Inhibition of theophylline metabolism by long-term allopurinol administration.

Administration of an oral dose of allopurinol (300 mg every 12 hr) for 14 consecutive days increased the mean theophylline area under the curve (AUC) 27% and mean theophylline half-life (t1/2) 25%, whereas the mean theophylline clearance (Cl) decreased 21%. Allopurinol did not alter either apparent volume of distribution (aVd) or gastrointestinal absorption (Cmax and tmax) of theophylline. After 28 consecutive days of allopurinol administration, theophylline disposition was the same as that on day 14. Thus, given in a dose of 300 mg every 12 hr for 14 or 28 days, allopurinol inhibits theophylline metabolism, despite the failure of allopurinol in lower doses given for only 7 days to alter theophylline disposition. These results emphasize the need to investigate several different doses and durations of administration within therapeutic ranges before firm conclusions can be drawn concerning the influence of one drug on the disposition of another.

Effects of lovastatin and pravastatin on sleep efficiency and sleep stages.

The effects on sleep of two 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (40 mg lovastatin and 40 mg pravastatin) were evaluated in 12 normal subjects in a double-blind placebo-controlled sleep laboratory study. Subjects were randomly assigned to each of two parallel groups (lovastatin and pravastatin). Each parallel-group protocol consisted of 22 consecutive nights including 4 placebo-baseline nights, 2 weeks of drug administration, and 4 placebo-withdrawal nights. Lovastatin did not disturb sleep initially (nights 5 through 7) but, with continued administration (nights 16 through 18), it significantly and markedly increased wake time after sleep onset and stage 1 sleep compared with baseline. By contrast, pravastatin was not associated with sleep disturbance either initially or with continued use. Neither drug caused any sleep disturbance after withdrawal. Lovastatin's sleep disturbing effects with continued administration are attributed to its high degree of lipophilicity in contrast with the hydrophilicity of pravastatin.

Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines.

In three parallel groups, brief and intermittent administration and withdrawal of triazolam, 0.5 mg, temazepam, 30 mg, and placebo were assessed in a 12-night sleep laboratory study of 18 subjects with insomnia. With this intermittent schedule both drugs improved sleep, with about one-third reduction in total wake time; this reduction was significant for temazepam but not for triazolam. Even though the periods of drug administration were quite brief, withdrawal of triazolam consistently produced rebound insomnia, with increases in total wake time above baseline of 61% and 51%, respectively, for the first night of each withdrawal period. With temazepam this effect was more variable, with total wake time increased only with the second withdrawal period (39%). Thus these findings indicate that even under conditions of brief, intermittent use and withdrawal, triazolam and, to a lesser degree, temazepam produce rebound insomnia after abrupt withdrawal, thereby predisposing to drug-taking behavior and increasing the potential for drug dependence.

Effects of nadolol on blood pressure, sleep efficiency, and sleep stages.

The effects of nadolol (20 and 80 mg) on blood pressure and sleep parameters were assessed in six patients with mild hypertension. A 32-night experimental protocol in the sleep laboratory was instituted consisting of four placebo-baseline nights followed by 4 weeks of drug administration. Both doses of nadolol had a clear-cut and consistent lowering effect on blood pressure throughout the night and during the day, with a greater reduction noted with the 80 mg dose. In fact, blood pressure values were reduced to normotensive levels. Neither dose had a disrupting effect on sleep, whereas the 80 mg dose improved sleep efficiency and also had a rapid eye movement-enhancing effect. This absence of sleep-disrupting effects is attributed to nadolol's low level of lipophilicity and lack of intrinsic sympathomimetic activity. The clinical significance of the lack of sleep disruption and possible improvement of sleep with nadolol is discussed in light of the well-recognized sleep disturbances produced by other beta-blockers.

Comparison of short and long half-life benzodiazepine hypnotics: triazolam and quazepam.

Two benzodiazepine hypnotics, triazolam, 0.25 mg, with a short elimination t1/2, and quazepam, 15 mg, with a long t1/2, were evaluated in 22-night sleep laboratory studies. Quazepam improved sleep significantly during both short- and intermediate-term use. Daytime sleepiness, which decreased with continued use, was the side effect most often associated with quazepam dosing. In contrast, triazolam dosing did not significantly improve any of the major sleep efficiency parameters, and there was a rapid development of tolerance for the drug's slight initial effectiveness. In addition, there were a number of behavioral side effects including amnesia, confusion, and disinhibition. Withdrawal of triazolam was associated with sleep and mood disturbances (rebound insomnia and rebound anxiety), whereas quazepam exerted carryover effectiveness. Thus the data in this study show that the 0.25 mg dose of triazolam, which is being prescribed increasingly, has a profile of side effects that is similar to that of the 0.5 mg dose.

