Any substance that crosses the blood-brain barrier will very likely have an effect on CNS receptors that affect sleep and wakefulness. Essentially all drugs that have been studied have been found to have such effects, and many that have not been studied are known by clinicians to influence sleep and wakefulness. Growing understanding of the physiological mechanisms of normal and abnormal sleep indicates that in addition to the classically understood brainstem sleep influences, the hypothalamus is a key center for sleep regulation. Sleep mechanisms were thought to be predominantly due to the interactions of acetylcholine, dopamine, serotonin, and norepinephrine primarily within the brainstem. More recent research findings indicated that the hypothalamic neurotransmit-ters adenosine, dopamine, gamma-aminobutyric acid (GABA), histamine, and hypocretin also play an important role in the physiological mechanisms of sleep. The latest observations suggest that connections between the thalamus (cortical activation, sleep spindle formation, and EEG synchronization), hypothalamus (sleep-wake switch), suprachiasmatic nucleus (circadian clock), and the brain stem (ascending cortical activation and REM sleep-wake switch) organize circadian, ultradian, and intrinsic sleep function.
Some CNS substances primarily affect the circadian pacemaker system, which is controlled by the suprachiasmatic nucleus (arginine-vasopressin, GABA, melatonin, gastrin-releasing peptide, neuropeptide Y, peptide histidine isoleucine, vasoactive intestinal peptide, glutamate, pancreatic polypeptide, and corticosteroids). Other substances affect intrinsic sleep parameters, such as sleep latency, awakenings, percentage of various stages of sleep, nocturnal wakefulness, and evidence of sleep interruptions manifested primarily at a sleep EEG study. Many drugs have known effects on primary sleep disorders such as restless legs syndrome, obstructive sleep apnea, and insomnia from many causes. Few drugs have unadulterated beneficial effects on sleep, and effects on healthy study subjects and on patients may not coincide. Rather than assume that these various factors are too complex to be useful in the psychiatric care of a medically ill patient, the consultation psychiatrist can learn the few basic groups of drugs with empirically demonstrated significant effects on sleep (). Combining this information with knowledge of the physiological mechanisms of sleep will allow the clinician to logically infer the effects of most other drugs on sleep.
The following are general rules about drugs that can help in application of sleep knowledge to patient care.
1. Most CNS drugs decrease slow wave and REM sleep, at least acutely. It is reasonable to learn the relatively short list of drugs known to increase REM sleep and assume that others will suppress or disrupt normal REM sleep function. The medications that increase REM sleep are reserpine, yohimbine (and other alpha-antagonists), and physostigmine (and other cholinomimetic drugs, perhaps including cholinesterase inhibitors such as donepezil).
2. Many drugs cause daytime sedation. It is reasonable to learn the short list of drugs that cause increased daytime alertness and perhaps anxiety as well (psychostimulants, modafinil, and caffeine) and to presume that most others will either be neutral or negative toward daytime alertness.
3. Stopping drugs suddenly commonly produces adverse effects. The entity suppressed will likely rebound. Thus stopping drugs that suppress REM sleep (most CNS agents) will often lead to REM sleep rebound, which can be associated with insomnia, nightmares, and even hallucinations.
4. Stopping drugs that stimulate the CNS (and have depleted or displaced stimulating neurotransmitters) can lead to temporary depression. This effect is surprisingly uncommon even in patients who have taken high doses of stimulants for a long time. Depression and decreased alertness are common but usually are transient.
5. Many drugs continue their activity on sleep and wake-fulness far beyond the intended therapeutic time. Many medications used to promote sleep are associated with some “hangover” experience the next day. The few exceptions are drugs with an ultrashort half-life, such as zaleplon (definitely demonstrated) and perhaps tri-azolam and zolpidem (less clearly demonstrated) (see Table 11).
6. Alternative therapies and herbal preparations may be helpful. Although effort similar to FDA efficacy and safety guidelines is increasingly being put into examining alternative therapies and herbal preparations, little definitive information is available. Many of these agents are pharmacologically active in the CNS, and many have interactions with prescribed medications.
