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ABSTRACTObjective: To examine the med-

ical evidence regarding the clinicalefficacy and cost-effectiveness of theapplication of continuous subcuta-neous metoclopramide and on-dansetron to treat nausea and vomit-ing during pregnancy.

Study design: All of the publishedpeer-reviewed articles on the subjectwere assembled and assigned a levelof evidence based on research design.The search uncovered one level IImatched, controlled trial and threelevel III uncontrolled, retrospectivecase series published in peer reviewjournals, as well as a book chapter.The book chapter, although not sub-jected to the peer-review process, isincluded in this review due to thepaucity of other evidence.

Results: The matched cohort trial

showed that continuous subcuta-neous metoclopramide is signifi-cantly less-tolerated than continuoussubcutaneous ondansetron (31.8%vs. 4.4%; P< 0.001). The four case se-ries reported complete symptom res-olution for 63.9% to 75% of the pa-tients. Complications arose in 24.9%to 30.5% of the selected cases thatwere severe enough to require dis-continuation of therapy. Complica-tions included side effects of a wors-ening of symptoms.

All of the trials are retrospectiveand observational in nature and,therefore, subject to the limitationsinherent in the research design. Ab-sent the benefit of meaningful cohortcontrols, comparative statements ef-fectiveness cannot be substantiatedwith the available data.

Conclusion: Randomized, con-trolled trials of sufficient power arenecessary before long-term continu-ous subcutaneous metoclopramideor ondansetron can be used on awidespread basis to treat nausea andvomiting during pregnancy.

Cost approximations in the caseseries are reported and, when com-pared to the cost of other methods oftreatment previously published in themedical literature, the therapy ap-pears to be cost-prohibitive. How-ever, definitive statements cannot bemade regarding cost-effectivenessuntil clinical efficacy is demonstratedthrough a sufficiently powered, well-designed, randomized control trial(RCT). Until such time, the therapy

should remain experimental and cov-erage be restricted to intractable hy-peremesis gravidarum (HG) that isunresponsive to more-conventionaltreatment options.

Keywords: metoclopramide(Reglan), ondansetron (Zofran), hy-peremesis gravidarum, reglan pump,Zofran, nausea and vomiting of preg-nancy

INTRODUCTIONIn the mid-eighties, continuous

subcutaneous antiemetic therapybegan to creep into clinical practicefor treating nausea and vomiting dur-ing pregnancy without the benefit ofpublished clinical evidence to sup-port the intervention. At that time,physicians began prescribing contin-uous subcutaneous metoclopramide(Reglan) via a portable, programma-ble micro-infusion pump (MiniMed404SP-MiniMed Technologies, Syl-mar, Ca.) called the Reglan pump.

In the late nineties, after on-dansetron (Zofran) was widely pro-moted as an anti-emetic for patientswith chemotherapy-induced nauseaand vomiting, obstetricians beganprescribing it in much the same wayas had been done a decade earlierwith metoclopramide. This becamecommonly referred to as a ZofranPump.

The purpose of this analysis is toassemble all of the medical evidenceon the therapy and assess its clinicalefficacy, safety, and cost-effectiveness.To our knowledge, this is the first ex-

Reviewing the Evidence for Using Continuous Subcutaneous Metoclopramide and Ondansetron To Treat Nausea & Vomiting During Pregnancy

James P. Reichmann, MBA; Michael S. Kirkbride, BSc, Pharm D

Disclosure/conflict of interestThe authors report no conflicts of interest in developing, preparing, andwriting this article.

Address for correspondence:James P. Reichmann, MBA1322 Garrick WayMarietta, GA 30068(615) 948–5910, phone(770) 541–5495 faxjim.reichmann@ahom.com, e-mail

Michael S. Kirkbride, BSc, Pharm DPO Box 227Huddleston, VA 24104(540) 529–0635, phonemskpharmd@aol.com, e-mail

A review of the available research identifies payment for services in the absence ofhigh-quality scientific evidence and presents an opportunity to use evidence-basedmedicine to develop a clinical coverage guideline

MAY 2012 / MANAGED CARE 45

haustive review of the medical evi-dence on the use of continuous sub-cutaneous anti-emetic therapy totreat nausea and vomiting duringpregnancy (NVP).

