Effect of Nortriptyline on Symptoms of Idiopathic Gastroparesis: The NORIG Randomized Clinical Trial

• Autores: Henry P. Parkman, Mark L. Van Natta, Thomas L. Abell, Richard W. McCallum, Linda, Nguyen, William J. Snape, Kenneth L. Koch, William L. Hasler, Gianrico Farrugia, Linda Lee, Aynur Unalp-Arida, James Tonascia, Frank Hamilton, Pankaj J. . Pasricha
• Localización: JAMA: the journal of the American Medical Association, ISSN 0098-7484, Vol. 310, Nº. 24, 2013, págs. 2640-2649
• Idioma: inglés
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• Resumen

  • 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 Gastroparesis remains a challenging syndrome to manage, with few effective treatments and a lack of rigorously controlled trials.1 Metoclopramide, the only medication currently approved in the United States for treatment of gastroparesis, is limited by its neurologic adverse effects.2 Domperidone, a peripherally acting analog, may be safer but is not approved by the US Food and Drug Administration.3,4 Both drugs accelerate gastric emptying and have independent antinausea effects. Erythromycin, an antibiotic and motilin receptor agonist that improves gastric emptying, is limited by tachyphylaxis.5 Further, it is unclear whether a pure prokinetic drug will be an effective therapy, because there is a poor correlation between gastric emptying and symptoms.6 An alternative approach to treatment of gastroparesis is based on the hypothesis that some of the symptoms (eg, nausea, pain) arise because of neuropathic changes in enteric and sensory nerves. In clinical practice, tricyclic antidepressants (TCAs) in low doses are used as neuromodulators for treatment of nausea, vomiting, and abdominal pain in patients with gastroparesis.1,7 However, there is little evidence to support this use.1 In one retrospective analysis of open-label treatment, TCAs reduced symptoms in functional vomiting.8 In 2 studies in functional dyspepsia, low-dose TCAs decreased dyspeptic symptoms and abdominal pain.9,10 In a retrospective evaluation of patients with diabetes and nausea and vomiting, low-dose TCAs improved symptoms.11 One-third of patients had delayed gastric emptying, suggesting that this is not a contraindication for TCAs related to their anticholinergic component.

    The primary aim of the NORIG (Nortriptyline for Idipathic Gastroparesis) trial from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) was to determine whether treatment with nortriptyline results in symptomatic improvement in patients with idiopathic gastroparesis. Nortriptyline, a secondary amine TCA, was selected because of fewer anticholinergic effects compared with the tertiary amines such as amitriptyline.12 This study used a dose-escalation strategy for nortriptyline, a practice conventionally used when treating patients with a TCA.