Doxepin

Doxepin is a medication belonging to the tricyclic antidepressant class of drugs used to treat major depressive disorder, anxiety disorders, difficult-to-treat chronic urticaria, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.
Common side effects include sleepiness, dry mouth, constipation, nausea, and blurry vision. Serious side effects may include increased risk of suicide in those under the age of 25, mania, and urinary retention. A withdrawal syndrome may occur if the dose is rapidly decreased. Use during pregnancy and breastfeeding is not generally recommended. Although how it works for treating depression remains an area of active inquiry, it may involve increasing the levels of norepinephrine, along with blocking histamine, acetylcholine, and serotonin.
Doxepin was approved for medical use in the United States in 1969. It is available as a generic medication. In 2023, it was the 166th most commonly prescribed medication in the United States, with more than 3million prescriptions.

Medical uses

Doxepin is used as a pill to treat major depressive disorder, anxiety disorders, and chronic hives, and for short-term help with trouble remaining asleep after going to bed. As a cream it is used for short-term treatment of itchiness caused by atopic dermatitis or lichen simplex chronicus.

Insomnia

Doxepin is used in the treatment of insomnia. In 2016, the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short-term help maintaining sleep, on the basis of weak evidence. The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar. A 2015 Agency for Healthcare Research and Quality review of treatments for insomnia had similar findings.
A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that doxepin had an effect size against placebo for treatment of insomnia at 4weeks of 0.30. The certainty of evidence was rated as very low, and no data were available for longer-term treatment. For comparison, the other sedating antihistamines assessed, trimipramine and doxylamine, had effect sizes at 4weeks of 0.55 and 0.47 , respectively. Benzodiazepines and Z-drugs generally showed larger effect sizes than doxepin, whereas the effect sizes of orexin receptor antagonists, such as suvorexant, were more similar.
Doses of doxepin used for sleep normally range from 3 to 6mg, but high doses of up to 25 to 50mg may be used as well.

Other uses

A 2010 review found that topical doxepin is useful to treat itchiness.
A 2010 review of treatments for chronic hives found that doxepin had been superseded by better drugs but was still sometimes useful as a second-line treatment.

Contraindications

Known contraindications include:

Hypersensitivities to doxepin, other TCAs, or any of the excipients inside the product used
Glaucoma
A predisposition to developing urinary retention such as in benign prostatic hyperplasia
Use of monoamine oxidase inhibitors in last 14 days
Pregnancy and lactation

Its use in pregnant and lactating women is advised against, although the available evidence suggests it is unlikely to cause negative effects on fetal development. The lack of evidence from human studies, however, means it is currently impossible to rule out any risk to the fetus and it is known to cross the placenta. Doxepin is secreted in breast milk and neonatal cases of respiratory depression in association with maternal doxepin use have been reported.

Side effects

Doxepin's side effects profile may differ from the list below in some countries where it is licensed to be used in much smaller doses.

Central nervous system: fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, difficulty sleeping, seizures, temporary confusion, rarely induction of hypomania and psychosis, extrapyramidal side effects, abuse in patients with polytoxicomania, ringing in the ears
Anticholinergic: dry mouth, constipation, even ileus, difficulties in urinating, sweating, precipitation of glaucoma
Antiadrenergic: Low blood pressure,, abnormal heart rhythms
Allergic/toxic: skin rash, photosensitivity, liver damage of the cholestatic type, hepatitis, leuko- or thrombocytopenia, agranulocytosis, hypoplastic anemia
Others: frequently increased appetite and weight gain, rarely nausea, rarely high blood pressure. May increase or decrease liver enzyme levels in the blood of some people.

The side effects of low-dose doxepin for insomnia in long-term clinical trials in adults and elderly people were as follows:

Overdose

Like other TCAs, doxepin is highly toxic in cases of overdose. Mild symptoms include drowsiness, stupor, blurred vision, and excessive dryness of mouth. More serious adverse effects include respiratory depression, hypotension, coma, convulsions, cardiac arrhythmia, and tachycardia. Urinary retention, decreased gastrointestinal motility, hyperthermia, hypertension, dilated pupils, and hyperactive reflexes are other possible symptoms of doxepin overdose. Management of overdose is mostly supportive and symptomatic, and can include the administration of a gastric lavage so as to reduce absorption of the doxepin. Supportive measures to prevent respiratory aspiration is also advisable. Antiarrhythmic agents may be an appropriate measure to treat cardiac arrhythmias resulting from doxepin overdose. Slow intravenous administration of physostigmine may reverse some of the toxic effects of overdose such as anticholinergic effects. Haemodialysis is not recommended due to the high degree of protein binding with doxepin. ECG monitoring is recommended for several days after doxepin overdose due to the potential for cardiac conduction abnormalities.

