Ciccaglione AF, Marzio L. Effect of acute and chronic administration of the GABAB agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease // BMJ Publishing Group & BSG. 2003;52:464-470.

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Авторы: Ciccaglione A.F. / Marzio L.

Effect of acute and chronic administration of the GABAB  agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease

AF Ciccaglione and L Marzio


Background and aims: The g-aminobutyric acid (GABAB) agonist baclofen has been shown to reduce reflux episodes during thefirst three postprandial hours in patients with gastro-oesophagealreflux disease (GORD) and in normal controls. The aim of the study was to assess the effect of acute (one day) and chronic(four weeks) administration of baclofen on  24 hour pH-metry and symptoms in GORD patients and normal controls.

Patients and methods: Acute study: 28 patients with GORD withnone or mild oesophagitis at endoscopy and 15 controls underwentoesophageal and gastric 48 hour pH metry in which baclofen or placebo was given for 24 hours in a double blinded manner. Chronicstudy: 16 GORD patients received baclofen (10 mg four timesdaily) or placebo for four weeks. Twenty four hour oesophageal pH-metry and reflux symptom scores were evaluated before andat the end of treatment.

Results: Acute study: the number of reflux episodes and percent time with pH <4 was significantly lower after baclofen in GORD patients and controls (p<0.003; p<0.0007). GastricpH increased significantly in GORD patients and controls (p<0.001;p<0.05). Chronic study: four weeks after initial administration of baclofen, the number of reflux episodes and percentage of time with pH <4 significantly decreased in all GORD patients (p<0.003; p<0.02). Symptom scores significantly improvedafter treatment with baclofen (p<0.0007).

Conclusions: The GABAB agonist baclofen reduces 24 hour gastro-oesophagealreflux and increases gastric pH in GORD patients and controls.When given for one month to GORD patients, baclofen reduces oesophageal acid refluxes and significantly improves symptoms. Baclofen may be useful in the therapy of GORD.

Keywords: baclofen; GABA; gastro-oesophageal reflux

Abbreviations: GORD, gastro-oesophageal reflux disease; GABA, g-aminobutyric acid; LOS, lower oesophageal sphincter; TLOSR, transient lower oesophageal sphincter relaxations

GABA (g-aminobutyric acid) is a potent inhibitory neurotransmitterin the central nervous system and antagonises the release ofneurotransmitters from vagal nerve afferents through its GABABreceptor.1 GABAB receptors are present in the nucleus tractussolitarius and in the dorsal motor nucleus of the vagus, whichare known as centres that integrate the afferent preganglionicsignal arising from gastric tension mechanoreceptors2 and thelower oesophageal sphincter (LOS).3 Physiology and pharmacologystudies in animals have shown that activation of GABA receptorswith the GABAB agonist baclofen inhibits transient LOS relaxation,gastro-oesophageal reflux,4,5 and gastric secretion.6 In normal human subjects and in patients with gastro-oesophageal refluxdisease (GORD), recent studies have shown that baclofen reducesthe rate of transient lower oesophageal sphincter relaxations(TLOSR), the rate of gastro-oesophageal acid reflux episodes,and increases basal LOS pressure.7,8 Baclofen therefore hasbeen proposed as potentially useful in the treatment of GORD.Studies with baclofen however have been limited to evaluationof a single oral dose on gastro- oesophageal acid reflux fora two hour postprandial period and more recently for 12 hours.9 Furthermore, as peak plasma levels of baclofen given orallyoccur two hours after administration, with disappearance fromblood 4–6 hours thereafter,10 a study with multiple oraldosing is essential to obtain coverage of a 24 hour period thatshould be necessary to set up a therapeutic programme in patientswith GORD. To date, there is no information on the effect of baclofen when administered in multiple doses over a 24 hourperiod either in normal subjects or GORD patients, or data onthe effect of chronic administration of baclofen on 24 hourgastro-oesophageal acid reflux and symptoms in patients affectedby GORD.

The aim of this study therefore was to assess the effects ofthe GABAB agonist baclofen on 24 hour oesophageal and gastricpH patterns in normal subjects and in patients with GORD. Moreover,we evaluated the effects of one month of treatment with baclofen versus placebo on the oesophageal pH pattern and symptoms inpatients with GORD.


