Nortriptyline for Idiopathic Gastroparesis (NORIG)

Gastroparesis, a syndrome in which patients experience delayed gastric emptying, is characterized by symptoms such as nausea, vomiting, bloating, abdominal pain, and early satiety. Management of gastroparesis is limited by few effective treatments, many of which function by accelerating gastric emptying. Based on the hypothesis that some symptoms of gastroparesis arise because of neuropathic changes in enteric and sensory nerves, tricyclic antidepressants (TCAs) in low doses have been used as neuromodulators to treat refractory symptoms of nausea, vomiting, and abdominal pain, but there is little evidence to support this use. The Nortriptyline for Idiopathic Gastroparesis (NORIG) study is a multicenter, randomized, clinical trial that was designed by the Gastroparesis Clinical Research Consortium (GpCRC) to test whether treatment with nortriptyline, a TCA with reduced anticholinergic side effects, results in symptomatic improvement in patients with idiopathic gastroparesis.

Individuals between the ages of 21 and 68 years old with moderate to severe symptoms of idiopathic gastroparesis for at least 6 months were enrolled. Participants were randomized to treatment with either nortiptyline or placebo. In both groups, dosing was escalated at 3-week intervals (10, 25, 50, 75 mg) up to 75 mg at 12 weeks. At follow-up study visits, which occurred every 3 weeks, symptom questionnaires were administered to assess gastrointestinal and psychological symptoms, quality of life, and TCA side effects. Electrogastrography (EGG) satiety tests and electrocardiography tests were also performed. Treatment was continued for 15 weeks, at which time study medication dose was tapered to zero with a final assessment at 18 weeks. The primary outcome measure was a decrease from the patient’s baseline Gastroparesis Cardinal Symptom Index (GCSI) score of at least 50% on two consecutive 3 week GCSI assessments over 15 weeks of treatment. Secondary outcome measures included physiological assessments during satiety testing, clinical and psychological symptom scores, and adverse event rates.

Overall symptomatic improvement, as defined by the primary outcome measure, did not differ between the treatment groups: 23% on nortriptyline versus 21% on placebo. Additionally, treatment with nortriptyline showed no improvement in nausea, fullness/satiety, bloating, or quality of life measures. These findings suggest that TCAs may not be effective in the treatment of idiopathic gastroparesis.

The NORIG study tested whether treatment with nortriptyline, a TCA with reduced anticholinergic side effects, results in symptomatic improvement in patients with idiopathic gastroparesis.

The primary outcome measure was a decrease from the patient’s baseline Gastroparesis Cardinal Symptom Index (GCSI) score of at least 50% on two consecutive 3 week GCSI assessments over 15 weeks of treatment. Secondary outcome measures included physiological assessments during satiety testing, clinical and psychological symptom scores, and adverse event rates.

Individuals between the ages of 21 and 68 years old who met the following criteria were eligible for the study:

• Symptoms of gastroparesis for at least 6 months prior to registration, with Gastroparesis Cardinal Symptom Index score ≥ 21 on the 0-45 point scale
• Documentation of delayed gastric emptying on gastric emptying scintigraphy, defined as greater than 60% retention at 2 hours or greater than 10% retention at 4 hours, within 2 years of registration
• Negative upper endoscopy or upper GI series within 2 years of registration
• No contraindications to nortriptyline use
• Not currently using any of the following medications: TCAs of any kind, daily narcotic analgesics, anticholinergic medications, calcium channel blockers, and erythromycin.

Patients having dyspeptic symptoms with normal gastric emptying or having diabetic gastroparesis or post-surgical gastroparesis including fundoplication were excluded.

Overall symptomatic improvement, as defined by the primary outcome measure, did not differ between the treatment groups: 23% on nortriptyline versus 21% on placebo. Additionally, treatment with nortriptyline showed no improvement in nausea, fullness/satiety, bloating, or quality of life measures. These findings suggest that TCAs may not be effective in the treatment of idiopathic gastroparesis.