Table 1.
Drugs that affect sleep: Mechanisms and clinical implications
| Drug class CNS | Examples of drugs | Affect on sleep architecture | Potential mechanism | Clinical implications |
|---|---|---|---|---|
| AEDs | Phenobarbital, carbamazepine, phenytoin | Very sedating. AEDs tend to ↑ TST, ↓ sleep latency. | Inhibits neuronal calcium influx, adenosine receptor or 5HT activity. | Sedation is dose-dependent, usually early on. |
| TCAs | Amoxapine, amitriptyline, imipramine, nortriptyline, desipramine, doxepin, clomipramine | Very sedating. Suppresses REM sleep, ↑ TST, ↑ stage 2 sleep. | Antimuscarinic activity, α1-receptor stimulation. | Suppressed REM sleep → ↓ motor inhibition → restlessness, psycho-motor agitation during sleep → subjectively ↓ sleep quality, ↑ daytime sleepiness. |
| Anxiolytic BzRAs* | Alprazolam, lorazepam, chlordiazepoxide, diazepam, oxazepam. | Very sedating. ↑ TST, ↓ sleep latency, ↓ SWS duration, ↓ REM, ↑ stage 2 sleep. | GABA type A receptor stimulation. | Minimize its use in daytime. Chronic BzRAs → ↓ SWS → long-term sequelae unknown. |
| SSRIs | Sedating: paroxetine, fluvoxamine. Activating: fluoxetine, sertraline, citalopram. | In general, SSRIs tend to ↑ TST, less sedating than TCAs. May ↓ REM, ↑ TWT, ↓ SE. | 5HT activity. | AM (if awakening) or PM (if sedating) dosing. |
| SNRI | Venlafaxine | Activating in some patients; sedating in 12–31%. ↓ TST. | 5HT and NE activity. | AM (if awakening) or PM (if sedating) dosing. |
| Lithium | Lithium | ↑ TST, ↑ SWS, ↑ stage 2 sleep, ↓ REM, ↓ REM latency. | Dose at night. | |
| Stimulants | Ephedrine, pseudoephedrine, modafinil. | Activating. ↓ TST, ↓ SWS, ↑ sleep latency. | DOPA, NE, and 5HT activity. | Avoid after 6 PM. |
| Anti-Parkinson | Bromocriptine, levodopa. | Sedating. Nightmares, ↓ SWS. | DOPA | Dose at night, if possible. |
| Cardiovascular | ||||
| Lipophillic β-Blockers | Propranolol, pindolol, metoprolol, timolol. | Activating. ↑ awakenings, ↑ TWT, ↓ REM, nightmares. | CNS β-blockade | Daytime sedation if dosed in AM whereas hydrophillic agents (atenolol, sotalol) do not. |
| CNS Agents | Norepinephrine, epinephrine | Activating. ↓ REM, ↓ SWS. | α1-receptor stimulation. | Minimize its use, if possible, especially at night. |
| Dopamine | Activating. ↓ REM, ↓ SWS. | D2-receptor and α1-receptor stimulation. | Minimize its use, if possible, especially at night. | |
| α2-receptor agonist | Clonidine | ↑ stage 1, ↓ REM, nightmares. | α2-receptor stimulation. | α2-agonists → ↑ daytime sleep and sleepiness directly. May be helpful to dose at night. |
| α1-receptor blockers | Doxazosin, prazosin, terazosin. | α1-receptor inhibition. | α1-receptor blockers → ↑ daytime sleepiness. | |
| Ca++Channel Blockers | Amlodipine, verapamil, nifedipine | Exacerbate medical condition. | ↓ Lower esophageal sphincter tone | |
| → nocturnal gastroesophageal reflux | ||||
| → sleep disturbance. | ||||
| Diuretics | HCTZ, furosemide. | PM diuresis → frequent awakenings → ↓ sleep. | ||
| Analgesics | ||||
| Opioids | Codeine, morphine, hydrocodone. | Sedating. ↓ SWS, ↓ REM. | μ-receptor stimulation. | Minimize its use, if possible, especially at night. |
| NSAIDs | Ibuprofen, indomethcin, celecoxib. | ↓ TST, ↓ SE. | prostaglandin synthesis inhibition. | Minimize its use, if possible, especially at night. |
| Other | ||||
| Methylxanthine | Theophylline | Activating. ↑ stage 1, ↓ REM. | Causes less restful sleep. | |
| Antihistamines | Diphenhydramine, promethazine. | Sedating | H1 receptor blockade. | Minimize its use, if possible, especially at night. |
| Corticosteroids | Dexamethasone, prednisone | Activating. ↓ REM, ↓ SWS, nightmares. | ↓ melatonin secretion. | Can disrupt sleep, ↑ anxiety, induce mania or psychosis. |
| H2 Blockers | Cimetidine, ranitidine, famotidine. | Sedating. ↑ TST. | H2 receptor blockade. | Sedating if >60 years old, renal impairment. |
| Quinolones | Ciprofloxacin, sparfloxacin, ofloxacin, grepafloxacin, levofloxacin | Activating. | GABA type A receptor stimulation. | Linezolid rarely causes sleep disturbances. |
Notes: Copyright @ 2006. Elsevier Ltd. Reproduced with permission based on Table 2 in Pandhardipande P, Ely EW. Sedative and analgesic medications: Risk factors for delirium and sleep disturbances in the critically ill. Crit Care Clin. 2006;22:313–327.
Abbreviations: AED, antiepileptic drugs; BzRAs, benzodiazepines; CNS, central nervous system; 5HT, serotonin, serotonergic; NE, norepinephrine; DOPA, dopamine; GABA, gamma-aminobutyric acid; H2, Histamine2-receptor; REM, rapid eye movement; MAOIs, monoamine oxidase inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs; SE, sleep efficiency; SNRI, serotonin norepinephrine reuptake inhibitor; SSRIs, selective serotonin reuptake inhibitors; HCTZ, hydrochlorothiazide; SWS, slow wave sleep (stage 3 and 4, or deep sleep); TCA, tricyclic and tetracyclic antidepressants; TST, total sleep time; TWT, total wake time; →, leads to or causes; ι, decrease or reduce; η, increase.