Sleeping Pills, Insomnia, and Medical Practice Report of a Study (1979) / Chapter Skim
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Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs
Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs
Pages 155-198
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From page 155... ...
3/ Thus, from a strictly objective point of view, the daytime benefits of hypnotic drugs would seem dubious, as their typical maximum effect is a shortening of sleep latency by 10-20 minutes and a lengthening of total sleep time by only 30-40 minutes. From a subjective point of view, of course, relief of daytime sleepiness by means of a nocturnal hypnotic would be valuable.
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From page 156... ...
But even without explication of specific mechanisms of action, efficacy studies could at least establish whether or not a hypnotic drug reliably alleviates the complaints of certain types of patients without increasing their risks. Unfortunately, until now objectively measured sleep parameters have not been related precisely to the complaint of the patient.
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From page 157... ...
Therefore, when studying a particular drug, it is important to study subjects comparable to those who will use that drug. One potentially misleading aspect of hypnotic' efficacy studies has been the custom of establishing arbitrary sleep laboratory criteria for "insomnia," such as greater than 30 minutes sleep latency, less than six or 6 1/2 hours total sleep time, or greater than 30 minutes wake time after sleep onset.
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From page 158... ...
Since obesity may be a factor in pharmacokinetics, height should also be reported, but almost never is. Nighttime Measures of Hypnotic Effects and Adverse Effects The simplest subjective measures for each night of sleep include the subjects' own estimates of sleep latency, number and duration of awakenings, total sleep time, and restfulness of sleep.
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From page 159... ...
Effects on respiration are particularly important because a depression of respiratory function could have lethal consequences in patients suffering from sleep apnea or other respiratory difficulties. Artificial awakenings of the subjects should be included to evaluate the subjects' ability to become reoriented, reasonably alert, and capable of good mobility should these be necessary in real life situations when hypnotics are used.
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From page 160... ...
Since substantial psychopathology is found in many insomniacs, it would be interesting to determine the effect of hypnotic treatment on measures of emotional disturbance. Because daytime sleepiness is one of the most common side effects of hypnotic agents, daytime alertness requires special evaluation procedures.
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From page 161... ...
An especially hazardous combination is the presence of impaired performance along with a subjective assessment of normal performance. Some authors have suggested there might actually be a small benefit to experiencing daytime sleepiness or other hangover effects of hypnotics -- these symptoms may serve to warn the subject that his body is still being influenced by these drugs.
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From page 162... ...
24/ Overall Study Design Assessment of a hypnotic drug's effects would logically include four different types of studies described by Kay, et al: 25/ (1) pilot studies, in which potential drug effects are described; (2)
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From page 163... ...
It is not clear from the available evidence that getting a good night's sleep is essential to maintaining skilled performance of psychomotor tasks, and there is some evidence to suggest that the residual deleterious effects of some hypnotic drugs on daytime functioning could outweigh any benefits which may be derived from a feeling of having slept well. More research is needed testing normals and insomniac patients at various times of the day with various doses of nocturnal hypnotics, as well as epidemiological studies of drivers and machinery operators*
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From page 164... ...
_/ A variety of studies have examined the influence of hypnotics on daytime performance measures, including tests that measure finger tapping rate, simple auditory reaction time, complex visual reaction time, adaptive tracking tests, card sorting speed, and the digit-symbol substitution test. The latter two tests may be divided into different components intended to parse out drug effects on motor skills and on cognitive functions.
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From page 165... ...
In the view of the authors, it was a motor impairment that flurazepam had induced. Anxious, insomniac patients who were tested in a British medical office practice on the eighth day after they had been receiving nightly doses of 30 mg of flurazepam manifested definite impairment of visualmotor coordination.
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From page 166... ...
28/ In Finland, normal volunteers were administered 30 mg of flurazepam for 14 nights and tested on the mornings after the 7th and 14th nights; they displayed significantly impaired psychomotor skills related to driving. 20/ Some subjects also received a standard dose of alcohol to drink prior to the morning's test -- equivalent to about three ounces of whiskey.*
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From page 167... ...