The study was divided into two parts. The first was a placebocontrolled randomised comparison of baclofen or placebo in patientswith GORD and normal controls. The second was a placebo controlledrandomized parallel group comparison of baclofen or placeboadministered for four weeks in GORD patients.

Patient selection

Patients were aged 18 years or older, both males and females,and were chosen on the basis of clinical symptoms indicatingGORD (heartburn, belching, and regurgitation) for at least threemonths before enrolment. In the week preceding the study, eachpatient underwent endoscopy to assess the presence and degreeof oesophagitis and other gastroduodenal pathology. Patientswith no signs of oesophagitis or only mild oesophagitis witherythema, hyperaemia, and/or friability with no visible macroscopicerosions were selected. Patients with oesophagitis grade 2–5,according to Hetzel and colleagues,11 oesophageal varices, activeor previous history of gastric or duodenal ulcer or gastrointestinalbleeding, erosive gastritis, duodenitis, inflammatory boweldisease, or recent history of gastrointestinal cancer treatmentwere excluded. Patients were also ineligible if they had receivedtherapeutic doses of proton pump inhibitors, aspirin, or non-steroidal anti-inflammatory drugs in the 30 days preceding the study.The number of antacid tablets consumed per week in the monthpreceding the study was also recorded.

A group of healthy subjects matched for age and sex to the GORDpatients was studied as a control group.

Each subject gave written informed consent to participate andthe protocol was approved by the ethics committee of G D’AnnunzioUniversity.

Data analysis

Oesophageal pH recording was analysed for the total number ofacid reflux episodes and per cent time with pH <4 in the24 hour observation period. The number of reflux episodes andper cent time pH <4 were also analysed every two hours. Areflux episode was considered as a drop in oesophageal pH below 4 until its return to a value of 4.2, lasting 10 seconds. GORDwas diagnosed when the total number of reflux episodes in a24 hour period was greater than 50, and/or per cent time withpH <4 was more than 5% in 24 hours.

Gastric pH was analysed as mean pH value every hour and as atotal value in the 24 hour period.

Study protocol

First part

Each subject or patient admitted to the study underwent 48 hour oesophageal and gastric pH metry starting after an overnightfast at about 8 am. Patients and subjects were divided intotwo groups: in the first group, baclofen 10 mg was given orallyat 10 am, 2 pm, 6 pm, and 10 pm in the first or second 24 hour period in a random manner. In the second group, placebo wasadministered instead of baclofen using the same schedule. This first or second 24 hour recording without baclofen or placebowas considered the basal period.

pH metric probes were kept anchored to the patient’s nosethroughout the whole recording period to reduce to a minimumartefacts due to probe displacement. At the end of the recording,the probes were removed and data were transferred to a personalcomputer and analysed using a dedicated program (Scan, System;SME, Solothurn, Switzerland). pH metry was performed using two glass pH flexible probes with distal incorporated electrode(SME). The pH electrodes were calibrated in buffers of pH 7and 4. Catheters were introduced nasally under fluoroscopy:one probe was positioned in the gastric body which has beenshown to be an optimum position in conjunction with the fundusto record ambulatory gastric acidity,12 and the other one was placed 5 cm above the LOS which was manometrically identifiedtwo days prior to the study. The probes were taped firmly tothe nose and connected to a portable data logger (GastroscanII; SME). The data logger was carried in a shoulder bag, allowingcontinuous recording with a freely moving subject.

In each 24 hour period, starting 30 minutes after pH probe positioning,all subjects and patients ate similar meals with equivalentcaloric content: breakfast (8 am) consisted of one croissantor two slices of toasted white bread and 200 ml whole milk atroom temperature (360 kcal); lunch (12 am) consisted of 150g pasta with tomato sauce, 100 g boiled chicken or veal, salad,one apple or peach, and 150 ml water (720 kcal); and supper(8 pm) consisted of 150 g fresh mozzarella cheese and boiledpotatoes, beans, or carrots (490 kcal).

No drug that could modify gastric pH was allowed during thewhole recording period.