MATERIALS AND METHODSUsing Google Scholar (http://

www. google.com/scholar) and PubMed (http://www.ncbi. nlm. nih. gov/pubmed), we conducted a literaturesearch using the key search terms ofsubcutaneous metoclopramide(Reglan), subcutaneous ondansetron(Zofran), Zofran pump, Reglan pump,and pharmaceutical treatment fornausea and vomiting of pregnancy.The search was not constrained byeither search dates or language limi-tations. A manual search of referenceswas subsequently performed to dis-cover additional articles. All authors’names on relevant identified articleswere searched to further mitigate thepossibility of inadvertently omittingany published work on the topic. Allidentified articles are included in thisreview; none were excluded.

EVIDENCE REVIEWThe published medical evidence

on continuous subcutaneous anti-emetic therapy consists of one level IIretrospective non-randomizedmatched cohort study, four level IIIuncontrolled retrospective descrip-tive case series, three published peer

reviewed articles, and a book chapter(Table 1). No comparative trials con-taining conventional lower-cost treat-ments as controls have been pub-lished to date.

Continuous subcutaneousmetoclopramide

In 1998, the first report was pub-lished on 301 patients receiving con-tinuous subcutaneous metoclo-pramide administered in the home.This retrospective chart review re-ported encouraging results, although,without controls, it is impossible todetermine the treatment effect of theintervention, if any existed. Authorsreported that 64.8% of patients hadcomplete resolution of symptoms,10.6% discontinued therapy due toside effects, and 14.3% discontinuedtherapy as a result of worseningsymptoms. An additional 5.2% dis-continued therapy for nonspecificreasons. A total of 54.5% sufferedsome side effects from the therapyand 11 patients experienced ex-trapyramidal symptoms (Buttino,1998).

Two years later, the same authorpublished another case series on con-tinuous subcutaneous metoclo-pramide. This study contained 646women with hyperemesis gravi-darum. Similarly to previously re-ported results, 63.9% of patients ex-perienced complete resolution of

symptoms and 30.5% reported atleast one side effect related to thetreatment. The author concludedfrom the uncontrolled retrospectivecase series that the therapy appearedto be safe and effective (Buttino,2000a).

Later in the year, the same authorwrote a book chapter describinghome continuous subcutaneousmetoclopramide administration fortreatment of nausea and vomiting ofpregnancy. The evidential weight ofthis book chapter is compromised bythe fact that 82.1% of the patientswere previously reported in the firsttwo published case series and thechapter, therefore, suffers from re-dundancy of publication (Buttino,2000b).

Another case series that looked atpatients who were switched frommetoclopramide to ondansetron ap-peared in a managed care journal sev-eral years later (Lombardi, 2004).This case series contained 428 womenand reported the incidence of treat-ment failure, hospitalizations/ER vis-its, ketonuria, and pregnancy-uniquequantification of emesis and nausea(PUQUE) score at the therapystart/stop. Symptoms of NVP im-proved for 89.3% of patients, while10.7% were switched to continuoussubcutaneous ondansetron adminis-tration.

