way to keep this option open.
Revisit goals of care explicitly whenever a major functional threshold is crossed — loss of independent ambulation, onset of respiratory insufficiency, or the need for a feeding tube — treating these as natural checkpoints for the conversation, not just the initial diagnosis visit.

Common Errors to Avoid

Withholding riluzole because its effect is "only modest" — a modest benefit is still a real benefit, and it should be offered to essentially every patient with confirmed ALS.
Missing the scheduled liver enzyme monitoring after starting riluzole, particularly in the first 3 months.
Prescribing a sedative-hypnotic (benzodiazepines, diphenhydramine) or an opioid for a non-pain, non-dyspnea indication without accounting for reduced respiratory reserve in a patient with ALS.
Waiting for a patient to become symptomatic in a respiratory crisis before discussing NIV, instead of raising it proactively as clinical thresholds are crossed.
Deferring the PEG discussion until a patient has already lost significant weight or pulmonary reserve, closing the safest window for the procedure.
Misattributing pseudobulbar affect to depression, or vice versa — the two can coexist but need different confirmation and treatment approaches; screen specifically for the involuntary, mood-incongruent quality of pseudobulbar episodes.
Over-drying secretions with an anticholinergic sialorrhea treatment to the point that thickened secretions become harder to clear and raise aspiration risk — titrate to the lowest dose that controls symptoms.
Assuming the dextromethorphan-quinidine combination product used for pseudobulbar affect elsewhere is available in Canada — it is not currently marketed here; use an alternative such as amitriptyline.
Delaying advance-care-planning and goals-of-care conversations until a patient has already lost the capacity or physical ability to communicate their wishes.
Treating each new symptom in isolation rather than through the multidisciplinary ALS clinic, which is the setting most consistently linked to better outcomes.

Clinical Decision Algorithm

Diagnosis and starting disease-modifying therapy

Progressive weakness with mixed UMN + LMN signs in bulbar, cervical, thoracic, and/or lumbosacral regions

Confirm with EMG/nerve conduction studies, MRI to exclude structural mimics, and baseline labs (CK, TSH, B12, HIV, SPEP, anti-GM1 if indicated, genetic testing if familial/young-onset)

ALS confirmed (revised El Escorial/Awaji criteria)

Start riluzole 50 mg PO BID; obtain baseline LFTs and CBC

Refer promptly to a multidisciplinary ALS clinic

Discuss edaravone eligibility (early-stage disease, preserved FVC, independence in ADLs) and patient preference

Atypical features present (isolated UMN or LMN >1 region for a prolonged period, sensory loss, early sphincter dysfunction, ophthalmoplegia)

Reassess for an ALS mimic: multifocal motor neuropathy, cervical myelopathy, Kennedy disease, myasthenia gravis, or inclusion body myositis

Respiratory monitoring and NIV timing

At every multidisciplinary visit: ask about orthopnea, morning headache, and daytime somnolence; measure FVC/SVC

Symptoms present, or FVC declining, or an abnormal sniff/inspiratory pressure

Refer for formal respiratory assessment (overnight oximetry +/- polysomnography, maximal inspiratory/sniff nasal pressure)

Offer an NIV trial once respiratory insufficiency is confirmed — do not wait for a crisis or for FVC to fall further before raising the conversation

No symptoms, FVC stable

Continue routine monitoring; reassess more frequently as bulbar or limb function declines

Discuss goals of care regarding NIV, tracheostomy/invasive ventilation, and end-of-life respiratory symptom management proactively, before a crisis forces the decision

Nutrition and PEG timing

Track weight and swallow function at every visit; screen for dysphagia, choking, and prolonged mealtimes

Weight loss or dysphagia developing, FVC still adequate

Discuss and offer PEG placement now, while pulmonary reserve is still adequate for safer sedation and procedure tolerance

Significant respiratory decline and PEG not yet placed

PEG carries higher procedural/anesthetic risk — involve respiratory support (NIV) periprocedurally and obtain specialist anesthesia input

Sialorrhea, stepped approach

Bothersome sialorrhea/drooling

First line: glycopyrrolate (or sublingual atropine drops) — favour glycopyrrolate if cognitive change is also a concern

Inadequate response, or anticholinergic burden becoming a problem

Consider amitriptyline (a dual benefit if depression or pseudobulbar affect is also present)

