Doxepin for insomnia

Low-dose doxepin—3 mg and 6 mg—has demonstrated efficacy for insomnia characterized by frequent or early-morning awakenings and an inability to return to sleep (Table 1).¹ FDA-approved in March 2010, doxepin (3 mg and 6 mg) is only the second insomnia medication not designated as a controlled substance and thus may be of special value in patients with a history of substance abuse.

Table 1

Doxepin: Fast facts

Clinical implications

Ramelteon, the other hypnotic that is not a controlled substance, is indicated for sleep initiation insomnia (ie, inability to fall asleep). In contrast, low-dose doxepin is for patients with sleep maintenance insomnia, which is waking up frequently or early in the morning and not falling back asleep.^1,2 A tricyclic antidepressant first approved in 1969, doxepin has long been available in larger doses (10-, 25-, 50-, 75-, 100-, and 150-mg capsules) to treat depression and anxiety and as a topical preparation (5% cream) for pruritus, but not in dosages <10 mg. An inexpensive generic doxepin oral solution (10 mg/ml) is available and can be titrated to smaller dosages by a dropper. Liquid doxepin costs 10 to 20 cents per dose. A pharmacist can provide a dropper, and patients should mix the medication in 4 ounces of water, milk, or juice; 0.3 ml of liquid doxepin contains 3 mg of active ingredient and 0.6 ml of solution contains 6 mg of doxepin. These other dosage forms of doxepin, however, are not FDA-approved for insomnia. (The retail price of low-dose doxepin was not available when this article went to press.)

How it works

Doxepin’s mechanism of action for treating depression and insomnia remains unknown. The antidepressant effect of doxepin is thought to result from inhibition of serotonin and norepinephrine reuptake at the synaptic cleft. Animal studies have shown anticholinergic and antihistaminergic activity with doxepin.² Doxepin is a potent histamine antagonist—predominantly at the H1 receptor—and its binding potency to the H1 receptor is approximately 100-times higher than its binding potency for monoamine transporters (serotonin and norepinephrine).^2,3 Brain histamine is believed to be 1 of the key elements in maintaining wakefulness, and the activation of the H1 receptor is thought to play an important role in mediating arousal. Blockade of the H1 receptor by doxepin likely plays a role in reducing wakefulness. Typically, therapeutic doses of antidepressants with anti-histaminergic properties, such as doxepin at antidepressant doses, amitriptyline, or desipramine, do not selectively block H1 receptors, but act at cholinergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors, which can cause adverse effects.³ However, low doses of doxepin (1, 3, and 6 mg) can achieve selective H1 blockade.^4,5 Patients taking >25 mg/d of doxepin may report clinically significant anticholinergic effects.

Pharmacokinetics

When doxepin, 6 mg, was administered to healthy, fasting patients, time to maximum concentration (Tmax) was 3.5 hours. Peak plasma concentration (Cmax) increased in a dose-related fashion when doxepin was increased from 3 mg to 6 mg. Doxepin, 6 mg, taken with a high-fat meal resulted in area under the curve increase of 41%, Cmax increase of 15%, and almost 3-hour delay in Tmax. Therefore, to prevent a delay in onset of action and to minimize the likelihood of daytime sedation, doxepin should not be taken within 3 hours of a meal.^1-3

Doxepin is metabolized primarily by the liver’s cytochrome P450 (CYP) 2C19 and CYP2D6 enzymes; CYP1A2 and CYP2D6 are involved to a lesser extent. If doxepin is coadministered with drugs that inhibit these isoenzymes, such as fluoxetine and paroxetine, doxepin blood levels may increase. Doxepin does not seem to induce CYP isoenzymes. This medication is metabolized by demethylation and oxidation; the primary metabolite is nordoxepin (N-desmethyldoxepin), which later undergoes glucuronide conjugation. The half-life is 15 hours for doxepin and 31 hours for nordoxepin. Doxepin is excreted in urine primarily as glucuronide conjugate.^1-3

Coadministration with cimetidine, an inhibitor of CYP isoenzymes, could double the doxepin plasma concentration; therefore, patients taking cimetidine should not exceed 3 mg/d of doxepin.

Efficacy

Doxepin reduced insomnia symptoms in 3 pilot studies at doses of 10, 25, and 50 mg, and in 2 phase III randomized, double-blind, placebo-controlled clinical trials using 1, 3, and 6 mg (Table 2).^4,5 Clinical studies lasted up to 3 months.^1-3,6-8

In the first phase III trial, 67 patients, age 18 to 64 with chronic primary insomnia, were randomly assigned to placebo or 1 mg, 3 mg, or 6 mg of doxepin for 2 nights. All patients received all treatments, and each treatment was followed by 8 hours of polysomnography (PSG) evaluation in a sleep laboratory.⁴ In this study, patients taking doxepin at all doses achieved improvement in objective (PSG-defined) and subjective (patient-reported) measures of sleep duration and sleep maintenance. Wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) improved with all doxepin doses, and wake time during sleep (WTDS)—which was the primary study endpoint—decreased with 3 mg and 6 mg doses, but not with 1 mg or placebo. In addition, PSG indicators of early-morning awakenings (terminal insomnia) were reduced, as shown by an increase in SE during the final third of the night and the 7^th and 8^th hours of sleep (1, 3, and 6 mg doses) and a reduction in wake time after sleep (WTAS) during the final third of the night (6 mg only). The effects on sleep duration and maintenance were more robust with 3 mg and 6 mg doses. Improved sleep onset was seen only with the 6 mg dose. Next-day alertness was assessed using the Visual Analogue Scale (VAS) for sleepiness, and the Digit-Symbol Substitution Test (DSST) and the Symbol-Copying Task (SCT) for psychomotor function. No statistically significant differences were found among placebo and any of the doxepin doses on the VAS, DSST, or SCT.