LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
`
`The Treatment of Narcolepsy-Cataplexy with Nocturnal
`Gamma-Hydroxy butyrate
`
`ROGER BROUGHTON AND MORTIMER MAMELAK
`
`SUMMARY: Sixteen patients with narco(cid:173)
`lepsy and cataplexy were treated with
`gamma-hydroxybutyrate (G H B) given at
`night and tailored to achieve as continuous
`a night's sleep as possible. The dosage
`usually consisted of 1.5-2.25 gm orally at
`bedtime and then one or twofurther 1.0-
`1.5 gm doses with mvakenings during the
`night, and totaled about 50 mg /kg. Apart
`from one patient who took only the
`hedtirne dose,
`the subjective quality of
`night sleep improved in all patients and the
`
`number of irresistable daytime attacks of
`sleep and cataplexy substantially diminish(cid:173)
`ed. Some residual daytime drowsiness
`remained and this usually responded well
`to low doses ofmethylphenidate. Improve(cid:173)
`ment has been maintained for up to 20
`months without the development of toler(cid:173)
`ance. nt·o patients experienced adverse
`side eff'ects necessitating withdrawal ol
`G H B treatment, hut no serious toxic
`have occurred.
`
`RESUME: Seize malades qui presentaient
`des episodes de narcolepsie et de cataplexie
`ont ete traites Ia nuit avec hydroxyhuty(cid:173)
`rate-ganuna. II etait dose pour donner un
`sommeil nocturne .fe plus continue/ pos(cid:173)
`sih/e. Le dosage normal hait de 1.5-2.25
`gm. par voie orale avant le coucher suivi
`par un ou deux autres dosages de 1.0-1.5
`gm. pour les reveils nocturnes. Le dosage
`total etait approximativement de 50 mgj
`kg. Le sommeil nocturne de
`tous les
`malades s'est ameliore, sauf pour un seul
`
`qui ne prenait que le dosage avant If
`coUl·her, et
`/e nombre d'episodes de
`sommeil diurne irresistible et de cataplexie
`haient tres diminues. Une somnolence
`residuelle et diurne persistait, ce qui
`habituellement repondait bien au dosage
`minime de methulphenidate. L'ameliora(cid:173)
`tion clinique a he maintenue jusqu'a 20
`mois sans /'apparition de tolham·e. Deux
`malades ont eu des eff'ets secondaires qui
`necessitaient /'arret du traitement, mais
`aucun eff'et toxique shieux n'a eu lieu.
`
`From the Division of Neurology. Ottawa General
`Hospital and l;niversity of Ottawa. and the Depart(cid:173)
`ment of Psychiatry. Sunnybrook Medical Centre and
`University of Toronto. Canada.
`
`Reprints requests to: Dr. Broughton. Department ol
`Medicine (Neurology), Ottawa General Hospital,
`Ottawa, Canada, KIN 5C8.
`
`INTRODUCTION
`The prevalence of narcolepsy has
`been shown in epidemiological studies
`to be about 0.1% (Roth, 1962; Dement
`et al., 1973). Therefore it is more
`frequent than a number of much better
`known chronic neurological condi(cid:173)
`tions,
`such as multiple sclerosis.
`Moreover, as it generally begins in
`young adulthood and remains for the
`patients' lifetime, and as it has marked
`detrimental effects involving employ(cid:173)
`inter(cid:173)
`ment, education, recreation,
`personal relations, driving, accidents
`in general and other parameters of
`everyday
`life
`(Broughton and
`Ghanem, 1976), the condition can be
`truly debilitating. The investigation of
`narcolepsy by modern polysomno(cid:173)
`graphic techniques has shown that of
`the classical so-called 'tetrad' of Daly
`and Y oss
`( 1960),
`the
`auxiliary
`symptoms (i.e. those other than sleep
`attacks) of cataplexy, sleep paralysis,
`and vivid hypnogogic hallucinations
`are all based upon abnormal rapid(cid:173)
`eye-movement (REM) sleep mechan(cid:173)
`attacks of
`isms, and that the
`patients with narcolepsy-cataplexy
`begin in REM sleep in 50-I 00% of
`attacks (Broughton, 1971; Zarcone,
`1973), depending upon the author.
`These findings have led to the ad(cid:173)
`dition of drugs which suppress REM
`sleep,
`i.e.
