Approach

Nonpharmacologic approaches to treating narcolepsy include general lifestyle measures and sleep hygiene (relatively strict sleep schedule; naps; and avoiding sleep deprivation, alcohol, smoking, and late-night exercise). Pharmacologic treatment is used to relieve excessive daytime sleepiness (EDS) and cataplexy.[93][94]

Patients with severe EDS are advised not to drive or take part in potentially dangerous activities at home or at work.[94]

Nonpharmacologic treatment

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] It is advisable to avoid alcohol or central nervous system (CNS)-suppressant medications. Adequate psychosocial support is important.[93][94][96] People with mild symptoms can be treated with nonpharmacologic therapy alone.

Treatment of EDS in adults

EDS is typically treated with CNS 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]​​[98][99][100]​​ 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]

Treatment of cataplexy in adults

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]

Antidepressants such as 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) may be used as second-line treatment for cataplexy, 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. Advice regarding avoidance of triggers is important.

Treatment of children with narcolepsy

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. It is advisable to contact and educate school staff about narcolepsy.[111] Advice about avoidance of triggers of cataplexy is also important.

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 approved in the US for the treatment of EDS and cataplexy in patients from age 7 years with narcolepsy. 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 narcolepsy in patients <7 years in the US. However, pitolisant is approved in children ≥6 years of age in Europe.[112]​ Other treatment options for children include modafinil or methylphenidate for EDS, and antidepressants (e.g., fluoxetine, venlafaxine, and clomipramine) for cataplexy.

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

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