Pharmacology

Doxepin inhibits the reuptake of serotonin and noradrenaline from the synaptic cleft (dual action). The reuptake-inhibition of dopamine is very weak.

It has antagonistic effects (blockade) on a variety of postsynaptic receptors:

   * Extremely strong : H1, H2
   * Strong : 5-HT2, Alpha1, Muscarinic
   * Moderate : 5-HT1
   * Weak : D2, Alpha2

These effects account for the actions as well for most side-effects (sedation, hypotension, anticholinergic side-effects, massive weight gain). Doxepin shows strong antagonism against the effects of Reserpin (amine depletion) in the animal model. Like other 'classical' antidepressants it has a sodium channel blocking activity, possibly accounting for its analgesic action. Additionally, Doxepin exerts a strong local-anaesthetic action.

Peak plasma levels are seen 2 to 3 hours after oral dosing.

Toxicology

acute toxicity:

   * Mouse : i.v. 15 - 20mg/kg body weight, oral 148 - 178mg/kg body weight
   * Rat : i.v. 13 - 19mg/kg body weight, oral 346 - 460mg/kg body weight
   * Human : Not exactly known, clinical experience indicates a rather high acute toxicity, as is the case with other tri-/tetracyclics. Fatal dose in sensitive adults may be as low as 500 to 1,000mg oral (7 to 14mg/kg). In children below 12 yrs. of age any oral intake is to be considered as serious.

chronic toxicity

   * Dog and Rat : Fat deposits in liver cells and decrease of triglyceride levels in plasma
   * Human : Data not available

Indications

Approved uses may vary by country. In the United States, the only Food and Drug Administration (FDA) approved use of doxepin is the treatment of depression. All other uses are considered off-label.

   * Depression
   * Anxiety disorder, longterm-treatment is possible.
   * Insomnia, also suitable for longterm-treatment (see Hajak et al., 2001).
   * Alleviation of the symptoms of alcohol and drug withdrawal (N.B.: Doxepin does not suppress seizure activity in alcoholics ('rum fits'). Cotreatment with benzodiazepines or barbiturates is needed to treat seizures effectively.)
   * Gastrointestinal ulceration and other GI-problems (eg. irritable bowel syndrome), whether part of depression or not. The action is due to strong H2-receptor antagonism. The efficiacy is comparable to H2-Receptor-Inhibitors.
   * Chronic pain, particular tension headaches, whether associated with depression or not
   * Topical (external) treatment of itching skin disease with Zonalon® and Xepin®

Contraindications

absolute :

   * known hypersensitivity to doxepin or other dibenzoxepines or other ingredients of the drug
   * acute intoxication with alcohol, sedatives, analgesics and other psychoactive drugs
   * acute delirium tremens
   * untreated closed angle glaucoma
   * hypertrophy of the prostate with urine retention
   * paralytic ileus

relative :

   * hypertrophy of the prostate without urine retention
   * reduced function of the bone marrow
   * organic brain disorders
   * increased risk of seizures, preexisting epilepsy
   * preexisting cardial damage, particular some arrhythmias (eg. sinoatrial blockage)

special caution is needed :

   * other forms of preexisting cardiac damage (other arrhythmias, insufficience)
   * MAO-Inhibitors of the irreversible type (tranylcypromine among others) : These drugs should normally be stopped at least 2 weeks before therapy with doxepin is started.

Children under 12 years of age should not be treated, because no sufficient clinical experience exists for this group of age.

Precautions

Before initiation of treatment a complete and differentiated blood count should be taken. If any value is pathologic, the blood count should be monitored closely under therapy with doxepin. If values are normal, blood counts should be taken during therapy in regular intervals (recommended: weekly during first month of therapy, monthly during the next 2 months, every 3 months afterwards).

Liver-function studies should be performed periodically.

Pregnancy and Lactation

If Doxepin is used chronically during pregnancy, the newborn may show a withdrawal syndrom with agitation, impaired cardio-respiratory functions, disturbed urination and defecation. Caution should be exerted in treating pregnant women on a regular basis.

Doxepin is found in significant amounts in the milk of lactating women. If therapy is necessary, lactation should be interrupted during treatment.

