Doxepin 20 mg for sleep

Doxepin for insomnia

Low-dose doxepin—3 mg and 6 mg—has demonstrated efficacy for insomnia characterized by frequent or early-morning awakenings and an inability to return to sleep (Table 1).1 FDA-approved in March 2010, doxepin (3 mg and 6 mg) is only the second insomnia medication not designated as a controlled substance and thus may be of special value in patients with a history of substance abuse.

Table 1

Doxepin: Fast facts

Brand name: Silenor

Indication: Insomnia characterized by difficulty with sleep maintenance

Approval date: March 2010

Availability date: September 7, 2010

Manufacturer: Somaxon Pharmaceuticals

Dosage forms: 3 mg and 6 mg tablets

Recommended dosage: 3 mg or 6 mg once daily within 30 minutes of bedtime

Clinical implications

Ramelteon, the other hypnotic that is not a controlled substance, is indicated for sleep initiation insomnia (ie, inability to fall asleep). In contrast, low-dose doxepin is for patients with sleep maintenance insomnia, which is waking up frequently or early in the morning and not falling back asleep.1,2 A tricyclic antidepressant first approved in 1969, doxepin has long been available in larger doses (10-, 25-, 50-, 75-, 100-, and 150-mg capsules) to treat depression and anxiety and as a topical preparation (5% cream) for pruritus, but not in dosages <10 mg. An inexpensive generic doxepin oral solution (10 mg/ml) is available and can be titrated to smaller dosages by a dropper. Liquid doxepin costs 10 to 20 cents per dose. A pharmacist can provide a dropper, and patients should mix the medication in 4 ounces of water, milk, or juice; 0.3 ml of liquid doxepin contains 3 mg of active ingredient and 0.6 ml of solution contains 6 mg of doxepin. These other dosage forms of doxepin, however, are not FDA-approved for insomnia. (The retail price of low-dose doxepin was not available when this article went to press.)

How it works

Doxepin’s mechanism of action for treating depression and insomnia remains unknown. The antidepressant effect of doxepin is thought to result from inhibition of serotonin and norepinephrine reuptake at the synaptic cleft. Animal studies have shown anticholinergic and antihistaminergic activity with doxepin.2 Doxepin is a potent histamine antagonist—predominantly at the H1 receptor—and its binding potency to the H1 receptor is approximately 100-times higher than its binding potency for monoamine transporters (serotonin and norepinephrine).2,3 Brain histamine is believed to be 1 of the key elements in maintaining wakefulness, and the activation of the H1 receptor is thought to play an important role in mediating arousal. Blockade of the H1 receptor by doxepin likely plays a role in reducing wakefulness. Typically, therapeutic doses of antidepressants with anti-histaminergic properties, such as doxepin at antidepressant doses, amitriptyline, or desipramine, do not selectively block H1 receptors, but act at cholinergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors, which can cause adverse effects.3 However, low doses of doxepin (1, 3, and 6 mg) can achieve selective H1 blockade.4,5 Patients taking >25 mg/d of doxepin may report clinically significant anticholinergic effects.


When doxepin, 6 mg, was administered to healthy, fasting patients, time to maximum concentration (Tmax) was 3.5 hours. Peak plasma concentration (Cmax) increased in a dose-related fashion when doxepin was increased from 3 mg to 6 mg. Doxepin, 6 mg, taken with a high-fat meal resulted in area under the curve increase of 41%, Cmax increase of 15%, and almost 3-hour delay in Tmax. Therefore, to prevent a delay in onset of action and to minimize the likelihood of daytime sedation, doxepin should not be taken within 3 hours of a meal.1-3

Doxepin is metabolized primarily by the liver’s cytochrome P450 (CYP) 2C19 and CYP2D6 enzymes; CYP1A2 and CYP2D6 are involved to a lesser extent. If doxepin is coadministered with drugs that inhibit these isoenzymes, such as fluoxetine and paroxetine, doxepin blood levels may increase. Doxepin does not seem to induce CYP isoenzymes. This medication is metabolized by demethylation and oxidation; the primary metabolite is nordoxepin (N-desmethyldoxepin), which later undergoes glucuronide conjugation. The half-life is 15 hours for doxepin and 31 hours for nordoxepin. Doxepin is excreted in urine primarily as glucuronide conjugate.1-3

Coadministration with cimetidine, an inhibitor of CYP isoenzymes, could double the doxepin plasma concentration; therefore, patients taking cimetidine should not exceed 3 mg/d of doxepin.