Second part

GORD patients diagnosed following the clinical and oesophagealpH metry described above who did not participate in the firstpart of the study were assigned to receive four weeks of treatmentwith placebo or baclofen at a dose of 10 mg orally three timesdaily (10 am, 2 pm, and 6 pm) for the first week, and then 10mg orally four times daily (10 am, 2 pm, 6 pm, and 10 pm) forthe remaining three weeks in a random manner. Baclofen was givenin increasing doses to avoid possible side effects. At the endof treatment, every patient underwent oesophageal 24 hour pHmetry, as described in the first part of the study. pH metrywas performed using a recorder different from that used in the first part of the study (pH-day2; MENFIS BioMedica srl, Bologna,Italy). With this recorder and its related software, refluxlasting longer than five minutes was also computed.

During the one month treatment period, patients were asked toreport any side effects to the medical personnel who were available24 hours a day.

The number of antacid tablets used per week was also monitored.Patients were requested to use antacid tablets only for thetreatment of heartburn recurrence and were free to use any antacidtablet commonly available on the market, except during the periodof pH recording.

Symptom assessment

Before and at the end of the treatment period, each patientcompleted a questionnaire related to the severity and frequencyof symptoms in the four weeks preceding and during the study.Symptoms evaluated were: bitter taste, belching, fasting epigastricpain, postprandial epigastric pain, night-time heartburn, daytimeheartburn, and acid regurgitation. The severity of each symptomwas classified as none, mild (symptom easily tolerated and lasting a short time), moderate (symptom caused some discomfort andinterfered with usual activities), severe (symptom caused muchdiscomfort and interfered with usual activities), and disabling(symptoms unbearable and interfered considerably with usualactivities), and was scored: 0=absent, 1=mild, 2=moderate, 3=severe,4=disabling. The frequency of each symptom was evaluated ona 0–4 scale (0=absent, 1=once/month, 2=once/week, 3=3times/week, 4=daily).


Data from 24 hour pH metry were analysed using the Wilcoxonsigned rank test for paired data and are presented as percentagedecrease and exact values (median and interquartile range).All other data are presented as mean (SEM). The GORD symptomscore was compared between the randomised groups at the beginningand after one month of treatment with baclofen or placebo usingthe Mann-Whitney U test. A p value of <0.05 was acceptedas indicating statistical significance.


First part

Twenty eight GORD patients (15 men and 13 women, mean age 40(8) years) and 15 control subjects (nine men and six women,mean age 43 (5) years) were evaluated using oesophageal andgastric pH measurement. These patients were included into thefinal evaluation. Fifteen GORD patients and nine controls received baclofen. Eight patients with GORD and four controls received baclofen in the first 24 hours of pH recording, and seven GORDand five controls received baclofen in the second 24 hour recordingperiod. Thirteen GORD patients and six controls received placebo.Seven GORD patients and three controls received placebo in thefirst 24 hour period and six GORD patients and three controlsreceived placebo in the second 24 hour period of recording.A summary of the protocol is described in fig 1.

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Figure 1 Summary of the first part of the study. GORD, gastro-oesophageal reflux disease.


Analysis of the total number of acid reflux episodes and per cent time pH <4 in the oesophagus during the 24 hour period

In all patients with GORD and in controls during treatment with baclofen, there was a decrease in the number of reflux episodes(GORD: basal 149 (110–235), baclofen 73 (22–118)(-51.01%); controls: basal 42 (27–54), baclofen 18 (4–41)(-57.14%)) and in per cent time with pH <4, which was highlystatistically significant (GORD: basal 6.4% (2.7–12.2), baclofen 2.7% (1.2–7.0) (-57.81%); controls: basal 1.5(0.4–2.0), baclofen 0.6 (0.2–1.0) (-60%)) (fig 2).During placebo, no significant change was noted for number ofreflux episodes (GORD: basal 271 (114–325), placebo 258(124–346); controls: basal 41 (6–54), placebo 40(16–54)) or per cent time pH <4 (GORD: basal 7.5% (3.7–12.4),placebo 6.6% (3.8–13.8); controls: basal 1.25% (0.2–2.9),placebo 1.75% (0.2–4.7)) (fig 2). It should be noted thatin the placebo group, GORD patients showed a statistically significantgreater average number of reflux episodes in comparison withGORD patients treated with baclofen (p<0.003).


gt02270.f2.gif (37950 bytes)

Figure 2 Number of reflux episodes (A, C, E, G) and mean per cent of time with pH <4 (B, D, F, H) in the 24 hour basal period and during baclofen administration (10 mg four times daily) in 15 patients with gastro-oesophageal reflux disease (GORD) (A, B) and nine controls (C, D), and in the basal period and during placebo administration in 13 GORD patients (E, F) and six controls (G, H). Individual data for each patient and median and interquartile range are shown for the basal period and during baclofen or placebo treatment. ***p<0.001 versus basal.


