Advances in Promoting Wakefulness in Narcolepsy

Michael Thorpy M.D.

Montefiore Medical Center

and

the Albert Einstein College of Medicine

Bronx, New York

NESS, Boston, March 27, 2010

Narcolepsy Treatment Goals Reduce excessive sleepiness Control cataplexy

Other associated REM-related symptoms (sleep paralysis, hypnagogic and hypnopompic hallucinations)

Improve nighttime sleep Reduce psychosocial problems

Krahn LE et al. (2001), Mayo Clin Proc 76(2):185-194; Black J (2001), Central Nervous System News Special Edition 25-29; U.S. Xyrem Multicenter Study Group (2002), Sleep 25(1):42-49

Narcolepsy: Management Approaches

Excessive daytime sleepiness Structured nocturnal sleep Naps: scheduled and prn Stimulants or wake-promoting agents Sodium Oxybate

Cataplexy Antidepressants (TCA, SSRI, NERI) Sodium oxybate

Parkes D (1994), Sleep 17(suppl):S93-S96; Mitler MM et al. (1994), Sleep 17(4):352-371; Daly DD, Yoss RE (1976), Narcolepsy. In: Handbook of Clinical Neurology Vol. 15, Vinken PJ, Bruyn GW, eds. New York: Elsevier Publishing, pp836-852; Bassetti C, Aldrich MS (1996), Neurol Clin 14(3):545-571; Mamelak M et al. (1986), Sleep 9(1 pt 2):285-289

Narcolepsy: Management Approaches (Cont.)

Sleep fragmentation Sleep hygiene Hypnotics Sodium oxybate

Sleep disorders Hypnagogic Hallucinations – TCA’s, sodium oxybate Nightmares – TCA’s, sodium oxybate Sleep Paralysis – TCA’s, sodium oxybate Periodic Limb Movements – Dopamine agonists REM Sleep Behavior Disorder – Clonazepam, melatonin

Parkes D (1994), Sleep 17(suppl):S93-S96; Mitler MM et al. (1994), Sleep 17(4):352-371; Daly DD, Yoss RE (1976), Narcolepsy. In: Handbook of Clinical Neurology Vol. 15, Vinken PJ, Bruyn GW, eds. New York: Elsevier Publishing, pp836-852; Bassetti C, Aldrich MS (1996), Neurol Clin 14(3):545-571; Mamelak M et al. (1986), Sleep 9(1 pt 2):285-289

Narcolepsy: Management Approaches (Cont.)

General Personal and family counseling Support –

Narcolepsy Network State funded support programs

Sleep hygiene Naps

Treatment of Excessive Sleepiness

Daytime Sleepiness Stimulants

Methylphenidate Dextroamphetamine Methamphetamine

Modafinil/ Armodafinil Sodium Oxybate

Physicians’ Desk Reference (2005), Montvale, N.J.: Medical Economics Company; Nishino S, Mignot E (2005), Wake-promoting medications: basic mechanisms and pharmacology. In: Principles and Practice of Sleep Medicine, Kryger MH et al., eds. Philadelphia: ElsevierPhysicians’ Desk Reference (2005), Montvale, N.J.: Medical Economics Company; Nishino S, Mignot E (2005), Wake-promoting medications: basic mechanisms and pharmacology. In: Principles and Practice of Sleep Medicine, Kryger MH et al., eds. Philadelphia: Elsevier

Stimulants and Wake-Promoting Medications

C-IV

C-II

C-II

C-II

C-II

Schedule

3-55-60 mg/dayTablets, SR, LAMethylphenidate

15200-400 mg/dayTabletsModafinil

10-135-60 mg/dayCapsules, XRAmphetamine sulfate/saccharate/aspartate (Adderall)

4-55-60 mg/dayTabletsMethamphetamine (Desoxyn)

125-60 mg/dayTablets, SRDextroamphetamine

T1/2

(Hours)DoseFormulationsDrug

C-IV 15150-250 mg/dayTabletsArmodafinil

Alerting Agents

Sympathomimetic: enhance neurotransmission of dopamine, norepinephrine, serotonin

Caffeine: adenosine receptor antagonist Modafinil: specific mechanism remains unclear

Mechanism

Considerations for Use of Stimulants and Wake-Promoting Agents

Drug-drug interactions: CYP 450

Adverse effects: anxiety/nervousness,

restlessness, insomnia, headache, tremor,

dyskinesia, tachycardia, hypertension, psychosis

Abuse potential

Tolerance

Medial Prefrontal Cortex Regions (BA 10) Activated by Caffeine vs. Placebo During Verbal Working Memory

Adapted from Koppelstaetter et al. (2008)

Caffeine

Rx

Adapted from Killgore et al. (2008)

Clock Time

Sites of Action of Amphetamines

Courtesy of Thomas Scammell, MD.

