Alimentary Pharmacology & Therapeutics

Review article: metoclopramide and tardive dyskinesia

A. S. RAO & M. CAMILLERI

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), College of Medicine, Mayo Clinic, Rochester, MN, USA Correspondence to: Dr M. Camilleri, Mayo Clinic, Charlton 8110, 200 First St. S.W., Rochester, MN 55905, USA. Email: camilleri.michael@mayo.edu

SUMMARY Background Metoclopramide is a dopamine receptor antagonist which has been used for treatment of a variety of gastrointestinal symptoms over the last thirty years. In 2009, the FDA issued a black box warning regarding long-term or high-dose use of this medication because of the risk of developing tardive dyskinesia. Aims To review the mechanism of action and pharmacokinetic properties of metoclopramide, the risk of metoclopramide-induced tardive dyskinesia, potential mechanisms that may alter and to summarize the clinical context for appropriate use of the drug. Methods We conducted a PubMed search using the following key words and combined searches: metoclopramide, neuroleptics, tardive dyskinesia, incidence, prevalence, dopamine, receptors, pharmacokinetic, pharmacology, pharmacogenetics, DRD3 Ser9Gly polymorphism, cytochrome P450, p-glycoprotein, risk factors, gastroparesis, outcome, natural history. Results Available data show that risk of tardive dyskinesia from metoclopramide use is likely to be <1%, much less than the estimated 110% risk previously suggested in national guidelines. Tardive dyskinesia may represent an idiosyncratic response to metoclopramide; pharmacogenetics affect pharmacokinetic and dopamine receptor pharmacodynamics in response to neuroleptic agents that cause similar neurological complications. Conclusion Community prevalence and pharmacogenetic mechanisms involved in metoclopramide-induced tardive dyskinesia require further study to dene the benet-risk ratio more clearly.
Aliment Pharmacol Ther 31, 1119

Publication data Submitted 14 August 2009 First decision 14 September 2009 Resubmitted 15 September 2009 Accepted 31 October 2009 Epub Accepted Article 3 November 2009

2010 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2009.04189.x

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INTRODUCTION
The risk of tardive dyskinesia (TD) with use of prolonged or high doses of metoclopramide is a matter of concern for all practising physicians because of the associated morbidity and medicolegal risks.1 The Food and Drug Administration (FDA) recently issued a black box warning regarding the use of metoclopramide, as summarized in Table 1. Metoclopramide has been available in the U.S. since 1979 and its use has increased in the last decade2 as it is currently the only FDA-approved medication for the treatment of gastroparesis. The FDA estimates that more than two million Americans are using this drug at the present time. In the past 5 years, guidelines from two national organizations on the treatment of gastroparesis suggested that the frequency of TD with metoclopramide use is 115%.3, 4 However, clinical experience suggests that the risk of TD is much less. There are several potential explanations for the discrepancy between the stated prevalence and clinical experience: First, TD may not be encountered by gastroenterologists because it is actually rarer than the minimum 1% frequency. Second, gastroenterologists may miss the complication. Third, the patient may seek advice from another physician such as a neurologist. In this brief overview, we will address the following questions: What is the mechanism of action of metoclopramide and how does it result in tardive dyskine-

sia? What is the true risk of TD reported in the literature in patients on metoclopramide? What clinical factors should be considered before prescribing metoclopramide to patients? Can pharmacogenetics explain why TD might occur in some patients? How should metoclopramide be prescribed?

METHODOLOGY OF REVIEW
We conducted a PubMed search using the following key words and combined searches: metoclopramide, neuroleptics, tardive dyskinesia, incidence, prevalence, dopamine, receptors, pharmacokinetics, pharmacology, pharmacogenetics, DRD3 Ser9Gly polymorphism, cytochrome P450, p-glycoprotein, risk factors, gastroparesis, outcome, natural history.

