Amitriptyline for pain and migraine

Generic Name

Amitriptyline

Brand Names

Elavil

Endep

Tryptanol

Laroxyl

Vanatrip

Various generics internationally

Drug Class

Tricyclic antidepressant (TCA)

Analgesic adjuvant

Neuropathic pain modulator

Serotonin-norepinephrine reuptake inhibitor (SNRI)

Mechanism of Action

Amitriptyline exerts its effects primarily by inhibiting the reuptake of serotonin and norepinephrine at the synaptic cleft, enhancing descending inhibitory pain pathways in the central nervous system

It also blocks sodium channels and has anticholinergic, antihistaminic, and alpha-adrenergic blocking activity

These properties contribute to both analgesia and sedation, which are beneficial in treating chronic pain and migraine

Its action on peripheral and central pain modulation circuits makes it effective in neuropathic and functional pain syndromes

THERAPEUTIC INDICATIONS (NON-DEPRESSIVE)

Neuropathic Pain

First-line agent for diabetic peripheral neuropathy, postherpetic neuralgia, and trigeminal neuralgia

Reduces pain intensity, burning, and tingling sensations by enhancing inhibitory pain modulation

Chronic Tension-Type Headache

Reduces headache frequency and intensity by modulating central pain sensitivity and improving sleep

Migraine Prophylaxis

Effective in reducing frequency, duration, and severity of migraine attacks

Acts through both pain inhibition and central suppression of cortical spreading depression mechanisms

Fibromyalgia

Used at low doses to improve widespread pain and associated sleep disturbances

Irritable Bowel Syndrome (IBS)–related Pain

Modulates visceral pain through gut-brain axis regulation

Especially helpful in IBS with predominant pain and diarrhea

Temporomandibular Joint Disorders (TMD)

Adjunct in treating facial or jaw-related myofascial pain

Atypical Facial Pain, Central Post-Stroke Pain, and Phantom Limb Pain

Utilized for central neuropathic mechanisms not responsive to NSAIDs or opioids

DOSAGE AND ADMINISTRATION

Neuropathic Pain and Migraine Prevention

Initial dose: 10 mg orally at bedtime

May be increased gradually in 10 mg increments every 1–2 weeks based on response and tolerance

Usual effective dose: 25–75 mg once daily at night

Maximum dose for pain: usually does not exceed 100 mg/day

Elderly and Frail Patients

Start at lower doses (5–10 mg) due to increased risk of sedation, anticholinergic effects, and orthostatic hypotension

Pediatric Migraine (off-label)

5–25 mg at bedtime in adolescents

Requires specialist supervision

Timing of Administration

Taken once daily 1–2 hours before bedtime to minimize sedation upon waking and improve sleep-related symptoms

May take 2–4 weeks to achieve maximal benefit for chronic pain or migraine prevention

PHARMACOKINETIC PROFILE

Bioavailability: ~50% due to extensive first-pass metabolism

Peak plasma concentration: 2–12 hours

Half-life: 10–28 hours (increased in elderly or hepatic impairment)

Metabolism: hepatic via CYP2D6 to active metabolite nortriptyline

Excretion: urine and feces

CONTRAINDICATIONS

Recent myocardial infarction

Arrhythmias (especially heart block)

Concomitant use of MAO inhibitors or within 14 days of discontinuation

Known hypersensitivity to amitriptyline or related TCAs

Narrow-angle glaucoma

Urinary retention or prostatic hypertrophy (relative contraindication)

Severe liver disease (caution)

PRECAUTIONS

Avoid in patients with seizure disorders – may lower seizure threshold

Caution in elderly – risk of cognitive decline, falls, anticholinergic burden

May cause or worsen suicidal ideation in young adults (especially in high doses used for depression)

Hepatic impairment – reduce dose, monitor liver function

Diabetes – may affect glycemic control

Use cautiously in patients with cardiac disease – ECG monitoring recommended in patients with cardiovascular risk

ADVERSE EFFECTS

Common

Dry mouth

Drowsiness and sedation (strong antihistamine activity)