Amphetamine Dopaminereuptake

transporter

VesicularMonoaminetransporter

Dopamine

Dopaminereceptors

MAO

+

High-dose Stimulants

58 patients who were taking high-dose stimulants for narcolepsy or idiopathic hypersomnia were compared with 58 control patients.

High dose stimulants were >120mg/day. The prevalence of psychosis, psychiatric

hospitalizations, tachyarrhythmias, polysubstance abuse, anorexia and weight loss were significantly increased in the stimulant group.

Auger et al. Risks of high dose stimulants in the treatment of disorders of excessive somnolence. A case control study. Sleep 2005;28:667-672

Pharmacotherapy: Sleepiness Modafinil

150 - 500 mg/day Moderate efficacy, long half life Best side effect profile Schedule IV, most expensive

Methylphenidate 5 - 100 mg/day Short half life formulation, variable dosing Used alone or in combination Sympathomimetic effects, mood alterations

Modafinil: Sites of Action Chemically unrelated to CNS stimulants Inhibits the dopamine transporter (DAT)

Contrary to amphetamine, may not induce release of dopamine

Activates wake-promoting neurons Inhibits norepinephrine transporter in the VLPO

Contrary to amphetamine, may not induce release of norepinephrine

Enhanced norepinephrine inhibits sleep promoting VLPO neurons

Stimulates hypocretin release Stimulates histamine release from the TMN

VLPO = Ventrolateral preoptic area

Modafinil: Sites of Action

VLPO = Ventrolateral preoptic area

Tuberomamillary nucleusStimulationHistamine

Lateral hypothalamusStimulationHypocretin

VLPOInhibition of the NE reuptake

transporter

Norepinephrine (NE)

Multiple arousal systemsInhibition of dopamine reuptake

transporter

Dopamine

Site of ActionMethod of actionNeurotransmitter

Proposed Sites of Action of Modafinil

Dopaminereuptake

transporter

Dopamine

Dopaminereceptors

MAO

MAO

Norepinephrinereuptake

transporter

Norepinephrine

Wake-promotingneurons

2 Norepinephrinereceptors

Sleep-promotingneurons

(GABA; VLPO)

Modafinil

+

-

–

Alerting Agents Stabilize Wakefulness

GABA

NorepinephrineHistamine

DopamineSerotonin

Acetylcholine

Wake

GABA(ventrolateral

Preopticarea)

Sleep

–

ModafinilAmphetamines

+

Modafinil

– NorepinephrineSerotonin

Pharmacokinetic Properties of Modafinil

Pharmacokinetics Linear, Independent of dose

Peak Plasma Concentration 2 - 4 hrs, Tmax delayed (~ 1 hr) by food

Plasma Protein Binding: Moderate (~60%)

Elimination Half-life 15 hrs

Metabolism: Metabolized by liver (~90%)

Urinary Excretion: < 10% of unchanged drug, All metabolites

-5.7+2.4+1.9

18.02.75.9

-4.4+1.9+2.1

17.43.06.1

ESSMSLTMWT

Narcolepsy II

-4.1+1.9+2.3

17.13.36.6

-3.5+1.8+2.3

17.92.95.8

ESSMSLTMWT

Narcolepsy I

---

---

-1.5+1.7-2.6

7.32.1

12.5

KSSMSLTPVT

SWD

-4.5+1.5

13.6-4.5+1.6

13.1ESSMWT

OSA II study

-4.6+1.2

14.27.4

--

--

ESSMSLT

OSA I study

Change from

baseline

BaselineChange from

baseline

Baseline

Modafinil 400mgModafinil 200mgMeasuresDisorder

Modafinil

MWT Sleep Latency: Split-Dose vs AM Dosing Regimens

MWT Sleep Latency: Split-Dose vs AM Dosing Regimens

Morning (9-11 AM)