`tricyclic antidepressants
`(imipramine, chlorimipramine, and
`desipramine) or less frequently MAO
`inhibitors (phenelzine) to traditional
`stimulant medication, usually methyl(cid:173)
`phenidate. The antidepressants have
`been largely effective in reducing the
`auxiliary symptoms of cataplexy,
`sleep paralysis and hypnogogic
`hallucinations, whereas methylpheni(cid:173)
`date has been most useful for the sleep
`attacks and for
`the more or less
`continuous daytime drowsiness
`
`Vol. 6 No. l
`
`FEBRUARY 1979-1
`
`Page 1
`
`Ranbaxy Ex. 1008
`IPR Petition - USP 9,050,302
`
`

`
`THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES
`
`presented by these patients (Zarcone,
`1973). Despite
`these
`therapeutic
`improvements over stimulants alone,
`the
`treatment of narcolepsy still
`remains unsatisfactory.
`In many
`patients control of symptoms is far
`from complete. Others show undesir(cid:173)
`able side effects discussed later.
`This situation
`led us
`to use a
`somewhat different
`therapeutic
`strategy. Rather than concentrating
`upon suppressing
`the daytime
`symptoms, we decided to attempt to
`improve their night-time sleep, which
`is characterized by early or direct entry
`into REM sleep (Rechtschaffen et al.,
`1963), much sleep fragmentation with
`particular inability to sustain periods
`of REM sleep (Montplaisir, 1976), and
`by other features, in the hope that
`daytime pressure for sleep-related
`symptoms would be reduced. There
`were
`at
`least
`two
`reasons
`for
`suggesting that disturbed nocturnal
`sleep might be
`central
`to
`the
`physiopathogenesis of narcolepsy with
`cataplexy. First, prolonged periods of
`sleep deprivation or of irregular sleep
`precede the onset of major symptoms
`of the disease in 50-75% of patients
`(Mitchell
`and Dement,
`1968;
`Broughton and Ghanem, 1976) with
`idiopathic narcolepsy. Secondly,
`narcoleptics are known to be very
`vulnerable to the effects of shift work,
`and therefore to alteration in their
`circadian sleep-wakefulness rhythms.
`Such disturbances regularly aggravate
`their symptoms (Broughton, 1971 ).
`We chose the sodium salt of gamma(cid:173)
`hydroxybutyrate
`(GHB)
`(Laborit,
`1964; Muzard and Laborit, 1977;
`Snead, 1977)
`in our attempt
`to
`"normalize"
`the nocturnal
`sleep
`patterns of patients with narcolepsy
`and cataplexy. This short chain fatty
`acid is a normal constituent of the
`human nervous system (Doherty and
`Roth, 1976).
`It possesses definite
`hypnotic properties. But in distinction
`to
`the commonly used synthetic
`hypnotics, it promotes sleep which
`more closely approximates that of
`normal sleep than do other hypnotics,
`since it does not inhibit either REM or
`NREM sleep (Jouvet et aL, 1961;
`Matsuzaki et aL, 1964; Mamelak et al.,
`1977; Muzard and Laborit, 1977).
`GHB also has an additional possible
`advantage over the synthetic hypno-
`
`tics in that animal studies had failed to
`demonstrate
`the development of
`tolerance to its hypnotic effects with
`prolonged use (Vickers, 1969). To date
`we have
`treated 16 patients with
`nocturnal G HB. Preliminary results in
`our first four patients have already
`been reported
`(Broughton and
`Mamelak, 1976).
`
`PATIENTS AND METHODS
`The sixteen patients, 8 men and 8
`women, ranged in age from 21-58
`years (Mean 41.8, s.d. 13.6; Table 1).
`All had histories of diurnal drowsi(cid:173)
`ness, irresistible sleep attacks, and
`cataplexy. The other main symptoms
`of the disease were also present in
`individual patients to varying degrees.
`In four patients, the symptoms had
`been particularly debilitating in spite
`of treatment with the usual combina(cid:173)
`tion of methylphenidate and tricyclic
`antidepressant drugs. The entire
`protocol and the investigative nature
`of the study were carefully explained
`to each patient and consent forms were
`signed. In all patients, a sleep onset
`REM period was observed during at
`least one daytime polysomnographic
`recording. Before starting treatment
`with G H B, all previous drug treatment
`for narcolepsy was discontinued for at
`least 14 days. A history and physical
`were performed and the following
`laboratory
`tests completed: hemo(cid:173)
`gram, liver survey, renal survey, chest
`x-ray, EEG and ECG. Each patient
`was
`also given
`a psychological
`examination and
`the Minnesota
`Multiphasic Personality Inventory.