Doxepin reduced insomnia symptoms in 3 pilot studies at doses of 10, 25, and 50 mg, and in 2 phase III randomized, double-blind, placebo-controlled clinical trials using 1, 3, and 6 mg (Table 2).4,5 Clinical studies lasted up to 3 months.1-3,6-8

In the first phase III trial, 67 patients, age 18 to 64 with chronic primary insomnia, were randomly assigned to placebo or 1 mg, 3 mg, or 6 mg of doxepin for 2 nights. All patients received all treatments, and each treatment was followed by 8 hours of polysomnography (PSG) evaluation in a sleep laboratory.4 In this study, patients taking doxepin at all doses achieved improvement in objective (PSG-defined) and subjective (patient-reported) measures of sleep duration and sleep maintenance. Wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) improved with all doxepin doses, and wake time during sleep (WTDS)—which was the primary study endpoint—decreased with 3 mg and 6 mg doses, but not with 1 mg or placebo. In addition, PSG indicators of early-morning awakenings (terminal insomnia) were reduced, as shown by an increase in SE during the final third of the night and the 7th and 8th hours of sleep (1, 3, and 6 mg doses) and a reduction in wake time after sleep (WTAS) during the final third of the night (6 mg only). The effects on sleep duration and maintenance were more robust with 3 mg and 6 mg doses. Improved sleep onset was seen only with the 6 mg dose. Next-day alertness was assessed using the Visual Analogue Scale (VAS) for sleepiness, and the Digit-Symbol Substitution Test (DSST) and the Symbol-Copying Task (SCT) for psychomotor function. No statistically significant differences were found among placebo and any of the doxepin doses on the VAS, DSST, or SCT.

About doxepin

Type of medicine A tricyclic antidepressant
Used for The treatment of depression
Available as Capsules

Doxepin belongs to a group of medicines called tricyclic antidepressants. It is prescribed for the treatment of depression. The exact cause of depression is not known. It can develop for no apparent reason or it may be triggered by a life event such as a relationship problem, bereavement, or illness. With depression you have a consistently low mood and other symptoms severe enough to interfere with your normal day-to-day activities.

Doxepin can help ease the symptoms of depression. It is particularly helpful if you also have difficulty sleeping. It is thought to work by interfering with brain chemicals (called neurotransmitters) which may be involved in causing the symptoms.

Before taking doxepin

Some medicines are not suitable for people with certain conditions, and sometimes a medicine may only be used if extra care is taken. For these reasons, before you start taking doxepin it is important that your doctor knows:

  • If you are pregnant or breast-feeding.
  • If you have an overactive thyroid gland.
  • If you have any problems with the way your liver works, or the way your kidneys work.
  • If you have epilepsy or sugar diabetes.
  • If you have had problems with constipation over a long time.
  • If you have any difficulties passing urine, or if you have had prostate trouble.
  • If you have a heart disorder or blood vessel disease.
  • If you have had a mental health problem – in particular, bipolar disorder or psychosis.
  • If you have increased pressure in your eyes (glaucoma).
  • If you have been told you have phaeochromocytoma – a tumour on your adrenal gland.
  • If you have porphyria – a rare inherited blood disorder.
  • If you are taking other medicines, including those available to buy without a prescription, as well as herbal and complementary medicines. This is especially important if you have recently taken a medicine for depression, known as a monoamine-oxidase inhibitor (MAOI).
  • If you have ever had an allergic reaction to a medicine.

How to take doxepin capsules

  • Before you start this treatment, read the manufacturer’s printed information leaflet from inside the pack. It will give you more information about doxepin and will provide you with a full list of the side-effects which you may experience from taking it.
  • Doxepin can make you feel sleepy so your doctor may advise you to take a small dose when you first start taking it, and then to increase your dose gradually as your body gets used to it.
  • Doxepin is often prescribed once a day at bedtime, although it can also be taken two or three times a day. Your doctor will tell you which is right for you and the directions will be printed on the label of the pack to remind you what the doctor has said. If you have any questions about how to take the capsules, ask your pharmacist for advice.
  • You can take doxepin before or after meals. Many people find if helps to swallow the capsule with a drink of water.
  • If you forget to take a dose, take it as soon as you remember unless your next dose is due. If it is nearly time for your next dose, then take the next dose when it is due but leave out the forgotten dose. Do not take two doses together to make up for a missed dose.