* Alcohol, when taken alone in low doses, generally impairs coordination much less than it does performance of divided attention tasks.
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From page 168... ...
_ / In one prospective study, it was shown that these divided attention tasks seemed to have the clearest correlation with actual driving skills. _ / In the same prospective study of Helsinki bus drivers, coordination skills also correlated with the ability to avoid accidents.
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From page 169... ...
19 /~ / In one study of secobarbital, it was found that al though the drug lengthened subj actively reported sleep times of both normal volunteers and psychiatric patients, only the normals experienced undesirable "hangover" effects ~ sleepiness and difficulty in concentrating ~ . 46/ The psychiatric patients did not report these phenomena any more often after secobarbital than after placebo; however, their background levels for sleepiness and concentration difficulties were already rather high.
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From page 170... ...
These have included the elderly, depressed patients, patients with liver disease, alcoholics, and individuals who must operate complex machinery, such as industrial workers, motorists or pilOtse This section describes three other especially vulnerable groups: patients with respiratory difficulties, patients with impaired kidney function, and women of childbearing age who may be pregnant. Patients with Respiratory Difficulties Sleep apnea syndromes have been described in Chapter 4.
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From page 171... ...
63/ Other sedative hypnotics have also been found to have respiratory depressant effects, particularly when administered in repeated doses. 64/ The literature includes a number of case reports of patients with a known sleep apnea syndrome who need emergency resuscitative measures, including tracheotomy, when they suffered respiratory arrest after receiving pre-anesthetic medication.
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From page 172... ...
me investigators at the Boston University Drug Epidemiology Unit have calculated a slightly elvated standardized relative risk ( 1.29 ~ for cardiovascular anomalies after antenatal exposure to phenobarbital. 80/ Risks for cardiovascular anomalies among babies exposed to secobarbital and amobarbital were also elevated, but the total numbers of cases were so small as to make interpretation very difficult.
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From page 173... ...
In a comparison of ten chronic insomniac patients who had been taking various hypnotic drugs nightly from four months to ten years with 15 insomniac controls who were drug free, Kales and associates _ / found that the medicated patients had as great or greater difficulty falling asleep and staying asleep as did the unmedicated insomniacs. In every chronic drug patient, at least one of the key indices for objectively assessing insomnia -- sleep latency, wake time after sleep onset, or total wake time -- was elevated.
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From page 174... ...
It is possible that a sedative or tranquilizing effect permits the patient to let himself fall and stay asleep -- the hypnotic drug induces a calm state of mind before and during sleep so that troubling thoughts do not intrude as much as they otherwise would. It is also possible that a powerful placebo effect is present, suggesting drowsiness to the patient.
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From page 175... ...
In two later studies, Clift and his co-workers studied the natural development of hypnotic drug dependence (nightly reliance on sleeping pills) in a prospective fashion.
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From page 176... ...
The administration of hypnotic agents undoubtedly affects normal physiology in ways not currently recognized. There is no way of judging the long-term consequences of these effects at this time (although there is no reason to assume that they will be as severe as tardive dyskinesia)
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From page 177... ...
The risks of adverse residual daytime effects and nighttime confusion must be considered, particularly in the elderly. Some elderly patients are misdiagnosed as "demented" because of these side effects.
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From page 178... ...
Yet, many investigators have studied normal volunteers rather than insomniac patients. With normal subjects who are already sleeping well, it is difficult to determine whether it will prove clinically significant that a drug shortens sleep latency, increases total sleep time, reduces wakefulness during the night, or increases subjective satisfaction with sleep.
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From page 179... ...
suggested that flurazepam 30 mg tended to increase total sleep time or decrease wakefulness ~ according to the studies and the measures employed ~ without development of complete tolerance at the end of a month; nor did signs of physical dependence, such as "rebound insomnia ," appear immediately upon withdrawal of the drug. 92/-93/ In the study which included non-EEG measures, 93/ subj ective assessments of sleep latency and total sleep time improved, and there was no problem in subj ective sleepiness, ascertained 15 minutes after arising in the morning.
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From page 180... ...
