Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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adults with excessive daytime sleepiness (EDS)

1st line – sleep hygiene + lifestyle changes

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adults with excessive daytime sleepiness (EDS)
1st line – 

sleep hygiene + lifestyle changes

Nonpharmacologic approaches include sleep hygiene, and ensuring regular and adequate amounts of sleep to minimize daytime sleepiness. Scheduled naps during the day aim to optimize daytime function; there is limited evidence of effectiveness, but the balance between desirable and undesirable effects is likely in favor of naps.[93][94][95]

Patients should be advised to avoid heavy meals, afternoon caffeinated beverages, and alcohol. Adequate psychosocial support should be given.[93][94][96]

Patients with mild symptoms can be treated with nonpharmacologic therapy alone.

If EDS is severe, patients should be advised not to drive or take part in potentially dangerous activities at home or at work.

Consider – pharmacotherapy

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adults with excessive daytime sleepiness (EDS)
Consider – 

pharmacotherapy

Treatment recommended for SOME patients in selected patient group

Pharmacotherapy in addition to sleep hygiene and lifestyle changes may be required initially for some patients with moderate to severe EDS. Patients with less severe EDS may only require pharmacotherapy if their symptoms are not controlled by nonpharmacologic treatments.

EDS is typically treated with central nervous system stimulants. First-line therapies include modafinil, pitolisant, sodium oxybate, or solriamfetol. Guidelines and meta-analysis conclude that the benefits of these agents outweigh the risks for patients with EDS.[93][94][95]

Pitolisant improves EDS compared with placebo and is well tolerated compared with modafinil and other pharmacologic agents used in the management of narcolepsy.[95][97]​​ The efficacy of pitolisant in improving EDS was maintained over a 12-month period in an open-label pragmatic study.[101]

Sodium oxybate improves EDS and reduces nocturnal sleep disruption.[95][102][103]​​ A multiple-salt oxybate formulation (calcium oxybate/magnesium oxybate/potassium oxybate/sodium oxybate) that reduces patient exposure to sodium is approved in the US for the treatment of EDS.[104][105][106]

In phase 3 trials of patients with narcolepsy, solriamfetol increased sleep latency and reduced Epworth Sleepiness Scale scores after 12 weeks' treatment.[107] Longer-term (up to 50 weeks) maintenance of the efficacy of solriamfetol has been demonstrated.[108]

Other options with evidence of effectiveness in treating EDS and a likely favorable balance of benefits and harms include armodafinil (the R-enantiomer of modafinil, which has a longer half-life), methylphenidate, and dextroamphetamine.[93][94][95] Short-acting methylphenidate or other stimulants may be used in combination with modafinil or armodafinil. Methamphetamine is considered a last-resort option because of high potency and abuse potential.

A lack of head-to-head trials makes it difficult to compare efficacy between different drugs. Treatment choices may change, and be affected by factors such as age, lifestyle, severity of the condition, drug tolerance, and comorbidities (including risk of dependency or drug misuse). Pharmacologic treatment may lead to rebound sleepiness. It is recommended that clinicians regularly discuss and assess treatment efficacy and safety during follow-up visits.[93][94]

Primary options

modafinil: 200 mg orally once daily in the morning initially, may increase to 400 mg/day given in divided doses in the morning and at noon

OR

pitolisant: 8.9 mg orally once daily in the morning for 1 week, increase to 17.8 mg once daily for 1 week, then adjust dose according to response and tolerability, maximum 35.6 mg/day (17.8 mg/day in CYP2D6 poor metabolizers)

OR

sodium oxybate: 4.5 to 9 g/day orally (immediate-release solution) given at night in 2 divided doses (at bedtime and then 2.5 to 4 hours later); 4.5 to 9 g/day orally (extended-release suspension) once daily at night

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OR

calcium oxybate/magnesium oxybate/potassium oxybate/sodium oxybate: 4.5 to 9 g/day orally given at night in 2 divided doses

OR

solriamfetol: 75 mg orally once daily in the morning initially, increase to 150 mg once daily after at least 3 days according to response and tolerability, maximum 150 mg/day