Severe, refractory to oral anticholinergics

Refer for botulinum toxin injection into the salivary glands

Drug Tables

How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

Disease-modifying therapy

Offer riluzole to essentially every patient with confirmed ALS; discuss edaravone as an additional option, particularly in early-stage disease with preserved respiratory function.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Riluzole	Adults: 50 mg PO BID	Hepatotoxicity (dose-related transaminase elevation, rare severe hepatitis), rare severe neutropenia, rare interstitial lung disease, nausea, asthenia, dizziness, elevated INR reported with concurrent warfarin	CYP1A2 substrate — levels may be increased by CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine) and decreased by CYP1A2 inducers (e.g., cigarette smoking, omeprazole, rifampin); smoking cessation after starting riluzole can raise riluzole levels	Take on an empty stomach — food significantly reduces absorption. Baseline and monthly (x3 months) then periodic LFTs. Discontinue for ALT/AST over 5x ULN, jaundice, or interstitial lung disease.
Edaravone	IV formulation: 60 mg IV once daily, 28-day cycle as above Oral suspension: 105 mg PO once daily, same 28-day cycle	Bruising, gait disturbance, and dermatitis (IV-site related), headache, contusion; oral suspension carries a sodium benzoate load requiring caution in hepatic/renal impairment	No major reported drug-drug interactions with riluzole	IV: infused over 60 minutes. Oral suspension: taken fasting in the morning; water only for 1 hour afterward. Regimen: initial cycle 14 days on then 14 days off; subsequent cycles 10 of 14 days on then 14 days off.

Spasticity

Drug	Dosage	Adverse effects	Drug interactions	Comments
Baclofen	Initial: 5 mg PO TID Usual maintenance: 20-30 mg PO TID-QID, titrated to effect and tolerability	Sedation, weakness (can reduce a patient's functional strength — titrate cautiously in ALS specifically), confusion, lowered seizure threshold at high doses	Additive CNS/respiratory depression with opioids, benzodiazepines, and other sedatives	Never discontinue abruptly — withdrawal can cause seizures, hallucinations, and rebound spasticity. Consider referral for intrathecal baclofen if oral therapy is inadequate for severe spasticity.
Tizanidine	Initial: 2 mg PO at bedtime Usual maintenance: 4-8 mg PO TID-QID	Sedation, hypotension, dry mouth, hepatotoxicity	CYP1A2 substrate — avoid with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin); additive CNS/respiratory depression with other sedatives	Monitor LFTs periodically. An alternative to baclofen when a shorter duration of action or a different side-effect profile is preferred.

Sialorrhea (excess salivation)

Step therapy: start with a first-line oral anticholinergic; move to botulinum toxin for severe, refractory symptoms.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Glycopyrrolate	Adults: 1-2 mg PO BID-TID, or via a compounded/parenteral protocol where swallowing is impaired	Dry mouth, constipation, urinary retention; over-treatment can thicken secretions and worsen aspiration risk	Additive anticholinergic burden with other anticholinergic drugs (e.g., amitriptyline, oxybutynin)	Preferred first-line choice — limited blood-brain barrier penetration means less confusion/sedation than atropine, an important advantage in a patient with any cognitive involvement.
Atropine sulfate 1% ophthalmic drops (sublingual use)	Adults: 1-2 drops sublingually, up to QID as needed	Confusion, delirium, tachycardia, blurred vision — readily crosses the blood-brain barrier	Additive anticholinergic burden with other anticholinergic drugs	An off-label, low-cost alternative when glycopyrrolate is unavailable or insufficient; avoid in a patient with significant cognitive impairment given the higher confusion/delirium risk.
Botulinum toxin type A, salivary gland injection	Per specialist protocol: Injected into the parotid and/or submandibular glands	Worsened dysphagia if toxin diffuses to swallowing muscles; injection-site discomfort	None specific to concurrent ALS drug therapy	Reserve for sialorrhea refractory to oral anticholinergics; requires an experienced injector given baseline dysphagia risk in ALS. Effect generally lasts approximately 3 months.

Pseudobulbar affect and mood

The dextromethorphan-quinidine combination product used for pseudobulbar affect in some other countries is not currently marketed in Canada; antidepressants are the practical Canadian option.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Amitriptyline	Adults: Initial 10-25 mg PO at bedtime, titrated as tolerated	Anticholinergic effects (can help sialorrhea but worsen constipation/urinary retention), sedation, QTc prolongation, orthostatic hypotension	Additive anticholinergic and sedative burden with other anticholinergics/CNS depressants; avoid with MAOIs	A practical multi-purpose choice for a patient with overlapping pseudobulbar affect, sialorrhea, and/or insomnia given its anticholinergic and sedating profile. Obtain a baseline ECG if cardiac risk factors are present.
SSRI (e.g., sertraline, citalopram)	Adults: Per standard antidepressant titration; consult the product monograph	GI upset, sexual dysfunction, hyponatremia (particularly in older adults), QTc prolongation with citalopram at higher doses	Serotonin syndrome risk with other serotonergic drugs	An alternative first-line option for comorbid depression and/or pseudobulbar affect when an anticholinergic profile is undesirable.