Afternoon (1-3 PM)

Evening (5-7 PM)

Mea

n (

+S

EM

) M

WT

ch

ang

e fr

om

bas

elin

e

0

5

10

15

* †

400 mg split-dose

400 mg qd

200 mg qd

The % of patients able to sustain wakefulness was highest in the morning with the 400-mg single dose and in the evening with the split dose regimen

*P<.001 vs 200 mg qd†P<.05 vs 400 mg qd Schwartz JRL, et al. Clin Neuropharmacol. 2003;26:252-257.

N=32

MWT Sleep Latency: MWT Sleep Latency: Comparing Split-Dose RegimensComparing Split-Dose Regimens

MWT Sleep Latency: MWT Sleep Latency: Comparing Split-Dose RegimensComparing Split-Dose Regimens

Morning (9-11 AM)

Afternoon (1-3 PM)

Evening (5-7 PM)

% o

f p

atie

nts

aw

ake

for

20 m

inu

tes *

* 400 mg split-dose

400 mg qd

200 mg qd

*P<.05 vs 200 or 400 mg qdSchwartz JRL, et al. J Neurol Clin Neurosci. 2004; 27(2): 74-79.

600 mg split-dose

0

50

70

80

40

30

20

10

60

N=24

Armodafinil (Nuvigil)

R-(-)-modafinil

Longer acting isomer of modafinil

Half life approximately 3 x S-(-)-modafinil

Armodafinil

+2.69.5+1.312.1MWTNarcolepsy

--+3.02.3MSLTSWD

--+2.323.7MWTOSA II

+2.223.3+1.721.5MWTOSA I

Change from

baseline

Baseline Change from

Baseline

Baseline

Armodafinil 250mgArmodafinil 150mgMeasuresDisorder

Modafinil / armodafinil

N/A100-400mgnoFatigueEDS

Traumatic Brain Injury

N/A200-400mgnoFatigueChronic fatigue syndrome

N/A100-400mgnoEDSParkinson’s disease

N/A200-400mgnoFatigueMultiple Sclerosis

N/A100-400mgnoFatigueDepression

150 – 250mg200-400mgyesEDSNarcolepsy

150mg200-400mgyesEDSShift Work Disorder

150 – 250mg200-400mgyesEDSObstructive Sleep Apnea

ArmodafinilDoses studied

ModafinilDoses studied

FDA approvalSymptomsDiagnosis

4%6%Diarrhea

not reported3%Hypertension

1%4%Flu syndrome

6%6%Back pain

not reported7%Rhinitis

5%5%Insomnia

4%5%Anxiety

1%7%Nervousness

5%5%Dizziness

7%11%Nausea

17%34%Headache

ArmodafinilModafinilAdverse Effects

Modafinil / Armodafinil

Sodium Oxybate: Physiology Endogenous metabolite of GABA

Affects the GHB and GABA-B receptors

Neuromodulator

GABA

Dopamine

Serotonin

Endogenous opioids

Evidence for role as neurotransmitter

Synthesized in neurons, stored in vesicles, released via depolarization into synaptic cleft, reuptake, specific receptors

Sodium Oxybate: Pharmacokinetics

Absorption Tmax = 0.5 h-1.25 h

Dose proportionality Nonlinear kinetics

Distribution <1% protein bound

Metabolism Bioavailability ~25% (hepatic first-pass metabolism)

Diffuse cellular metabolismEnd product CO2 + H2O

No active metabolite

Elimination Predominantly metabolized

~5% unchanged in urine

T1/2 = 40-60 min

Food Slows bioavailability (AUC 30% with full meal)

AUC = area under the curve.

