What is the use of Amitriptyline (AMI) hydrochloride?

From the Guidelines

Amitriptyline hydrochloride should be prescribed at a dose of 10 mg at bedtime for patients with irritable bowel syndrome with diarrhea (IBS-D), as it has been shown to have greater efficacy than placebo in this patient population. This recommendation is based on the most recent and highest quality study available, which found that amitriptyline 10 mg at bedtime had greater efficacy than placebo in patients with IBS-D 1. The efficacy of tricyclic antidepressants (TCAs) in IBS was studied in 8 placebo-controlled RCTs in 523 patients, and the results showed that TCAs were associated with global symptom relief and abdominal pain relief compared with placebo. However, the quality of evidence was rated down due to indirectness, risk of bias, and imprecision.

Key Points to Consider

• The dose of amitriptyline used in the study was 10 mg at bedtime, which is lower than the typical starting dose for depression.
• The study found that amitriptyline had greater efficacy than placebo in patients with IBS-D, but the overall certainty in evidence was rated as low due to indirectness, risk of bias, and imprecision.
• TCAs have multiple actions, including inhibition of serotonin and noradrenergic reuptake and blockade of muscarinic 1, a1 adrenergic, and histamine 1 receptors, which can cause adverse events such as dry mouth, sedation, and constipation.
• Amitriptyline should be used with caution in elderly patients and those with heart conditions, glaucoma, or urinary retention, as anticholinergic side effects may be dose limiting and restrict use in individuals ≥65 years of age 1.

Potential Side Effects and Interactions

• Common side effects of amitriptyline include drowsiness, dry mouth, constipation, blurred vision, and weight gain.
• Amitriptyline can interact with other medications, such as monoamine oxidase inhibitors (MAOIs), and should be used with caution in patients taking these medications.
• Patients should not stop taking amitriptyline abruptly, as this can cause withdrawal symptoms.

From the FDA Drug Label

Amitriptyline HCl is an antidepressant with sedative effects. Its mechanism of action in man is not known. It is not a monoamine oxidase inhibitor and it does not act primarily by stimulation of the central nervous system. Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression It should be noted that amitriptyline hydrochloride is not approved for use in treating bipolar depression. Amitriptyline may enhance the response to alcohol and the effects of barbiturates and other CNS depressants In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage. Delirium has been reported with concurrent administration of amitriptyline and disulfiram Usage in Pregnancy Pregnancy Category C Teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose 1) Studies in literature have shown amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of 28 to 100 mg/kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies without other signs of embryotoxicity. In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of cranial bones Amitriptyline has been shown to cross the placenta. Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy. There are no adequate and well-controlled studies in pregnant women Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Amitriptyline is excreted into breast milk In one report in which a patient received amitriptyline 100 mg/day while nursing her infant, levels of 83 to 141 ng/mL were detected in the mother’s serum. Levels of 135 to 151 ng/mL were found in the breast milk, but no trace of the drug could be detected in the infant’s serum Because of the potential for serious adverse reactions in nursing infants from amitriptyline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age. Schizophrenic patients may develop increased symptoms of psychosis; patients with paranoid symptomatology may have an exaggeration of such symptoms. Depressed patients, particularly those with known manic-depressive illness, may experience a shift to mania or hypomania In these circumstances the dose of amitriptyline may be reduced or a major tranquilizer such as perphenazine may be administered concurrently. The possibility of suicide in depressed patients remains until significant remission occurs. Potentially suicidal patients should not have access to large quantities of this drug. Prescriptions should be written for the smallest amount feasible Concurrent administration of amitriptyline hydrochloride and electroshock therapy may increase the hazards associated with such therapy. Such treatment should be limited to patients for whom it is essential. When possible, the drug should be discontinued several days before elective surgery. Both elevation and lowering of blood sugar levels have been reported Amitriptyline hydrochloride should be used with caution in patients with impaired liver function. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with amitriptyline hydrochloride and should counsel them in its appropriate use A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for amitriptyline hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking amitriptyline hydrochloride Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication While on therapy with amitriptyline hydrochloride, patients should be advised as to the possible impairment of mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle Drug Interactions Topiramate Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA) In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g.,

Amitriptyline Hydrochloride is an antidepressant with sedative effects.

• Mechanism of Action: Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons.
• Indications: It is used to treat depression.
• Contraindications: It is not approved for use in treating bipolar depression.
• Warnings and Precautions:
  • It may enhance the response to alcohol and the effects of barbiturates and other CNS depressants.
  • It should be used with caution in patients with impaired liver function.
  • It should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
  • It is excreted into breast milk, and a decision should be made whether to discontinue nursing or to discontinue the drug.
  • It is not recommended for patients under 12 years of age.
• Drug Interactions:
  • Topiramate may increase amitriptyline concentration.
  • Drugs metabolized by P450 2D6 may inhibit the activity of this isozyme and increase plasma concentrations of amitriptyline. 2, 2, 2

From the Research

Amitriptyline Hydrochloride Overview

• Amitriptyline hydrochloride is a tricyclic antidepressant used to treat chronic neuropathic pain and major depressive disorder 3, 4.
• It is recommended as a first-line treatment for neuropathic pain in many guidelines, despite limited evidence for its efficacy in this condition 3.

Efficacy in Neuropathic Pain

• A systematic review of 17 studies found that amitriptyline was significantly better than placebo in only two of seven studies reporting useful efficacy data, with very low quality evidence 3.
• The review concluded that there is no first-tier or second-tier evidence for amitriptyline in treating any neuropathic pain condition, and that the available evidence is of low quality 3.
• Another study found that chronic amitriptyline administration attenuated neuropathic pain-related behavior in rats, but the effect was dependent on the presence or absence of a depressive-like phenotype 5.

Efficacy in Major Depressive Disorder

• A systematic review of 39 trials found that amitriptyline was significantly more effective than placebo in achieving acute response in patients with major depressive disorder, with a moderate to large effect size 4.
• The review also found that amitriptyline was associated with a number of side effects, including anticholinergic side effects, tachycardia, dizziness, and weight gain 4.

Safety and Tolerability

• A systematic review found that more participants experienced at least one adverse event with amitriptyline than with placebo, with a risk ratio of 1.5 and a number needed to treat for an additional harmful outcome of 5.2 3.
• Another review found that amitriptyline was associated with a number of side effects, including anticholinergic side effects, tachycardia, dizziness, and weight gain 4.