Getting the most from your treatment

  • Try to keep your regular appointments with your doctor. This is so your doctor can check on your progress.
  • You may feel that doxepin is not working for you straightaway. It can take a week or two for the effect to build up, and 4-6 weeks before you feel the full benefit. It is important that you do not stop taking it thinking that it is not helping.
  • While you feel depressed, you may have distressing thoughts and think about harming yourself or ending your life. If this happens, it is very important that you tell your doctor about it straightaway.
  • If you drink alcohol, ask your doctor for advice. Your doctor is likely to recommend that you do not drink alcohol while you are on doxepin as it increases the risk of side-effects, such as feeling sleepy.
  • There are several types of antidepressants – each type works in a slightly different way and can have different side-effects. If you find that doxepin does not suit you then let your doctor know, as another antidepressant may be found that does.
  • Some people who take doxepin find that their skin becomes more sensitive to sunlight than usual. Do not use sunbeds and try to avoid strong sunlight until you know how your skin reacts. Use a sun cream with a high sun protection factor.
  • Your doctor may ask you to carry on taking doxepin even after you feel better. This is to help stop your symptoms from returning.
  • If you buy any medicines, check with a pharmacist that they are suitable for you to take. This is because a number of medicines can increase the risk of side-effects from doxepin, including some painkillers, flu remedies and antihistamines which can be bought from pharmacies.
  • If you have diabetes you may need to check your blood sugar (glucose) more frequently. This is because doxepin can alter the levels of sugar in your blood. Your doctor will advise you about this.
  • If you are due to have any medical treatment, tell the person carrying out the treatment that you are taking a tricyclic antidepressant, as they can interfere with some anaesthetics.
  • Continue to take doxepin unless your doctor tells you otherwise. Stopping treatment suddenly can sometimes cause problems and your doctor may want you to reduce your dose gradually if this becomes necessary.

Can doxepin cause problems?

Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. The table below contains some of the most common ones associated with doxepin. You will find a full list in the manufacturer’s information leaflet supplied with your medicine. The unwanted effects often improve as your body adjusts to the new medicine, but speak with your doctor or pharmacist if any of the following continue or become troublesome.

Common doxepin side-effects What can I do if I experience this?
Blurred vision, feeling sleepy or tired If this happens, do not drive or use tools or machines. Do not drink alcohol
Dry mouth Try chewing sugar-free gum or sucking sugar-free sweets
Constipation Try to eat a well-balanced diet containing plenty of fibre and drink plenty of water
Feeling faint or light-headed, especially when getting up from a sitting or lying position Getting up more slowly may help. If you begin to feel faint, sit down until the feeling passes
Headache Ask your pharmacist to recommend a suitable painkiller
Feeling sick (nausea) or being sick (vomiting), diarrhoea Stick to simple meals – avoid rich or spicy foods. Drink plenty of water to replace lost fluids
Sweating, flushing, difficulty in passing urine, increased appetite, feeling confused or anxious, disturbed sleep, lack of concentration, feeling shaky, itchy skin rash, weight changes, changes in sexual function, breast tenderness, changes in the way things taste, ringing in your ears, fast heartbeat If any of these become troublesome, speak with your doctor for advice

If you experience any other symptoms which you think may be due to the medicine, speak with your doctor or pharmacist for further advice.

How to store doxepin capsules

  • Keep all medicines out of the reach and sight of children.
  • Store in a cool, dry place, away from direct heat and light.

Important information about all medicines

Never take more than the prescribed dose. If you suspect that you or someone else might have taken an overdose of this medicine, go to the accident and emergency department of your local hospital at once. Take the container with you, even if it is empty.

This medicine is for you. Never give it to other people even if their condition appears to be the same as yours.

Do not keep out-of-date or unwanted medicines. Take them to your local pharmacy which will dispose of them for you.

If you have any questions about this medicine ask your pharmacist.


Tricyclic antidepressants (TCAs)

Amitriptyline and doxepin are some of the more commonly used TCAs in the treatment of insomnia (Walsh, 2004a). Their therapeutic effects in depression are related to inhibition of serotonin and norepinephrine reuptake, whereas their effects on sleep are probably mediated by their antagonistic effects on histamine type 1 (H1), serotonin type 2 (5HT2) and α-adrenergic type 1 receptors. TCAs have long half-lives, which often leads to daytime sedation and other adverse effects. In general, when used to promote sleep they are prescribed at doses lower than those recommended for treating depression.