Side-effects

   * Central Nervous System : fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, insomnia, seizures (infrequently), delirium, rarely induction of hypomania and schizophrenia (stop medication immediately), extrapyramidal side-effects (rarely), abuse in patients with polytoxikomania (rarely)

   * Anticholinergic : dry mouth, obstipation, even ileus (rarely), difficulties in urinating, sweating, precepitation of glaucoma

   * Antiadrenergic : hypotension, postural collapse (if patient arises too fast from lying/sitting position to standing), arrhythmias (sinus-tachycardia, bradycardia, av-blockade)

   * Allergic/toxic : skin rash, photosensitivity, liver damage of the cholostatic type (rarely), hepatitis (extremely rare), leuko- or thrombopaenia (rarely), agranulocytosis (very rarely), hypoplastic anaemia (rarely)

   * Others : frequently increased appetite, massive weight gain, rarely nausea, frequently impaired sexual function in men (impotence, ejaculation-difficulties), rarely hypertension, rarely polyneuropathy, in both sexes breast-enlargement and galactorrhea (rarely)

Suicidal Patients

Patients with suicidal thoughts, or those with previous suicidal attempts, should be monitored closely under treatment with Doxepin. Perhaps, the decision is made to hospitalize high risk patients until remission or to prescribe an additional sedating drug like a benzodiazepine or chlorprothixene for 2-4 weeks of initial treatment with Doxepin (until significant remission). At least, the smallest amount of Doxepin should be prescribed at one time to minimize the risk of deliberate overdose.

Drug Abuse and Dependence

Doxepin has an extremely low potential for abuse and psychological dependence (mostly noted with polytoxicomaniacs, possibly due to the strong anxiolytic action of Doxepin).

Withdrawal symptoms frequently seen when treatment with doxepin is stopped abruptly (agitation, anxiety, insomnia, sometimes activation of mania or rebound depression) are not indicative of addiction and can be avoided by reducing the daily dose of Doxepin gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine (eg. Lorazepam, Clonazepam, or Alprazolam) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.

Other remarks

Doxepin may worsen psychotic conditions like schizophrenia and should be given with caution. The antipsychotic treatment should be continued.

With Zonalon® and Xepin; in most countries an external form (cream) is available for the treatment of itching skin disease; the effect is probably due to the affinity of doxepin for H1 and H2 receptors and action on muscarininc receptors.

Interactions

   * Irreversible MAO-Inhibitors : agitation, delirium, coma, hyperpyrexia (high fever), seizures and severe changes in blood pressure. N.B. Treatment-resistant and hospitalized patients may be treated concomitantly with an MAO-Inhibitor, if they are closely monitored and if the initial dose of the MAO-Inhibitor is low.

   * Increased drug actions :
   * other antidepressants, barbiturates, narcotics, sedating anthistaminics, anticonvulsive drugs, alcohol - resulting in increased central depression
   * anticholinergics (antiparkinsonian agents, tri- and tetracyclic antidepressants) - resulting in increased anticholinergic action (dry mouth, obstipation etc.)
   * Cimetidine : impairs the excretion of Doxepin - increased central depression and anticholinergic effects
   * Sympathomimetics (also those used in local anaesthetics like Noradrenaline) : sympathomimetic effects increased (increased blood pressure, pulse rate, paleness of skin etc)
   * Nitrates and Antihypertensives (eg. Beta-Blockers) - increased antihypertensive action with pronounced fall in blood pressure

   * Decreased drug actions :
   * Guanethidin, Reserpin, Guanfacin : antihypertensive effects decreased
   * Clonidin : antihypertensive effects decreased and risk of (massive) rebound hypertension.

Dosage

   * Depending on the disease to be treated, clinical condition, age, weight and liver function :

Initial doses may be as low as 5mg in the evening for treatment of insomnia or as high as 100mg oral as bedtime single dose or in divided doses in severely agitated depressive patients. Patients with severe opioid withdrawal symptoms often even require 3 times 50mg or more in the first few days. Generally, initial doses should be low and increased step by step. Outpatients should not receive more than 150mg daily. Hospitalized patients may receive up to 300mg orally in divided doses. Up to 150mg may be given as single bedtime dose. The dose for i.m.-injections and i.v.-infusions is usually 1/2 or less of the oral dose. Infusions should be given very slowly and the patient should lie during the infusion and for some hours afterwards in order to avoid severe postural hypotension.

It has been shown that Doxepin is able to decrease the risk of relapse of serious depression when given as longterm treatment after the remission is stable. If this applies for you, your physician will determine as well the daily dose and the duration of longterm treatment. The daily dose might be lower than the dose needed for full remission of your depression.

   * External use : As directed by physician.

Overdose

If overdose is suspected, local poison control centers or emergency departments can provide advice. United States residents can call the US national poison hotline at 1-800-222-1222. Other worldwide poison centers can be found at the World directory of poisons centers.

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.

History

Doxepin was synthesized by Stach and Spingler from the German drug manufacturer C. F. Boehringer & Söhne GmbH in Mannheim. It was tested from 1963 to 1968 in different German and Swiss psychiatric institutions and was approved in Germany and elsewhere thereafter. The antidepressive effects were found to be excellent. Strong anxiolytic and sedative properties were also demonstrated. Doxepin has been in clinical use for several decades. The drug plays an important role in many indications today, not only in psychiatry/neurology.