Randomized Controlled Double-blind Trial Comparing Haloperidol Combined With Conventional Therapy to Conventional Therapy Alone in Patients With Symptomatic Gastroparesis

Design

Randomized, double-blind, placebo-controlled trial

N= 33

Objective

To determine whether haloperidol as an adjunct to conventional therapy would improve symptoms in gastroparesis patients presenting to the emergency department (ED)

Study Groups

Haloperidol (n= 15)

Placebo (n= 18)

Inclusion Criteria

Adult patients with a previous diagnosis of gastroparesis who presented to the ED with nausea, vomiting, and abdominal pain attributable to their gastroparesis 

Exclusion Criteria

Age < 18 years, past history or current evidence of QT prolongation, hypotension (systolic blood pressure < 90 mm Hg), presence of other acute abdominal pathologic conditions, allergy to haloperidol, pregnancy, incarcerated status, or an inability to give informed consent

Methods

Patients were randomized 1:1 to treatment with haloperidol, administered 5 mg intravenously or an equivalent volume of placebo. Patients were observed for symptoms and adverse events every 15 minutes for 1 hour after administration. At this point, additional therapy could be given, if needed. All patients also received conventional therapy, as determined by the treating physician. 

Intensity of abdominal pain was measured at randomization and 15-minute intervals for 1 hour using a 10-point visual analog scale (VAS). Nausea was also scored using a 5-point VAS scale at the same time points, with higher numbers demonstrating increased symptom severity. Nausea resolution was defined as the patient not requesting additional antiemetic medication.

Duration

Intervention: 1 hour

Outcome Measures

Primary: change in intensity of abdominal pain and nausea 1 hour after administration

Secondary: disposition status (hospital admission or discharge), ED length of stay, nausea resolution at 1 hour

Baseline Characteristics

Haloperidol (n= 15)

Placebo (n= 18)

Age, years

Female

White

Pain at arrival

Nausea at arrival

Results

Endpoint

Haloperidol (n= 15)

Placebo (n= 18)

Mean difference‡

Abdominal pain

Before treatment

At 15 min

At 30 min

At 45 min

At 60 min

p-value vs. before treatment

8.50 ± 1.82

6.13 ± 2.85

4.67 ± 3.59

3.20 ± 3.56

3.13 ± 3.60

-

Reference

-2.37

-3.83

-5.30

-5.37 

≤ 0.001 

8.28 ± 1.77

8.22 ± 1.66

8.06 ± 1.86

7.82 ± 1.91

7.17 ± 2.81

-

Reference

-0.05

-0.21

-0.59

-1.11

0.11

-

-

-

-

-

- 

Nausea

Before treatment

At 15 min

At 30 min

At 45 min

At 60 min

p-value vs. before treatment

4.53 ± 0.83

3.27 ± 1.74

2.20 ± 1.96

1.86 ± 1.91

1.83 ± 1.92 

-

Reference

-1.26

-2.33

-2.64

-2.70 

≤ 0.001

4.11 ± 0.96

3.67 ± 1.24

3.67 ± 1.37

3.88 ± 1.45

3.39 ± 1.68

-

Reference

-0.44

-0.44

-0.30

-0.72

0.05

-

-

-

-

-

-

Reduction at 1 hour^§

Pain

p-value vs. before treatment

Nausea

p-value vs. before treatment

5 (n= 9)

≤ 0.001

2.61 (n= 9)

≤ 0.01

1.31 (n= 13)

0.14

0.77 (n= 13)

0.13

-

-

-

-

0.009

0.77

†Based on VAS scale scores

‡Compared to before treatment (reference value)

^§Difference in pain and nausea at 1 hour was analyzed in 21 patients who did not receive opioids before intervention.

Adverse Events

Study Author Conclusions

This is the first randomized, double-blind, placebo-controlled trial to assess the efficacy of haloperidol as an adjunctive therapy for gastroparesis symptoms in the ED. Haloperidol was superior to placebo in reducing nausea and pain, and the findings suggest that the addition of haloperidol to conventional therapy was better than conventional therapy alone. And therefore, this study suggests that haloperidol is an effective first-line agent in combination with standard analgesic and antiemetic agents for the treatment of gastroparesis in the ED.

InpharmD Researcher Critique

This study incorporated an extremely limited sample size, increasing the risk of type I error that may be more evident in a larger sample size. Similarly, less common adverse events like QT prolongation and dystonic reactions may not have been observed due to the small number of included patients. Notably, conventional therapy implemented was not consistent among patients, making it more challenging to attribute symptomatic improvements strictly to haloperidol alone. 