`Polysomnographic assessment of
`sleep-waking patterns was done for at
`least 48 continuous hours
`in
`the
`baseline state and then at regular
`intervals while on GHB. In the Ottawa
`patients
`(N 9)
`recordings were
`performed without hospitalization
`using a portable 4-channel apparatus
`which permitted the monitoring of
`patients at their habitual activity levels
`in
`the normal home or work
`environment. In the Toronto studies,
`patients
`(N 7) were hospitalized
`during the recording periods and the
`usual polysomnographic techniques
`were employed. None of the patients
`had histories of loud snoring or of the
`peculiar gutteral inspiratory snormg
`which
`characterizes
`sleep
`apnea.
`
`Moreover, this symptom was formally
`excluded by respiratory monitoring
`(nasal thermistor and abdominal belt
`transducer) in Toronto studies, where
`sufficient recording channels made
`this possible. The Stanford Sleepiness
`Scale (Hoddes et al., 1973), which is a
`self-assessed 1 to 7 scale of alertness,
`was filled in every 30 minutes over at
`least 3 consecutive days during
`wakefulness in the pre-GHB baseline
`period, and during
`reassessments
`while on the drug.
`Treatment with G HB was started
`once the initial baseline data was
`gathered. The treatment schedule was
`tailored to achieve as continuous a
`night's sleep as possible. The patient's
`body weight and his polysomno(cid:173)
`graphic response to GHB were used as
`guides. Since each sleep inducing oral
`dose of GHB lasts only two or three
`hours (Mamelak et aL, 1977)-indeed
`the substance is only detectable in
`blood that long (Helrich et al., I 964)
`-and because our aim was
`to
`maximize
`the duration of sleep
`produced by the drug while minimiz(cid:173)
`ing its anaesthetic effects, multiple
`doses were used. The usual initial dose
`was 1.5-2.25 gm ( I0-15 ml) hs, followed
`by further multiple 1.0-1.5 gm doses
`during the night with each major
`reawakening, if at least 2.5 hours had
`passed since the previous dose. Usually
`only 2 or 3 doses per night were neces(cid:173)
`sary. Each dose was about 30 mgj kg,
`but the total quantity of GHB given
`each night ranged from 3.75 to 6.25
`gms, corresponding to approximately
`50 mgjkg.
`
`After seven to ten nights on G HB,
`the 48 hour polysomnographic
`recording was
`repeated with
`the
`patient continuing to use the drug
`according to the optimal dose schedule
`previously established. Major reas(cid:173)
`sessments were again performed after
`at least one month, six months and 12
`months on GHB. On each of these
`occasions, the clinical effects of the
`treatment were assessed, the blood and
`urine studies, chest x-ray and ECG
`were
`repeated, and any adverse
`reactions
`to
`the drug noted and
`investigated.
`GHB was obtained from Labora(cid:173)
`toire Egic in France, who market this
`drug in syrup form under the trade
`
`2-FEBRUARY 1979
`
`Narcolepsy and Gamma-Hydroxybutyrate
`
`Page 2
`
`

`
`LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
`
`Patients' Symptoms, Previous Treatment and Response to Nocturnal Gamma Hydroxy Butyrate
`
`TABLE I.
`
`.
`
`Patient Age
`21
`I
`22
`2
`3
`23
`4
`25
`32
`5
`6
`38
`
`Major
`Symptoms
`Sex
`F N,SP,HH rare C
`M N,C,SP,HH
`F N,C,SP,HH
`F N,C,SP
`F N,C,SP,HH
`F N,C,SP,HH
`
`Duration
`of Illness
`6 years
`4 years
`3 years
`5 years
`14 years
`15 years
`
`7
`
`40
`
`M N,C,SP,HH
`
`28 years
`
`8
`
`43
`
`F N,C,SP,HH
`
`13 years
`
`Previous
`Medication
`diazepam hs
`diazepam sedn
`none
`benzedrine
`dexedrine
`dexedrine
`methylphenidate
`chlorimipramine
`dexedrine
`methylphenidate
`imipramine
`chlorimipramine
`phenelzine
`dexedrine
`methylphenidate
`imipramine
`chlorimipramine
`phenelzine
`phenytoin
`carbamazepine
`dexedrine
`methylphenidate
`
`Usual GHB
`Dosage
`gm/night Response
`+++
`3.0
`+
`3.75
`+++
`3.75
`2.25
`0
`+++
`5.25
`+++
`3.75
`
`Toxicity
`none
`none
`none
`none
`none
`none
`
`4.50
`
`+++
`
`none
`
`Comments
`
