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.
Norethisterone
At contraceptive and hormone replacement dosages (0.35 to 1 mg/day), norethisterone has essentially progestogenic side effects only. In most clinical studies of norethisterone for contraception or menopausal hormone therapy, the drug has been combined with an estrogen, and for this reason, it is difficult to determine which of the side effects were caused by norethisterone and which of them were caused by estrogen in such research. However, NETE, an intramuscularly administered prodrug of norethisterone which is used as a long-acting contraceptive, is used without an estrogen, and hence can be employed as a surrogate for norethisterone in terms of understanding its effects and tolerability. In clinical studies, the most common side effect with NETE has been menstrual disturbances, including prolonged bleeding or spotting and amenorrhea. Other side effects have included periodic abdominal bloating and breast tenderness, both of which are thought to be due to water retention and can be relieved with diuretics. There has been no association with weight gain, and blood pressure, blood clotting, and glucose tolerance have all remained normal. However, a decrease in cholesterol has been observed.