Study of Haloperidol for Abdominal Pain in the Emergency Department (SHAPE)

Design

Retrospective chart review 

N= 214

Objective

To evaluate whether haloperidol decreases milligram morphine equivalent (MME) for the treatment of non-specific abdominal pain diagnoses in the emergency department (ED), including gastroparesis, cyclic vomiting, cannabinoid hyperemesis syndrome, and unspecified abdominal pain

Study Groups

Haloperidol encounter (n= 107)

Control encounter (n= 107)

Inclusion Criteria

Aged ≥18 years, admitted to an ED, administered haloperidol 2 mg-5 mg intramuscular (IM) or intravenous (IV) for abdominal pain (haloperidol-encounter) 

Exclusion Criteria

Allergy or sensitivity to haloperidol; chronic use of haloperidol as a prior-to-admission medication; urgent abdominal surgery; and administration of haloperidol for acute agitation secondary to delirium, psychosis, or for sedation

Methods

Electronic health records comprised of large academic medical centers, regional hospitals, and freestanding EDs were retrospectively reviewed to identify eligible patients and to self-match for control encounters where patients received opioids as conventional therapy. To ensure treatment washout, all comparison encounters requiring analgesia must have been separated by a minimum of three days from other hospital encounters. A gap of up to 365 days of the haloperidol encounter was allowed to minimize variability in patient presentation between encounters; the most recent haloperidol encounters were used. Underlying causes of abdominal pain included gastroparesis, cyclic vomiting, cannabinoid hyperemesis syndrome, and unspecified abdominal pain. 

Duration

Between July 1 and December 1, 2018

Outcome Measures

Primary: difference in MME administration between the self-matched H- and C-encounters

Secondary: disposition, adverse events, difference in pain scores, ED length of stay, repeat ED encounters within 30 days, and use of rescue medications

Baseline Characteristics

All participants (n= 107)

Age, years

Female

Haloperidol use

Median haloperidol dose, mg (interquartile range [IQR])

IV

IM

5.0 (2.0 to 5.0)

81.3%

18.7%

Haloperidol encounter chronologically after control encounter

Results

Endpoint

Haloperidol encounter (n= 107)

Control encounter (n= 107)

p-value

MME, mg (IQR)

IV

IM

0.0 (0.0 to 2.5)

0.0 (0.0 to 4.0)

0.0 (0.0 to 0.0)

5.7 (4.0 to 8.0)

5.8 (4.0 to 8.0)

5.0 (3.3 to 8.0)

< 0.001

< 0.001

< 0.001

Concurrent analgesia 

Opioid 

Ketorolac

Mean dose, mg (confidence interval)

47.2%

38.9%

17.1 (15.1 to 19.2)

100%

14.0%

-

< 0.001

0.02

-

Rescue analgesics

Six patients who received haloperidol for abdominal pain required a repeat dose. Haloperidol was not used as rescue therapy for any of the C-encounters.

There were no statistically significant differences in ED length of stay, admission rate, mean pain score difference between encounters, adverse events, and 30-day repeat encounters related to abdominal pain. 

Adverse Events

Common Adverse Events: haloperidol encounter vs. control encounter 0 vs. 0.01% 

Serious Adverse Events: None reported 

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Encounters in which patients received haloperidol and ketorolac for abdominal pain had a statistically significant reduction in MME administered and lower rates of rescue therapy administration than encounters in which patients were treated with opioids.

InpharmD Researcher Critique

The study included patients with different underlying causes of abdominal pains without a specific subgroup analysis of patients with gastroparesis. Additionally, the effectiveness of haloperidol in pain reduction needs further evaluation, as only 21 out of 107 patients in the haloperidol encounters had pre- and post-analgesic pain scores recorded, compared to 101 out of 107 in control encounters.

Haloperidol undermining gastroparesis symptoms (HUGS) in the emergency department

Design

Retrospective, observational study

N= 52

Objective

Study Groups

Study patients (N= 52)

Inclusion Criteria

Exclusion Criteria

Methods

Data was collected from the electronic medical record of a single institution in California. Patients received HP as a 5 mg intramuscular (IM) injection and case-matched with themselves on the most recent previous visit for GP N/V and P where HP was not administered.

