Download Suggestion from clinicians

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 safety 34.3 (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 neurology 5.1 (1992): 40-44.
eCPS (2015)
Class
Drug
Dose
Adverse Effects
Drug Interactions
Cos
ta
Tricyclic
Antidepressant
s
amitriptyline Initial:b25
generics
–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
Antidepressant
s
nortriptyline
Aventyl,
generics
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.
$
Initial:b25
–50
mg/daypo
Usual:75–
150
mg/daypo
High:c200
mg/day p
o
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
amitriptyline
Uses
depression
Contraindications (CI),
drug interactions (DI)
or cautions
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
Adverse Effects
(common and severe)
Initial dose; typical dose
MI, stroke, seizure,
Adults: 50-100mg at
paralytic ileus, urinary nights Children >12yrs
retention, constipation, 20mg at nights
blurred vision,
hyperpyrexia, rash,
bone marrow
depression, testicular
swelling,
gynecomastia,
alopecia, edema
Monitoring
monitor
lithium
levels
every 2
months