Analysis of the number of reflux episodes and per cent time with pH <4 in the oesophagus every two hours

A general decrease in the number of reflux episodes and percent time pH <4 was found with baclofen during daytime fastingand after eating. Specifically, with baclofen there was a significantreduction in the number of acid reflux episodes during the daybetween 12 and 2 pm, 2 and 4 pm, 4 and 6 pm, and 8 and 10 pmin controls and between 10 am and 12 pm, 2 and 4 pm, 6 and 8pm, and 8 and 10 pm in GORD patients (fig 3).

gt02270.f3.gif (32980 bytes)

Figure 3 Number of acid reflux episodes (A, C) and per cent time pH <4 (B, D) every two hours for a total of 24 hours during the basal period and after baclofen administration (10 mg four times daily) in 15 patients with gastro-oesophageal reflux disease (GORD) (A, B) and nine controls (C, D). Values are median and interquartile range. Arrows indicate the time of baclofen administration and M=meal. *p<0.05 versus basal.


Per cent time pH <4 in every two hour period was found tobe significantly lower in controls between 12 and 2 pm, 2 and4 pm, 6 and 8 pm, 8 and 10 pm, and 10 and 12 am, and in GORDpatients between 10 am and 12.00 pm, 12 and 2 pm, 2 and 4 pm,6 and 8 pm, and 10 pm and 12 am (fig 3). A statistically significantdecrease in the number of reflux episodes and in per cent timewith pH <4 was found with baclofen in the two hours aftermeals both in GORD and controls (fig 3). No changes were foundwith placebo (data not shown).

Analysis of mean pH in the stomach during the 24 hour period

GORD patients showed a statistically significant higher mediangastric pH compared with control (controls: 2.02 (1.25–2.92);GORD: 3.15 (1.50–4.50); p<0.0001). A statisticallysignificant increase in mean gastric pH value in the 24 hourperiod was noted with baclofen in nine control subjects andin 15 GORD patients (controls: basal 2.02 (1.25–2.92), baclofen 2.34 (1.31–3.72), p<0.002; GORD patients:basal 3.15 (1.50–4.50), baclofen 4.04 (2.31–5.52),p<0.0004). No change was noted with placebo (controls (sixsubjects): basal 2.59 (1.71–4.93), placebo 2.46 (1.91–4.78),NS; GORD (13 patients): basal 3.62 (1.62–5.07), placebo3.34 (1.86–4.91), NS).

Analysis of the gastric pH curves every hour after baclofen and placebo showed similar behaviours, including the postprandialneutralisation reacidification phase, with greater values for baclofen that reached statistical significance one or two hoursafter meals (fig 4).

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Figure 4 Gastric pH evaluated every hour (mean (SEM)) during the basal, placebo, and baclofen periods in patients with gastro-oesophageal reflux disease (GORD) (A) and in controls (B). Arrows indicate the time of baclofen administration and M=meal. *p<0.02 versus basal.  

Second part

Analysis of the total number of acid reflux episodes and per cent time pH <4 in the oesophagus after one month of treatment with baclofen or placebo.

Eighteen GORD patients (eight males, 10 females, mean age 45(5) years) were evaluated. Twelve received baclofen and six placebo. Two patients (one male and one female) in the baclofen group withdrew from the study because of side effects. In theremaining 10 GORD patients treated with baclofen, the number of reflux episodes and per cent time pH <4 was significantlydecreased at the end of treatment in comparison with valuesreported at the beginning of treatment with baclofen (numberof reflux episodes: basal 220 (160–266), baclofen 52 (33–77)(-76.36%); percentage of time pH <4: basal 5.8% (4.0–10.4), baclofen 2.7% (1.2–3.9) (-53.45%)). The median numberof reflux episodes and per cent time with pH <4 in patientswith GORD treated with placebo was not changed (number of refluxepisodes: basal 118 (89–134), placebo 124 (90–180);per cent time pH <4: basal 6.5% (4.2–9.8), placebo 6.0% (4.0–10.9)) (fig 5).