Buspirone: sedative or stimulant effect?

OBJECTIVE: The primary objectives of this study were to evaluate the effects of initial and continued administration of buspirone on sleep induction and maintenance and sleep stage parameters, to determine the presence or absence of any drug-induced side effects, and to ascertain the presence or absence of sleep disturbances following abrupt withdrawal of the drug. METHOD: Six insomniac subjects who had chronic complaints of difficulty falling asleep and/or staying asleep and who were in good physical health, were not suffering from any major mental disorders, and had not used any medication for at least the last month participated in a 16-night sleep laboratory protocol. The protocol consisted of 4 placebo-baseline nights, 7 nights on which buspirone, 10 mg at bedtime, was administered, and 5 placebo-withdrawal nights. RESULTS: Wake time after sleep onset increased moderately during the first 3 nights of drug administration (there was a marked and significant increase on the first night) and increased by lesser degrees with continued drug administration. Overall, reports of side effects were infrequent. Following drug termination, there was a delayed and mild increase in sleep difficulty above baseline. CONCLUSIONS: These data not only confirm that buspirone lacks sedative effects but also suggest that the drug may have stimulant properties. Further, these findings suggest that buspirone has limited usefulness in anxious patients with concomitant sleep difficulties.

Diagnostic concordance for DSM-IV sleep disorders: a report from the APA/NIMH DSM-IV field trial.

OBJECTIVE: The frequency and ranking of DSM-IV sleep disorder diagnoses of clinical patients with complaints of insomnia, as well as rates of diagnostic agreement and disagreement between two types of interviewers, were investigated. METHOD: Interviewers at five clinical sites assessed 216 patients referred for insomnia complaints. One sleep specialist and one general clinician interviewed each patient in an unstructured clinical interview, assigned DSM-IV diagnoses, and indicated their reactions to the diagnostic system. RESULTS: Insomnia due to another mental disorder was the most frequent DSM-IV diagnosis across sites, followed by primary insomnia. Interviewers at the five sites differed significantly in the rankings they assigned to different diagnoses. In addition, sleep specialists at most sites diagnosed psychiatric forms of insomnia more frequently than nonspecialists. Kappa values for agreement between the two types of clinicians on multiple DSM-IV sleep diagnoses ranged from 0.26 to 0.80 across sites, indicating moderate agreement overall. Kappa values for individual diagnoses varied across sites and specific diagnoses and ranged from poor to excellent. Interviewers' ratings of their confidence in diagnoses and the fit and ease of use of the DSM-IV categories also showed significant variability related to site and type of interviewer. CONCLUSIONS: The distribution of diagnoses highlights the importance of psychiatric and behavioral factors in the assessment of insomnia. Site-related variability indicates a need for greater standardization in the application of sleep disorder diagnostic criteria. Diagnostic concordance for these diagnoses, while only moderately good, likely reflects actual clinical practice and would be improved through the use of standardized (or structured) interviews and increased training.

Clinical factors contributing to the differential diagnosis of primary insomnia and insomnia related to mental disorders.

OBJECTIVE: Primary insomnia and insomnia related to mental disorders are the two most common DSM-IV insomnia diagnoses, but distinguishing between them is difficult in clinical practice. This analysis was performed to identify clinical factors used by sleep specialists to distinguish primary insomnia from insomnia related to mental disorders. METHOD: Clinicians evaluated 216 patients referred for insomnia at five clinical sites, rated a list of clinical factors judged to contribute to each patient's presentation, and assigned diagnoses. Analysis of variance was performed, with contributing factors as the dependent variable and diagnostic group and clinic location as independent variables. RESULTS: Sleep specialists rated a psychiatric disorder as a stronger factor for insomnia related to mental disorders and rated negative conditioning and sleep hygiene as stronger factors for primary insomnia. However, a psychiatric disorder was rated as a contributing factor for 77% of patients who received a first diagnosis of primary insomnia. CONCLUSIONS: While neither sleep hygiene nor negative conditioning is a diagnostic criterion in DSM-IV, these results support the face validity of these clinical factors distinguishing between primary insomnia and insomnia related to mental disorders. The use of a psychiatric disorder as an inclusion criterion for insomnia related to mental disorders and an exclusion criterion for primary insomnia reinforces a categorical distinction between the two diagnoses, but the contribution of psychiatric symptoms in primary insomnia appears to be a clinically relevant one. These findings suggest the need for studies on the validity of negative conditioning and sleep hygiene in the etiology of primary insomnia, as well as on the significance of psychiatric disorders, especially depression, in primary insomnia.

