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Home , Adrenergic, Doxepin, Fluoxetine, Histamine, Melatonin, Nordoxepin

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Doxepin for

Dimitri Markov, MD, and Karl Doghramji, MD

ow-dose —3 mg and 6 mg— Table 1 Low-dose doxepin has demonstrated for insom- may relieve 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 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 , the other 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 effect of - the morning and not falling back asleep.1,2 epin is thought to result from inhibition A antidepressant first approved of and 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 and antihistamin- mg capsules) to treat depression and ergic activity with doxepin.2 Doxepin and as a topical preparation (5% ) for is a potent 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 to the H1 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 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 , 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 . Blockade of the H1 tion; therefore, patients taking receptor by doxepin likely plays a role in should not exceed 3 mg/d of doxepin. reducing . Typically, thera- peutic doses of with anti- Efficacy properties, such as doxepin Doxepin reduced insomnia symptoms in 3 at antidepressant doses, , pilot studies at doses of 10, 25, and 50 mg, or , do not selectively block and in 2 phase III randomized, double- H1 receptors, but act at , sero- blind, -controlled clinical trials us- tonergic, , 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 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 ’s (CYP) 2C19 night and the 7th and 8th hours of sleep (1, 3, and CYP2D6 ; 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 third of the night (6 mg only). The effects that inhibit these isoenzymes, such as on sleep duration and maintenance were and , 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 (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 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 and were report- continued on page 74 Out of the Pipeline

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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 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 , 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. Adverse events safety and efficacy of 1, 3, and 6 mg dox- were mild or moderate; 1 incident of chest epin in patients age ≥65.5 Seventy-six pain was reported, but it was determined adults with primary insomnia were ran- not to be of cardiac origin and not related domly assigned to receive placebo or dox- to study . There were no spontane- epin for 2 nights; all patients received all ous reports of anticholinergic side effects treatments, and each treatment was fol- associated with higher doses of doxepin. lowed by an 8-hour PSG. Patients taking There were no reports of memory impair- any doxepin dose achieved objective and ment.5 subjective improvement in sleep dura- tion and sleep maintenance, which lasted into the final hours of the night. WTDS Clinical studies that evaluated the safety (primary study endpoint), WASO, TST, of doxepin lasted up to 3 months. Som- and overall SE improved at all doxepin nolence/sedation, , and upper re- doses compared with placebo, and WTAS spiratory tract were reported by and SE at hours 7 and 8 improved at dox- >2% of patients taking doxepin and were epin doses of 3 mg and 6 mg compared more common than in patients treated with placebo. These findings suggest that with placebo.1 All reported adverse events Current Psychiatry 74 October 2010 doxepin, 3 mg and 6 mg, can help older were mild to moderate. continued on page 76 Out of the Pipeline

