Out of the Pipeline p Doxepin for insomnia Dimitri Markov, MD, and Karl Doghramji, MD ow-dose doxepin—3 mg and 6 mg— Table 1 Low-dose doxepin has demonstrated efficacy for insom- may relieve sleep Doxepin: Fast facts Lnia characterized by frequent or early- maintenance morning awakenings and an inability to Brand name: Silenor insomnia and is return to sleep (Table 1).1 FDA-approved in Indication: Insomnia characterized by difficulty not designated March 2010, doxepin (3 mg and 6 mg) is only with sleep maintenance as a controlled the second insomnia medication not des- Approval date: March 2010 ignated as a controlled substance and thus Availability date: September 7, 2010 substance may be of special value in patients with a Manufacturer: Somaxon Pharmaceuticals history of substance abuse. Dosage forms: 3 mg and 6 mg tablets Recommended dosage: 3 mg or 6 mg once Clinical implications daily within 30 minutes of bedtime Ramelteon, the other hypnotic that is not a controlled substance, is indicated for sleep initiation insomnia (ie, inability to fall How it works asleep). In contrast, low-dose doxepin is for Doxepin’s mechanism of action for treat- patients with sleep maintenance insomnia, ing depression and insomnia remains un- which is waking up frequently or early in known. The antidepressant effect of dox- the morning and not falling back asleep.1,2 epin is thought to result from inhibition A tricyclic antidepressant first approved of serotonin and norepinephrine reuptake in 1969, doxepin has long been available in at the synaptic cleft. Animal studies have larger doses (10-, 25-, 50-, 75-, 100-, and 150- shown anticholinergic and antihistamin- mg capsules) to treat depression and anxiety ergic activity with doxepin.2 Doxepin and as a topical preparation (5% cream) for is a potent histamine antagonist—pre- pruritus, but not in dosages <10 mg. An in- dominantly at the H1 receptor—and its expensive generic doxepin oral solution (10 binding potency to the H1 receptor is mg/ml) is available and can be titrated to approximately 100-times higher than its smaller dosages by a dropper. Liquid dox- binding potency for monoamine trans- epin costs 10 to 20 cents per dose. A phar- porters (serotonin and norepinephrine).2,3 macist can provide a dropper, and patients Brain histamine is believed to be 1 of the should mix the medication in 4 ounces of key elements in maintaining wakeful- water, milk, or juice; 0.3 ml of liquid doxepin ness, and the activation of the H1 recep- contains 3 mg of active ingredient and 0.6 ml of solution contains 6 mg of doxepin. These Dr. Markov is assistant professor of psychiatry and human behav- ior, assistant professor of medicine, Jefferson Medical College, other dosage forms of doxepin, however, are attending physician, Jefferson Sleep Disorders Center, Thomas Jef- not FDA-approved for insomnia. (The retail ferson University, and Dr. Doghramji is professor of psychiatry and human behavior, professor of medicine, professor of neurology, price of low-dose doxepin was not available Jefferson Medical College, and medical director, Jefferson Sleep Current Psychiatry when this article went to press.) Disorders Center, Thomas Jefferson University, Philadelphia, PA. Vol. 9, No. 10 67 Out of the Pipeline tor is thought to play an important role double the doxepin plasma concentra- in mediating arousal. Blockade of the H1 tion; therefore, patients taking cimetidine receptor by doxepin likely plays a role in should not exceed 3 mg/d of doxepin. reducing wakefulness. Typically, thera- peutic doses of antidepressants with anti- Efficacy histaminergic properties, such as doxepin Doxepin reduced insomnia symptoms in 3 at antidepressant doses, amitriptyline, pilot studies at doses of 10, 25, and 50 mg, or desipramine, do not selectively block and in 2 phase III randomized, double- H1 receptors, but act at cholinergic, sero- blind, placebo-controlled clinical trials us- tonergic, adrenergic, histaminergic, and ing 1, 3, and 6 mg (Table 2, page 74).4,5 Clini- muscarinic receptors, which can cause cal studies lasted up to 3 months.1-3,6-8 adverse effects.3 However, low doses of In the first phase III trial, 67 patients, age doxepin (1, 3, and 6 mg) can achieve se- 18 to 64 with chronic primary insomnia, lective H1 blockade.4,5 Patients taking >25 were randomly assigned to placebo or 1 Clinical Point mg/d of doxepin may report clinically mg, 3 mg, or 6 mg of doxepin for 2 nights. Blockade of the significant anticholinergic effects. All patients received all treatments, and H1 receptor by each treatment was followed by 8 hours Pharmacokinetics of polysomnography (PSG) evaluation in doxepin likely plays When doxepin, 6 mg, was administered a sleep laboratory.4 In this study, patients a role in reducing to healthy, fasting patients, time