Amitriptyline vs. Nortriptyline

Replacement to the List

Peer Feedback:

Multiple suggestions made for this substitution.

"replace with nortriptyline – nortriptyline is a metabolite of amitriptyline that has less adverse effects (less anticholinergic effects and hypotensive) and is effect for depression and neuropathic pain.”

“Nortriptyline - less fall risk in elderly, same efficacy”

“Nortyptiline - better tolerated, similar efficacy"

"e.g., venlafaxine - similar mechanism and indications but considered first line over TCAs due to better ADR and DI profile"

Note: the 4th comment calls for the removal of TCAs in replacement of other 1st line therapies. Setraline and fluoxetine are on the list. Venlafaxine is a suggested addition addressed separately.

Literature Review Question:

Does nortriptyline have equal or greater efficacy in comparison to amitriptyline?

Is nortriptyline a safer and more tolerable option in comparison to amitriptyline?

Is nortriptyline an effective treatment for neuropathic pain?

Literature Search:
Cochrane Library searched
Pubmed searched for ‘(Tricyclic OR (amitriptyline AND nortriptyline)) AND efficacy AND depression;
nortriptyline AND amitriptyline AND (adverse effects OR side effects OR safety OR tolerability)
eCPS - Psychiatric Disorders: Depression

Nortriptyline Cochrane 2015 (Neuropathic Pain)

No study provided first or second tier evidence for any outcome. Only one study reported our primary outcome of people with at least 50% reduction in pain. There was no indication that either nortriptyline or gabapentin was more effective in postherpetic neuralgia (very low quality evidence). Two studies reported the number of people with at least moderate pain relief, and one reported the number who were satisfied with their pain relief and had tolerable adverse effects. We considered these outcomes to be equivalent to our other primary outcome of Patient Global Impression of Change (PGIC) much or very much improved.

We could not pool data, but third tier evidence in individual studies indicated similar efficacy to other active interventions (gabapentin, morphine, chlorimipramine, and amitriptyline), and to placebo in the conditions studied (very low quality evidence). Adverse event reporting was inconsistent and fragmented. More participants reported adverse events with nortriptyline than with placebo, similar numbers with nortriptyline and other antidepressants (amitriptyline and chlorimipramine) and gabapentin, and slightly more with morphine (very low quality evidence). No study reported any serious adverse events or deaths.

We found little evidence to support the use of nortriptyline to treat the neuropathic pain conditions included in this review. There were no studies in the treatment of trigeminal neuralgia. The studies were methodologically flawed, largely due to small size, and potentially subject to major bias. The results of this review do not support the use of nortriptyline as a first line treatment. Effective medicines with much greater supportive evidence are available, such as duloxetine and pregabalin.

Derry, Sheena, et al. "Nortriptyline for neuropathic pain in adults."The Cochrane Library(2015).

Amitriptyline Cochrane Review 2012

The review also documented amitriptyline’s well-known side effects such as the various anticholinergic effects (constipation, dry mouth, nasal congestion, urination problems, vision problems), dizziness, sedation, tachycardia, sexual dysfunction and weight gain. The overall tolerability of amitriptyline was lower than that of placebo. According to the ’Summary of findings’ table 165 out of 1000 amitriptyline-treated participants compared to 45 out of 1000 placebo-treated patients discontinued the studies due to adverse events.

Leucht, Claudia, Maximilian Huhn, and Stefan Leucht. "Amitriptyline versus placebo for major depressive disorder."The Cochrane Library(2012).

Safety of Nortriptyline (2011)

Our systematic review has not uncovered any evidence of mortality and serious adverse events associated with nortriptyline use at doses between 208 Dhippayom et al. 75 and 100 mg. However, nortriptyline use by patients without underlying cardiovascular disease was significantly associated with orthostatic hypotension, while the risks of developing other cardiovascular adverse events were not established. The most common adverse effects associated with nortriptyline use related to its anticholinergic properties

Dhippayom, Teerapon, Nathorn Chaiyakunapruk, and Thitima Jongchansittho. "Safety of Nortriptyline at Equivalent Therapeutic Doses for Smoking Cessation."Drug safety34.3 (2011): 199-210.

Sertraline versus other antidepressive agents (Cochrane 2010)

Note: Most recent Cochrane review that included both amitriptyline and nortriptyline in the comparison.