The effects of TCAs on sleep have been studied more frequently in patients with major depressive disorder, where they have been shown to reduce latency to sleep onset and increase sleep efficiency (Roth et al., 1982; Shipley et al., 1985). PSG studies in adults and elderly adults with primary insomnia showed that low doses of doxepin (1, 3, or 6 mg) led to improvements in objective sleep and subjective sleep maintenance and duration in comparison with placebo, with no evidence of side-effects such as anticholinergic effects, hangover, or memory impairment (Roth et al., 2007; Scharf et al., 2008). TCAs at higher doses have profound effects on sleep architecture, most notably suppression of REM sleep (Obermeyer and Benca, 1996; Mayers and Baldwin, 2005). REM sleep rebound and sleep disturbance may thus occur following abrupt discontinuation of TCAs, making them less attractive for intermittent dosing.

TCAs can also have adverse effects on sleep, including the exacerbation of restless legs syndrome or periodic limb movements, or precipitation of REM behavior disorder (Wilson and Argyropoulos, 2005). They can also induce hypomania or mania in patients with underlying bipolar disorder, which is generally associated with severe insomnia.

All tricyclics have significant anticholinergic effects, which leads to many of their side-effects, including dry mouth, constipation, urinary retention, and sweating, although amitriptyline has the strongest effects. Orthostatic hypotension can result from α1-receptor antagonism, increasing the risk of falls. The TCAs also have quinidine-like effects on cardiac conduction, which can result in prolongation of the QT interval; cardiotoxicity is a major concern and these drugs have a high risk of fatality in overdosage.

Although there are relatively few studies documenting its effects on sleep, trazodone has been one of the most frequently prescribed drugs for insomnia, and is probably used almost exclusively for this purpose at present, usually in doses of up to 100 mg at bedtime. Its popularity is probably due to its low cost, low abuse potential, and lack of restrictions on long-term use. Its effects on sleep are probably due to its antihistaminergic effects at the H1 receptor, α1-receptor antagonism, and 5HT2 receptor antagonism. In several studies in depressed patients, trazodone administration resulted in reduced sleep latency, and increased sleep efficiency and total sleep (Mendelson, 2005). In the one double-blind, placebo-controlled study that has been performed in primary insomnia, trazodone 50 mg and zolpidem 10 mg were compared with placebo over a 2-week period (Walsh et al., 1998). During the first week, trazodone and zolpidem led to subjective reductions in sleep latency, increases in total sleep and sleep quality, and decreased wakefulness after sleep onset, but zolpidem produced a greater reduction in sleep latency than trazodone. During the second week, trazodone did not differ from placebo, whereas zolpidem still produced a significantly shorter sleep latency and more total sleep. There are insufficient data to conclude that trazodone does not lead to tolerance or rebound insomnia.

Trazodone is associated with a number of frequent adverse effects, including daytime sedation/drowsiness, dizziness, dry mouth, gastrointestintal upset, blurred vision, and headache; these have led to fairly high discontinuation rates in clinical trials (Mendelson, 2005). Although less common, significant cardiovascular effects, such as orthostatic hypotension, prolonged QT interval, and cardiac arrhythmias may occur. Priapism, although quite rare, is a medical emergency and can occur even with low doses. One of the major metabolites of trazodone, meta-chlorophenylpeperazine (m-CPP), has serotonergic effects and may contribute to serotonin syndrome (confusion/delirium, hyperreflexia, autonomic instability) when trazodone is used in combination with other serotonergic agents. These potential side-effects raise concerns about using trazodone in elderly or medically ill populations.

Mirtazapine tends to be used at low doses (7.5–15 mg) as a sleep-inducing agent and probably affects sleep through antagonism of H1 receptors, 5HT2 receptors, and α1-adrenergic receptors. It is generally believed that lower doses of mirtazapine are more sedating than higher doses, but there are few objective clinical data to support this or other efficacy claims for mirtazapine. Common side-effects of mirtazapine include drowsiness, daytime sedation, dry mouth, increased appetite, and weight gain. Its low toxicity is an advantage over some of the other sedating antidepressants.