Pain and cramps

Drug	Dosage	Adverse effects	Drug interactions	Comments
Mexiletine	Adults: 300 mg PO daily in divided doses, guided by tolerability	GI upset, tremor, dizziness, cardiac conduction effects	Avoid with other class I antiarrhythmics; caution with strong CYP1A2/CYP2D6 inhibitors	Obtain a baseline ECG. Reduces muscle cramp frequency and severity in randomized trial data without affecting overall disease progression.
Gabapentin	Initial: 100-300 mg PO at bedtime Usual maintenance: 300-900 mg PO TID, titrated to effect	Sedation, dizziness, peripheral edema	Additive CNS/respiratory depression with opioids and other sedatives	Titrate slowly given reduced respiratory reserve. An alternative for cramps, and a first-line option for neuropathic-type pain.
Opioids (e.g., morphine)	Starting dose: Individualized; start low and titrate per a stepwise palliative approach	Sedation, constipation, respiratory depression at high or rapidly escalated doses	Additive CNS/respiratory depression with benzodiazepines, gabapentinoids, and other sedatives	Used deliberately for pain not controlled by non-opioid measures, and for dyspnea/air hunger in advanced disease as part of a goals-of-care-aligned palliative approach — start low and titrate to effect.

Sleep and appetite

Drug	Dosage	Adverse effects	Drug interactions	Comments
Mirtazapine	Adults: Initial 15 mg PO at bedtime, titrated as tolerated to 15-45 mg at bedtime	Sedation (more pronounced at lower doses), increased appetite/weight gain, dizziness	Additive sedation with other CNS depressants; avoid with MAOIs	A useful choice when insomnia, depression, and poor appetite/weight loss coexist — the appetite-stimulating effect is a genuine advantage in ALS-related weight loss.
Trazodone	Adults: 25-100 mg PO at bedtime	Sedation, orthostatic hypotension, rare priapism	Additive sedation with other CNS depressants; serotonin syndrome risk with other serotonergic drugs	A reasonable option when insomnia is the dominant symptom without significant weight loss. Avoid benzodiazepines and diphenhydramine where possible given reduced respiratory reserve in ALS.

Evidence note: Drug inventory, dosing, adverse effects, interactions, and comments reflect standard Canadian practice, cross-checked against the Canadian best practice recommendations for ALS management and current AAN practice parameters.^[1]^[2]

References

Canadian best practice recommendations for the management of amyotrophic lateral sclerosis — Canadian Medical Association Journal (Shoesmith C, Abrahao A, Benstead T, et al.). CMAJ 2020;192(46):E1453-E1468
Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-based review) — Neurology, Quality Standards Subcommittee of the American Academy of Neurology (Miller RG, Jackson CE, Kasarskis EJ, et al.). Neurology 2009;73(15):1218-1226, reaffirmed
Home mechanical ventilation for patients with Amyotrophic Lateral Sclerosis: A Canadian Thoracic Society clinical practice guideline — Canadian Journal of Respiratory, Critical Care, and Sleep Medicine (Rimmer KP, Kaminska M, Nonoyama M, et al.). Can J Respir Crit Care Sleep Med 2019;3(1):9-27
Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial — The Lancet Neurology (Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group). Lancet Neurol 2017;16(7):505-512
Dear Healthcare Professional Letter: ALBRIOZA (sodium phenylbutyrate and ursodoxicoltaurine) — voluntary withdrawal from the Canadian market — Health Canada / Amylyx Pharmaceuticals Inc.. Health Canada, 2024
A randomized trial of mexiletine in ALS: safety and effects on muscle cramps and progression — Neurology (Weiss MD, Macklin EA, Simmons Z, et al.). Neurology 2016;86(16):1474-1481
Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: Multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review) — Neurology, Quality Standards Subcommittee of the American Academy of Neurology (Miller RG, Jackson CE, Kasarskis EJ, et al.). Neurology 2009;73(15):1227-1233, reaffirmed

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.