Cipriani, Andrea, et al. "Sertraline versus other antidepressive agents for depression."The Cochrane Library(2010).

The Use of Antidepressants in the Elderly: 1986 and 1989 (1992)

Antidepressants with the Most Side Effects.

Amitriptyline and doxepin cause marked sedation, orthostatic hypotension, and anticholinergic side effects."" Amitriptyline is also more likely to cause delirium than imipramine or desipramine. 153 Doxepin was once thought to have fewer adverse cardiovascular side effects, but the data do not support this.I7 Since amitriptyline and doxepin cause the most side effects, one could argue that these should be rarely used, either alone or in combination.

Antidepressants with Mild Side Effects

Desipramine is mildly sedating and anticholinergic, but moderately hypotension producing. It is the least anticholinergic of the older tricyclic antidepressants, but all the newer antidepressants (trazodone, fluoxetine,and bupropion) are less so. Nortriptyline is moderately sedating, mildly anticholinergic, and causes very little hypotension, making it a good choice for many elderly patient.

Since all antidepressants considered here have equal efficacy (proven in adults but not specifically tested with al drugs in the elderly), those with the most beneficial side effect profiles are to be recommended for all patients, particularly for the elderly. Therefore, the iizitid choice of antidepressants should be limited to four drugs: desipramine, nortriptyline, fluoxetine, and possibly bupropion.

Dewan, Mantosh J., et al. "The use of antidepressants in the elderly: 1986 and 1989."Journal of geriatric psychiatry and neurology5.1 (1992): 40-44.

eCPS (2015)

Class / Drug / Dose / Adverse Effects / Drug Interactions / Costa
Tricyclic Antidepressants / amitriptyline
generics / Initial:b25–50 mg/daypo
Usual:75–200 mg/daypo
High:c250–300 mg/daypo
/ Anticholinergic (dry mouth, blurred vision, constipation, urinary hesitancy, tachycardia, delirium), antihistaminergic (sedation, weight gain), orthostatic hypotension, lowered seizure threshold; sexual dysfunction. / Use with MAOIs may lead to potentially fatal reaction initially presenting with tremor, agitation, hypomania, hyperthermia and/or hypertension.
Barbiturates, carbamazepine and rifampin may decrease effect; cimetidine and antipsychotics may increase effect and toxicity; possible interaction with antiarrhythmics (may lead to increased effect of either drug); may reduce antihypertensive effect of clonidine; may augment hypotensive effect of thiazides. / $
Tricyclic Antidepressants / nortriptyline
Aventyl,
generics / Initial:b25–50 mg/daypo
Usual:75–150 mg/daypo
High:c200 mg/daypo
/ Anticholinergic (dry mouth, blurred vision, constipation, urinary hesitancy, tachycardia, delirium), antihistaminergic (sedation, weight gain), orthostatic hypotension, lowered seizure threshold; sexual dysfunction. / Use with MAOIs may lead to potentially fatal reaction initially presenting with tremor, agitation, hypomania, hyperthermia and/or hypertension.
Barbiturates, carbamazepine and rifampin may decrease effect; cimetidine and antipsychotics may increase effect and toxicity; possible interaction with antiarrhythmics (may lead to increased effect of either drug); may reduce antihypertensive effect of clonidine; may augment hypotensive effect of thiazides. / $

Psychiatric Disorders: Depression; Sidney H. Kennedy, MD, FRCPC, Sagar V. Parikh, MD, FRCPC and Sophie Grigoriadis, MD, PhD, FRCPC; Date of revision: March 2015

Medication / Uses / Contraindications (CI), drug interactions (DI) or cautions / Adverse Effects
(common and severe) / Initial dose; typical dose / Monitoring
amitriptyline / depression / CI: MAOI therapy, acute MI recovery phase, use with cisapride
DI:sedatives, SSRIs, cimetidine, thyroid meds Increases suicidal ideation in children and adolescents Dose modify in elderly / MI, stroke, seizure, paralytic ileus, urinary retention, constipation, blurred vision, hyperpyrexia, rash, bone marrow depression, testicular swelling, gynecomastia, alopecia, edema / Adults: 50-100mg at nights Children >12yrs 20mg at nights / monitor lithium levels every 2 months