The PUQUE score, hospital/ER

TABLE 1Continuous subcutaneous anti-emetic pump evidence

Study NResearch

designLevel of

evidenceSymptom resolution

Symptom improvement

Failed therapy

Side effectrate

Buttino 1998 301 Case series III 195 (64.8%) - 91 (30.1%) 164 (54.5%)

Buttino 2000a 646 Case series III 413 (63.9%) - NR 192

Buttino 2000b 11541 Case series III N/A N/A N/A N/A

Lombardi 20042 428 Case series III 382 (89.3% NR 167 (39%)

Klauser 2011 355 –CSMT3

521- CSOT3Matched cohort

II 68.2% 95.8%

NR NR

31.8% 4.4%

NR NR

N/A, not applicable; NR, not reported.1947 (82.1%) of the patients were previously reported in the first two trials.2Included patients receiving subcutaneous metoclopramide as well as patients moved to continuous subcutaneous ondansetron. Reported results ren-dered continuous subcutaneous ondansetron outcomes indiscernible.3CSMT = Continuous subcutaneous metoclopramide and CSOT = Continuous subcutaneous ondansetron.

visits, and ketonuria decreased sig-nificantly from initiation of therapyto completion as expected, since NVPis a self-limited condition. No controlgroup was used as a comparison co-hort, so it is not possible to deter-mine if either intervention wouldperform better than other inexpen-sive or less-invasive therapies (Lom-bardi, 2004).

Continuous subcutaneous ondansetron

There exists one retrospective non-randomized, descriptive level II trialand one level III retrospective un-controlled case series included pa-tients who were administered con-tinuous subcutaneous ondansetron(Klauser, 2011; Lombardi, 2004).Once previously discussed descrip-tive analysis moved patients whofailed to see symptoms resolved fromcontinuous subcutaneous metoclo-pramide to ondansetron. Of the 428patients who were originally admin-istered continuous subcutaneousmetoclopramide, 46 (10.7%) womenwere subsequently switched to con-tinuous subcutaneous ondansetron.These patients were reportedly moreacute because they previously failedcontinuous subcutaneous metoclo-pramide, although no differenceswere noted between patients whofailed initial therapy and those whodid not.

Patients remained on therapy for amean of 22.3 +/– 20.2 days. No out-comes were reported for the subset ofpatients who failed continuous sub-cutaneous metoclopramide and sub-sequently started on continuous sub-cutaneous ondansetron; their resultswere reported in conjunction withpatients who remained on the origi-nal therapy (Lombardi, 2004).

The second trial, containing pa-tients receiving continuous subcu-taneous ondansetron, was publishedrecently and compared those pa-tients with a group receiving con-tinuous subcutaneous metoclo-pramide (Klauser, 2011). The

retrospective, non-randomized,matched cohort study compared 355women in the metoclopramidegroup to 521 in the ondansetrongroup. The major scientific contri-bution of this trial is that signifi-cantly fewer women tolerated meto-clopramide administered viasubcutaneous pump than those re-ceiving ondansetron in a similarfashion (31.8% vs. 4.4% P < 0.001).

The authors acknowledge, “Theretrospective, non-randomized de-scriptive design of our study limitsour ability to make conclusions re-garding superiority of one medica-tion versus the other. We are unable toprove that either intervention is ef-fective or ineffective without a controlgroup …” (Klauser, 2011).

COST CONSIDERATIONSA recently published article on

cost-effective pharmacologic treat-ments for nausea and vomiting ofpregnancy (Reichmann, 2008) com-pared the published cost of continu-ous subcutaneous anti-emetic ther-apy to cost of hospitalization orintermittent homecare for the treat-ment of hyperemesis gravidarum(Neaf, 1995) and the costs were$4,432, $2,701, and $701 respectively.Given this high relative cost of ther-apy, cost-effectiveness may be diffi-cult to establish.

DISCUSSIONStudies often are designed, con-

ducted, analyzed, and written by in-dustry employees or people paid di-rectly or indirectly by industry(Kassirer, 2006; Dietz, 2007). Unfor-tunately, a growing body of evidencedemonstrates that industry-spon-sored trials are much more likely tofind in favor of the studied interven-tion than independently funded stud-ies (Bekelman, 2003; Buchkowsky,2004; Als-Nielsen, 2003; Goetzsehe,2005; McHenry, 2010).