`Took only hs dose
`Sister of pat. 4
`Old gastrectomy
`
`4.50
`
`++
`
`abdominal pain, No evidence for
`muscle weak-
`epilepsy
`ness
`
`6.25
`4.50
`
`3.75
`
`3.75
`3.75
`
`4.50
`5.25
`3.75
`
`+
`+++
`
`+++
`
`+++
`+++
`
`+++
`+++
`+++
`
`none
`temporary
`muscle weakness
`none
`
`none
`dysthesiae
`left hand
`none
`none
`none
`
`Impotence on
`previous R
`
`Post-traumatic
`epilepsy
`
`9
`lO
`
`II
`
`12
`13
`
`14
`15
`16
`
`45
`45
`
`52
`
`55
`56
`
`57
`57
`57
`
`F N,C,SP
`M N,C,SP,HH
`
`23 years
`3 years
`
`M N,C,SP
`
`14 years
`
`desoxyn
`
`M N,C
`M N,C,SP
`
`30 years
`31 years
`
`methylphenidate
`methylphenidate
`
`M N,C
`M N,C,SP,HH
`F N,C,SP,HH
`
`43 years
`33 years
`37 years
`
`ephedrine
`dexedrine
`dexedrine
`methylphenidate
`impramine
`chlorimipramine
`
`0 = no effect; +I- = 0-20% improvement; +
`20-40% improvement
`++
`40-70% improvement; +++ over 75% reduction of symptoms from baseline
`cataplexy; SP = sleep paralysis; HH
`N = irrisistible sleep attacks; C
`vivid hypnagogic hallucinations
`
`name "GammaOH". We found it best
`to dilute the syrup in milk or juice, in
`order to reduce the gastrointestinal
`upset caused in some patients when the
`drug was given in undiluted form.
`Dilution also retarded G HB's rate of
`absorption somewhat, so that sleep
`induction was experienced as gradual
`and more normal.
`
`RESULTS
`to report our clinical
`We wish
`observations here. The polysomno(cid:173)
`grapic and Stanford Sleep Scale data
`
`and our psychological findings are still
`being analyzed and will be presented in.
`a future publication. The patient and
`clinical results are summarized in
`Table 1.
`
`CLINICAL RESPONSE
`The ameliorating effects of GHB on
`the major daytime symptoms of
`narcolepsy appeared gradually. By
`comparison, the subjective quality of
`night-time sleep
`improved very
`rapidly. Over the first 2 to 5 nights,
`nocturnal sleep became less restless
`
`and nightmares, hallucinations, and
`attacks of sleep paralysis vanished.
`Some episodes of intense awakenings
`at about 2-3 hours after taking the
`initial doses were encountered. These
`appeared to represent a drug-related
`rebound
`phenomenon. Although
`dreaming
`continued,
`it
`lost
`its
`frightening qualities. All patients
`found it easier to stay awake during
`the day and noted that after a number
`of weeks, the irresistible pressure for
`diurnal sleep and
`the attacks of
`cataplexy virtually disappeared. When
`cataplexy did occur, the attacks were
`
`Broughton and Mamelak
`
`FEBRUARY 1979-3
`
`Page 3
`
`

`
`THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES
`
`usually relatively brief, less intense,
`and tended to occur late in the day
`when the individual was very tired.
`Most patients said that they were
`much more refreshed after their night
`sleep and were better able to cope
`during the daytime. Despite these
`the major
`effects on
`beneficial
`symptoms of the disease and on the
`subjective quality of sleep, many
`patients continued to feel somewhat
`tired and drowsy during the day. We
`then added 5 to 10 mg of methylphe(cid:173)
`nidate
`three times a day to their
`treatment regimen. It was taken on an
`empty stomach before breakfast and
`lunch, and then again in the mid(cid:173)
`afternoon. With this addition, the
`daytime drowsiness
`and
`fatigue
`became minimal.
`Our patients generally reported that
`sleep gradually consolidated into a
`to eight hour period. One
`seven
`patient, however, reported that if she
`slept through the night and failed to
`take her second dose of G H B, the
`attacks of narcolepsy and cataplexy
`recurred on the following day. The
`single patient (No. 4) who failed to
`respond at all to G H B treatement,
`turned out to be taking only the single
`h.s. dose of the drug. Some patients on
`their own tried to discontinue G HB
`treatment and to rely on methylphe(cid:173)
`nidate
`alone, but
`they noticed
`recurrence of their symptoms after a
`few days.