Alprazolam: effects on sleep and withdrawal phenomena.

Alprazolam was evaluated in chronic insomniacs in a 1-mg bedtime dose. The 16-night sleep laboratory protocol included four placebo-baseline nights followed by seven nights of drug administration and five placebo-withdrawal nights. On the first three drug nights (nights 5 to 7), the drug was highly effective in inducing and maintaining sleep with this short-term use. By the end of the one week of administration (nights 9 to 11), however, the drug had lost about 40% of its efficacy. During drug use, one subject reported some difficulty in controlling expression of inappropriate emotions when interacting with others, which suggested the presence of disinhibition. On the third night following drug termination, there was a significant increase in sleep difficulty above baseline levels (rebound insomnia). This worsening was of comparable magnitude to the peak improvement of sleep with drug administration. Thus, the clinical utility of alprazolam when administered to insomniac patients appears to be limited because of a relatively rapid development of tolerance and possible disinhibitory reactions during drug use and the occurrence of rebound insomnia following withdrawal.

An update on sleep disorders.

Sleep disorders are so common that approximately 38% of the general population complains about a current sleep problem and 52% complains about a current or past sleep problem. Psychiatric factors are prominent in virtually all sleep disorders, either as primary factors (insomnia and adult parasomnias) or as significant secondary consequences (sleep apnea and narcolepsy). The authors describe normal sleep; delineate the prevalence of sleep disorders, both those associated with psychiatric disturbance and those of organic etiology; and outline procedures for evaluation and treatment, which is multidimensional and comprises general measures, psychotherapy, and, when indicated, pharmacotherapy.

Clinical neuropharmacology of sleep disorders.

Within the context of the comprehensive treatment of sleep disorders, which includes medical, neurologic, psychiatric, and social interventions, use of medication is often indicated. Among the three benzodiazepine hypnotics that are available in the United States for the treatment of insomnia, flurazepam is effective for both sleep induction and maintenance, and it retains most of its efficacy over a 4-week period of nightly administration; temazepam is effective only for sleep maintenance, and triazolam improves both sleep induction and maintenance with initial but not with continued administration. Rebound phenomena are more frequent and intense with the more rapidly eliminated drug, triazolam, and to a lesser degree with temazepam. Also, with triazolam, certain behavioral side effects, such as amnesia and psychotic-like symptoms, have been reported. With flurazepam, which is a slowly eliminated benzodiazepine, daytime sedation is more frequent than with the other two drugs. When insomnia is secondary to major depression, antidepressant medication should be administered. Methylphenidate, amphetamines, or other stimulant medications are used for the symptomatic treatment of the sleepiness and sleep attacks of narcolepsy and hypersomnia. For cataplexy and the other two auxiliary symptoms of narcolepsy, imipramine or other tricyclics are the drugs of choice. Protriptyline and medroxyprogesterone have been used in treating mild cases of obstructive sleep apnea, but their efficacy is limited. Similarly, for the treatment of central sleep apnea, medroxyprogesterone and acetazolamide have shown only limited effects. Medication for patients with sleepwalking, night terrors, or nightmares should be prescribed judiciously, and primarily when treatment of an underlying psychiatric condition is desired. The neuropharmacology of sleep should also consider drugs that may cause sleep disorders. Medications with sleep disturbing effects include various antihypertensives, bronchodilators, and the energizing antidepressants. Withdrawal of REM-suppressant drugs, such as the barbiturates, may cause nightmares in association with a REM rebound. Occasionally, a drug or a combination of drugs may produce somnambulistic-like activity in some patients.

Disorders of excessive sleepiness: narcolepsy and hypersomnia.