Secondary options

armodafinil: 150-250 mg orally once daily in the morning

OR

methylphenidate: 10-60 mg/day orally (immediate-release) given in 2-3 divided doses; 10-60 mg/day (extended-release) given in 1-2 divided doses

OR

dextroamphetamine: 5-60 mg/day orally (immediate-release) given in 1-3 divided doses; 5-60 mg/day (extended-release) given in 1-2 divided doses

Tertiary options

modafinil: 200 mg orally once daily in the morning initially, may increase to 400 mg/day given in divided doses in the morning and at noon

and

methylphenidate: 10-60 mg/day orally (immediate-release) given in 2-3 divided doses

OR

armodafinil: 150-250 mg orally once daily in the morning

and

methylphenidate: 10-60 mg/day orally (immediate-release) given in 2-3 divided doses

OR

methamphetamine: 20 mg/day orally given in divided doses in the morning and at noon, maximum 60 mg/day

adults with cataplexy

1st line – avoidance of triggers + pharmacotherapy

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adults with cataplexy
1st line – 

avoidance of triggers + pharmacotherapy

Patients should be advised to avoid triggers and start medical therapy. They should also have adequate psychosocial support.[93][94][96]

Sodium oxybate or pitolisant is recommended as first-line treatment for cataplexy.[93][94][95] The multiple-salt oxybate formulation reduced the weekly number of cataplexy attacks compared with placebo in a double-blind, randomized trial of adult patients with narcolepsy with cataplexy.[104]

One study found that pitolisant reduced the number of cataplexy attacks each week, from baseline to the stable dosing period, by 75% compared with 38% in patients receiving placebo.[109] The efficacy of pitolisant in reducing cataplexy attacks was maintained over a 12-month period.[101]

Primary options

sodium oxybate: 4.5 to 9 g/day orally (immediate-release solution) given at night in 2 divided doses (at bedtime and then 2.5 to 4 hours later); 4.5 to 9 g/day orally (extended-release suspension) once daily at night

More

OR

calcium oxybate/magnesium oxybate/potassium oxybate/sodium oxybate: 4.5 to 9 g/day orally given at night in 2 divided doses

OR

pitolisant: 8.9 mg orally once daily in the morning for 1 week, increase to 17.8 mg once daily for 1 week, then adjust dose according to response and tolerability, maximum 35.6 mg/day (17.8 mg/day in CYP2D6 poor metabolizers)

2nd line – antidepressant

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adults with cataplexy
2nd line – 

antidepressant

Serotonin-norepinephrine-reuptake inhibitors (e.g., venlafaxine), tricyclic antidepressants (TCAs; e.g., clomipramine), selective norepinephrine-reuptake inhibitors (e.g., atomoxetine), or selective serotonin-reuptake inhibitors (SSRIs; e.g., fluoxetine, paroxetine) may be used as second-line therapy, although evidence for effectiveness is limited.[93][94][95][110]

SSRIs have been associated with an increased risk of suicidality in children, adolescents, and young adults with major depressive or other psychiatric disorders. TCAs have significant anticholinergic effects.

If the patient has coexisting depressive symptoms, or if the abuse potential of oxybates may pose a problem, it is reasonable to use any of these drugs as first-line therapy.

Monoamine oxidase inhibitors (MAOIs) are rarely used, and evidence for efficacy is inconclusive. They are considered a last-line therapy for people whose cataplexy is resistant to other agents, due to their significant drug-drug interactions and adverse effects.[95] Specialist consultation is required for use of MAOIs in cataplexy.

Antidepressants can be used to treat hypnagogic/hypnopompic hallucinations and sleep paralysis.