Constipation

Weight gain

Dizziness and orthostatic hypotension

Blurry vision

Urinary retention

Increased appetite

Less Common

Cognitive impairment

Tachycardia

Palpitations

Photosensitivity

Excessive sweating

Serious and Rare

Prolonged QT interval and arrhythmias (especially in overdose)

Seizures

Mania or hypomania in predisposed individuals

Liver enzyme elevation or hepatotoxicity

Bone marrow suppression

SIADH and hyponatremia

Angle-closure glaucoma

Neuroleptic malignant syndrome (rare)

WITHDRAWAL SYNDROME

Abrupt cessation may cause nausea, headache, irritability, sleep disturbance, and flu-like symptoms

Taper dose gradually if discontinuation is needed

PREGNANCY AND LACTATION

Pregnancy

Generally not first-line but not contraindicated

No clear evidence of teratogenicity

Use only if potential benefit outweighs risks

May cause neonatal withdrawal or toxicity (jitteriness, seizures, respiratory distress)

Lactation

Excreted in breast milk in small amounts

American Academy of Pediatrics considers it compatible with breastfeeding

Monitor infants for sedation or feeding problems

DRUG INTERACTIONS

CNS Depressants (alcohol, opioids, benzodiazepines)

Additive sedation and respiratory depression

Avoid or monitor closely

MAO Inhibitors

Risk of serotonin syndrome or hypertensive crisis

Requires 14-day washout

SSRIs (fluoxetine, paroxetine)

Inhibit CYP2D6, increasing amitriptyline levels and toxicity

Increased risk of serotonin syndrome

Prefer nortriptyline or adjust dose accordingly

Anticholinergics (oxybutynin, antihistamines)

Increased anticholinergic side effects such as confusion and constipation

Avoid or monitor elderly closely

CYP2D6 Inhibitors (quinidine, terbinafine)

Increase amitriptyline levels

QT-Prolonging Agents (haloperidol, quinolones, macrolides)

Increased risk of arrhythmia

Monitor ECG in high-risk individuals

Clonidine or Guanethidine

Antihypertensive effects may be blunted

Antihistamines or antiarrhythmics

Additive cardiac or CNS toxicity possible

CLINICAL MONITORING

Symptom response (pain intensity, migraine frequency)

Sleep quality and energy levels

ECG in elderly or cardiac disease

Weight and appetite changes

Anticholinergic burden (especially in elderly)

Mood status and suicidal ideation in young patients

Liver function in long-term or high-dose therapy

CLINICAL ADVANTAGES FOR PAIN

Low dose required (10–50 mg) compared to depressive treatment (75–150 mg)

Effective in various neuropathic and chronic pain syndromes

Beneficial effect on comorbid insomnia, anxiety, and fibromyalgia

Well studied in migraine prophylaxis compared to other antidepressants

DISADVANTAGES AND LIMITATIONS

Sedation and anticholinergic side effects limit use in elderly

Slow onset (may take 2–4 weeks for pain relief)

Risk of cardiac effects in overdose – caution in suicidal patients

Interaction with multiple medications, especially in polypharmacy cases

COMPARATIVE NOTES

Compared to nortriptyline – nortriptyline has fewer anticholinergic and sedative side effects

Compared to duloxetine – duloxetine better for diabetic neuropathy and fibromyalgia, especially with comorbid depression

Compared to gabapentin – gabapentin better tolerated in elderly but less effective for headaches

Compared to propranolol in migraine – amitriptyline preferred in patients with insomnia, anxiety, or depression

STORAGE AND FORMULATION

Available as tablets: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

Store at room temperature

Protect from moisture and light

No controlled-release forms for pain

PATIENT COUNSELING POINTS

Take at bedtime due to sedation

Do not stop suddenly without consulting your doctor

Avoid alcohol and driving until you know how it affects you

Dry mouth and constipation are common – stay hydrated and use laxatives if needed

Report any signs of chest pain, palpitations, confusion, or mood changes

Inform your doctor of all medications you take to prevent interactions

May take several weeks for full pain or migraine benefit