Doxepin Side Effects

Incidence not known

Abdominal or stomach pain


black, tarry stools

bleeding gums

blood in the urine or stools

blurred vision

burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings

canker sores

chest pain


clay-colored stools

cold sweats

confusion about identity, place, and time


cool, pale skin

cough or hoarseness

dark urine

decrease in the frequency of urination

decrease in urine volume

decreased urine output


difficulty in passing urine (dribbling)

difficulty with breathing

difficulty with speaking

dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


dry mouth

fast, pounding, or irregular heartbeat or pulse

feeling of warmth


flushed, dry skin

fruit-like breath odor

general feeling of tiredness or weakness


hearing loss


increased hunger

increased thirst

increased urination


itching or rash


lip smacking or puckering

loss of appetite

loss of balance control

loss of bladder control

lower back or side pain

mood or mental changes

muscle spasm or jerking of all extremities

muscle trembling, jerking, or stiffness

muscle twitching




noisy breathing

painful or difficult urination

pinpoint red spots on the skin

pounding in the ears

puffing of the cheeks

rapid or worm-like movements of the tongue

rapid weight gain

redness of the face, neck, arms, and occasionally, upper chest


ringing or buzzing or other unexplained noise in the ears that continues

seeing, hearing, or feeling things that are not there


shakiness and unsteady walk

shakiness in the legs, arms, hands, or feet

shuffling walk

sore throat

sores, ulcers, or white spots on the lips, tongue, or in the mouth

slurred speech

stiffness of the limbs


sudden loss of consciousness


swelling of the face, ankles, or hands

swollen glands

tightness in the chest

troubled breathing

twisting movements of the body

uncontrolled chewing movements

uncontrolled movements, especially of the arms, face, legs, neck, and back

unexplained weight loss

unpleasant breath odor

unsteadiness, trembling, or other problems with muscle control or coordination

unusual bleeding or bruising

unusual tiredness or weakness

vomiting of blood

yellow eyes or skin

Antidepressants have helped millions of people cut through the dark fog of depression. Many others try these medications but stop taking them, often because of side effects such as weight gain. A study from a Harvard-based team shows that the amount gained is usually small, and that it differs little from one antidepressant to another.

Earlier studies linking antidepressant use to weight gain were usually small and short. This one, led by researchers with Massachusetts General Hospital’s Center for Experimental Drugs and Diagnostics, included more than 19,000 men and women and lasted for a year.

Using electronic health records, the researchers identified men and women who took an antidepressant for at least three months. Medications used included amitriptyline (Elavil), bupropion (Wellbutrin), citalopram (Celexa), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac), mirtazapine (Remeron), nortriptyline (Pamelor), paroxetine (Paxil), venlafaxine (Effexor), or sertraline (Zoloft). They also identified another 3,400 people who took some other type of medication for a non-depression ailment. Each person’s weight was checked every three months for a year.

The researchers chose citalopram as a reference, because earlier studies suggested that it is “average” when it comes to weight gain. In this study, the weight gain experienced by people taking citalopram averaged one to two pounds. Compared to citalopram, the weight gain linked to other antidepressants was small.

Bupropion was associated with the least amount of weight gain, close to none. Two others that also appeared to have less weight gain were amitriptyline and nortriptyline. Amitriptyline and nortriptyline are older drugs. Because newer drugs tend to have fewer side effects, those two aren’t prescribed as frequently. At the other end of the spectrum, citalopram caused the most weight gain. Even so, the differences between the drugs were small. The results of the study were published in JAMA Psychiatry.

Not everyone taking antidepressants gained weight. Some actually lost a few pounds.

Tip for choosing an antidepressant

The results of this study indicate that worries about weight gain shouldn’t influence the choice of antidepressant for most people. One antidepressant is generally as effective as another. If you need to choose an antidepressant, let cost and potential side effects be your guide.

Many antidepressants are available as generics. Generics work as well as brand name drugs, but cost less.

Here are some tips for choosing a treatment based on common side effects:

  • Sexual side effects, such as difficulty having an orgasm. Bupropion may be less likely to cause this side effect. It’s also the one associated with the least amount of weight gain.
  • Sleepiness. Some antidepressants make you sleepy. If you have trouble falling asleep or staying asleep, taking one of these before bed, like trazodone, might be a good idea. Paroxetine is another good choice.
  • Decreased energy level. No antidepressant leads the pack in terms of being more stimulating. Perhaps bupropion or fluoxetine might be a good first choice.

If you start taking an antidepressant, don’t expect to see a major improvement right away. It often takes 6 to 8 weeks to see a response to an antidepressant. And don’t give up if the first one doesn’t work. Trying a different one may do the trick.

Another option to consider is psychotherapy, especially if the first drug doesn’t work. People who do not respond to the first antidepressant can often do as well with talk therapy as they would with another drug.

Keep in mind that a small number of people have a condition called atypical major depression. Instead of the more usual problems of decreased appetite and difficulty sleeping, their depression causes an increased appetite and sleeping too much. This leads to weight gain regardless of drug therapy. For them, it’s probably best to stay away from an antidepressant that causes even more weight gain.

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