Interactions

Doxepin should not be used within 14 days of using a monoamine oxidase inhibitor such as phenelzine due to the potential for hypertensive crisis or serotonin syndrome to develop. It is advised not to be used in those taking potent CYP2D6 inhibitors such as fluoxetine, paroxetine, sertraline, duloxetine, bupropion, and quinidine owing to the potential for its accumulation in the absence of full CYP2D6 catalytic activity. Hepatic enzyme inducers such as carbamazepine, phenytoin, and barbiturates are advised against in patients receiving TCAs like doxepin owing to the potential for problematically rapid metabolism of doxepin to occur in these individuals. Sympathomimetic agents may have their effects potentiated by TCAs like doxepin. Doxepin also may potentiate the adverse effects of anticholinergic agents such as benztropine, atropine and hyoscine. Tolazamide, when used in conjunction with doxepin has been associated with a case of severe hypoglycaemia in a type II diabetic individual. Cimetidine may influence the absorption of doxepin. Alcohol may potentiate some of the CNS depressant effects of doxepin. Antihypertensive agents may have their effects mitigated by doxepin. Cotreatment with CNS depressants such as the benzodiazepines can cause additive CNS depression. Co-treatment with thyroid hormones may also increase the potential for adverse reactions.

Pharmacology

Doxepin is a tricyclic antidepressant. It acts as a serotonin–norepinephrine reuptake inhibitor , with additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities.

Pharmacodynamics

Doxepin is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor, and has additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities. It is specifically an antagonist of the histamine H₁ and H₂ receptors, the serotonin 5-HT_2A and 5-HT_2C receptors, the α₁-adrenergic receptor, and the muscarinic acetylcholine receptors. Similarly to other tricyclic antidepressants, doxepin is often prescribed as an effective alternative to SSRI medications. Doxepin is also a potent blocker of voltage-gated sodium channels, and this action is thought to be involved in both its lethality in overdose and its effectiveness as an analgesic. The potencies of doxepin in terms of its receptor antagonism specifically are as follows:

Extremely strong: Histamine H₁ receptor
Strong: α₁-adrenergic receptor, 5-HT_2A and muscarinic acetylcholine receptors
Moderate: 5-HT_2C and 5-HT_1A receptors
Weak: α₂-adrenergic and D₂ receptors

Based on its values for monoamine reuptake inhibition, doxepin is relatively selective for the inhibition of norepinephrine reuptake, with a much weaker effect on the serotonin transporter. Although there is a significant effect that takes place at one of the specific serotonergic binding sites, the 5-HT_2A serotonin receptor subtype. There is negligible influence on dopamine reuptake.
The major metabolite of doxepin, nordoxepin, is pharmacologically active similarly, but relative to doxepin, is much more selective as a norepinephrine reuptake inhibitor. In general, the demethylated variants of tertiary amine TCAs like Nortriptyline, Desipramine and nordoxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities.
Antidepressant doses of doxepin are defined as 25 to 300 mg/day, although are typically above 75 mg/day. Antihistamine doses, including for dermatological uses and as a sedative/hypnotic for insomnia, are considered to be 3 to 25 mg, although higher doses between 25 and 50 mg and in some cases even up to 150 mg have been used to treat insomnia. At low doses, below 25 mg, doxepin is a pure antihistamine and has more of a sedative effect. At antidepressant doses of above 75 mg, doxepin is more stimulating with antiadrenergic, antiserotonergic, and anticholinergic effects, and these activities contribute to its side effects.
Doxepin is a mixture of and stereoisomers with an approximate ratio of 85:15. When doxepin was developed, no effort was made to separate or balance the mixture following its synthesis, resulting in the asymmetric ratio. -Doxepin is more active as an inhibitor of serotonin and norepinephrine reuptake than -doxepin. The selectivity of doxepin for inhibition of norepinephrine reuptake over that of serotonin is likely due to the 85% presence of -doxepin in the mixture. Most other tertiary amine TCAs like amitriptyline and imipramine do not exhibit E-''Z'' isomerism or such mixture asymmetry and are comparatively more balanced inhibitors of serotonin and norepinephrine reuptake.