This bias is demonstrated to bepresent in cohort-controlled trialsand is much more likely to be present

in uncontrolled case series producedand authored by industry, particu-larly when the selection process is notwell-described by the authors. In ad-dition, physicians sometimes fail todiscount for conflict of interest whenevaluating medical literature (Silver-man, 2010; Chaudry, 2002).

While recognizing the importantrole that case series play in the ad-vancement of obstetrics, the Ameri-can College of Obstetricians and Gy-necologists (ACOG) issued acommittee opinion, cautioning that,“Practitioners need to be careful notto adopt innovative procedures or di-agnostic tests on the basis of promo-tional and marketing campaignswhen the value of such proceduresand tests has not yet been proved”and that “innovations should be sub-jected to systematic formal researchas soon as feasible” (ACOG Commit-tee on Ethics, 2006).

The findings from these promisingstudies should be used to formulate ahypothesis for trials containingmeaningful comparative controls andadequate randomization. It may bedifficult to conduct a randomized,placebo-controlled trial regarding thetreatment of hyperemesis gravi-darum, but evidence exists that a trialcomparing unproven therapies to awell-accepted conventional one canbe executed, even with extreme cases(Sullivan, 1996).

MANAGED CARE PERSPECTIVEWellCare Health Plans, Inc. has put

a Clinical Coverage Guideline in placefor “Treatment of Nausea and Vom-iting (Hyperemesis Gravidarum)during Pregnancy with SubcutaneousMicroinfusion Pump.” The guidelineapplies to women diagnosed with HGafter nine weeks of gestation whenall other causes of NVP have beenruled out. A continuous subcuta-neous anti-emetic pump is consid-ered not medically necessary unlessall other pharmacologic treatmenthas been attempted and failed, in-cluding:

46 MANAGED CARE / MAY 2012

1. Prochlorperazine (Compazine IM/PO);

2. Trimethobenzamide (TiganPR) (No longer available; seeFederal Register, 2007, FDAWithdrawal of Approval);

3. Promethazine (PhenerganIM/PO/PR);

4. Metoclopramide (Reglan PO);or

5. Ondansetron (Zofran PO).

Another requirement is that intra-venous metoclopromide (Reglan) orintravenous ondansetron (Zofran)have been attempted and failed(WellCare Health Plans, Clinical Cov-erage Guideline Number HS-016,2008).

An extensive Internet search re-vealed no additional health plans thathave published clinical coverageguidelines to ensure that only appro-priate patients are administered thisexpensive and as yet unproven ther-apy. An additional, previously pub-lished recommendation called for afailed trial of Zofran ODT before au-thorizing continuous subcutaneousanti-emetic pump (Reichmann,2008).

CONCLUSIONThe entire body of evidence in-

volving continuous subcutaneousanti-emetic therapy for treatment ofnausea and vomiting during preg-nancy consists of five industry-sponsored and -authored non-randomized reports.

These therapies do not appear,based on published payment levels, tobe cost-effective when compared toconventional treatment alternativesincluding episodic hospitalization(Reichmann, 2008). Managed careorganizations that design evidence-based clinical coverage guidelinesmay want to limit the use to ex-tremely recalcitrant cases of hyper-emesis gravidarum until sufficientlypowered, independent, randomized,controlled trials demonstrate clinicalefficacy and cost-effectiveness.

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WellCare Health Plans, Inc. CoverageGuideline, Treatment of Nausea andVomiting (Hyperemesis Gravi-darum) during Pregnancy with Sub-cutaneous Misroinfusion Pump,Guideline Number: HS-016, Originaleffective date: 4/3/2008; RevisionDate: 6/5/2009. Available at:http:www.wellcare.com/WCAssets/corporate/assets/HS016_Treatment_of_%20Nausea_and_Vomiting_in_Preg-nancy_with_Subcutaneous_Pump.pdf. Retrieved October 27, 2010.

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