Treatment of narcolepsy with methamphetamine.

Eight pairs of subjects (each consisting of a narcoleptic and a control matched on the basis of age, sex, educational background and job) were evaluated under the following double-blind, randomized treatment conditions: baseline, placebo, low dose and high dose methamphetamine. Subjects were drug-free for 2 weeks prior to beginning the protocol. Methamphetamine was the only drug taken during the protocol and was given in a single morning dose of 0, 20 or 40-60 mg to narcoleptics and 0, 5 or 10 mg to controls. The protocol was 28 days long, with each of the four treatment conditions lasting 4 days followed by 3 days of washout. Nighttime polysomnography and daytime testing were done during the last 24 hours of each treatment condition. Daytime sleep tendency was assessed with the multiple sleep latency test (MSLT). Daytime performance was assessed with performance tests including a simple, computer-based driving task. Narcoleptics' mean MSLT sleep latency increased from 4.3 minutes on placebo to 9.3 minutes on high dose, compared with an increase from 10.4 to 17.1 minutes for controls. Narcoleptics' error rate on the driving task decreased from 2.53% on placebo to 0.33% on high dose, compared with a decrease from 0.22% to 0.16% for controls. The effects of methamphetamine on nocturnal sleep were generally dose-dependent and affected sleep continuity and rapid eye movement (REM) sleep. Elimination half life was estimated to be between 15.9 and 22.0 hours. Mild side effects emerged in a dose-dependent fashion and most often involved the central nervous system and gastrointestinal tract. We concluded that methamphetamine caused a dose-dependent decrease in daytime sleep tendency and improvement in performance in both narcoleptics and controls. Methamphetamine at doses of 40-60 mg allowed narcoleptics to function at levels comparable to those of unmedicated controls.

The treatment of excessive somnolence with stimulant drugs.

Controlling the symptom of excessive sleepiness is an important responsibility of sleep medicine. Our group has reported that methamphetamine, given in the morning at doses of 40-60 mg, allowed narcoleptics to function throughout the day at normal levels of sleep tendency and psychomotor functioning as measured by multiple sleep latency and performance testing. These findings are important because they are the first to show normalization of function in narcolepsy with pharmacotherapy and because the dose of stimulant utilized was more than twice the maximum recommended by the manufacturer. Because it is possible to essentially eliminate the disabling sleepiness of narcolepsy, at least in the short term, we suggest that the following principles be applied in the therapeutic use of stimulant drugs: 1) Pathological sleepiness warrants aggressive treatment when sustained alertness is necessary for individual or public safety; 2) Stimulant drugs are important in the therapeutic approach to patients with pathological sleepiness; 3) The prime goal, although sometimes unachievable, should be symptom-free daytime functioning. It is important that, during therapy, a period of symptom-free daytime functioning be achieved for a frame of reference for evaluating future treatments; 4) Treatment efficacy should be assessed periodically with objective techniques such as the multiple sleep latency test or the maintenance of wakefulness test; 5) In some cases, stimulant doses may exceed the manufacturer's recommendations. However, the clinician should be guided by the prime goal of therapy, the patient's needs and the patient's ability to tolerate the chosen therapy.

Relative efficacy of drugs for the treatment of sleepiness in narcolepsy.

A survey was conducted on 10 polysomnographic studies on the pharmacologic treatment of the sleepiness of narcolepsy. Three studies employed the MSLT and 7 employed the MWT as their polygraphic measure of sleep tendency. Statistically and clinically significant therapeutic changes were apparent for pemoline, modafinil, dextroamphetamine and methylphenidate. Codeine, ritanserin and protriptyline did show statistically significant effects. The common feature among the drugs that did produce clinically significant improvements seems to be facilitatory action on central catecholaminergic transmission. Within this group of drugs, only methylphenidate and dextroamphetamine brought MWT sleep latencies to approximately 70% of normal levels.

Narcolepsy.

Narcolepsy is a neurological condition with a prevalence of up to 1 per 1,000 that is characterized by irresistible bouts of sleep. Associated features include the pathological manifestations of rapid-eye-movement (REM) sleep: cataplexy, sleep paralysis, hypnagogic hallucinations, and abnormal sleep-onset REM periods and disturbed nocturnal sleep. The condition is strongly associated with the HLA-DR2 and DQw1 phenotype. The phenomenology of narcolepsy is discussed, and diagnostic procedures are reviewed. Treatment modalities involving central nervous system stimulants for somnolence and tricyclic drugs for REM-sleep abnormalities are discussed. Sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine, protriptyline, and viloxazine are presented. Data suggest that: (1) methylphenidate and dextroamphetamine objectively improve somnolence; (2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence but may improve certain aspects of performance; and (3) protriptyline and viloxazine are effective anticataplectic agents that produce little improvement in somnolence.