Aside from the likelihood that herbal preparations may be contaminated with unknown substances (e.g., anti-inflammatory agents, steroids, diuretics, antihistamines, tranquilizers, hormones, and heavy metals), more information is becoming available about potential adverse effects of herbal preparations taken as sleep aids, as daytime stimulants, and for other purposes. A review of complementary therapies from an Eastern perspective describes in detail an extensive list of Chinese herbal treatments and their potential toxicities. A number of authors have reviewed the safety of complementary therapies as they apply to the practice of emergency medicine and oncology. Melatonin, 5-hydroxytryptamine, catnip, chamomile, gotu kola, hops, L-tryptophan, lavender, passionflower, skullcap, and valerian are agents that have been used to manage sleep disorders. The toxicities of herbal substances most commonly used for sedative or stimulant purposes among consultation-liaison populations are shown in Table Herbal medications with sleep-wake toxicity:
|Herbal medications used as sedatives|
|Broom (Cytisus scoparius)||Vomiting, uterine contractions, and bradycardia|
|Kava kava (Piper methysticum)||Dermatitis, hallucinations, and shortness of breath|
|Passionflower (Passiflora caerulea)||Seizures, hypotension, and hallucinations|
|Valerian ( Valeriana officinalis)||Dystonic reactions and hepatotoxicity|
|Miscellaneous herbal preparations with excessive stimulation and insomnia as side or toxic effects|
|Echinacea (Echinacea angustifolia or E. purpurea)||Central nervous system stimulation, dermatitis, and anaphylaxis|
|Ginseng (Panax ginseng)||Hypertension, mastalgia, agitation, anxiety, depression, and insomnia|
|Golden seal (Hydrastis canadensis)||Nausea and vomiting, central nervous system stimulation, paralysis and paresthesia, and respiratory failure|
|Ma huang (Ephedra sinica)||Mania and psychosis, hypertension, and tachycardia|
|Yohimbine bark (Pausinystalia yohimbine or Corynanthe yohimbe)||Hallucinations and anxiety, hypertension and tachycardia, and nausea and vomiting|
Because melatonin is readily available and patients commonly self-administer it, a brief review of this agent is pertinent. Melatonin is sold over the counter in airports, health food stores, and other venues and is widely used to manage jet lag and insomnia in general. This agent is also being used as an antioxidant. The safety and efficacy of health-food-store melatonin have been studied formally in only a limited way. In one analysis of three commercially prepared over-the-counter melatonin preparations, investigators found several contaminants in each preparation. The substances found included structural analogues of contaminants found in preparations of L-tryptophan that had been associated with eosinophilia-myalgia syndrome. Other evidence suggests that even with pharmacologically pure preparations, the varying bioavailability of oral doses of melatonin results in as much as a 20-fold difference in plasma levels of the agent.
A careful review of the literature on jet lag indicates that melatonin is remarkably effective in preventing jet lag, and occasional short-term use appears to be safe. However, the pharmacological and toxicological mechanisms of melatonin need systematic study, and routine pharmacological quality control of melatonin products must be established. There is evidence that a low dose (0.5 mg) of melatonin improves initial sleep quality in selected elderly persons with insomnia. However, large, randomized, controlled trials are yet to be conducted. The literature contains reports of many adverse effects that have yet to be systematically defined so that an appropriate risk-benefit discussion can take place. The reports include autoimmune hepatitis, optic neuropathy, fragmented sleep, psychosis, nystagmus, seizures, headache, skin eruption, and confusion from overdose.
The mechanisms of action of melatonin are not clearly defined, although there is evidence of an active feedback process between the pineal gland and the suprachiasmatic nucleus. The known interaction in the dopaminergic system has led to investigation of melatonin as an agent in the treatment of parkinsonism, neurodegenerative disorders, tardive dyskinesia, and postoperative delirium.
In summary, the long-term use of over-the-counter melatonin has not been demonstrated to be safe or effective, and studies of pure preparations of this hormone in carefully controlled research settings have not yet established appropriate indications or risk-benefit assessments. Preferential use of other medications and methods of improving sleep for medically ill patients is recommended.
Selections from the book: “Textbook of Psychosomatic Medicine”, 2005.