Duration

Outcome Measures

Baseline Characteristics

Study patients (N= 52)

Age, years

Female

Results

Endpoint

HP use (N= 52)

No HP use (N= 52)

p-Value

Hospital admission (95% confidence interval [CI])

10% (3% to 21%)

27% (16% to 41%)

0.02

Morphine equivalent dose of analgesia (95% CI)

6.75

10.75

0.009

ED length of stay, hours

9.2

25.4

0.128

Hospital length of stay, hours

Adverse Events

No dystonic reactions, akathisia, excessive sedation, or cardiovascular complications were observed

Study Author Conclusions

InpharmD Researcher Critique

Aripiprazole reversed gastroparesis in a child with 1q21.1-q21.2 microdeletion

Design

Case presentation

An 11-year-old Caucasian boy, with a microdeletion in the 1q21.1–q21.2 region, had multiple medical conditions, including gastroparesis, documented initially at age 5. Relevant past medical histories included gastro-esophageal reflux disease (GERD), constipation, and multiple food allergies. He had a longstanding history of extensive therapy with a multidisciplinary team, and treatments comprised of frequent antibiotics for reflux-related otolaryngologic infections, dietary restrictions, a substantial proportion of his daily calories as an elemental formula, monthly parenteral gamma globulin replacement, acid suppression, a variety of stool softeners and cathartics, nebulizers for respiratory symptoms and infections, psychopharmacological agents and ongoing counseling for behavioral issues.

A gastric emptying study showed markedly delayed gastric emptying, with 60% of residual activity still remaining in the stomach after 4 hours, and results reminded the same upon a repeat scan years after. While the initial trial of metoclopramide improved weight gain at the age of 6 years, the medication was later discontinued due to worsening behavior. Since then, his weight-for-age Z-score continued to drop, and his conditions progressed over time, with a gastrojejunal feeding tube placed at 10 years to allow him to increase enteric feeds to gain weight without experiencing gastro-esophageal reflux complications. Upon a psychiatric consultant at age 11, the decision was made to initiate aripiprazole (dose not specified), soon after which the persistent mild nausea disappeared. He began to eat more frequently and in larger amounts, leading to more rapid weight gain. The tube feedings were slowed down and ultimately were discontinued with sustained weight gain at age 12. 

A repeat gastric emptying study on aripiprazole demonstrated less than 8% of radiolabeled material remaining in the stomach after 4 hours, which was interpreted as normal. Ultimately, enteral feeding tube was removed 23 months after starting aripiprazole. With increased appetite, increased intake, weight gain, and normalized Z-score, the psychologist attempted to lower the dose of aripiprazole; in less than a week, nausea returned with anorexia. When the dose was restored, the patient’s appetite returned. 

Study Author Conclusions

Aripiprazole is a unique dopamine agonist that has been characterized as a dopamine regulator or stabilizer. In the current case study, it yielded a significant subjective and objective improvement in gastric emptying and nutritional intake. As the onset of action is rapid, a trial of aripiprazole in patients with gastroparesis is a simple, non-invasive, cost-effective option that can be employed in patients who are suffering from this condition. If aripiprazole is proven to reverse gastroparesis in placebo-controlled trials, investigating its pharmacology may lead to a better understanding of the complex signaling pathways which regulate gastric emptying.

Mirtazapine for severe gastroparesis unresponsive to conventional prokinetic treatment

Design

Case presentation

A 27-year-old woman with type I diabetes and triopathy presented with depression associated with uncontrolled nausea and vomiting. The patient had been hospitalized 6 times in the previous 7 months for a total duration of 4 months to treat postprandial discomfort, nausea, and vomiting. An upper gastrointestinal endoscopy revealed mild hemorrhagic gastritis, multiple shallow duodenal ulcers, and a 2-cm hyperplastic mucosal polyp on the posterior wall of the gastric antrum but no specific outlet obstruction. The patient was prescribed anti-ulcer medications, including a protein-pump inhibitor, resulting in healing of ulcers. Prokinetics, including erythromycin, itopride, and metoclopramide, were ineffective in relieving postprandial discomfort, nausea, and vomiting. The patient continued to experience delayed gastric emptying, failing treatment with additional medications prior to current admission. Finally, the patient was initiated on an evening regimen of mirtazapine 15 mg orally disintegrating tablet (ODT). The following day, nausea and vomiting were reduced by 30% (based on subjective assessment). Gastric symptoms gradually resolved, and patient was able to resume solid foods with no gastric symptoms within 7 days. 

Sleep disturbances and agitation also resolved within a few days after starting mirtazapine. Other depressive symptoms subsequently resolved in the following days. At 3-month follow-up after discharge, the patient was symptom and side-effect free. 

Study Author Conclusions

This is the first report to show that mirtazapine may be a good alternative for gastroparesis that is resistant to conventional treatments. It may also be a useful antidepressant when depression and gastroparesis present concurrently. Controlled trials of mirtazapine for gastroparesis are warranted.