Amitriptyline (Elavil®) versus Venlafaxine (Effexor®)

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

Amitriptyline advantages over Venlafaxine

  • Suitable choice for patients with sleep problems, anxiety, or chronic pain syndromes.

Venlafaxine advantages over Amitriptyline

  • Venlafaxine produces fewer anticholinergic, antihistaminic, and sympatholytic side effects.
  • Venlafaxine has broader therapeutic index and lower toxicity in overdose.
  • Unlike the amitriptyline, venlafaxine does not significantly affect cardiac conduction.


Difference between Amitriptyline and Venlafaxine

Table 1. Comparison of Amitriptyline and Venlafaxine

Amitriptyline Venlafaxine
Brand names
Elavil® Effexor®
Effexor XR®
Drug class
Tricyclic antidepressant (TCA) Serotonin-norepinephrine reuptake inhibitor (SNRI)
Dose formulations
• Tablets • Tablets
• Tablets, extended release
• Capsules, extended release
Legal status
• Rx only
• Not a controlled drug
FDA-approved indications
• Depression
  Generalized anxiety disorder
Social anxiety
Panic attacks
"Off-label" uses
• Neuropathic pain1
• Prevention of migraine
• Chronic pain syndromes
• Insomnia
• Panic disorder
• Anxiety
Binge eating disorder
Hot flashes
Premenstrual dysphoric disorder
Posttraumatic stress disorder
Mechanism of action
TCAs and SNRIs share dual inhibition effects on presynaptic reuptake of norepinephrine and serotonin.
Equally inhibits serotonin and noradrenaline reuptake.
Amitriptyline also blocks histamine-H1 receptors, alpha-1 adrenergic receptors and muscarinic receptors.

Although venlafaxine mechanism of action is similar to that of amitriptyline, it acts more specifically at noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine) receptors.
Does not significantly affect muscarinic, histamine, or adrenergic receptors, which are responsible for the side effects of TCAs.
• 10-26 hours • 5 hours
• 11 hours for active metabolite O-desmethylvenlafaxine
Oral bioavailability
• 30–60% • 45%
Metabolism, Elimination
• Amitriptyline is extensively metabolized in the liver by hepatic enzymes CYP2C19 and CYP2D6 to its primary active metabolite, nortriptyline, and other metabolits.
• Eliminated mainly in urine (18% of the dose as unchanged drug), small amounts in feces.
• Venlafaxine is metabolized in the liver via the CYP2D6 to its active metabolite, O-desmethylvenlafaxine (ODV).
• The primary route of elimination of venlafaxine and its metabolite is renal. About 87% of a dose is recovered in urine.
• Concurrent use with a monoamine oxidase (MAO) inhibitors or within 14 days of stopping an MAOI
• Hypersensitivity to amitriptyline
• Acute recovery period after myocardial infarction
• Hypersensitivity to venlafaxine, desvenlafaxine
Side effects
What gives amitriptyline a different unfavourable adverse effects profile is its ability to block histamine-H1, alpha-1 adrenergic and muscarinic receptor.
• Dry mouth
• Constipation
• Urinary retention
• Blurred vision
• Hypotension
• Hypertension
• Tachycardia
• Palpitation
• Arrhythmias
• Sedation
• Nausea
• Vomiting
• Drowsiness
• Dizziness
• Increased appetite
• Weight gain
• Excessive sweating
Venlafaxine lacks most of tricyclic antidepressants side effects.
• Nausea - the most commonly reported side effect
• Headache
• Insomnia
• Dizziness
• Weakness
• Hypertension
• Ejaculation disorder
• Sexual dysfunction
• Anorgasmia
• Somnolence
• Dry mouth
• Sweating
• Anorexia
• Nervousness

Venlafaxine may cause pronounced discontinuation symptoms, even after missing a single dose.
Drug interactions
• Additive effects with CNS depressants
• Monoamine oxidase inhibitors - concomitant use contraindicated
• Drugs that inhibit cytochrome P450 2D6 - concomitant use with amitriptyline may require lower doses for either the amitriptyline or the other drug.
• Cimetidine - increased level of tricyclic antidepressant
• Drugs that affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, SNRIs, linezolid, lithium, tramadol.

Head-to-head comparative studies

Migraine prophylaxis
Both antidepressants have significant beneficial effect on pain parameters 2. Venlafaxine prevents headaches in mostly the same way as the amitriptyline but with a much more tolerable side effect profile. Venlafaxine may be preferred for migraine prophylaxis in persons involved in intense daily activities (e.g. work, learning).

Major depression
Both medications are effective in the treatment of depression. There are no significant differences in efficacy 3.
Venlafaxine can improve social functioning more than amitriptyline. This effect may be linked to the higher rate of side effects with amitriptyline 4.

Side effects
Venlafaxine is associated with the lower rate of adverse effects than amitriptyline 2, 3.


Further reading


  • 1. Gallagher HC, Gallagher RM, Butler M, Buggy DJ, Henman MC.Venlafaxine for neuropathic pain in adults.Cochrane Database Syst Rev. 2015 Aug 23;(8):CD011091)
  • 2. Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M, Mungen B. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg. 2004 Dec;107(1):44-8. PubMed
  • 3. Benedictis E. Double-blind comparison of venlafaxine and amitriptyline in outpatients with major depression with or without melancholia. J Psychopharmacol. 2000 Mar;14(1):61-6. PubMed
  • 4. Gorenstein C, Andrade L, Moreno RA, Artes R. Social adjustment in depressed patients treated with venlafaxine and amitriptyline. Int Clin Psychopharmacol. 2002 Jul;17(4):171-5.

Published: October 18, 2017
Last updated: October 18, 2017


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