Sodium Oxybate: Sites of Action

GABA

Sodium Oxybate

H2N

OH

O

NaOOH

O

GABA-AGABA-B GHB receptor

-O

OH

O

Na+

Sodium Oxybate: CNS Pharmacology

Binds to GABAB receptor Antagonism and deletion of GABAB in animal

models inhibits sodium oxybate–induced sleep and some neuromodulation effects

Dual effect on noradrenergic locus coeruleus Inhibition during administration of sodium

oxybate Potentiation following cessation of treatment

Sodium Oxybate - Modafinil: 8-Week, Double Blind, Placebo-Controlled Trial Treatment Arms

N=222. SXB-22 .

*Placebo: sodium oxybate; †Placebos: modafinil + sodium oxybate; §Placebo: modafinil.

Data on file, Orphan Medical.

Sodium oxybate§6.0 g 9.0 g

n=50

200 to 600 mg/day

Modafinil*(unchanged dosing)

n=63

200 to 600 mg/day200 to 600 mg/day

Modafinil(single blinded *)

Placebo† (modafinil withdrawn)

n=55

200 to 600 mg/day

Week

6.0 g 9.0 gModafinilSodium oxybate

-4 0 4 8

n=54200 to 600 mg/day200 to 600 mg/day

Baseline Endpoint

N=230. SXB-22. MWT = Maintenance of Wakefulness Test.Data on file, Orphan Medical.

0

1

2

3

4

5

6

7

Placebo(modafinil withdrawn)

Modafinil Sodium oxybate

Modafinil +sodium oxybate

Dif

fere

nc

e o

f th

e m

ea

ns

(m

in)

Difference from placebo (modafinil withdrawn)

P<0.001

P=0.002

P<0.001

Sodium Oxybate - Modafinil: 8-Week, Placebo-Controlled Trial MWT Sleep Latency

Treatment SuggestionsMain Symptom: Severe or moderate daytime sleepiness: Modafinil

Moderate or mild sleepiness, and disturbed nocturnal sleep: Sodium oxybate

Severe sleepiness and severe cataplexy: Sodium oxybate and modafinil

Mild sleepiness and cataplexy: Sodium oxybate

Nocturnal sleep symptoms: Fragmented sleep, hypnagogic hallucinations and nightmares: Sodium oxybate

Agents Under Development Non-hypocretin-based therapies

Histaminergic H3 antagonist/inverse agonists Novel monoaminergic reuptake inhibitors Novel SWS enhancers TRH analogues

Hypocretin-based Therapy Hypocretin-1 Hypocretin peptide agonist Nonpeptide agonist Hypocretin cell transplantation Gene therapy

Immune-based therapies Steroids IVIg Plasmapheresis

** p<0.01 ANOVA with post-hoc, vs. N. Controls

Histamine in Sleep Disorders

0 400 600 800 10002 0 0

CSF histamine levels (pg / ml)

**

**

**

**

(B2) Hcrt-/N/C/med+

(B1) Hcrt-/N/C/med-

(C) Hcrt+/N/C/med-

(D1) Hcrt-/N/woC/med-

(D2) Hcrt-/N/woC/med+

(E) Hcrt+/N/woC/med-

(F1) IHS/med-

(F2) IHS/med+

(G) OSAS

(A) Neurological controls

Kanbayashi T, Kodama T, Kondo H, Satoh S, Inoue Y, Chiba S, Shimizu T, Nishino S. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep. 2009 Feb 1;32(2):181-7.

Histamine and Sleep Histamine neurons project to practically all brain regions, including areas

important for vigilance control, such as the hypothalamus, basal forebrain, thalamus, cortex, and brainstem structures.

Hcrtr 1 is enriched in the ventromedial hypothalamic nucleus, tenia tecta, hippocampal formation, dorsal raphe, and locus coeruleus (LC).

Hcrtr 2 is enriched in the paraventricular nucleus, cerebral cortex, nucleus accumbens, ventral tegmental area, substantia nigra, and histaminergic TMN.

TMN exclusively expresses Hcrtr 2.

Hypocretin potently excites TMN histaminergic neurons through Hcrtr 2.   Wake-promoting effects of hypocretins are totally abolished in histamine

H1 receptor KO mice, Therefore, the wake-promoting effects of hypocretin is dependent on the

histaminergic neurotransmission 1

1. Barbier AJ, Bradbury MJ. Histaminergic control of sleep-wake cycles: recent therapeutic advances for sleep and wake disorders. CNS Neurol Disord Drug Targets 2007;6:31-43.