Effect of triazolam on sleep and arterial oxygen saturation in patients with chronic obstructive pulmonary disease.

We compared the effects of a placebo with 0.125 and 0.25 mg of triazolam (Halcion) on sleep quality, oximetry, and respiratory events during sleep in ten stable outpatients with chronic obstructive pulmonary disease. The subjects had a forced expiratory volume in 1 s ranging from 17% to 76% of the predicted value (mean +/- SD, 38.1% +/- 19%) and a waking arterial oxygen pressure from 46 to 84 mm Hg (mean +/- SD, 67 +/- 12 mm Hg). Polysomnography was done on three nights within a two-week period after the patients received on a "blinded" basis either placebo or 0.125 or 0.25 mg of triazolam. Triazolam produced improvements in total sleep duration, time spent in stage 2 nonrapid eye movement (NREM) sleep, and subjective of sleep quality. For most patients, there was a nighttime drop in arterial oxygen percentage of saturation (SaO2) in the placebo condition, but triazolam did not cause a significant worsening, of the mean SaO2, minimum SaO2, or the number of apneic and hypopneic events. Across all experimental conditions, we documented little desaturation during wakefulness (mean low, 87.2% +/- 10.2%), more during NREM sleep (mean low, 83.2% +/- 12.6%), and most desaturation in REM sleep (mean low, 80.1% +/- 15.7%). We conclude that single-night use of triazolam improved the quality and duration of sleep in patients with chronic obstructive pulmonary disease. In patients without severe waking hypoxemia and without carbon dioxide retention, triazolam did not increase either nocturnal hypoxemia or respiratory events during sleep.

Narcolepsy. Diagnosis, treatment, and management.

Narcolepsy is a syndrome of unknown origin characterized by the irresistible urge to sleep. Other important features are disturbed nocturnal sleep and abnormal manifestations of REM sleep such as cataplexy, sleep paralysis, and abnormal sleep-onset REM periods. Narcolepsy is not a rare condition. With a prevalence between 2 and 10 per 10,000 individuals, it is about as common as multiple sclerosis. Like multiple sclerosis, narcolepsy can be disabling and have profound consequences for job capability, public safety, sense of self-worth, and social image.

When people die. Cause of death versus time of death.

A sample of 4,920 disease-related deaths from New York City for 1979 (8.7 percent of all relevant data from New York City's files) showed a 60 percent rise in death rate beginning at 2 A.M. and reaching a peak at 8 A.M. A smaller peak was also noted at 6 P.M. The rise in human mortality beginning at 2 A.M. and peaking at 8 A.M. might be explained by: artifact of deaths occurring anytime during the night that are discovered after daybreak, effect of less efficient health care between 2 A.M. and 8 A.M., and disease processes that somehow increase risk of death between 2 A.M. and 8 A.M. An attempt was made to differentiate among these possibilities by comparing time of death for various subsamples. The bimodal pattern appeared only in the temporal distribution of deaths of persons over 65 years of age; deaths of persons under 65 did not show significant temporal concentration. There were also prominent differences in the distribution of deaths for different reported causes of death. Ischemic heart disease, which numerically accounted for over 50 percent of the sample, showed peak mortality at 8 A.M. for both males and females. Hypertensive disease showed a significant peak in mortality at 1 A.M. for females only. Cerebrovascular disease peaked significantly at 6 A.M. with a significant peak only for males. The age and disease specificity of the 2 A.M. to 8 A.M. rise in death is consistent with a disease-related explanation for the bimodal circadian pattern in mortality. The quality and efficiency of health care could be improved with more precise information on peak periods of risk for specific morbid conditions.

Effects of spatially structured stimulus fields on pattern reversal visual evoked potentials.

Pattern-reversal visual evoked potentials (PRVEPs) were tested in 11 healthy individuals. A photic stimulator for pattern production on a TV monitor, an electroencephalograph for EEG signal amplification and a computer for averaging the potentials and displaying the traces were used in the experiments. The peak latencies and both trough-to-peak and baseline-to-peak amplitudes of the main PRVEP components were found to be closely related to both the check size of checkerboard pattern and the bar width of barred pattern. The latencies decreased exponentially and amplitudes varied non-monotonically with check size or bar width. Most of the amplitudes of these components were greatest when checkerboard patterns with check sizes subtending visual angles of 60--70 min of arc, or barred patterns with bar widths subtending angles of 7--15 min of arc, were presented.