Amitriptyline (Elavil®) versus Nortriptyline (Pamelor®)

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

Difference between Amitriptyline and Nortriptyline

Table 1. Comparison of Amitriptyline and Nortriptyline

Amitriptyline Nortriptyline
Brand names
Elavil® Pamelor®
Drug class
Tertiary amine tricyclic antidepressant,
dibenzocycloheptadine derivative
Secondary amine tricyclic antidepressant, an
active metabolite of amitriptyline
Dose formulations
• Tablets • Capsules
• Solution (oral)
Legal status
• Rx only
• Not a controlled drug
FDA-approved indications
• Depression
"Off-label" uses
• Neuropathic pain
• Panic disorder
• Anxiety
• Migraine prophylaxis
• Sleep disturbances
• Chronic pain syndromes
•Attention deficit hyperactivity disorder 1
• Smoking cessation2
Mechanism of action
Amitriptyline inhibits serotonin and noradrenaline reuptake equally, whereas nortriptyline is a more potent inhibitor of noradrenaline than of serotonin reuptake3.
Half-life
• 10-26 hours • 18-56 hours
Oral bioavailability
• 30–60% • 51%
Metabolism, Elimination
• Amitriptyline is extensively metabolized in the liver by hepatic enzymes CYP2C19 and CYP2D6 to its primary active metabolite, nortriptyline, and other metabolits4.
• Eliminated mainly in urine (18% as unchanged drug), small amounts in feces.
• Nortriptyline is extensively metabolized in the liver by hepatic enzyme CYP2D6.
• Mostly excreted in urine, small amounts in feces.
Contraindications
• Concurrent use with a monoamine oxidase (MAO) inhibitors
• Acute recovery period after myocardial infarction
• Hypersensitivity to amitriptyline • Hypersensitivity to nortriptyline
Side effects
• Dry mouth
• Constipation
• Urinary retention
• Blurred vision
• Hypotension
• Hypertension
• Tachycardia
• Palpitation
• Arrhythmias
• Sedation
• Nausea
• Vomiting
• Drowsiness
• Dizziness
• Increased appetite
• Weight gain
• Excessive sweating
• Amitriptyline causes more anticholinergic effects (tachycardia, urinary retention, and dry mouth) than nortriptyline  
Drug interactions
• Additive effects with CNS depressants
• Monoamine oxidase inhibitors - concomitant use contraindicated
• Cimetidine - increased level of tricyclic antidepressant
• Amitriptyline is more potent CYP450 inhibitor than nortriptyline
• Drugs that inhibit cytochrome P450 2D6 - concomitant use with amitriptyline may require lower doses for either the amitriptyline or the other drug.
• Minimal cytochrome P450 interaction propensity

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Amitriptyline advantages over Nortriptyline

  • Remains one of the most favored tricyclic antidepressant for a wide variety of chronic pain syndromes, including neuropathic pain, fibromyalgia, and migraine.

Nortriptyline advantages over Amitriptyline

  • Nortriptyline is generally better tolerated than amitriptyline. It has much less sedation and anticholinergic side effects.
  • The mortality from nortriptyline in overdose is similar to that from SSRIs5.
  • Nortriptyline is the least problematic of the tricyclic antidepressants in terms of drug interactions5. It is relatively safe to combine it with certain SSRIs (sertraline and citalopram).
  • Nortriptyline is better choice for elderly.
  • Nortriptyline is unique among the antidepressants in that its blood level demonstrates the classical therapeutic window effect9.

Head-to-head comparative studies

Postherpetic neuralgia

Both amitriptyline and nortriptyline have a similar analgesic efficacy in postherpetic neuralgia6. Nortriptyline causes fewer side effects and is better tolerated than amitriptyline.

Depression

Which antidepressant is more effective? Amitriptyline may be more effective in the treatment of endogenous depressive illness.

Nortriptyline was compared with amitriptyline in the treatment of 50 patients suffering from primary depression and classified as reactive and endogenous depressions7. All patients received promazine hydrochloride in addition to specific antidepressant. Comparison without diagnostic classification showed no significant difference in outcome between the two drugs, although amitriptyline was consistently more effective. Improvement of symptoms of endogenous depressions treated with amitriptyline was significantly better than all other diagnostic groups. Reactive depressions on amitriptyline showed the least improvement but not significantly inferior to reactive and endogenous cases on nortriptyline, the latter two groups having almost identical results.

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Which antidepressant works faster? Nortriptyline provides more rapid antidepressant effect8.

In a double-blind trial9 after 1 week patients treated with nortriptyline had a significantly greater mean reduction in Hamilton depression score (55% compared to 25% for amitriptyline patients).

Further reading

References

  • 1. Otasowie J, Castells X, Ehimare UP, Smith CH. Tricyclic antidepressants for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev. 2014 Sep 19;(9):CD006997. PubMed
  • 2. Prochazka AV, Waver MJ, Keller RT, Fryer GE, Licari PA, Lofaso D. A randomized trial of nortriptyline for smoking cessation. Arch Intern Med. 1998 Oct 12;158(18):2035-9. PubMed
  • 3. Hyttel J, Christensen AV, Fjalland B. Neuropharmacological properties of amitriptyline, nortriptyline and their metabolites. Acta Pharmacol Toxicol (Copenh). 1980
  • 4. L Dean. Amitriptyline Therapy and CYP2D6 and CYP2C19 Genotype. March 23, 2017
  • 5. Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007 Jul;151(6):737-48. PubMed
  • 6. Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology. 1998 Oct;51(4):1166-71. PubMed
  • 7. Rose JT, Leahy MR, Martin IC, Westhead TT. A comparison of nortriptyline and amitriptyline in depression. Br J Psychiatry. 1965 Nov
  • 8. Mendels J. Comparative Trial of Nortriptyline and Amitriptyline in 100 Depressed Patients. Am J Psychiatry. 1968 Feb
  • 9. Lehmann LS, Bowden CL, Redmond FC, Stanton BC. Amitriptyline and nortriptyline response profiles in unipolar depressed patients. Psychopharmacology (Berl). 1982

Published: October 16, 2017
Last updated: October 16, 2017

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