MECHANISM OF ACTION AND PHARMACOKINETIC PROPERTIES OF METOCLOPRAMIDE

Metoclopramide is a substituted benzamide derivative with a chemical structure similar to that of procainamide, but without antiarrhythmic effects. Its use is indicated for symptomatic treatment of post-operative or chemotherapy-induced nausea and vomiting, gastrooesophageal reux, and gastroparesis. Its mechanism of action and therapeutic efcacy result from prokinetic effects on gut motility and inhibition of emesis, as outlined below.

Table 1.

Summary of FDA warning on long-term or high-dose use of metoclopramide

Chronic use of metoclopramide has been linked to tardive dyskinesia even after the drugs are no longer taken. Manufacturers will be required to implement a risk evaluation and mitigation strategy, or REMS, to ensure that patients are provided with a medication guide that discusses this risk. The chronic use of metoclopramide therapy should be avoided in all but rare cases where the benet is believed to outweigh the risk. Current product labelling warns of the risk of tardive dyskinesia with chronic metoclopramide treatment. The development of this condition is directly related to the length of time a patient is taking metoclopramide and the number of doses taken. Those at greatest risk include the elderly, especially older women, and people who have been on the drug for a long time. Tardive dyskinesia is rarely reversible and there is no known treatment. However, in some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped. It is recommended that treatment does not exceed 3 months. Recently published analyses suggest that metoclopramide is the most common cause of drug-induced movement disorders. Another analysis of study data by the FDA showed that about 20 percent of patients in that study who used metoclopramide took it for longer than 3 months. The FDA has also become aware of continued spontaneous reports of tardive dyskinesia in patients who used metoclopramide, a majority of whom had taken the drug for more than 3 months.

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Actions on gut motility

Metoclopramide stimulates gastric motility by affecting multiple receptor systems within the gut wall. Most importantly, it is an antagonist of the dopamine D2 receptor subtype. The effects of dopamine at this receptor in the GI tract include inhibition of lower oesophageal sphincter (LES) pressure and gastroduodenal motility.5 Metoclopramide results in prokinesis by four mechanisms: inhibition of presynaptic D2 receptors and stimulation of presynaptic excitatory 5-HT4 receptors, thereby allowing acetylcholine (ACh) release from intrinsic cholinergic motor neurons; inhibition of D2 postsynaptic receptors;6 and antagonism of the presynaptic inhibition of muscarinic receptors, leading to further augmentation of ACh release.7, 8 In summary, these receptor-mediated effects of metoclopramide result in increased LES tone, increased gastric tone and intragastric pressure and increased antroduodenal coordination and acceleration of gastric emptying.8

Actions on emesis
Emesis is a complex process mediated within the central nervous system; it involves visceral afferent input from the gastrointestinal and other organ systems. This leads to the motor responses of gastric relaxation and initiation in the small intestine of retrograde giant contractions, which are observed mainly in animals.9 The anti-emetic effects of metoclopramide result from inhibition of D2 and 5-HT3 receptors within the chemoreceptor trigger zone.

