Doxepin
At very low doses, doxepin has not shown discontinuation or withdrawal effects nor rebound insomnia. Sustained effectiveness without apparent tolerance was demonstrated in clinical studies of up to 12 weeks duration. This appears to be in contrast to over-the-counter antihistamines like diphenhydramine and doxylamine and all other first-generation antihistamines, which are associated with rapid development of tolerance and dependence (by day 3 or 4 of continuous dosing) and loss of hypnotic effectiveness. It is for this reason that, unlike doxepin, they are not recommended for the chronic management of insomnia and are advised for only short-term treatment (i.e., 1 week). It is not entirely clear why doxepin and first-generation antihistamines are different in this regard, but it has been suggested that it may have to do with the lack of selectivity for the H receptor of the latter or may have to do with the use of optimal doses. Unlike very-low-dose doxepin, most first-generation antihistamines also have marked anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention, and confusion. This is particularly true in older people, and antihistamines with concomitant anticholinergic effects are not recommended in adults over the age of 65. Anticholinergic activity notably may interfere with the sleep-promoting effects of H receptor blockade.
Aminoglutethimide
AG has many side effects and is a relatively toxic medication, although its side effects are described as usually relatively mild. The side effects of AG include lethargy, fatigue, weakness, malaise, drowsiness, somnolence, depression, apathy, sleep disturbances, stomach discomfort, nausea, vomiting ataxia, joint aches and pains, fever, skin rash, hypotension or hypertension, high cholesterol levels, virilization, hypothyroidism, thyroid abnormalities, elevated liver enzymes, jaundice, hepatotoxicity, weight gain, leg cramps, personality changes, blood dyscrasias, and adrenal insufficiency (e.g., hyponatremia, hypoglycemia, others). Lethargy is the most common side effect and has been found to occur in 31 to 70% of people treated with AG. It is the most common reason for discontinuation of AG. Skin rash and hypotension have both been observed in about 15% of people. At least one side effect will occur in 45 to 85% of people. Severe toxicity is seen in 10% of people, including circulatory collapse thought to be due to adrenal insufficiency. Hematological and bone marrow toxicity, including marked depression of white blood cell count, platelets, or both, occurs rarely, with an incidence of about 0.9%. It is usually seen within the first 7 weeks of treatment and resolves within 3 weeks following discontinuation. AG is discontinued in 5 to 10% of people due to intolerable side effects. The central nervous system side effects of AG are due to its nature as an anticonvulsant and relation to glutethimide.