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adverse effects occurring at higher doses Related Resources of the drug. • Doghramji K, Grewal R, Markov D. Evaluation and Severe or death from overdose management of insomnia in the psychiatric setting. Focus. 2009;8(4):441-454. is presumably less likely with hypnotic • Psychiatric Clinics of North America. December 2006. All doses of doxepin than with higher doses, articles in this issue address sleep disorders encountered in although this has not been systematically psychiatric practice. explored. If an insomniac overdosed on a • National Sleep Foundation. www.sleepfoundation.org. 30-day supply of an hypnotic dose (3 or 6 Drug Brand Names mg), he or she would take only 90 to 180 Amitriptyline • Elavil Doxepin cream • Prudoxin Cimetidine • Tagamet Fluoxetine • Prozac mg of doxepin, which would be unlikely to Desipramine • Norpramin Paroxetine • Paxil cause severe toxicity or death.2-4 Doxepin (3 mg and 6 mg) Ramelteon • Rozerem • Silenor Symptoms of withdrawal and rebound Doxepin (10 to 150 mg, oral) insomnia—an increase in WASO com- • Sinequan pared with baseline after discontinuing Clinical Point Disclosure the medication—were assessed in a 35-day The authors report no financial relationship with any double-blind study of adults with chronic There is no evidence company whose products are mentioned in this article or with 1 of withdrawal manufacturers of competing products. insomnia. There was no evidence of with- drawal syndrome as measured by Tyler’s syndrome or Symptom Checklist after doxepin 3 mg rebound insomnia and 6 mg was discontinued. Discontinua- after discontinuing Doxepin appears to be better tolerated tion period-emergent nausea and doxepin, 3 mg or at hypnotic doses (3 mg and 6 mg) than was noted in 5% of patients taking 6 mg of at antidepressant doses (50 to 300 mg/d), doxepin, but not in those taking placebo or 6 mg although direct comparative studies are 3 mg of doxepin. There was no evidence of not available.2,4,5 Additionally, psycho- rebound insomnia after doxepin 3 mg and motor function assessed using DSST and 6 mg was discontinued.1 SCT and next-day sedation assessed using VAS in patients receiving hypnotic doses Contraindications of doxepin (1 and 3 mg) were the same Doxepin is contraindicated in patients with as placebo. Two studies noted small-to- hypersensitivity to doxepin hydrochloride, modest decreases in DSST, SCT, and VAS with severe , with narrow when doxepin, 6 mg, was administered.1 angle , and who have used mono- Patients taking doxepin at antidepressant oxidase inhibitors (MAOIs) within doses report significant anticholinergic the previous 2 weeks. Serious adverse ef- side effects, including sedation, , fects, including hypertensive crisis and urinary retention, , blurred death, have been reported with coadmin- vision, and dry mouth. also istration of MAOIs and certain drugs, such has been reported at antidepressant doses, as antidepressants and some and there seems to be a dose-dependant derivatives. There are no reports of cardiotoxicity, with higher incidence of concomitant use of doxepin with MAOIs.1

Bottom Line Low-dose doxepin may be an effective option for patients with insomnia characterized by difficulties with sleep maintenance. At 3 and 6 mg, doxepin appears to be effective and well tolerated. Doxepin is not designated as a controlled substance. Unlike GABA , low-dose doxepin appears to selectively block Current Psychiatry 76 October 2010 histaminergic action; it is essentially inactive at receptor sites. Bipolar News You Dosing Can’t Afford To Miss In adults, the recommended hypnotic dose for doxepin is 6 mg taken 30 minutes be- fore bedtime. For patients age ≥65, the rec- ommended starting hypnotic dose is 3 mg dited by Current Psychiatry 30 minutes before bedtime, which can be Deputy Editor Joseph F. increased to 6 mg if indicated.1 E Goldberg, MD, associate References clinical professor of psychiatry, 1. Silenor [package insert]. San Diego, CA: Somaxon; 2010. Mt. Sinai School of Medicine, 2. Goforth HW. Low-dose doxepin for the treatment of insomnia: emerging data. Expert Opin Pharmacother. 2009; our new Bipolar Update is a 10(10):1649-1655. 3. Stahl SM. Selective histamine H1 antagonism: novel monthly e-newsletter that keeps you informed hypnotic and pharmacologic actions challenge classical notions of . CNS Spectr. 2008;13(12): of the latest research affecting how you diagnose 1027-1038. 4. Roth T, Rogowski R, Hull S, et al. Efficacy and safety and treat patients with . of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555-1561. 5. Scharf M, Rogowski R, Hull S, et al. Efficacy and safety Each month, Dr. Goldberg provides his of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo- scientifically informed, expert commentary controlled crossover study. J Clin Psychiatry. 2008;69:1557- 1564. on major bipolar studies as well as those that 6. Hajak G, Rodenbeck A, Adler L, et al. Nocturnal and sleep after doxepin administration in chronic might have slipped past your radar, concisely primary insomnia. Pharmacopsychiatry. 1996;29:187-192. 7. Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in edited with links to the original source, vetted the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry. by Current Psychiatry, a source you can trust. 2001;62:453-463. 8. Rodenbeck A, Cohrs S, Jordan W, et al. The sleep-improving effects of doxepin are paralleled by a normalized plasma If you’re already receiving Current Psychiatry’s secretion in primary insomnia. A placebo-controlled, double-blind, randomized, cross-over study followed monthly e-mail alerts, look for Bipolar by an open treatment for 3 weeks. . 2003;170:423-428. Update in your inbox soon. If not, sign up at: CurrentPsychiatry.com/frm_emailalert.asp