Pharmacokinetics
Metoclopramide undergoes rst-pass hepatic metabolism; there is a signicant individual variation in metabolism and oral bioavailability ranges from 30 to 100%.10 Approximately 2030% of the drug is excreted in urine, unchanged. Drug clearance is impaired in patients with cirrhosis11 and renal failure.12 Metoclopramide is metabolized at least in part by the cytochrome P450 system. Desta et al.13 showed that metoclopramide is primarily metabolized to monodeethylmetoclopramide mainly by the CYP2D6 isoform and possibly by CYP3A and CYP1A2. Genetic polymorphisms of these enzymes have been linked to tardive dyskinesia in patients treated with neuroleptic agents, potentially through modulation of the pharmacokinetic response of medications.14
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Metoclopramide is not only a substrate for CYP2D6 but also a competitive inhibitor of the isoform, analogous to neuroleptic agents such as haloperidol, thioridazine, chlorpromazine, perphenazine and risperidone.15 As the therapeutic relevance of the metabolite monodeethylmetoclopramide remains unknown, it is unclear how these two properties (being an inhibitor and a substrate of the same enzyme) ultimately impact the action of the drug. At therapeutic concentrations, the Ki of metoclopramide is 4.7 + 1.3 lM,13 between those of thioridazine and chlorpromazine and about 20% of the inhibition by risperidone.15 Therefore, concomitant use of metoclopramide with a neuromodulating drug affecting the same CYP2D6 isoform may lead to increased plasma concentrations of either drug, predisposing to the development of TD. To date, there have been no studies conducted that have specically examined the interaction of altered CYP metabolism and use of metoclopramide (alone or in association with neuroleptic agents) and the development of TD. However, if the same genetic polymorphisms are found to link TD and patients treated with metoclopramide, this may provide a valuable, new clinical approach to help predict those patients at risk for development of TD. Figure 1 illustrates how pharmacogenetics may impact the development of tardive dyskinesia. In comparisons of wild-type and mdr 1a 1b knockout mice, which are used to study P-glycoprotein (P-gp) mediated transport of drugs, a substantial difference in the brain plasma (B P) ratio of metoclopramide was found. B P ratios were greater than 1.0 in both strains, but were nearly 7-fold greater in the knockout animals. The authors therefore recommended that further investigation be pursued in humans to assess the potential impact of P-gp on metoclopramide potency and CNS side effects.16

METOCLOPRAMIDE-ASSOCIATED INVOLUNTARY MOVEMENTS INCLUDING TD

There are ve different dopamine receptors: two in the D1 group (D1 and D5), and three in the D2 group (D2, D3, D4).17 Dopamine acting on D1 or D2 group receptors in the striatum of the brain activates or inhibits adenylate cyclase.17 The D1 group of receptors are found within the direct nigrostriatal pathway in contrast to the D2 group which are located in the indirect striatopallidal projection; these pathways regulate the basal ganglia output which controls movement.17

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Pharmacokinetic effects, e.g. CYP2D6, 1A2 Pharmacogenetics Pharmacodynamic effects, e.g. DRD3 Ser9Gly gene polymorphism

Neuroleptic drugs and metoclopramide

Dopamine receptor L-dopa

Supersensitivity resulting from chronic inhibition of dopamine receptor

Tardive dyskinesia

Figure 1. Factors modulating dopamine receptor function which ultimately lead to manifestation of tardive dyskinesia.

Imbalance of these mechanisms has been implicated in Parkinsons disease.17 Metoclopramide readily crosses the blood-brain barrier18, 19 to inhibit central D2 group receptors, resulting in an imbalance of the nigrostriatal and striatopallidal pathways, which may lead to the movement-related side effects observed with chronic use. The spectrum of involuntary movements include acute dystonic reactions typically within the rst few hours of starting therapy and resolving with drug discontinuation; akathisia (inner restlessness resulting in the need for constant movement); drug-induced parkinsonism, which usually develops within the rst 3 months of therapy and is usually reversible within a few months of withdrawal of the drug and the most feared TD, an extrapyramidal disorder characterized by potentially disguring and irreversible involuntary movements.

RISK OF METOCLOPRAMIDE-INDUCED TD
There are no prospective data that have evaluated the risk of TD with metoclopramide use. Therefore, the information available is based on reports via MedWatch or comparable programmes in other countries, published series that originate from specialty involuntary movement clinics or prescription databases and case-controlled observational studies. Table 2 provides a summary of the relevant literature. In the United Kingdom, there were approximately 15.9 million prescriptions given for metoclopramide between 1967 and 1982.20 Of 479 reports of extrapyramidal symptoms found in the national registry of adverse drug events, only four were classied as TD.20

