Metoclopramide in the Treatment of Diabetic Gastroparesis

Expert Commentary

Prevalence of TD Associated with Metoclopramide

National guidelines estimate the risk of developing TD from metoclopramide to be 1–15%. Chronic use of metoclopramide certainly appears to increase the risk of developing TD.^[72] However, it is currently impossible to calculate the true risk of developing TD from metoclopramide from the current studies available. No prospective studies exist to truly delineate risk. In all but four studies available to date, the number of patients exposed to chronic metoclopramide is unknown, which is essential for determining prevalence.^{[64,65,71,73]} To add to the uncertainty, in two separate Veterans Administration studies, there was no statistically significant difference in the rate of TD in patients on chronic metoclopramide therapy compared with controls.^[65,73] One of these studies by Ganzini et al.^[65] is referenced by both national guideline positions as the estimate of risk for TD from metoclopramide.^[59,70]

Increased Use of Metoclopramide

Usage of metoclopramide has been increasing since 2000, likely because Cisapride was withdrawn from the market at that time and metoclopramide is currently the only medication approved for the treatment of gastroparesis.^[16] Whether this will lead to an increased rate of TD from metoclopramide is unknown as all but two of the studies available were published before 2000.^[16,72] Metoclopramide is available in oral, liquid, intranasal and sublingual formulations as well as subcutaneous and intravenous injections. Owing to inconsistent emptying of solid gastric contents, liquid, intranasal and sublingual formulations may lead to more predictable plasma drug levels. Perhaps this will allow physicians to identify the lowest possible dose for patients and lead to a decreased side effect profile.

When to Use Metoclopramide

Metoclopramide is currently indicated for the treatment of postoperative- or chemotherapy-induced nausea and emesis, gastroesophageal reflux disease, and gastroparesis. Certainly, with the introduction of 5-HT₃ receptor antagonists and proton pump inhibitors, there are safer agents available for the treatment of nausea and gastroesophageal reflux disease. Metoclopramide should not be the first-line therapy for these indications. However, in the case of gastroparesis, there are fewer agents available and inadequate treatment of this disease can lead to significant morbidity and mortality.^[79,80]

Risk Stratification

Metoclopramide has been demonstrated to be effective for the short-term treatment of gastroparesis. However, chronic therapy over 3 weeks has not been demonstrated to be effective and is associated with an increased risk for TD. This leads to the clinical paradox that long-term use of metoclopramide has not been demonstrated to be effective and leads to an increased risk of serious adverse events, but unfortunately, no other medical therapies are currently approved for the treatment of gastroparesis.

Therefore, it is important to evaluate the risk/benefit profile before initiating treatment. Risk factors for the development of extrapyramidal reactions include female gender, advanced age, renal insufficiency, cirrhosis, being an alcoholic, being a patient with an underlying movement disorder or those on concurrent neuroleptic medications. Diabetes is also a known risk factor, which further complicates the situation, as diabetes is a risk factor for the development of gastroparesis.

Prior to initiating treatment with metoclopramide, informed consent with the physician, patient, family members and nurse should take place. This should also be documented in the medical chart for medicolegal reasons. Patients should be counseled on the potential side effects of metoclopramide, including potential irreversible effects such as TD, before initiating treatment. Physicians should start with the smallest possible dose and then titrate the medication as needed. Consideration of alternative formulations, such as liquid, sublingual or intranasal forms, may be beneficial in providing more consistent absorption of the medication and may potentially allow for the lowest efficacious dose to be used. Physicians can also consider 'drug holidays' to minimize total drug exposure if clinically possible. Patients should also be educated on signs and symptoms of extrapyramidal reactions, especially lip smacking, abnormal movements and facial grimaces, as this may represent early TD. Patients and family members should be instructed to immediately discontinue the drug and notify the physician if they notice any alarming symptoms. Both the patient and physician should be especially vigilant in monitoring for TD, as it may be potentially reversible if recognized early. Refills should be prescribed only by gastrointestinal specialists and healthcare professionals who are trained and educated in monitoring for side effects from metoclopramide. Close follow-up monitoring by the prescribing physician should also be performed while the patient is on metoclopramide as problems may occur if the patient is followed only by the referring physician who may not be as knowledgeable about the potential adverse risks associated with metoclopramide.

Finally, if there is an adverse risk profile, it may be necessary to consider alternative agents, such as domperidone or erythromycin. However, these agents are not approved for use in gastroparesis and domperidone requires an investigational new drug application prior to initiating treatment.