`In patients responding to G HB, the
`improvement was maintained through(cid:173)
`out the trial period. The development
`of tolerance requiring increasing dose.s
`for the same clinical effect on night
`sleep, sleep attacks or cataplexy has
`not been encountered. As with
`traditional forms of treatment, it was
`found
`that having patients keep
`regular hours of retiring and of
`morning awakening was important for
`optimal therapeutic effectiveness. At
`the time of writing, one patient has
`been on G H B nightly for nearly two
`years, three others have been on it for
`over a year. and the remainder have
`been on it for three months to a year.
`
`SIDE EFFECTS
`There have been very fe\v adverse
`clinical effects with this treatment and
`no abnormal
`laboratory
`findings.
`
`Minor side effects of G HB have been
`seen for the first few days in a number
`of patients which consisted of a "thick
`head", ocular discomfort, and other
`apparent hangover effects, but these
`were rare after one week. Impotence or
`reduced
`libido
`has never been
`encountered. We decided
`to dis(cid:173)
`continue the drug in two patients. One
`(patient No. 8) complained of non(cid:173)
`specific abdominal pain while using
`G H B plus muscular weakness in the
`morning, to the point where she found
`it difficult to initiate movement. Both
`of these symptoms disappeared when
`the drug was stopped. A second
`patient (No. 13), a male with a post(cid:173)
`traumatic narcolepsy and cataplexy,
`experienced
`disturbing
`left
`arm
`dysthesiae. He had previously had
`similar symptoms after the initial head
`tnJury. A
`third patient (No. 10)
`complained of muscular weakness in
`the morning, also limited to his left
`arm. This man had suffered a neck
`injury a few weeks before starting
`G H B and his
`left arm was weak
`following the event. It had gradually
`been recovering, but the weakness
`recurred when he started using the
`drug. Because his narcolepsy improv(cid:173)
`ed so dramatically on G H B, we
`continued to use the drug in spite of
`the effect on his arm and the weakness
`gradually disappeared over a
`few
`weeks.
`Several patients have also mention(cid:173)
`ed that G HB caused urinary urgency.
`On one occasion, enuresis occurred in
`a patient about an hour after the drug
`had been given. On
`the whole,
`however, urgency has not been a
`serious problem and our patients
`report
`that
`they void no more
`frequently during the night on G H B
`than they did before starting the drug.
`Another complaint from a number of
`patients was that GHB produced a
`dream-like confusional state which
`could be unpleasant and frightening.
`This happened when the drug was
`taken before they were ready for sleep,
`or when they fought against its sleep
`promoting actions. This phenomenon
`is rare if patients cooperate with the
`drug's hypnotic effects and use it at the
`minimal dose
`required
`for sleep
`induction and maintenance. No other
`side-effects were encountered and, in
`sum, most patients felt they had fewer
`
`side-effects and substantially better
`relief from symptoms on G HB than on
`any previous medication.
`
`DISCUSSION
`The salient finding in this study was
`improvement
`the marked clinical
`produced by nocturnal G H B
`in
`patients with narcolepsy-cataplexy.
`This action was coupled with a paucity
`of adverse clinical or
`laboratory
`findings. When G HB was used at
`night, and supplemented with small
`doses of methylphenidate during the
`day, all
`the major symptoms of
`narcolepsy were markedly reduced.
`The project has
`involved detailed
`study of a limited number of patients
`over substantial periods of time. It is
`not a double-blind controlled design.
`But, the therapeutic effects on patients
`previously uncontrolled by the more
`traditional drug regimens and
`the
`rapid deterioration
`in
`those who
`discontinued the use of the drug on
`their own for several nights leave little
`doubt about the compound's effective(cid:173)
`ness.
`The use of G H B for the treatment of
`this disease has a number of clear
`advantages over more conventional
`therapies. As mentioned, the latter
`usually use
`substantial doses of
`stimulants such as methylphenidate or
`d-amphetamine, alone, or in combina(cid:173)
`tion with tricyclic antidepressants such
`as
`imipramine or chlorimipramine.
`The
`stimulants,
`however,
`cause
`irritability and anxiety
`in many
`patients and more serious side effects
`in others. One of our patients
`previously had had a gastrectomy for
`ulcers attributed to stimulant medica(cid:173)
`tion. The antidepressant drugs, on the
`other hand, may cause dry mouth,
`sweating, and
`impotence in males
`(Zarcone, 1973; Dement et al., 1976).
`The stimulant-antidepressant combi(cid:173)
`nation does not consolidate sleep, and
`in fact may even further disrupt it.