Besides sleep apnea, the main disorders of excessive daytime sleepiness include narcolepsy and hypersomnia. Narcolepsy is characterized by periods of irresistible sleepiness and sleep attacks of brief duration and, most often, by one or more of the auxiliary symptoms: cataplexy, sleep paralysis, and hypnogogic hallucinations. Generally, sleepiness and sleep attacks in hypersomnia are of longer duration and are more resistible than in narcolepsy; also, the auxiliary symptoms are absent. There are three types of hypersomnia: idiopathic, secondary, and periodic. Nocturnal sleep is typically disrupted in narcolepsy, whereas in idiopathic hypersomnia it is prolonged and in secondary hypersomnia it is variable. The exact causes of narcolepsy and idiopathic hypersomnia are unknown; however, there is evidence for genetic predisposition for either disorder. In secondary hypersomnia causative factors include: neurologic, such as head injuries, cerebrovascular insufficiency, and brain tumors; general medical, such as metabolic disorders, various intoxications, and conditions leading to brain hypoxia; and psychiatric, most notably depression. Although the cause of periodic hypersomnia is unclear, most research supports the notion of underlying organic disease. Often, the evaluation of patients with excessive daytime sleepiness can be completed in the office setting, based on the sleep history and a thorough neurologic, general medical, and psychiatric assessment. Whenever indicated, ancillary laboratory studies, such as computed tomography and magnetic resonance scans, should be performed. Sleep laboratory recordings generally are not necessary unless there is suspicion of sleep apnea or narcolepsy in the absence of auxiliary symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Validity and clinical utility of sleep laboratory criteria for insomnia.

The sensitivity, specificity, and positive predictive value of two proposed sleep laboratory criteria for the diagnosis of insomnia were evaluated in 375 adults with a primary complaint of insomnia and 150 noninsomniac controls. The two criteria used results in either low sensitivity and moderately strong specificity or high sensitivity and low specificity and, accordingly, in both cases weak positive predictive values (diagnostic accuracy), both for one night and multiple nights of recordings. Further, an empirically optimized criterion also resulted in an unsatisfactory diagnostic accuracy. Finally, the optimized MMPI criteria were superior to optimized sleep criteria in differentiating insomniacs from controls. In conclusion, sleep laboratory recordings provide little relevant information for confirming or excluding the presence of insomnia.

Uvulopalatopharyngoplasty as a treatment of obstructive sleep apnea precipitated by uvular prolapse.

Two patients are discussed in whom obstructive sleep apnea was precipitated by uvular prolapse into the larynx and successfully treated by uvulopalatopharyngoplasty. Although tracheostomy has been the definitive treatment for obstructive sleep apnea, uvulopalatopharyngoplasty has also been used as an alternative surgical procedure. However, indications for its successful use have not been clearly defined. Our experience illustrates that the surgical approach to obstructive sleep apnea is dependent on a thorough diagnostic evaluation that includes a sleep history, head and neck examination, hypnopolygraphic recording and, if indicated, nocturnal fiberoptic endoscopy.

Usefulness of polysomnographic studies in the differential diagnosis of insomnia.

The prevalence of sleep apnea, sleep apneic activity, nocturnal myoclonus, and nocturnal myoclonic activity was assessed in 375 outpatient insomniacs and 150 normal controls. Only a small percentage of insomniacs (n = 8, 2.3%) and normal controls (n = 2, 1.3%) presented > or = 30 apneic events per night. Only one of these subjects, an insomniac, met the laboratory and clinical criteria of sleep apnea sufficient to recommend treatment. A limited amount of sleep apneic activity per subject (only 3-29 apneic events per night) was evenly distributed between insomniacs (n = 52, 13.9%) and normal controls (n = 22, 14.7%). Also, small percentages of insomniacs (n = 43, 11.5%) and normal controls (n = 11, 8.5%) displayed nocturnal myoclonus (five or more leg movements per hour) or nocturnal myoclonic activity (less than five movements per hour). Thus, these results do not support the claim that sleep apnea or nocturnal myoclonus are common causes of insomnia. In addition, different cutoff points of REM latency (based on first-night recordings) were associated with very low sensitivity and moderately high specificity resulting in inadequate levels of diagnostic accuracy in differentiating depressed insomniacs from non-depressed insomniacs. Finally, empirically optimized values for REM variables were less successful than similarly optimized MMPI values in differentiating depressed insomniacs from nondepressed ones. In conclusion, with our current level of knowledge, polysomnography has limited clinical usefulness in the differential diagnosis of insomnia.

Efficacy of progesterone vaginal suppositories in alleviation of nervous symptoms in patients with premenstrual syndrome.

