Why is amitriptyline (tricyclic antidepressant) discontinued?

Why Amitriptyline is Discontinued

Amitriptyline is most commonly discontinued due to poor tolerability, particularly anticholinergic side effects (dry mouth, sedation, constipation, urinary retention), orthostatic hypotension, and cardiac effects, which significantly impact quality of life despite its efficacy. 1

Primary Reasons for Discontinuation

Adverse Effects Profile

The burden of side effects is the leading cause of amitriptyline discontinuation:

• Anticholinergic effects are the most common reason patients stop amitriptyline, including dry mouth, sedation, constipation, blurred vision, and urinary retention 1, 2
• Dropout rates due to side effects are significantly higher with amitriptyline compared to SSRIs (odds ratio 4.15,95% CI 2.71 to 6.35; number needed to harm = 12) 1
• Overall side effect burden: 64% of patients on amitriptyline experience at least one adverse event versus 40% on placebo (number needed to harm = 4.1) 3

Specific High-Risk Populations

Older adults are particularly vulnerable to discontinuation-requiring adverse effects:

• Elderly patients experience heightened sensitivity to anticholinergic effects including cognitive impairment, psychomotor slowing, confusion, sedation, delirium, and increased fall risk 2
• Cardiovascular concerns include arrhythmias, sinus tachycardia, prolonged conduction time, orthostatic hypotension, and tachycardia—especially problematic in older adults 2, 1
• Tertiary amine TCAs (including amitriptyline) pose greater safety concerns than secondary amine TCAs (desipramine, nortriptyline) or SNRIs 1

Lack of Efficacy

Treatment failure necessitates discontinuation in some patients:

• Only 38% of participants achieve adequate pain relief with amitriptyline versus 16% with placebo in neuropathic pain conditions—meaning most patients do not get satisfactory benefit 3
• Withdrawal due to lack of efficacy occurs in 5% of amitriptyline-treated patients versus 12% on placebo 3

Safety Concerns Requiring Discontinuation

Specific medical conditions mandate stopping amitriptyline:

• Cardiovascular disease: Myocardial infarction and stroke have been reported; close supervision required in patients with cardiovascular disorders 2
• Angle-closure glaucoma: Even average doses may precipitate an acute attack 2
• Seizure history: Use with caution; may lower seizure threshold 2
• Urinary retention: Atropine-like action contraindicates use in patients with history of retention 2

Drug Interactions

Problematic interactions necessitate discontinuation:

• Absolute contraindication with MAOIs due to risk of serotonin syndrome 2
• Cytochrome P450 2D6 interactions: Poor metabolizers or those on CYP2D6 inhibitors (SSRIs, quinidine, cimetidine) may experience 8-fold increases in plasma concentrations leading to toxicity 2
• At least 5 weeks must elapse after discontinuing fluoxetine before starting amitriptyline due to long half-life 2

Discontinuation Syndrome

Abrupt cessation causes withdrawal symptoms requiring gradual taper:

• Withdrawal syndrome includes irritability, dream and sleep disturbance, restlessness, dizziness, fatigue, myalgias, chills, headaches, nausea, vomiting, diarrhea, anxiety, and agitation 4, 5
• Recommended tapering protocol: 25% dose reductions every 1-2 weeks until complete discontinuation 4
• Recurrence of depression occurs in 8 of 10 patients (80%) within 3-15 weeks after discontinuation of long-term treatment 5

Clinical Context

Despite high discontinuation rates, amitriptyline remains clinically valuable:

• Amitriptyline is slightly more effective than other tricyclics and SSRIs (odds ratio 1.12,95% CI 1.01-1.23; number needed to treat = 50), though clinical significance is modest 1, 6
• Tolerability disadvantage is counterbalanced by higher efficacy, particularly in severe depression and inpatient settings 1
• Decades of successful treatment in many patients supports continued use despite lack of unbiased evidence meeting current standards 3

Preferred Alternatives

When discontinuing amitriptyline, consider:

• SNRIs (duloxetine) offer comparable analgesic efficacy with better safety profile, particularly in older adults 1
• Secondary amine TCAs (desipramine, nortriptyline) have fewer anticholinergic effects than amitriptyline 1
• SSRIs have significantly better tolerability (dropout rate odds ratio 0.84,95% CI 0.75-0.95; number needed to harm = 40) though possibly less efficacy 1