Nortriptyline safer than amitriptyline?

The review of the Canadian Pain Society’s recent consensus statement on chronic neuropathic pain that appeared in the November 2017 issue of Canadian Family Physician reads as follows:

When prescribing TCAs [tricyclic antidepressants], secondary amines (nortriptyline, desipramine) are usually better tolerated in terms of sedation, postural hypotension, and anticholinergic effects when compared with tertiary amines (amitriptyline and imipramine) with comparable analgesic efficacy.¹

The reference cited for this statement by the Canadian Pain Society is a review published in 1996.² We combed through this review and could not find any evidence to substantiate this claim. On the matter of adverse events, it finds that “The two reports with dichotomous data on comparisons of different tricyclics did not show any significant difference.”²

The 2015 Cochrane systematic review of nortriptyline for neuropathic pain reiterates the general view that “nortriptyline is sometimes preferred to amitriptyline because it reputedly has a lower incidence of associated adverse effects.”³ The reviewers subsequently describe the state of adverse event reporting in nortriptyline trials as “inconsistent and fragmented.”³ However, in a contemporary neuropathic pain trial involving randomization to nortriptyline, dry mouth (a classic anticholinergic harm) seems to us remarkably common—affecting almost 60% of participants receiving the drug.⁴

This leads us to a couple of questions:

1. If nortriptyline is the principal active metabolite of amitriptyline,³ is it likely that nortriptyline offers a meaningful safety advantage?

2. Do tricyclic antidepressants even “work”? The 2015 Cochrane systematic review for nortriptyline identified 6 trials enrolling just 310 participants.³ The reviewers write, “The studies were methodologically flawed, largely due to small size, and potentially subject to major bias.”³