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Figure 5 Number of reflux episodes (A, C) and per cent time pH <4 (B, D) before and after four weeks of treatment with baclofen (10 gastro-oesophageal reflux disease (GORD) patients) (A, B) or placebo (six GORD patients) (C, D). Individual data for each patient and median and interquartile range are shown for the periods before and after four weeks of treatment with baclofen or placebo. ***p<0.001 versus basal.

The number of reflux episodes longer than five minutes was assessedin five cases treated with baclofen and in three cases treatedwith placebo. With baclofen, a significant reduction was found(basal: 7 (4–11), baclofen 2 (1–4); p<0.002)while no change was noted with placebo (basal: 7 (3–8), placebo 8 (2–9); NS).

Symptoms and side effects

The intensity and frequency of symptoms were found to be significantlyimproved after treatment with baclofen in all patients, whilewith placebo the total symptom scores did not change (fig 6).

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Figure 6 Intensity (A, C) and frequency (B, D) of reflux symptoms (median and interquartile range) before and after four weeks of treatment with baclofen (10 mg four times daily) (A, B) in 10 gastro-oesophageal reflux disease (GORD) patients and with placebo (C, D) in six GORD patients. *p<0.05.


The number of antacid tablets consumed was 7 (2) per week beforeplacebo, 8 (2) per week during placebo (NS), 8 (1) per weekbefore baclofen, and 2 (1) per week during baclofen (p<0.01).

Two patients withdrew from the study after 10 days of treatmentwith baclofen, one because of low blood pressure (90/80 mm Hg)with dizziness, and the other due to nocturnal anxiety withsleepiness. The drug was well tolerated in all other patients. 


We have shown that the oral GABAB agonist baclofen, in comparisonwith placebo, reduced the total number of acid reflux episodesand per cent time pH was <4 in the oesophagus during a 24hour period when given in multiple doses over 24 hours, andcaused an increase in mean gastric pH value in patients withGORD and in normal controls. In patients with GORD, baclofen given for four weeks reduced oesophageal acid reflux and significantlyimproved reflux symptoms.

Current pharmacological treatment of GORD is based on acid suppressionwith anti-H2 receptor antagonists or proton pump inhibitors,or both.13 Drugs that have less activity on acid secretion havealso been evaluated with various results. Prokinetic agentssuch as cisapride have been shown to reduce meal induced refluxsymptoms14 but use has been limited due to serious side effects.15 Dicyclomine, a peripheral anticholinergic agent, induces a decreasein the number of reflux episodes only in the first postprandialhour,16 hyoscine N- butylbromide, a peripheral anticholinergicagent, in contrast increases the number of reflux episodes,17 while pirenzepine, a muscarinic subtype 1 receptor antagonist,appears to be no better than placebo.18 Atropine seems to producea favourable effect on reflux when administered before a meal,with a significant reduction in the postprandial number of refluxes.19,20 Atropine however is available only for intravenous or intramuscularuse, and cannot be used for prolonged periods due to variousside effects.

Baclofen, a GABAB receptor agonist, is already available fortherapeutic purposes in gastroenterology and other branchesof internal medicine. Lidums and colleagues 7 have demonstratedthat baclofen 40 mg in a single dose caused a reduction in thetotal number of gastro-oesophageal acid reflux episodes in normalsubjects and related this effect to the ability of the drugto inhibit TLOSR and to induce a slight increase in basal LOSpressure. More recently, Zhang and colleagues8 and Cange andcolleagues9 in a similar study in patients with GORD reportedinhibition of postprandial gastro-oesophageal acid reflux witha maximum effect within a period of four hours after a singledose of baclofen 40 mg, while data presented in our study showedthat inhibition of gastro-oesophageal acid reflux may be extendedto 24 hours providing that the same dose of baclofen is givenin four separate administrations of 10 mg each at four hourintervals. It must be noted however that while in the acutestudies baclofen was equally effective in patients with oesophagitisor hiatal hernia, so far a beneficial effect after prolongedadministration has been shown only in a selected populationof GORD patients with mild or no signs of oesophagitis.