PURPOSE: To further investigate the efficacy of progesterone in the treatment of the symptoms of premenstrual syndrome (PMS). MATERIALS AND METHODS: From an initial cohort of 25 subjects diagnosed with moderate to severe PMS, 17 reproductive age females completed the 7-month, double-blind, placebo controlled trial using 200-mg vaginal progesterone suppositories. Multiple modalities for evaluating symptoms were employed, including the Spielberger self-evaluation rating, the Beck depression inventory, and the Hamilton anxiety scale. In addition, each subject was interviewed by a psychiatrist on a monthly basis; ovulation was determined monthly using a basal body temperature chart; serum hormonal assays included beta endorphin, progesterone, follicle stimulating hormone, luteinizing hormone, estradiol, and prolactin. RESULTS: Hormonal assays confirmed no differences between treatment and control groups. Overall scores on all test vehicles were likewise not significantly different between the two groups; however, in the subcategory of nervous symptoms, a significant improvement was found in symptoms relating to tension, mood swings, irritability, anxiety and lack of control. CONCLUSIONS: Metabolites of progesterone (pregnanolone and allopregnanolone) may play a physiologic role as anxiolytic agents, perhaps modifying mood and anxiety; the current study confirms the utility of twice daily, 200-mg progesterone vaginal suppositories, in the alleviation of some PMS symptoms relating to anxiety and irritability. Further evaluation may be warranted to ascertain which patients in the known heterogeneous PMS population may be most likely to benefit from such treatment.

Clonazepam: sleep laboratory study of efficacy and withdrawal.

Clonazepam 0.5 mg was evaluated in a sleep laboratory study of 6 insomniac patients. The 16-night protocol consisted of 4 placebo-baseline nights, 7 nights of drug administration and 5 placebo-withdrawal nights. Clonazepam produced a significant decrease in total wake time initially (nights 5-7), as well as with continued administration (nights 9-11). With later but not immediate withdrawal, significant rebound insomnia occurred, on the 3rd withdrawal night, both wake time after sleep onset and total wake time increased markedly, with the latter significantly increased. These findings are discussed in light of clonazepam's increasing use for panic disorder; specifically, due to its maintained efficacy, it has the advantage of avoiding interdose rebound anxiety which is frequently reported with use of alprazolam.

Narcolepsy/cataplexy. III: Nocturnal sleep and wakefulness patterns.

Nocturnal sleep and wakefulness patterns of 50 patients with narcolepsy and cataplexy were compared to those of 50 control subjects. A sleep onset REM period (SOREM) occurred in 22 (44%) of the patients but in none of the controls. Comparisons among patients showing a SOREM, patients without this abnormality, and controls demonstrated that the timing, number and duration of the remaining REM periods did not differ across the three groups. Thus, the basic REM sleep disturbance in narcolepsy appears to relate to the timing of onset of the initial REM period. This finding lends further support to the theory of dual control of REM-NREM cycling. While narcoleptics took significantly less time to fall asleep, they had significantly more awakenings, wake time after sleep onset and total wake time. The disturbed sleep experienced by patients could not be accounted for by the presence of a sleep onset REM period or the use of medication. Nocturnal wakefulness appeared to be distributed in a regular oscillating manner throughout the recording period similar to the pattern of daytime vigilance previously reported in normal subjects. Thus, typical nocturnal dampening of daytime ultradian vigilance rhythms may be lost in the narcoleptic patient.

Next-day memory impairment with triazolam use.

The prevalence, rate, and degree of memory impairment for next-day activities during a short, intermittent course of bedtime doses of triazolam, temazepam, and placebo were assessed in a double-blind parallel-group study. 5 of the 6 subjects in the triazolam group reported at least one episode of next-day memory impairment/amnesia, with a total of 12 episodes being reported for the 30 subject-drug nights (a rate of 40%). In the temazepam group there were no such episodes of memory impairment. Immediate and delayed recall were also tested and related to whether active drug or placebo had been taken the night before. Impairment of delayed recall was significantly and several times greater than that in the temazepam or placebo groups. Next-day memory impairment/amnesia after a bedtime dose of triazolam tended to increase with continued or intermittent drug use. Cognitive impairments associated with triazolam probably represent a spectrum of organic brain dysfunction, with memory impairment/amnesia and confusion being the commonest, and milder manifestations and hallucinations and delusions the more severe and less common, features.