to maxi- taking doxepin at all doses achieved im- wakefulness mum concentration (Tmax) was 3.5 hours. provement in objective (PSG-defined) and Peak plasma concentration (Cmax) in- subjective (patient-reported) measures of creased in a dose-related fashion when sleep duration and sleep maintenance. doxepin was increased from 3 mg to 6 mg. Wake after sleep onset (WASO), total sleep Doxepin, 6 mg, taken with a high-fat meal time (TST), and sleep efficiency (SE) im- resulted in area under the curve increase proved with all doxepin doses, and wake of 41%, Cmax increase of 15%, and al- time during sleep (WTDS)—which was the most 3-hour delay in Tmax. Therefore, to primary study endpoint—decreased with prevent a delay in onset of action and to 3 mg and 6 mg doses, but not with 1 mg minimize the likelihood of daytime seda- or placebo. In addition, PSG indicators of tion, doxepin should not be taken within early-morning awakenings (terminal in- 3 hours of a meal.1-3 somnia) were reduced, as shown by an Doxepin is metabolized primarily by increase in SE during the final third of the the liver’s cytochrome P450 (CYP) 2C19 night and the 7th and 8th hours of sleep (1, 3, and CYP2D6 enzymes; CYP1A2 and and 6 mg doses) and a reduction in wake CYP2D6 are involved to a lesser extent. time after sleep (WTAS) during the final If doxepin is coadministered with drugs third of the night (6 mg only). The effects that inhibit these isoenzymes, such as on sleep duration and maintenance were fluoxetine and paroxetine, doxepin blood more robust with 3 mg and 6 mg doses. levels may increase. Doxepin does not Improved sleep onset was seen only with seem to induce CYP isoenzymes. This the 6 mg dose. Next-day alertness was as- medication is metabolized by demethyl- sessed using the Visual Analogue Scale ation and oxidation; the primary metabo- (VAS) for sleepiness, and the Digit-Symbol lite is nordoxepin (N-desmethyldoxepin), Substitution Test (DSST) and the Symbol- which later undergoes glucuronide conju- Copying Task (SCT) for psychomotor func- gation. The half-life is 15 hours for doxe- tion. No statistically significant differences pin and 31 hours for nordoxepin. Doxepin were found among placebo and any of the is excreted in urine primarily as glucuro- doxepin doses on the VAS, DSST, or SCT. nide conjugate.1-3 Doxepin was well tolerated. Reported Coadministration with cimetidine, adverse events were mild or moderate. Current Psychiatry 68 October 2010 an inhibitor of CYP isoenzymes, could Headaches and somnolence were report- continued on page 74 Out of the Pipeline continued from page 68 Table 2 Evidence of effectiveness of doxepin for insomnia Study Subjects Dosages Results Roth et al, 20074; 67 patients 1, 3, or 6 Improvement vs placebo in PSG-defined phase III, randomized, age 18 to 64 mg given WASO, TST, SE, and SE during the final third multi-center, double- with chronic once daily at of the night. 6-mg dose significantly reduced blind, placebo- primary bedtime for 2 subjective latency to sleep onset. Safety controlled, 4-period insomnia nights profile of all 3 doses was comparable to crossover, dose- placebo. No difference in residual sedation response study Scharf et al, 20085; 76 patients 1, 3, or 6 mg Reduction vs placebo in WTDS and WASO phase III, randomized, age ≥65 at bedtime for at all 3 doses. Increase in TST and SE at multi-center, double- with primary 2 nights all 3 doses. No difference in number of blind, placebo- insomnia awakenings after sleep onset and latency to controlled, 4-period persistent sleep at all 3 doses. WTAS was Clinical Point crossover, dose- reduced only at 3 and 6 mg doses. Patient- response study reported WTAS was decreased at all doses. Doxepin is better Patient-reported latency to sleep onset decreased only with 6 mg. Safety profile tolerated at hypnotic of all 3 doses was comparable to placebo doses than at and there were no differences among placebo and all 3 doses doxepin in next-day antidepressant doses, sleepiness or psychomotor function although direct PSG: polysomnography; SE: sleep efficiency; TST: total sleep time; WASO: wake after sleep onset; WTAS: wake time after sleep; WTDS: wake time during sleep comparative studies Source: References 4,5 are not available ed by >2% of patients. The incidence of insomnia patients with early morning adverse events, including next-day seda- awakenings. tion, was similar to that of placebo. Ad- In this study, no statistically significant ditionally, there were no spontaneous differences were found among placebo reports of anticholinergic side effects, and any doxepin doses on VAS, DSST, or which are associated with higher doxepin SCT or next-day residual sedation. The doses.4 incidence of side effects was low and The second phase III trial examined similar to that of placebo.