`Moreover, tolerance develops in time
`both
`to
`the
`level of stimulants
`generally employed and to antidepres(cid:173)
`sants so that after a number of months,
`many patients complain that their
`symptoms are again every bit as
`troublesome as they were to begin
`with. None of these problems occur
`with G H B. Nocturnal sleep was restful
`
`4-FEBRUARY 1979
`
`IVarco/epsr and Gamma- Hydroxrhutyrate
`
`Page 4
`
`

`
`Lt: JVUKl'IAL LAl'IAUl.tl'\1 U.t:') :')Lll::l'IIL.t:') 1'\l.t:UKULUVl\,lU.t:')
`
`and sustained and patients a woke alert
`and well rested. There were few side
`effects and, specifically, no impotence
`or reduced libido. Tolerance to the
`drug's actions did not develop, nor did
`it develop to the relatively small doses
`of methylphenidate taken during the
`day, when taken in combination with
`nocturnal G H B.
`Some of the therapeutic and side(cid:173)
`effects of G H B may be related to its
`influence on motor mechanisms. It is
`known to inhibit muscle tone (Vickers,
`to block
`the H -reflex
`1969) and
`response (Uspenskii, 1965; Muzard
`and Laborit, 1977). In narcoleptics, as
`the H -reflex
`in normals,
`well as
`response can be abolished by GHB
`and remains somewhat attenuated for
`some time after the patient awakens
`( Mamelak, Sowden and Caruso,
`unpublished observations). The latter
`may be due to residual effects of small
`quantities of unmetabolized drug.
`This effect may account for
`the
`weakness experienced by two of our
`patients upon arising in the morning.
`The sustained hypotonia throughout
`sleep may be as important as any effect
`on sleep patterns in the subjective
`feeling of having had a deep refreshing
`night's sleep. As far as the urinary
`urgency is concerned, this has been
`noted by some patients even if they
`empty their bladders before bedtime,
`but it has not proved to be a treatment
`problem. It is intriguing to speculate,
`that the combination of
`however,
`profound sleep and enuresis observed
`in childhood might be related to a
`higher brain G HB concentration
`present in the early years of life.
`G H B's mechanisms of action in the
`treatment of the major symptoms of
`narcolepsy remains uncertain. It has
`been known for many years that
`hypnotic drugs can be helpful for at
`least some narcoleptic patients
`(Daniels,
`1934; Zarcone,
`1973).
`studies have shown
`that
`Recent
`narcoleptics do not sleep more in the
`24-hour period than normal indivi(cid:173)
`duals (Hishikawa eta!., 1976). Thus,
`consolidating the fragmented sleep of
`these patients into a seven or eight
`hour period by means of hypnotic
`drugs should theorectically decrease
`the need for daytime sleep. Perhaps
`this is how ordinary hypnotics benefit
`
`these patients. But, it must be noted
`that some of our narcoleptic patients
`slept reasonably soundly at night and
`that in these patients nocturnal sleep in
`fact became more fragmented after
`starting G HB, because they had to
`wake up for the second dose. If they
`to
`take
`it
`their symptoms
`failed
`recurred. Furthermore, a preliminary
`review of our polysomnographic data
`indicates that G HB did not substan(cid:173)
`tially increase the overall duration of
`sleep in the eight hour night-time
`period. G H B. then, likely has more
`specific actions on sleep mechanisms
`than simply increasing the duration of
`nocturnal sleep or its gross continuity.
`As yet, basic neurochemical studies
`offer few real insights into the drug's
`mechanism of action, although it has
`been shown that G H B may be derived
`from GABA (Roth and Giarman,
`1969), and may act as a GABA agonist
`(Roth et al., 1977) and that it alters
`dopamine (Roth and Suhr, 1970),
`serotonin (Spano et a!., 1970), and
`acetylcholine (de la Mora et aL 1970)
`metabolism. The last three, at least.
`have been implicated in sleep control
`mechanisms (Jasper and Koyama,
`1969; J ouvet, 1969; Cordeau, 1970;
`Morgane and Stern, 1972).
`Whatever its precise mode of action.
`this essentially non-toxic constituent
`of the normal brain does appear to
`have important clinical therapeutic
`effects even in otherwise refractory
`cases of narcolepsy. Moreover, its
`effectiveness, when given in the night(cid:173)
`time period, adds strong support for
`importance of the
`the postulated
`quality of night sleep in the
`of
`daytime sleep attacks and cataplexy. It
`gives promise that G H B itself or
`similar substances (we have also used
`gamma-butylactone sucessfully) may
`lead to substantial improvement in the
`control of this debilitating neurolog(cid:173)
`ical disease. The main disadvantage at
`present is its relatively short duration
`of action. It is hoped that this might be
`extended by use of slow
`release
`capsules or another approach in order
`to produce a sustained 7-8 hour
`overnight effect.
