Doxepin is a tricyclic antidepressant that was FDA approved in 1969 to treat major depressive disorder. Doxepin was primarily approved to treat depression; however, it can also target multiple receptors and has proven beneficial in the treatment of other disorders. Doxepin displays antagonist effects on alpha-adrenergic, muscarinic, and histaminic receptors. With such a wide variety of receptors to block, oral formulations of doxepin have been FDA approved to treat insomnia and anxiety, and topical formulations have approval to manage skin pruritus.[1][2][3][4] 

In literature and research studies, doxepin has proven to be an effective analgesic in the treatment of neuropathic pain.[5][6] It also has been used as a prophylactic agent against migraines.[7][8] Doxepin has not yet received FDA approval for the treatment of neuropathic pain and migraines. 

Depression appears to result from a chemical imbalance and a lack of neurotransmitters in the brain. The different classes of antidepressant medications have been formulated to perform unique mechanisms by targeting different receptors and increasing the availability of neurotransmitters. Doxepin is in the tricyclic antidepressants (TCA) drug class; these agents work by increasing the concentration of the neurotransmitter’s serotonin (5-HT) and norepinephrine (NE) in the brain. This action prolongs the availability of the neurotransmitters (5-HT and NE) within the synaptic cleft and enhances their neurotransmission by preventing their reuptake back into the presynaptic terminal. 

Doxepin also displays antagonistic properties in the central nervous system by blocking the following receptors: histamine (H1), alpha-1 adrenergic, and muscarinic. It also inhibits sodium and potassium channels in cardiomyocytes.[9][10]

Antidepressants are commercially available in the form of oral tablets, capsules, and solutions. Oral administration is the most common method used by the population and comes in two dosages, 3 mg, and 6mg. Oral capsules come in dosages of 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg. Oral solutions come in doses of 10 mg/mL. Other forms available include topical creams (5%) and transdermal patches. Topical creams of doxepin act as a local anesthetic in the management of pain and have been useful in the treatment of urethral irritation and dysuria.[11][12][13] Transbuccal delivery of doxepin has been a topic of research, but not enough data has been reported to support its effectiveness.[14] 

Methods such as intranasal, sublingual, and rectal administration have yet to be studied.[15]

Doxepin is a unique antidepressant because it produces different adverse effects based on the receptor it antagonizes. Doxepin antagonizes three different receptors, which include: histamine, adrenergic, and muscarinic. Doxepin blocks histamine H1 receptor and causes sedation and somnolence; therefore, FDA has approved low-dose doxepin, 3 mg, and 6 mg dosages to be used as a first-line agent in depressed patients with sleep disturbances and depression associated with anxiety. Proper education is necessary to prevent patients from self-medicating and overdosing on such pills. Doxepin also has the potential to cause a significant increase in weight and was assessed in a study of 329 patients treated with doxepin and amitriptyline.[16][17][18]

Doxepin blocks alpha-adrenergic receptors and should be carefully monitored in those with cardiovascular disorders because it can cause orthostatic hypotension.[19]

Lastly, doxepin blocks muscarinic receptors and produces anticholinergic side effects such as dry mouth, constipation, dizziness, lightheadedness, tachycardia, and prolonged QT interval.[20][21][22]

Patients prescribed an antidepressant, such as doxepin, require careful observation due to the black box warning that states a possible increase in suicidality.[23]

Physicians are required to get a thorough medical history as well as medication history from patients before prescribing medications such as antidepressants. Antidepressants may cause serious adverse effects when combined with other medications such as different classes of antidepressants, opioids, alcohol, herbal medication, and even psychedelics. An interaction between two different classes of antidepressants may lead to excess serotonin in the central nervous system. This effect leads to a condition known as serotonin syndrome, sometimes described as serotonin toxicity. Serotonin toxicity induces symptoms such as mental status changes, autonomic stimulation, and neuromuscular excitation. Patients experience symptoms such as agitation, confusion, vital sign changes such as tachycardia, hyperthermia, flushing, tremor, and neuromuscular changes such as rigidity, increased reflexes, and clonus.[24][25] 

Another contraindication to prescribing doxepin is in patients with cardiovascular disorders such as preexisting bundle branch blocks. Literature has reported cases where patients developed atrioventricular heart block, orthostatic hypotension, and abnormalities in conduction after taking doxepin.[26][27] 

Lastly, doxepin has a poor safety profile in postpartum lactating mothers and is contraindicated in breastfeeding due to its sedative and respiratory depressive effects.[28][29]

Patients with hypersensitivity should also avoid doxepin.