30 mg of oxazepam and lo mg of diazepam each lengthened total sleep time by about 35 minutes and 25 minutes, respectively. Diazepam shortened the sleep latency in normal volunteers by 11 minutes (from an average of 31 minutes down to an average of 21 minutes)
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From page 181... ...
; time of drug administration; total sleep time, whether patients were allowed to sleep late until they awakened naturally; information about subjective evaluation of sleep; and measures of daytime alertness, mood, and performance. Although total sleep time was not presented, it can be estimated to have been about 400 minutes during baseline, and to have increased to about 440 minutes during the first three nights of drug administration, after which tolerance developed.
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From page 182... ...
studies reviewed; 104/-105/ in the third, it induced sleep more promptly than placebo or glutethimide. 101/ The two available EEG sleep studies in insomniacs indicate that its effects were weak, short lived, and not statistically different from placebo 106/, 17/ although it did improve sleep latency and some other variables.
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From page 183... ...
It has not apparently been shown to be effective in insomniac patients in a sleep laboratory study, aside from one report of initial reduction in sleep latency. 112/ This study was conducted, however, in insomniacs with little evidence of objective sleep disturbance.
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From page 184... ...
The sleep-promoting effects of "non-hypnotics" -- phenothiazines, tricyclic antidepressants, daytime anxiolytics and antihistamines -need further study since these drugs appear to be used fairly often as sleeping aids in insomniac patients. Each type of drug has some limited research evidence supporting its utility, but none have been studied extensively.
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From page 185... ...
9:355-357, 1967. Dement, W.C., Carskadon, M.A., et al., Prolonged use of flurazepam: A sleep laboratory study.
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From page 186... ...
and Mattilla, M.J., Drug Interaction on psychomotor skills related~to driving: Diazepam and Alcohol. European Journal of Clinical Pharmacology 5:186-194, 1973.
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From page 187... ...
and Maki, M., The effect of treatment with diazepam or lithium and alcohol on psychomotor skills related to driving. European Journal of Clinical Pharmacology 7:337-342, 1974.
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From page 188... ...
, British Journal of Clinical Pharmacology 5:469-472, 1978. Linnoila, M., Erwin, C.W., et al., Effects of alcohol on psychomotor performance of men and women.
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From page 189... ...
and Thomas, E.L., Effect of benzodiazepines upon saccadic eye movements in man. Clinical Pharmacology and Theraceutics 12: 563-574, 1971.
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From page 190... ...
In Sleep Apnea Syndromes C Guilleminault and W
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From page 191... ...
. In Sleep Apnea Syndromes, C
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From page 192... ...
Orr, W., and Imes, N., Sleep Apnea Sybdrome in Symptomatic and Asymptomatic Groups. Sleep Research 6 : 177, 1977.
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From page 193... ...
A general practice study of dependence on some non-barbiturate hypnotic drugs" and "Prediction of the dependence-prone patient -a general practice investigation-personality of drug effect," in Sleep Disturbance and Hypnotic Drug Dependence, Clift, A.D., fed.) Amsterdam: Excerpta Medica)
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From page 194... ...
83-210, 1976. Kales, A., Bixler, E.O., Scharf, M., and Kales, J.D., Sleep laboratory studies of flurazepam: A model for evaluating hypnotic drugs.
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From page 195... ...
Kales, A., Bixler, E.O., Kales, J.D. and Scharf, M.B., Comparative effectiveness of nine hypnotic drugs: Sleep laboratory studies.
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From page 196... ...
Journal of Clinical Pharmacology 110:258-268, 1970. Kales, A
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From page 197... ...
Morgan, H., Scott, DeFe and Joyce, C.R.Be, The effects of four hypnotic drugs and placebo on normal subjects sleeping and dreaming at home. British Journal of Psychiatry 117:649-652, 1970.
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From page 198... ...
~ ~_J a_ ~ ~ eA&C&~11] ~ ~ ~~ ~ &1C ~ Clinical Pharmacology and TherapeuKaracan, I., Blackburn, A.B., Thornby, J.Ie ~ Okawa, Me ~ Salis, PeJ and Williams, ReLe ~ The effect of doxepin HC1 (Sinequan)
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