Thus, the incidence of metoclopramide-induced TD in this large prescription database was far less than 0.1% based on the total number of people exposed. However, it remains unclear how many patients prescribed metoclopramide were on chronic therapy. A Scandinavian study estimated that from total drug sales and prescription statistics, the incidence of tardive dyskinesia during treatment with metoclopramide was estimated to be one in 20002800 treatment years.21 Kenney et al.22 performed a retrospective analysis of 434 patients referred for TD to a tertiary care centre movement disorder clinic. All the patients had documented exposure to a dopamine receptor blocking drug for at least 3 months prior to the onset of symptoms. Overall, metoclopramide was the second most common medication to induce TD, after haloperidol, and was responsible for 39.4% of cases in the series. Interestingly, after the year 2000, metoclopramide surpassed haloperidol as the most common medication to induce TD,22 the year that cisapride was withdrawn from the US market because of the increased risk of cardiac arrhythmias. Shaffer et al. found that the number of metoclopramide prescriptions in the US began to increase in 20002 (coincident with the withdrawal of cisapride from the market) and this paralleled the increase in metoclopramide-induced TD observed. Sewell et al.23 analysed 67 case reports of metoclopramide-induced tardive dyskinesia in the literature. Affected patients tended to be older [mean age (s.d.) 70 10 years], women (3:1 ratio), on higher doses (mean dose of 32 7 mg), and on longer duration of treatment (20 15 months). The mean follow-up was
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Table 2. Reference

Summary of studies on metoclopramide-induced tardive dyskinesia Study design Scandinavian prescription database 19771981, voluntary reporting UK prescription database 196782, unknown # on chronic treatment Analysis of 67 case reports of metoclopramideinduced TD in literature Number studied 11 million Rx of daily doses of metoclopramide Result 37 reports of extrapyramidal symptoms: 11 TD, all women, mean 76 years old, 444 (median 14) months after start of Rx 479 reports of extrapyramidal symptoms, 4 with TD Estimated prevalence 1 in 20002800 patient-years; 1 in 17 800 prescriptions

Wiholm et al. (1984)

Bateman et al. (1985)

15.9 million Rx of metoclopramide

1 in 35 000 prescriptions; 1 in 5235 in F, 1219 years old

Sewell et al. (1992)

67 case reports; 52 patients with at least 30 days metoclopramide Rx

Ganzini et al. (1993)

Sewell et al. (1994)

Veterans Administration centre, using exposed unexposed design, matched for age, gender, diabetes and average of 4 other illnesses Veterans administration centre, crosssectional study

51 chronic users of metoclopramide 51 unexposed; TD assessed by AIMS 5-point scale

Mean age (s.d.) 70 10 years, 3F:1M, dose 32 7 mg, and Rx duration 20 15 months; 47% TD cases persisted at 6 months despite discontinuation of metoclopramide Age 63.9 10.8 years (mean s.d.), almost all males, dose of metoclopramide 31.0 11 mg, duration of treatment 2.6 2.0 years; 24% diabetics

Not estimable

Metoclopramide users: 29% TD vs. 17.6% non-users (P = 0.08); mean AIMS score in metoclopramide users [4.1 2.4 (s.d.)] vs. non-users (2.9 2.3; P < 0.001 by paired t test)

Shaffer et al. (2004)

Kenney et al. (2008)

International metoclopramide adverse event reports and continental US drug-use data Observational in tertiary care centre movement disorder clinic

Duration of metoclopramide 51 patients with treatment at least 30 days metoclopramideassociated TD; 35 non-users matched for age, race, gender, and diabetes 87 case reports Women 67% average daily dose (33 14 mg): use for 753 951 days; 37% used concomitant drugs, 18% comorbid diseases with TD risk 434 patients referred Metoclopramide accounted for for TD 39.4% of TD, second after haloperidol

Metoclopramide users: 27% TD vs. 12% non-users (P = 0.08); patients on metoclopramide and diabetic were more likely to develop TD (P = 0.05) Not estimable; reports increased with cisapride withdrawal

Not estimable

TD, tardive dyskinesia; Rx, prescription; AIMS, abnormal involuntary movements scale.