Table 1. Risk of tardive dyskinesia with metoclopramide.
Study (year)	Study design	Number studied	Result	Estimated prevalence	Ref.
Wilholm et al. (1984)	Scandinavian prescription database, 1977–1981	11 million Rx of metoclopramide	37 reports of EPS with 11 TD casesAll females, mean age of 76 years	One in 2000–28,000 patient-years, one in 17,800 perscriptions	^[71]
Bateman et al. (1985)	UK prescription database, 1967–1982	15.9 million Rx of metoclopramide	479 reports of EPS, four with TD	One in ~35,000 prescriptions, significantly higher risk in females, especially those 12–19 years old	^[64]
Sewell et al.(1992)	Analysis of 67 case reports of metaclopramide-induced TD	52 patients on at least 30 days of metoclopramide	Mean age of 70 ± 19 years, 3:1 female predominance and Rx duration of 20 ± 15 months; 47% TD cases persisted at 6 months despite discontinuation of metoclopramide	Not estimable	^[74]
Ganzini et al. (1993)	VA study using exposed/unexposed design, matched for age, gender, diabetes and comorbidities	51 chronic Rx of metoclopramide; 51 unexposed	Mean age of 63.9 ± 10.8 years, male predominant, duration of treatment 2.6 ± 2.0 years	29% TD in metoclopramide Rx vs 17.6% in nonusers (p = 0.08)	^[65]
Sewell et al. (1994)	VA cross-sectional study	51 patients with metoclopramide-associated TD; 35 controls matched for age, race, gender and diabetes	Duration of metoclopramide treatment of at least 30 days	27% TD in metoclopramide Rx vs 12% nonusers (p = 0.08) Patients on metoclopramide and diabetic more likely to develop TD (p = 0.05)	^[73]
Shafter et al. (2004)	International metoclopramide adverse event reports and US drug-use data	87 case reports	Mean duration of Rx of 753 ± 951 days; 37% used concomitant drugs, 18% had comorbid diseases with TD risk	Not estimableIncreased use of metoclopramide afer cisapride withdrawal	^[16]
Kenney et al. (2008)	Observational study in a tertiary-care movement-disorder clinic	434 patients referred for TD	Metoclopramide accounted for 39.4% of TD, the second-leading cause of TD after haloperidol	Not estimable	^[72]

Table 1. Risk of tardive dyskinesia with metoclopramide.

Study (year)

Study design

Number studied

Result

Estimated prevalence

Ref.

Wilholm et al. (1984)

Scandinavian prescription database, 1977–1981

11 million Rx of metoclopramide

37 reports of EPS with 11 TD casesAll females, mean age of 76 years

One in 2000–28,000 patient-years, one in 17,800 perscriptions

^[71]

Bateman et al. (1985)

UK prescription database, 1967–1982

15.9 million Rx of metoclopramide

479 reports of EPS, four with TD

One in ~35,000 prescriptions, significantly higher risk in females, especially those 12–19 years old

^[64]

Sewell et al.(1992)

Analysis of 67 case reports of metaclopramide-induced TD

52 patients on at least 30 days of metoclopramide

Mean age of 70 ± 19 years, 3:1 female predominance and Rx duration of 20 ± 15 months; 47% TD cases persisted at 6 months despite discontinuation of metoclopramide

Not estimable

^[74]

Ganzini et al. (1993)

VA study using exposed/unexposed design, matched for age, gender, diabetes and comorbidities

51 chronic Rx of metoclopramide; 51 unexposed

Mean age of 63.9 ± 10.8 years, male predominant, duration of treatment 2.6 ± 2.0 years

29% TD in metoclopramide Rx vs 17.6% in nonusers (p = 0.08)

^[65]

Sewell et al. (1994)

VA cross-sectional study

51 patients with metoclopramide-associated TD; 35 controls matched for age, race, gender and diabetes

Duration of metoclopramide treatment of at least 30 days

27% TD in metoclopramide Rx vs 12% nonusers (p = 0.08) Patients on metoclopramide and diabetic more likely to develop TD (p = 0.05)

^[73]

Shafter et al. (2004)

International metoclopramide adverse event reports and US drug-use data

87 case reports

Mean duration of Rx of 753 ± 951 days; 37% used concomitant drugs, 18% had comorbid diseases with TD risk

Not estimableIncreased use of metoclopramide afer cisapride withdrawal

^[16]

Kenney et al. (2008)

Observational study in a tertiary-care movement-disorder clinic

434 patients referred for TD

Metoclopramide accounted for 39.4% of TD, the second-leading cause of TD after haloperidol

Not estimable

^[72]

Box 1. Effects of metoclopramide.
Gastric motility D₂receptor antagonist Stimulation 5-HT₄receptors Muscarinic receptor antagonist Symptoms of gastroparesis Promotes gastric emptying Anti-emetic effects via central pathways Normalization of gastric slow wave dysrhythmias Modulates visceral hypersensitivity

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Metoclopramide in the Treatment of Diabetic Gastroparesis

Expert Commentary

Prevalence of TD Associated with Metoclopramide

Increased Use of Metoclopramide

When to Use Metoclopramide

Risk Stratification

Tables

Tables

References

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