Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial

Abstract

Importance: Gastroparesis remains a challenging syndrome to manage, with few effective treatments and a lack of rigorously controlled trials. Tricyclic antidepressants are often used to treat refractory symptoms of nausea, vomiting, and abdominal pain. Evidence from well-designed studies for this use is lacking.

Objective: To determine whether treatment with nortriptyline results in symptomatic improvement in patients with idiopathic gastroparesis.

Design, setting, and participants: The NORIG (Nortriptyline for Idiopathic Gastroparesis) trial, a 15-week multicenter, parallel-group, placebo-controlled, double-masked, randomized clinical trial from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC), comparing nortriptyline with placebo for symptomatic relief in idiopathic gastroparesis. One hundred thirty patients with idiopathic gastroparesis were enrolled between March 2009 and June 2012 at 7 US academic medical centers. Patient follow-up was completed in October 2012. Inclusion criteria included delayed gastric emptying and moderate to severe symptom scores using the Gastroparesis Cardinal Symptom Index (GCSI). INTERVENTIONS Nortriptyline vs placebo. Study drug dose was increased at 3-week intervals (10, 25, 50, 75 mg) up to 75 mg at 12 weeks.

Main outcomes and measures: The primary outcome measure of symptomatic improvement was a decrease from the patient's baseline GCSI score of at least 50% on 2 consecutive 3-week GCSI assessments during 15 weeks of treatment.

Results: The primary symptomatic improvement outcome did not differ between 65 patients randomized to nortriptyline vs 65 patients randomized to placebo: 15 (23% [95% CI, 14%-35%]) in the nortriptyline group vs 14 (21% [95% CI, 12%-34%]) in the placebo group (P = .86). Treatment was stopped more often in the nortriptyline group (19 [29% {95% CI, 19%-42%}]) than in the placebo group (6 [9%] {95% CI, 3%-19%}]) (P = .007), but numbers of adverse events were not different (27 [95% CI, 18-39] vs 28 [95% CI, 19-40]) (P = .89).

Conclusions and relevance: Among patients with idiopathic gastroparesis, the use of nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms. These findings do not support the use of nortriptyline for idiopathic gastroparesis.

Trial registration: clinicaltrials.gov Identifier: NCT00765895.

Figure 1. Screening, randomization and follow-up of study patients

130 patients were randomized: 65 patients received nortriptyline and 65 patients received placebo.

Figure 2. Changes from baseline in GCSI subscores and total score by treatment group

There were no differences in changes during the trial in the three GCSI subscores (nausea, fullness/satiety and bloating) and total GCS score between the nortriptyline group compared to placebo. The p-values for the overall treatment effect from a repeated measures analysis adjusting for the baseline value of the outcome are nausea subscore 0.46, fullness/early satiety subscore 0.16, bloating subscore 0.87, and total GCSI 0.27.

Figure 3. Changes from baseline in GSRS scores by treatment group

There was an overall decrease in the abdominal pain score but otherwise no differences in other outcomes between the nortriptyline group compared to placebo. The p-values for the overall treatment effect from a repeated measures analysis adjusting for the baseline value of the outcome are reflux symptom 0.25, abdominal pain 0.04, indigestion 0.94, diarrhea 0.80, constipation 0.56, mean 0.90.