16 6.5 months and notably 47% of cases had persistent TD at 6 months despite discontinuation of the drug. These two series22, 23 identied patients with TD,
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but an accurate estimate of the true risk remains unclear as the overall number of patients exposed to metoclopramide is unknown.

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A study by Ganzini et al.24 evaluated the prevalence of TD in a cohort of 51 chronic users of metoclopramide at a single Veterans Administration (VA) centre, using an exposed unexposed design. Clinical characteristics of the exposed group included age of 63.9 10.8 (mean s.d.) years, almost exclusively men, metoclopramide dose of 31.0 11 (mean s.d.) mg, duration of treatment of 2.6 2.0 (mean s.d.) years and 24% diabetics. The unexposed group comprised fty-one individuals who were matched for age, gender, and diabetes. Both groups had an average of 4 other illnesses. TD was assessed by the Abnormal Involuntary Movement Scale (AIMS) ve-point scale from 0 (no abnormal movements) to 4 (severe abnormal movements). Rated body parts include the face, jaw, lips, tongue, trunk, upper extremities and lower extremities. The sum of all item scores determines the total severity score (maximum, 28). Among metoclopramide users, 29% met criteria for TD compared to 17.6% of nonusers (P = 0.08). The calculated relative risk of developing TD on metoclopramide was 1.67 (95% CI, 0.932.97). The mean AIMS summed score was signicantly higher in metoclopramide users [4.1 2.4 (s.d.)] compared with nonusers (2.9 2.3; reported P < 0.001 by paired t test). It is not clear why paired statistical analysis was used for the contrast between two different groups. It is also relevant to note that the summed AIMS score is low relative to the maximum possible score of 28 and that 17.6% of nonusers fullled the criteria for TD suggesting that there were confounding problems in the unexposed population. In addition, the study by Ganzini et al. was underpowered to show statistical signicance. A sample size calculation with a = 0.05 and power of 80% would require 100 patients per group to detect a 15% difference between the 2 groups with a 12% prevalence for TD in the unexposed group. Another cross-sectional study by Sewell et al.25 used stricter eligibility criteria to evaluate 51 patients with metoclopramide-associated TD at a different VA centre. Patients received metoclopramide for 30 days or longer, had no prior exposure to other neuroleptic drugs, no psychiatric diagnoses, no alcohol or other substance abuse problems and no pre-existing movement disorders. Thirty-ve metoclopramide nonusers were matched for age, race, gender and presence of diabetes. Twenty-seven percent of metoclopramide users vs. 12% of nonusers met criteria for TD (P = 0.08); patients who were on the medication and diabetic were more likely to develop TD (P = 0.05).

COMMENTS ON REPORTED PREVALENCE OF TD ASSOCIATED WITH METOCLOPRAMIDE USE

Although there appears to be a numerically greater incidence of TD in patients receiving chronic metoclopramide therapy, it is impossible to calculate the actual risk, based on the studies performed to date. The fundamental problem with the literature that precludes estimation of a rate of TD is that the denominator or number exposed is unknown in all but four studies.20, 21, 24, 25 In addition, the studies of Ganzini et al.24 and Sewell et al.25 did not reveal a statistically signicant difference in prevalence of TD in subjects who were on metoclopramide therapy compared to matched controls. This contrasts with the impression and the reported frequency of TD in the national guidelines,3, 4 which refer to the Ganzini reference as the source for the risk estimate provided. In addition, these two series included patients attending VA centres and found that 1217% of the controls met criteria for TD, which appears to overestimate the prevalence of TD in the general population; therefore, results may only reect the VA population and may not be generalizable. The currently validated method of measuring TD via the AIMS measures severity, but it does not discriminate the types of involuntary movement observed, e.g. TD vs. essential tremor or parkinsonism, which requires recognition by the physician. The reported AIMS summed scores for the controls and metoclopramide users in the study by Ganzini et al. were similar with means of 2.9 and 4.1 out of a possible 20. These papers also do not provide the proportion of patients with the distressing or disguring orofacial dyskinesias, or the reversibility or amelioration of so-called TD with cessation of metoclopramide. It is noteworthy that the annual incidence of metoclopramide-induced TD dramatically increased after the withdrawal of cisapride from the U.S. market in 2000.22 This probably reects the fact that metoclopramide is currently the only medication approved by the FDA for gastroparesis, a debilitating and chronic condition, which may require prolonged or indenite treatment. In contrast, the availability of newer antipsychotic medications has led to decreased use of classical neuroleptics like haloperidol and a reduction in the TD induced by those antipsychotic agents.

