Transcript Test 1 - North East Sleep Society

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
Stimulants and Wake-Promoting Medications
Drug
Formulations
Schedule
Dose
T1/2
(Hours)
Dextroamphetamine
Tablets, SR
C-II
5-60 mg/day
12
Methamphetamine
(Desoxyn)
Tablets
C-II
5-60 mg/day
4-5
Amphetamine
sulfate/saccharate/
aspartate (Adderall)
Capsules, XR
C-II
5-60 mg/day
10-13
Methylphenidate
Tablets, SR, LA
C-II
5-60 mg/day
3-5
Modafinil
Tablets
C-IV
200-400
mg/day
15
Armodafinil
Tablets
C-IV
150-250
mg/day
15
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: Elsevier
Alerting Agents
Mechanism



Sympathomimetic: enhance neurotransmission
of dopamine, norepinephrine, serotonin
Caffeine: adenosine receptor antagonist
Modafinil: specific mechanism remains unclear
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
Caffeine
Medial Prefrontal Cortex
Regions (BA 10)
Activated by Caffeine vs.
Placebo During Verbal
Working Memory
Adapted from Koppelstaetter et al. (2008)
Caffeine Taken at 44 hrs Awake
Mean (+SE) Speed as % of Baseline
110
100
90
80
70
60
Placebo
Caffeine 600 mg
Rx
50
0800
1600
0000
0800
1600
0000
0800
1600
Clock Time
Adapted from Killgore et al. (2008)
Sites of Action of Amphetamines
Amphetamine
Dopamine
reuptake
transporter
MAO
Vesicular
Monoamine
transporter
Dopamine
Dopamine
receptors
+
Courtesy of Thomas Scammell, MD.
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
Neurotransmitter
Method of action
Site of Action
Dopamine
Inhibition of dopamine
reuptake
transporter
Multiple arousal systems
Norepinephrine (NE)
Inhibition of the NE
reuptake
transporter
VLPO
Hypocretin
Stimulation
Lateral hypothalamus
Histamine
Stimulation
Tuberomamillary nucleus
VLPO = Ventrolateral preoptic area
Proposed Sites of Action of Modafinil
MAO
Norepinephrine
Norepinephrine
reuptake
transporter
Dopamine
reuptake
transporter
Sleep-promoting
neurons
(GABA; VLPO)
2 Norepinephrine
receptors
Modafinil
Wake-promoting
neurons
MAO
Dopamine
receptors
Dopamine
+
Alerting Agents Stabilize Wakefulness
Modafinil
Amphetamines
GABA
Sleep
Norepinephrine
Histamine
GABA
(ventrolateral
Preoptic
area)
–
–
Dopamine
Serotonin
Acetylcholine
Norepinephrine
Serotonin
Modafinil
– +
Wake
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
Modafinil
Disorder
Measures
Modafinil 200mg
Modafinil 400mg
Baseline
Change
from
baseline
Baseline
Change
from
baseline
OSA I study
ESS
MSLT
-
-
14.2
7.4
-4.6
+1.2
OSA II study
ESS
MWT
13.1
-4.5
+1.6
13.6
-4.5
+1.5
SWD
KSS
MSLT
PVT
7.3
2.1
12.5
-1.5
+1.7
-2.6
-
-
Narcolepsy I
ESS
MSLT
MWT
17.9
2.9
5.8
-3.5
+1.8
+2.3
17.1
3.3
6.6
-4.1
+1.9
+2.3
Narcolepsy II
ESS
MSLT
MWT
17.4
3.0
6.1
-4.4
+1.9
+2.1
18.0
2.7
5.9
-5.7
+2.4
+1.9
MWT Sleep Latency:
Split-Dose vs AM Dosing Regimens
Mean (+SEM) MWT
change from baseline
N=32
15
*†
10
200 mg qd
400 mg qd
400 mg split-dose
5
0
Morning
(9-11 AM)
Afternoon
(1-3 PM)
Evening
(5-7 PM)
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.
MWT Sleep Latency:
Comparing Split-Dose Regimens
N=24
% of patients awake
for 20 minutes
80
200 mg qd
70
*
*
60
50
400 mg qd
400 mg split-dose
600 mg split-dose
40
30
20
10
0
Morning
(9-11 AM)
Afternoon
(1-3 PM)
*P<.05 vs 200 or 400 mg qd
Schwartz JRL, et al. J Neurol Clin Neurosci. 2004; 27(2): 74-79.
Evening
(5-7 PM)
Armodafinil (Nuvigil)