The reduction in gastro-oesophageal acid reflux after baclofen in patients and normal subjects suggests that the drug modifiesa physiological mechanism responsible for gastro- oesophagealacid reflux. This probably involves TLOSR more than other mechanismsas TLOSR are present both in normal subjects and in GORD patients,with the difference that in GORD patients the number of TLOSR may be increased compared with normal controls 21 or that, whenTLOSR occur in GORD, they are more likely to be associated with reflux.22

Baclofen may also decrease gastro-oesophageal acid reflux throughan inhibitory effect on gastric pH. In the present study, baclofen induced an increase in gastric pH before and after a meal comparedwith placebo, with peak values greater than 5.0 recorded inGORD patients one to two hours postprandially. The postprandialneutralisation-reacidification curve also showed a similar slopefor placebo and baclofen, with higher values of pH for the latter,suggesting a direct effect on gastric hydrochloric acid production for baclofen rather than an indirect effect on gastric motility.To date, there are no studies in humans in this area and animalstudies do not help to clarify this hypothesis as they describea generic dual inhibitory and stimulatory effect of baclofen on gastric secretion 6,23,24 and an increase in gastric toneand amplitude of contractions.25

The reduction in the number of gastro-oesophageal acid refluxepisodes was approximately 51% in GORD patients and 57% in controlsafter the first 24 hours of treatment with baclofen. This valueincreased to approximately 76% after four weeks of treatmentin GORD patients, suggesting there is no tachyphylaxia but mostimportantly that there is a strengthening of the effect. Thismay be due to an increase in plasma levels of the drug duringtreatment. Pharmacokinetic studies in patients with multiplesclerosis and spinal cord injury treated with a stable dosingregimen of baclofen at a higher dosage (80–300 mg/dayfor up to 16 weeks) than that used in the present study showed that baclofen caused blood levels to rise gradually over time,probably as a result of impaired renal clearance.26 These datamay explain why the effect noted after four weeks of therapywas greater than that shown after the one day treatment andindicate that more studies are necessary on renal function andon plasma levels of the drug when chronically administered toGORD patients.

All GORD symptoms significantly improved after one month oftreatment with baclofen in all patient treated. The number ofantacid tablets taken for heartburn recurrence was also significantlyreduced during baclofen therapy from 8 to 2 per week. Althoughwe did not report a daily or weekly score of symptoms, patientsreported a beneficial effect a few days after the start of treatment.This rapid improvement may be explained by the fact that baclofen is effective in reducing gastro-oesophageal acid reflux immediatelyafter its first administration, as shown in the first part ofthis study.

Side effects were not reported in our patients, except for twowho interrupted their participation because of low blood pressureand nocturnal anxiety that were assumed to be due to baclofen. Baclofen has been reported to be a well tolerated drug and severeside effects have been reported at higher dosages in patientstreated for periods much longer than those used in the presentstudy.27

In summary, in the present study the GABAB agonist baclofen in multiple doses reduced gastro-oesophageal acid reflux fora 24 hour period in terms of the number and period of acid exposurein the oesophagus in both normal subjects and in patients withGORD without or with only mild oesophagitis. The improvementin reflux parameters and of symptoms related to gastro-oesophagealreflux in patients with GORD treated for four weeks with baclofen suggest a potential therapeutic role for this drug in the treatment of gastro-oesophageal reflux disease.  


The authors thank Dr Samuela Bartolacci for help in collectingdata and Catherine Di Placido for reviewing the English styleof the manuscript. Preliminary data from this study were presentedas an oral presentation at the 102nd Annual Meeting of the AmericanGastroenterological Association, May 20–23, 2001, Atlanta,and were published in abstract form in Gastroenterology 2001;120:A34. 


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Effect of acute and chronic administration of the GABAB agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease

A F Ciccaglione
and L Marzio

University G d’ Annunzio, Chieti-Pescara, Italy

BMJ Publishing Group & British Society of Gastroenterology.   2003;52:464-470


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