Histamine Receptor Subtypes There are four histamine receptor subtypes, (H1R-H4R) All G protein coupled receptors (GPCRs). Greater than 50% of

the most successful pharmaceutical treatments are drugs that act via GPCRs pathways.

H1R blockers have sedative effects are anti-allergy. H2R based drugs are anti-ulcer drugs. H3R antagonists activate histaminergic neurons, increasing

histamine, and producing wakefulness. H4R is expressed in hematopoietic cells suggesting a strong

role in inflammatory and immunomodulatory processes.

Histaminergic H3R Antagonists H3R, presynaptic autoreceptor of histamine neurons.

Histamine inhibits its own synthesis and release by a negative feedback process and that these actions are mediated by H3 receptors.

Stimulation of H3R causes sedation, antagonism causes wakefulness.

H3R is densely located centrally in the hippocampus, amygdala, nucleus accumbens, globus pallidus, hypothalamus striatum, substantia nigra, and the cerebral cortex.

Peripherally, H3R are also located in the GI tract, airways and cardiovascular system.

H3R antagonists are being studied for sleep wake disorders, ADHD, epilepsy, cognitive impairment, schizophrenia, obesity, and neuropathic pain.

Histamine 3 receptor (H3R) antagonists

Effective in canines on sleepiness and cataplexy Promotes wakefulness in mice with ablation of hypocretin

neurons (ataxin-3)

H3R antagonists thioperamide, carboperamide, and ciproxifan have been tested in rats, mice and cats.

Increase in wakefulness without rebound hypersomnolence or increasing locomotor activity.

APD916 is currently in Phase 1 trials for narcolepsy by Arena Pharmaceuticals

1. Barbier AJ, Bradbury MJ. Histaminergic control of sleep-wake cycles: recent therapeutic advances for sleep and wake disorders. CNS Neurol Disord Drug Targets 2007;6:31-43.

Histaminergic H3R Inverse Agonists- Tiprolisant

Tiprolisant or BF2.649 is the first H3 inverse agonist that passed clinical Phase II trials in the treatment of EDS in narcolepsy.

In a pilot study single blinded with 22 patients, receiving a placebo followed by tiprolisant for one week, the ESS was reduced from baseline of 17.6, by 5.9 with tiprolisant compared to 1.0 for placebo.

Effect similar to modafinil.

Tiprolisant has been granted orphan drug status by the European Medicine Agency for the therapeutic treatment of narcolepsy.

Multiple other compounds in development: Conessine , JNJ-637940 , GSK 189254

Lin JS, Dauvilliers Y, Arnulf I, et al. An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients. Neurobiol Dis 2008;30:74-83.

Hypocretin

Intracerebroventricular hypocretin replacement, intranasal hypocretin administration, hypocretin cell transplantation, hypocretin gene therapy, and hypocretin stem cell transplantation are being studied for narcolepsy.

Hypocretin-1 low permeability to the blood-brain barrier. Hypocretin-2 does not cross the blood-brain barrier. Hypocretin-1 more stable in the blood and CSF than

hypocretin-2. Hypocretin-1 binds with two to three times the affinity to

HCTR-1 than hypocretin-2

Systemic and ICV Hypocretin-1

Intra-cerebro-ventricular (ICV) hypocretin-1 can suppress cataplexy and improve sleep in narcoleptic mice and canines.

Not effective in hcrt2 mutated dogs.

Systemic administration of hypocretin-1 in canines with narcolepsy produces increases in activity levels, wake times, reduces sleep fragmentation, and has a dose dependent reduction in cataplexy.

Small peptide hypocretin analogues might be an alternative.

Intranasal hypocretin administration holds promise.

Intranasal Hypocretin-1

Intranasal hypocretin bypasses the blood brain barrier with the added benefits of onset of action within minutes and fewer peripheral side effects.

Intranasal delivery works through the olfactory and trigeminal nerves.

The mechanism of action is extracellular so there is no dependence on receptors or axonal transport for drug delivery.

Csf fluid levels are detectable after intranasal delivery of hypocretin. Intranasal hypocretin concentrations were highest in the

hypothalamus and the trigeminal nerve.