`
`ACK:\OWLEDGEME:\ IS
`
`l'ar1~ lor >uppiYJng th.:
`Wt: thank L.al:wratnin:
`gamma-h~drox\bUt\ratc and the Health Prntt:cti<>n
`Branch. Health and Wellarc Canada (Dr !. Da S1hal
`
`clearance to import the substance for the
`We also thank Tom
`Jagdish
`Maru. Olga Stokan. Vicky Caruso and
`Stewart
`for their technical a'>sistance with this
`The
`ha~ been supported by the
`of Canada.
`
`REFERENCES
`
`BROUGHTON. R.(l971). Neurologyandsleep
`research. Can. Psychiatr. Assoc. J., 16, 283-
`292.
`BROUGHTON. R. and GHANEM, Q. (1976).
`A study of
`the
`of compound
`narcolepsy on the
`of the patient. In
`Narcolepsy, edited by C. Guilleminault,
`W. C. Dement and P. Passouant. pp. 201-
`220. Spectrum: New York.
`
`BROUGHTON, R. and MAMELAK. M.
`in
`the
`( 1976). Gamma-hydroxybutyrate
`treatment of compound narcolepsy: A pre(cid:173)
`liminary report. In Narcolepsy, edited by
`C. Guilleminault. W. C. Dement and
`P. Passouant, pp. 659-667. Spectrum:
`New York.
`CORDEAU. J. P. ( 1970). Monoammes m the
`physiology of sleep and waking. In L-Dopa
`and Parkinsonism. edited by A. Barbeau and
`F. H. McDowell, pp. 369-383. Davis:
`Philadelphia.
`( 1960).
`DALY. D. D. and YOSS. R. E.
`Narcolepsy. Med. Clin. 7\orth Am .. 44. 953-
`968.
`( 1934). ::\arcolepsy. Medicine
`DANIELS. L
`(Baltimore), 13. 1-22.
`DE LA MORA. M. and TAPIA. R. ( 1970).
`pn>y·:-.wtog1ca1 aspects of
`acid as a natural
`soporific. Ann. Ins tit. BoiL Auton. Mex .. I,
`41-53.
`DE\rlE~T. W. C .. CARSKADO~. M. A ..
`GUILLEMI;>.;AULT. C.. and ZARCONE,
`V. P. ( 1976) Narcolepsy: diagnosis and
`treatment. Primary Care. 3. 609-623.
`DEME::\T. W. C .. CARSKADO:\'. M. and
`(1973). The prevalence of
`LEY. R.
`narcolep~y. I L Sleep Research, 2. 147.
`DOHERTY. J. D. and ROTH. R. H. ( 1976).
`Identification of gamma-hydroxybutyric
`acid as an endogenous metabolite present in
`monkey and human brain. Fed. Proc., 35,
`270.
`HELRlCH. M .. McASLAN. T. C.. SKOLNIK.
`S .. BESS MAN. S. P. ( 1964). Correlation of
`blood levels of 4-hydroxybutyrate w1th state
`of consciousness. Anaethesiology. 25. 771-
`775.
`HISKIKAWA. Y .. WAKAMATSU. H ..
`FURUYA. L. SLGIIA. Y .. MASAOKA.
`S .. KANEDA. H .. SATO, M .. ~AN'NO.
`IL and KANEKO. Z. ( 1976). Sleep satiation
`in narcoleptic patients. Electroenccphalogr.
`Clin. Neuroph) siol., 41. 1-1 X.
`HODDfS. L ZARCO:'\E. v· .. SMYTHE. H ..
`PHILI.IP. S .. and DE\1E:\T. \V. ( 1973).
`Quantification o! sleepiness: A new
`approach. Psychophysiology. 10. 431-436.
`
`Broughton and Mamelak
`
`FEBRUARY 1979-5
`
`Page 5
`
`

`
`THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES
`
`JASPER. H. and KOYAMA, I. ( 1969). Rate of
`release of amino acids from cerebral cortex
`in the cat as affected by brainstem and
`thalamic stimulation. Can.
`J. Physiol.
`Pharmacol., 47, 889-905.
`JOUVET, M. (1969). Biogenic amines and the
`states of sleep. Science, 163, 32-41.
`JOUVET, M., CIER, A., MOUNIER, D.,
`VALATX, J. L.
