Nortriptyline Is More Likely to Cause Constipation Than Pristiq
Nortriptyline carries a significantly higher and more predictable risk of constipation compared to desvenlafaxine (Pristiq), making Pristiq the preferred choice when constipation is a clinical concern. 1
Mechanistic Basis for Differential Constipation Risk
The constipation profiles of these two agents differ fundamentally due to their distinct pharmacologic mechanisms:
Nortriptyline causes constipation through anticholinergic blockade of gastrointestinal smooth-muscle receptors, a well-established mechanism that consistently produces this side effect across patient populations. 1
Desvenlafaxine produces bidirectional gastrointestinal effects (either constipation or diarrhea) rather than a dominant constipating tendency, reflecting its sympathetic activation mechanism that can alter gastric motility in variable ways. 1
The two drugs operate through entirely separate pathways: nortriptyline via anticholinergic inhibition versus desvenlafaxine via sympathetic activation. 1
Clinical Evidence on Constipation Frequency
Nortriptyline demonstrates a consistent and predictable constipation risk across patients, with higher plasma levels (80-120 ng/ml) associated with significantly more frequent constipation compared to lower levels (40-60 ng/ml). 1, 2
Research in elderly patients maintained on nortriptyline for 3 years showed constipation occurred significantly more often at therapeutic plasma levels of 80-120 ng/ml. 2
Desvenlafaxine may produce either constipation or diarrhea depending on the individual patient, making the outcome less predictable but overall less constipating than nortriptyline. 1
A 2021 systematic review and meta-analysis of gastrointestinal side effects across antidepressants provides broader context, though it does not directly compare these two specific agents. 3
Comparative Context with Other Antidepressants
Tricyclic antidepressants as a class (including nortriptyline) cause more constipation-type gastrointestinal adverse events than SSRIs and SNRIs. 4
Anticholinergic agents are well-established causes of constipation, a category that includes nortriptyline but not desvenlafaxine. 5
Desvenlafaxine's gastrointestinal effects are mediated through sympathetic mechanisms that actually inhibit gastric slow waves and contractions, which can lead to either constipation or diarrhea rather than predictable constipation. 6
Clinical Decision-Making Algorithm
When constipation risk is a primary concern, select desvenlafaxine over nortriptyline. This recommendation is particularly important in:
- Elderly patients, who are more susceptible to anticholinergic side effects 1
- Patients with baseline constipation 1
- Individuals already taking other constipating medications 1
If nortriptyline must be used despite constipation concerns:
- Initiate at a low dose (e.g., 10 mg at night) and titrate slowly to mitigate the adverse effect. 1
- Monitor closely for constipation development, as it is a predictable and dose-dependent side effect. 1, 2
Important Caveats
While one older study (1999) in elderly patients did not detect a statistically significant association between nortriptyline and constipation compared to placebo during long-term maintenance, 7 this finding contradicts the broader evidence base and mechanistic understanding. The weight of evidence, including more recent guideline recommendations, supports nortriptyline's consistent constipating effect. 1, 2
Desvenlafaxine's bidirectional gastrointestinal effects mean that while it is less likely to cause constipation than nortriptyline, some patients may still experience this side effect—though others may experience diarrhea instead. 1