ORLANDO, Florida — In the first adequately powered randomized clinical trial of a neuromodulator in gastroparesis, nortriptyline did not improve overall symptoms during a 15-week period, although improvements in appetite, satiety, and body mass index were noted early on.
"Nortriptyline did not improve overall symptoms in idiopathic gastroparesis utilizing the doses and escalation strategy of the trial," said Henry Parkman, MD, from Temple University School of Medicine in Philadelphia, Pennsylvania. Side effects were also an issue, with 29% of this group discontinuing therapy because of side effects.
Gastroparesis remains a challenging syndrome to manage, with few effective prokinetic treatments. In clinical practice, tricyclic antidepressants are often used as neuromodulators for visceral hypersensitivity to treat symptoms of nausea, vomiting, and abdominal pain.
Here at Digestive Disease Week (DDW) 2013, Dr. Parkman presented the results of a multicenter, prospective, randomized, double-blind, dose-escalated clinical trial that evaluated a tricyclic antidepressant in gastroparesis.
He said the study was needed to determine whether these agents can be effective. "Data for the use of tricyclics in gastroparesis are based primarily on retrospective reports involving small numbers of patients." Evidence from well-designed studies is lacking.
Rigorous Study Design
This study compared nortriptyline with placebo for symptomatic relief in 65 patients with idiopathic gastroparesis recruited from 7 academic medical centers. Patients had delayed gastric emptying by scintigraphy and symptom scores > 21 on the 0- to 45-point 9-symptom Gastroparesis Cardinal Symptom Index (GCSI). Nortriptyline was escalated at 3-week intervals (10, 25, 50, 75 mg) to reflect the way physicians typically use the drug.
The primary outcome was a decrease from the baseline GCSI score of at least 50% on 2 consecutive 3-week visits during 15 weeks of follow-up. The GCSI has 3 subscores — for nausea, bloating, and fullness and satiety.
Investigators also used the Gastrointestinal Symptom Rating Scale (GSRS) of common gastrointestinal symptoms, including abdominal pain, and the Clinical Global Patient Impression (CGPI) questionnaire for quantifying overall symptomatic relief. The question asked was, "Compared to the way you usually felt before entering the study, how would you rate your relief of symptoms during the past week?" Responses could range from -3, indicating considerably worse, to +3, indicating completely better.
More patients in the 130-patient study discontinued treatment after randomization to nortriptyline (19 vs 6). The primary analysis was intent-to-treat and included 65 patients per group.
Overall symptomatic improvement, the primary outcome, did not differ between patients randomly assigned to nortriptyline vs those randomly assigned to placebo, 23% in the nortriptyline group vs 21% in the placebo group, for a relative improvement rate of 1.06 (95% confidence interval, 0.56, 2.00; P = .86), Dr. Parkman reported.
The nortriptyline group did, however, experience a greater decrease in nausea (P = .04) and abdominal pain (P = .004) at 3 weeks, but not after that time point, he said.
At 15 weeks, the nortriptyline group had a greater improvement in appetite, trended toward greater improvement in the ability to finish a meal (P = .08), and had a greater increase in body mass index, 0.5 vs -0.2 kg/m2 (P = .03), Dr. Parkman reported.
For patients on the starting dose of 10 mg, some improvements were observed.
Table. Effect of Nortriptyline on Gastroparesis
|Parameter||Nortriptyline (n = 65)||Placebo (n = 65)||P-Value|
|Overall symptom improvement||23%||21%||860
|Total gastroparesis score with 10 mg||-6.9||-5.1||.15|
|Gastroparesis nausea subscore with 10 mg||-2.7||-1.3||.010|
|Mean gastrointestinal score with 10 mg||-0.4||-0.4||.780|
|Gastrointestinal abdominal pain subscore with 10 mg||-0.8||-0.2||.004|
|Mean Clinical Global Patient Impression score||1.1||0.8||.070|
|Total gastroparesis score, change from baseline||-8.8||-7.2||.470|
Treatment was stopped more often with nortriptyline than placebo (n = 19 vs 6, respectively; P = .007), primarily because of side effects (n = 10 vs 3, respectively) — especially dry mouth. A change in pulse rate was observed in 7.9% of the nortriptyline group (P = .0005), and a nonsignificant change in QTc interval was also observed in a few patients.
"Nortriptyline did not improve overall symptoms, as defined by our primary outcome measure, in idiopathic gastroparesis over a 15-week period," Dr. Parkman concluded. "Early improvement in nausea and abdominal pain was present at low doses, but not sustained over time as dosing was increased."
Higher doses were associated with some improvement in appetite, satiety, and body weight, but side effects led to more discontinuations. Further studies are needed to determine the role for tricyclic antidepressants and other neuromodulators in patients with idiopathic and other forms of gastroparesis, he added.
Richard Peek, MD, from Vanderbilt University Medical Center in Nashville, Tennessee, and American Gastroenterological Association Program chair, told Medscape Medical News that he was not impressed with the effect of nortriptyline in this study.
"There may be some mild early effects, but sustained effects are not apparent, at least with the dosing used, which reflects what is used in practice," he said. "And every time you increase the dose, you will heighten the risk for side effects. Based on the evidence presented today, I probably would not use this drug in my patients."
Dr. Parkman has served on Advisory Committees or Review Panels for Tranzyme Pharmaceuticals and has been a consultant for Evoke, SmartPill Corporation, GlaxoSmithKline, Rhythm Inc, and Prostraken Inc. Dr. Peek has disclosed no relevant financial relationships.
Digestive Disease Week (DDW) 2013. Abstract 5. Presented May 18, 2013.
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Cite this: Nortriptyline Minimal Benefit in Gastroparesis - Medscape - May 19, 2013.