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WHEN SHOULD METOCLOPRAMIDE BE USED?

Although the FDA recommends that the chronic use of metoclopramide therapy should be avoided in all but rare cases where the benet is believed to outweigh the risk, patients with gastroparesis are being increasingly recognized and require treatment. Gastroparesis is a disorder for which treatment cannot be withheld while the patient is symptomatic, as it may lead to dehydration or, in diabetics, worsening of diabetic control, including ketoacidosis. In addition, there is a need to control chronic symptoms in these patients and recent studies of natural history and outcome have demonstrated an increase in mortality in patients with gastroparesis compared to age- and sexspecic expected survival as well as increased morbidity, hospitalizations and doctor visits.26, 27 Some patients appear to be at increased risk for the development of TD. Advanced age, female gender, presence of diabetes, renal failure, cirrhosis, alcoholism, tobacco use, schizophrenia, known organic CNS pathology, and concomitant use of neuroleptics that also alter the dopaminergic pathways of the brain are all risk factors.2830 This risk also appears to correlate with chronic treatment of at least 3 months or longer duration. On the other hand, the UK national prescription study actually identied young adults, and especially girls aged 1219 years, as having the highest risk of dystonia and dyskinesia (191 million prescriptions).20

dopamine D3 receptor (DRD3) knockout mice exhibited increased locomotor behaviour during a test of exploration. The DRD3 Ser9Gly gene polymorphism results in higher dopamine binding afnity to D3 receptors.32 This appears to have a strong correlation with development and intensity of TD symptoms.14 A metaanalysis has demonstrated that, in non-Asians, antipsychotic medication-associated TD is more likely to occur in patients with the DRD3 Ser9Gly gene polymorphism (odds ratio 1.39, 95% CI, 1.071.81).33 Of note, the precise antipsychotics involved are not provided in the original articles, or the antipsychotics are expressed in chlorpromazine equivalents. These allelic variations may therefore modulate the CNS response to prolonged treatment with drugs which affect the dopamine pathways. While an association between this DRD3 single nucleotide polymorphism and metoclopramide has not been reported, there is evidence that metoclopramide binds to D3 receptors, with 10 fold lower afnity than anti-psychotics like haloperidol.34 Therefore, it is also conceivable that genetic variation in the DRD3 gene may alter pharmacodynamic responses to metoclopramide. Studies are warranted to test this hypothesis which might explain, in part, the risk of developing TD with metoclopramide treatment.

RISK STRATIFICATION FOR APPROPRIATE USE OF METOCLOPRAMIDE

Use of metoclopramide for indications such as gastrooesophageal reux and chemotherapy-induced emesis should be avoided since there are now safer alternatives such as proton pump inhibitors, 5-HT3 receptor antagonists, or NK1 receptor antagonists, which should be strongly considered as the rst-line therapies. Until safer therapies are approved for the treatment of gastroparesis, the risks vs. benets of metoclopramide use should be individualized to each patient. In patients who are elderly, women, cirrhotic, uremic, alcoholic, schizophrenic, have a pre-existing movement disorder, or are on concomitant neuroleptics, the risk to anticipated benet should be carefully evaluated prior to initiation of metoclopramide.11, 12, 2830 Although diabetes is a known risk factor for the development of TD,25, 30 the clinical conundrum is that many patients have gastroparesis secondary to diabetes. Alternatively, domperidone, a peripherally restricted dopamine D2 antagonist, has minimal risk of TD35 and