Hanson LR , Taheri M, Kamsheh L, et al. Intranasal administration of hypocretin 1 (orexin A) bypasses the blood-brain barrier and target the brain: a new strategy for the treatment of narcolepsy. . Drug Deliv Tech 2004;4:1-10.

Born J, Lange T, Kern W, et al.. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002;5:514-6.

Hypocretin Gene Therapy

Aimed at stimulating the production of hypocretin. Ectopic transgenic expression of hypocretin in mice

prevents cataplexy even with hypocretin neuron ablation.

Hypocretin gene therapy with viral vectors are a potential future treatment for narcolepsy-cataplexy.

Mieda M, Willie JT, Hara J, et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci U S A 2004;101:4649-54.

Hypocretin Cell Transplantation

Normal subjects have approximately 70,000 hypocretin neurons and in narcolepsy-cataplexy, 85-95% of hypocretin neurons are lost.

A minimum of 10% of hypocretin producing cells need to be replaced for a therapeutic effect.

Transplantation is limited by graft survival and immune reactions. Transplantation of neonatal rat hypothalami into the brainstem of

adult rats produced poor graft survival. Donor supply may be a problem if the survival of grafts is

improved.

The barrier of graft survivability, graft reactions, and cost barriers could be reduced if genetically engineered cells or employing stem cell techniques were used instead.

Thyrotrophin-releasing Hormone Agonists

TRH is a small peptide of 3 amino acids

TRH receptor-1 is found predominantly in the hypothalamus. TRH receptor-2 is more widespread and in the reticular nucleus of

the thalamus.

TRH in high dose stimulates wakefulness and anticataplectic in the narcoleptic canine

TRH is excitatory on neurons and enhances dopamine and adrenergic transmission.

May promote wakefulness by direct effect on thalamocortical pathways

Nishino S, Arrigoni J, Shelton J, et al. Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy. J Neurosci 1997;17:6401-8

Thyrotrophin-releasing hormone agonists

Three compounds had a significant impact on cataplexy, whereas only two of the three had benefit in excessive sleepiness.

Oral CG-3703 at two weeks was shown to reduced cataplexy and excessive sleepiness in a dose dependent manner. The effective dose in producing wakefulness was similar to a

reasonable dose of D-amphetamine. The action CG-3703 is due to enhancement of dopaminergic

effects.

TRH-degrading enzyme inhibitor, metallopeptidase, may be promising.

Nishino S, Arrigoni J, Shelton J, et al. Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy. J Neurosci 1997;17:6401-8

Immune-based Therapies

Steroids: Ineffective in 1 human and 1 canine case

Plasmapheresis Little data available More invasive than IVIg

IVIg Effective in two studies

May need to be used early (<1 year of onset) No placebo controlled trials Generally safe but can cause life threatening side effects.

Intravenous Immunoglobulin (IVIg)

One case study 10 year old (Lecendreaux et al.) Sleepiness and cataplexy improved.

4 case studies (Dauvilliers et al.) Cataplexy improved.

4 cases (Zuberi et al.) Sleepiness improved more than cataplexy.

Lecendreux M, Maret S, Bassetti C, Mouren MC, Tafti M. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res. 2003 Dec;12(4):347-8.

Yves Dauvilliers MD, Bertrand Carlander MD, François Rivier MD, PhD, Jacques Touchon MD, Mehdi Tafti, PhD. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset Ann Neurol. 2004 Dec;56(6):905-8.

Zuberi SM, Mignot E, Ling L, McArthur I. Variable response to intravenous immunoglobulin therapy in childhood narcolepsy. J Sleep Res., 2004;13(suppl1) 828.

Future Directions

Other potential targets for reducing EDS will likely involve: Developing novel neuropeptides Targeting:

proteins such as circadian clock proteins,

specific ion channels such as prokineticin or neuropeptide S.

Conclusion

Pharmacological treatment of Narcolepsy involves not only treatment of Daytime Sleepiness and Cataplexy, but also Nocturnal Sleep.

Current treatment involves the use of Modafinil, Stimulants, Sodium Oxybate, adrenergic/serotonergic inhibitors.

New experimental treatment options for early onset narcolepsy include immune suppression treatments.

Future treatments may target hypocretin and histaminergic systems.