Primary options

venlafaxine: consult specialist for guidance on dose

OR

clomipramine: consult specialist for guidance on dose

Secondary options

fluoxetine: consult specialist for guidance on dose

OR

paroxetine: consult specialist for guidance on dose

OR

atomoxetine: consult specialist for guidance on dose

Tertiary options

desipramine: consult specialist for guidance on dose

OR

imipramine: consult specialist for guidance on dose

OR

selegiline: consult specialist for guidance on dose

OR

isocarboxazid: consult specialist for guidance on dose

OR

phenelzine: consult specialist for guidance on dose

OR

tranylcypromine: consult specialist for guidance on dose

children with excessive daytime sleepiness (EDS)

1st line – sleep hygiene + lifestyle changes

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children with excessive daytime sleepiness (EDS)
1st line – 

sleep hygiene + lifestyle changes

All children and their parents or caregivers should be advised about sleep hygiene measures, with a recommended 9-hour duration or more of total nocturnal sleep.[5] Scheduled naps are usually taken at lunchtime or in the afternoon.

Patients should be advised to avoid heavy meals and afternoon caffeinated beverages.

Adequate psychosocial support should be given to the child and family, and school staff should be educated about narcolepsy.[93][94][96][111]

Children with mild symptoms can be treated with nonpharmacologic therapy alone.

If EDS is severe, patients should be advised not to drive or take part in potentially dangerous activities at home or at school.

Consider – pharmacotherapy

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ONGOING
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children with excessive daytime sleepiness (EDS)
Consider – 

pharmacotherapy

Treatment recommended for SOME patients in selected patient group

Children whose narcolepsy is not controlled by nonpharmacologic interventions are treated with medicines; however, the evidence base is limited.

Sodium oxybate is recommended for the treatment of EDS and cataplexy in children.[93][94][95] Sodium oxybate and the multiple-salt formulation are both approved in the US for the treatment of EDS in patients from age 7 years with narcolepsy.

No specific medications have received approval to treat narcolepsy in patients under <7 years in the US. However, pitolisant is approved in children ≥6 years of age in Europe.[112]

Modafinil and methylphenidate have been used (off-label) with success in children.

Very close attention must be paid to safety and to the risk:benefit ratio of any pharmacologic treatment for narcolepsy in children. Any medications that have not been approved for this indication and age group should be prescribed under specialist guidance only.

Primary options

sodium oxybate: children ≥7 years of age: consult specialist for guidance on dose

OR

calcium oxybate/magnesium oxybate/potassium oxybate/sodium oxybate: children ≥7 years of age: consult specialist for guidance on dose

OR

pitolisant: children ≥6 years of age: consult specialist for guidance on dose

Secondary options

modafinil: consult specialist for guidance on dose

OR

methylphenidate: consult specialist for guidance on dose

children with cataplexy

1st line – avoidance of triggers + pharmacotherapy

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ONGOING
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children with cataplexy
1st line – 

avoidance of triggers + pharmacotherapy

Patients should be advised to avoid triggers and to start medical therapy.

Adequate psychosocial support should be given to the child and family, and school staff should be educated about narcolepsy.[93][94][96][111]

Sodium oxybate and the multiple-salt formulation are both approved in the US for the treatment of narcolepsy with cataplexy in patients from age 7 years. Sodium oxybate is approved in Europe for the treatment of narcolepsy with cataplexy in patients from age 7 years.

No specific medications have received approval to treat cataplexy in patients <7 years in the US. However, pitolisant is approved in children ≥6 years of age in Europe.[112]

Some antidepressants (e.g., fluoxetine, venlafaxine, and clomipramine) have been used with success for treating cataplexy in children.

Very close attention must be paid to safety and to the risk:benefit ratio of any pharmacologic treatment for narcolepsy in children. Any medications that have not been approved for this indication and age group should be prescribed under specialist guidance only. Selective serotonin-reuptake inhibitors, such as fluoxetine, have been associated with an increased risk of suicidality in children, adolescents, and young adults with major depressive or other psychiatric disorders.

Primary options

sodium oxybate: children ≥7 years of age: consult specialist for guidance on dose

OR

calcium oxybate/magnesium oxybate/potassium oxybate/sodium oxybate: children ≥7 years of age: consult specialist for guidance on dose

OR

pitolisant: children ≥6 years of age: consult specialist for guidance on dose

Secondary options

fluoxetine: consult specialist for guidance on dose

OR

venlafaxine: consult specialist for guidance on dose

OR

clomipramine: consult specialist for guidance on dose

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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