`(1961). Effets du 4-
`butyrolactone et du 4-hydroxybutyrate de
`sodium sur I'EEG et le comportement du
`chat. C. R. Soc. Bioi. (Paris), 155, 1313-
`1316.
`LABORIT. H. (1964). Sodium-4-hydroxybuty(cid:173)
`rate. Int. J. 1\'europharmacol., 3, 433-451.
`MAMI::LAK, M., ESCRIU,
`J. M. and
`STOKAN, 0. (1977). The effects of gamma(cid:173)
`hydroxybutyrate on sleep. Bioi. Psychiatry,
`12, 273-288.
`
`MATSUZAKI, M .. TAKAGI, H. and
`TOKIZANE, T. ( 1964). Paradoxical phase
`of sleep: Its artificial induction in the cat by
`sodium butyrate. Science, 146, 1328-1329.
`
`MITCHELL, S. A. and DEMEl\'T, W. C.
`( 1968). Narcolepsy syndromes: antecedent,
`contiguous and concomitant nocturnal sleep
`disordering and deprivation. Psychophysio(cid:173)
`logy, 4, 398.
`
`MONTPLAISIR, J. (1976). Disturbed noctur(cid:173)
`nal sleep. In Narcolepsy, edited by C.
`Guilleminault, W. C. Dement and P.
`Passouant, pp. 43-56. Spectrum: New York.
`MORGANE, P. J. and STERl\', W. C. ( 1972).
`Relationship of sleep to neuroanatomical
`circuits biochemistry, and behavior. Ann.
`N.Y. Acad. Sci., 193, 95-111.
`MUZARD. J. P. and LABORIT, H. (1977).
`Gammahydroxybutyrate. In Psychothera(cid:173)
`peutic Drugs, Part II, edited by E. Usdin and
`I. Forrest. Marcel Dekker: New York.
`RECHTSCHAFFEN, A., WOLPERT, E.,
`DEMENT, W., MITCHELL, S. and
`FISHER, C. ( 1963). Nocturnal sleep of
`narcoleptics.
`Electroencephalogr. Clin.
`Neurophysiol., 15, 599-609.
`ROTH, B. (1962). Narcolepsie und Hyper(cid:173)
`somnie. V.E.B. Verlag Volk und Gesundheit:
`Berlin, p. 428.
`ROTH, R. H. and GIARMAN, N.J. (1969).
`Conversion in vivo of gamma-aminobutyric
`to gamma-hydroxybutyric acid in the rat.
`Biochem. Pharmacol., 18, 147-250.
`(1970).
`ROTH, R. H.
`and SUHR, Y.
`Mechanism of the gamma-hydroxybutyrate
`induced increase in brain dopamine and its
`relationships to "sleep". Biochem. Pharma(cid:173)
`coL 19, 3001, 3012.
`
`NOWYCKY, M. C.,
`ROTH, R. H.,
`WALTERS, J. R. and MORGENROTH,
`V. H.
`( 1977). Gammahydroxybutyrate:
`Effects
`on Nonstriated Dopaminergic
`1\'eurons. Adv. Biochem. Psychopharmacol.,
`16, 483-488.
`
`SNEAD, 0. C. (1977). Gammahydroxybuty(cid:173)
`rate. Life Sci., 20, 1935-1944.
`
`SPANO, P .. NEFF. N. and COSTA, E. (1970).
`Effect of gammahydroxybutyrate on the
`synthesis rate of brain amines. Trans. Am.
`Soc. Neurochem., I, 69.
`
`US PENS Kll, A. E. ( 1965). Effect of sodium salt
`of gamma-hydroxybutyric acid on synaptic
`transmission in the spinal cord. Fed. Proc ..
`24, 673-675.
`
`VICKERS, M.D. (1969). Gamma-hydroxybut(cid:173)
`yric acid. Int. Anaesthesiol. Clin., 7. 75-89.
`
`YAMADA, Y .. YAMAMOTO. J., FUJIKI, A.,
`HISHIKA W A, Y. and KANE DO, Z.
`(1967). Effect of butyrolactone and gamma(cid:173)
`hydroxybutyrate in the EEG and sleep cycle
`in man. Electroencephalogr. Clin. Neuro(cid:173)
`physio., 22, 558-562.
`
`ZARCONE, V. (1973). Narcolepsy. N. Engl. .1.
`Med., 288, 1156-1166.
`
`6-FEBRUARY 1979
`
`Narcolepsy and Gamma-Hydroxybutyrate
`
`Page 6