Drug Criteria & Outcomes: Drug-induced nightmare
By Amanda Tucker, PharmD
Written as a PharmD candidate at Auburn University, Auburn, AL
Nightmares are terrifying episodes that are filled with anxiety in which the dreamer is awakened from sleep. They can be unsettling and profoundly disturbing experiences. The dreamer is typically awakened from rapid eye movement (REM) sleep and is able to describe a detailed, associative, and bizarre dream plot; often the cause is unknown.
Nightmares are fairly common in adults, with nearly 80% of the general adult population experiencing nightmares that occur sporadically. The results of a general population study by Ohayon et al revealed that of 1,049 persons with insomnia, 18.3% had nightmares. Nightmares were more common in women, and were associated with increases in nocturnal awakenings, sleep onset insomnia, daytime memory impairment, and anxiety following poor nocturnal sleep. Other studies have shown that approximately 5-8% of the population reports a current problem with nightmares.
According to the International Classification of Sleep Disorders (ICSD) nightmares are classified as "parasomnias usually associated with REM sleep" (see Table 1). The REM sleep cycle occurs about every 90 minutes during the night and is associated with high brain activity, rapid spontaneous eye movements, and suppressed voluntary motor activity. Dreaming can occur in all stages of REM sleep; however, nightmares usually occur in the later stages. When REM sleep is suppressed there can be an increase in the REM episodes, which can manifest as nightmare.
In the general population nightmares also are associated with the use of certain medications. Drugs whose mechanism of action suppresses REM sleep should be considered in the etiology of nightmares. The pharmacologic mechanism for the vast majority of therapeutic agents implicated in causing nightmares is not known; however, there are groups of drugs with similar pharmacologic actions that cause nightmares.
Thompson and Pierce compiled and assessed the English-language medical literature on drug-induced nightmares. Their search excluded nightmares secondary to drug withdrawal or drug-associated night terrors. In the overview of clinical trials, betablockers accounted for 30 cases (34%), amphetamine-like drugs accounted for 14 cases (16%), and sedative/ hypnotic drugs accounted for 13 cases (15%) of drug-induced nightmares. The remaining 37% of reported cases included examples of drugs associated with nightmares in addition to other adverse effects.
Betablockers are known to induce nightmares by REM suppression; the betablockers with the highest lipophilicity (carvedilol, labetalol, metoprolol, penbutolol, pindolol, and propranolol) most likely would be expected to cause nightmares. This suggests that central adrenergic receptors may be involved in the nightmare process.
Other drugs that affect the central nervous system, such as dopamine agonists, may induce nightmares as a result of dopamine receptor stimulation. Levodopa, the metabolic precursor to dopamine, causes numerous mild-to-severe central nervous system (CNS) effects, including decreased attention span, memory loss, nervousness, anxiety, restlessness, confusion, insomnia, vivid dreams, nightmares, paranoid delusions, and hallucinations. There are other dopamine agonists such as pergolide and cabergoline that have been implicated in drug-induced nightmares by direct stimulation of post-synaptic dopamine receptors.
Amphetamine-like drugs, such as the dietary substance fenfluramine, can produce a psychosis that is linked with nightmares. Medications that affect neurotransmitter levels of the central nervous system, such as antidepressants, narcotics, or barbiturates, also could cause nightmares.
REM sleep rebound can be associated with intense frightening dreams that may occur during the withdrawal of drugs such as ethanol, barbiturates, and benzodiazepines.
It is difficult to accurately associate the cause of a nightmare with a particular drug. The suggestion of causality in most case reports of drug-induced nightmare is based on the author’s clinical judgment and the temporal relationship to the drug. Causality assessment also is difficult to evaluate in clinical trials because many trials combine reporting of nightmares with other unrelated adverse drug effects.
Recognizing a drug-induced nightmare can be difficult and may be impossible due to other confounding factors. If drug-induced nightmares are suspected, the patient’s drug therapy should be re-evaluated. When possible, an alternative drug class should be used; for example, a calcium channel blocker could be used to treat hypertension instead of a beta-blocker. Alternatively, a similar drug less likely to cause nightmares could be tried (i.e., a less lipophilic betablocker). Appropriate dose tapering to minimize drug withdrawal symptoms can treat nightmares that are caused by REM sleep rebound due to withdrawal of ethanol, barbiturates, or benzodiazepines.
Nightmares associated with medication use can be a genuine problem. However, the high background rate of nightmares in the general population makes causality assessment difficult. According to clinical trials and case reports, it appears that the most common drug-related causes include use of beta-blockers, amphetamine-like drugs, and sedative/ hypnotics. The mechanism of action of these drug classes can pharmacologically explain why they could cause nightmares. However, the vast majority of medications that have been implicated in causing nightmares have no obvious pharmacologic mechanism. Health care providers must be aware that drug-induced nightmares can and probably will happen to some patients. The key is recognizing the problem and treating it appropriately.
Resources
• Katzung BG, ed. Basic and Clinical Pharmacology. 7th edition. Stamford, CT: Appleton and Lange; 1998.
• Mort JR. Nightmare cessation following alteration of ophthalmic administration of a cholinergic and a beta-blocking agent. Ann Pharmacother 1992; 26:914-916.
• Ohayon MM, et al. Prevalence of nightmares and their relationship to psychopathology and daytime functioning in insomnia subjects. Sleep 1997; 20:340-348.
• Pagel JF. Nightmares. Am Fam Physician 1989; 39:145-148.
• Pagel JF. Nightmares and disorders of dreaming Am Fam Physician 2000; 61:2037-2042, 2044.
• Thompson DF, Pierce DR. Drug-induced nightmare. Ann Pharmacother 1999; 33:93-98.
• Wood JM, Bootzin RR. The prevalence of nightmares and their independence from anxiety. J Abnorm Psychol 1990;99:64-68.
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