R-(-)-modafinil

Longer acting isomer of modafinil

Half life approximately 3 x S-(-)-modafinil
Armodafinil
Disorder
Measures
Armodafinil 150mg
Armodafinil 250mg
Baseline
Change
from
Baseline
Baseline
Change
from
baseline
OSA I
MWT
21.5
+1.7
23.3
+2.2
OSA II
MWT
23.7
+2.3
-
-
SWD
MSLT
2.3
+3.0
-
-
Narcolepsy
MWT
12.1
+1.3
9.5
+2.6
Modafinil / armodafinil
Diagnosis
Symptoms
FDA approval
Modafinil
Doses studied
Armodafinil
Doses studied
Obstructive
Sleep Apnea
EDS
yes
200-400mg
150 – 250mg
Shift Work
Disorder
EDS
yes
200-400mg
150mg
Narcolepsy
EDS
yes
200-400mg
150 – 250mg
Depression
Fatigue
no
100-400mg
N/A
Multiple
Sclerosis
Fatigue
no
200-400mg
N/A
EDS
no
100-400mg
N/A
Chronic fatigue
syndrome
Fatigue
no
200-400mg
N/A
Traumatic Brain
Injury
Fatigue
EDS
no
100-400mg
N/A
Parkinson’s
disease
Modafinil / Armodafinil
Adverse Effects
Modafinil
Armodafinil
Headache
34%
17%
Nausea
11%
7%
Dizziness
5%
5%
Nervousness
7%
1%
Anxiety
5%
4%
Insomnia
5%
5%
Rhinitis
7%
not reported
Back pain
6%
6%
Flu syndrome
4%
1%
Hypertension
3%
not reported
Diarrhea
6%
4%
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 metabolism
End product CO2 + H2O
No active metabolite
Elimination
Predominantly metabolized
~5% unchanged in urine
T1/2 = 40-60 min
Food
AUC = area under the curve.
Slows bioavailability
(AUC 30% with full meal)
Sodium Oxybate: Sites of Action
Sodium Oxybate
OH
NaO
GABA
O
OH
OH
H2N
O
-O
O
GABA-A
GABA-B
GHB receptor
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
Baseline
Endpoint
n=55
Placebo†
200 to 600 mg/day
(modafinil withdrawn)
n=63
200 to 600 mg/day
Modafinil*
200 to 600 mg/day
(unchanged dosing)
Modafinil
n=50
(single blinded *)
200 to 600 mg/day
6.0 g
9.0 g
n=54
200 to 600 mg/day
-4
6.0 g
0
200 to 600 mg/day
4
9.0 g
Sodium oxybate§
Modafinil
Sodium oxybate
8
N=222. SXB-22.
Week
†
*Placebo: sodium oxybate; Placebos: modafinil + sodium oxybate; §Placebo: modafinil.
Data on file, Orphan Medical.
Sodium Oxybate - Modafinil: 8-Week, PlaceboControlled Trial  MWT Sleep Latency
7
Difference from placebo (modafinil withdrawn)
P<0.001
Difference of the
means (min)
6
5
4
P<0.001
3
P=0.002
2
1
0
Placebo
(modafinil
withdrawn)
Modafinil
N=230. SXB-22. MWT = Maintenance of Wakefulness Test.
Data on file, Orphan Medical.
Sodium
oxybate
Modafinil +
sodium
oxybate
Treatment Suggestions
Main 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





Hypocretin-based Therapy






Histaminergic H3 antagonist/inverse agonists
Novel monoaminergic reuptake inhibitors
Novel SWS enhancers
TRH analogues
Hypocretin-1
Hypocretin peptide agonist
Nonpeptide agonist
Hypocretin cell transplantation
Gene therapy
Immune-based therapies
 Steroids
 IVIg
 Plasmapheresis
Histamine in Sleep Disorders
CSF histamine levels (pg / ml)
0
2 0 0
400
600
800
1000
(A) Neurological con trols
(B1 ) Hcrt- /N /C /med-
**
(B2 ) 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
** p<0.01 ANOVA with post-hoc, vs. N. 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.