POTENTIAL ROLE OF PHARMACOGENETICS IN METOCLOPRAMIDE-INDUCED TD

It is conceivable that the predilection for developing TD may have a genetic basis; for example, predisposition may result from alterations of pharmacokinetic responses to metoclopramide. Certain variants of both the CYP2D6 and CYP1A2 genes have been associated with increased TD and may reect altered metabolism of neuroleptic drugs.14 It is worth noting that metoclopramide is metabolized by CYP2D6 and possibly CYP1A2. The amount of metoclopramide crossing the blood-brain barrier may be higher in patients with reduced effective CYP metabolism or combination therapy that inhibits CYP2D6. Genetic variation in the function of the D3 receptors may predispose individuals to develop TD when receiving neuroleptic drugs. Accili et al.31 found that
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is available for prescription using an IND application to the FDA. Patients being considered for metoclopramide treatment for gastroparesis should be made aware of this risk and agree to its use before initiating the drug. It is essential to identify early manifestations of TD; thus, it is the responsibility of the prescribing physician to monitor these patients at regular intervals. TD may be reversible and early recognition followed by discontinuation of the drug may lead to its resolution. As with all drug treatment, the lowest effective dose for the individual patient should be sought. Given the erratic emptying of solids from the stomach in patients with gastroparesis, the liquid formulation may have the advantage of more predictable plasma drug levels, as emptying of liquids from the stomach is usually normal. The liquid formulation also allows for easier dose titration to identify the lowest effective dose for the patient. Judicious use of metoclopramide should start with a test dose (e.g. 5 mg, 15 min before meals and at bedtime), titrating the drug to identify lowest efcacious dose. It is appropriate to give the patient drug holidays or dose reductions (e.g. 5 mg, before two main meals of the day) whenever clinically possible. This may result in control of gastroparesis symptoms and enhance glycaemic control while maintaining hydration and nutrition.

CONCLUSION
The absolute risk of metoclopramide-induced TD remains unknown, but it does not appear to be as high as indicated in national guidelines on gastroparesis treatment. The recent FDA black box warning may dissuade physicians from prescribing this medication. While the increased use of metoclopramide for chronic treatment of gastroparesis is one of the reasons that TD is becoming increasingly recognized as an adverse effect of the medication, there are risk factors, separate

from metoclopramide and possibly including pharmacogenetics, which may predispose individuals to the development of TD. Patients with multiple risk factors should be carefully evaluated prior to initiation of the medication and should be regularly monitored for development of TD throughout the duration of therapy. It is important for physicians to understand the impact of gastroparesis on the natural history of diabetes and to treat it appropriately. There is a need for robust systems to identify and quantify adverse events and provide epidemiologically rigorous and clinically helpful information to effectively manage drug risks,36 while being cognizant of the pitfalls in database studies including data validity, lack of detailed clinical information, and a limited ability to control confounding.37 There are several questions that can be addressed in future research. First, what is the true prevalence of TD in metoclopramide users in the community? Second, is the propensity to develop adverse effects like TD because of drug interactions, individual genetic variation in CYP2D6 or CYP1A2 metabolism or genetic variation in the D3 receptor which appears to be critical to the development of involuntary movements with psychotropic agents? For these pharmacogenetic studies, it would probably be necessary to establish a consortium to collect information about the adverse effects as well as to collect DNA for genotyping. Until other drugs are approved for treatment of gastroparesis, and given the weakness of the data regarding the risk of TD in association with metoclopramide use, we recommend that physicians use metoclopramide judiciously following the guidelines provided above.

ACKNOWLEDGEMENT
Declaration of personal and funding interests: The authors have no disclosures or nancial interests.

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Aliment Pharmacol Ther 31, 1119 2010 Blackwell Publishing Ltd