Low-dose lactose in drugs neither increases breath hydrogen

Low-dose lactose in drugs neither increases breath hydrogen excretion nor causes gastrointestinal symptoms

M.MONTALTO,A.GALLO,L.SANTORO,F.D’ONOFRIO,V.CURIGLIANO,M.COVINO,

G.CAMMAROTA,A.GRIECO,A.GASBARRINI&G.GASBARRINI

Institute of Internal Medicine,Catholic University,Rome,Italy

Correspondence to:

Dr M.Montalto,Istituto di Medicina Interna,Policlinico‘‘A.Gemelli’’, Universita`Cattolica del Sacro Cuore, Largo A.Gemelli,8–00168Roma, Italia.

E-mail:mmontalto@rm.unicatt.it

Publication data

Submitted16May2008

First decision30May2008 Resubmitted14July2008 Resubmitted21July2008

Accepted22July2008

Epub Accepted Article24July2008SUMMARY

Background

Despite the reported tolerance to a low dose of lactose,many lactose malabsorbers follow a rigorous lactose-free diet also avoiding lactose-containing drugs.Up to now,only a few case reports have described the onset of gastrointestinal symptoms in lactose malabsorbers follow-ing the ingestion of these drugs.It has been suggested that capsules?tablets contain no more than400mg of lactose.

Aim

To evaluate breath H2excretion and intolerance symptoms after inges-tion of a capsule containing400mg of lactose or placebo through a randomized,cross-over,double-blind,controlled study.

Methods

Seventy-seven lactose maldigesters with intolerance underwent two H2 breath tests with both400mg of lactose and400mg of placebo.Gastro-intestinal symptoms occurring in the8h following the ingestion of dif-ferent substrates were evaluated by a visual-analogue scale.

Results

Ingestion of400mg of lactose did not cause a signi?cant difference in breath H2excretion or in the severity of gastrointestinal symptoms compared to placebo.

Conclusion

In patients with lactase de?ciency,drugs containing400mg of lactose or less can be used safely.

Aliment Pharmacol Ther28,1003–1012 Alimentary Pharmacology&Therapeutics

a2008The Authors1003 Journal compilationa2008Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2008.03815.x

INTRODUCTION

Lactose malabsorption is a very common condition caused by a de?ciency of the intestinal enzyme that hydrolyses lactose into its components,galactose and glucose.1High concentrations of lactase are physiolog-ically present in neonates while,after weaning,a genetically programmed and irreversible reduction in its activity occurs in a majority of the world’s popula-tion.2Therefore,hypolactasia should not be considered a disease but rather a common pattern in human physiology.3

Undigested lactose causes an increased osmotic load in the bowel lumen,leading to a greater secretion of electrolytes and?uids;it is also fermented by the colonic micro?ora to short-chain fatty acids and gas.4 Sugar malabsorption does not necessarily result in the development of intolerance symptoms(e.g.abdominal bloating and pain,?atulence,nausea,borborygmi, diarrhoea),such symptoms occurring only in about one third to a half of lactose maldigesters.5–7

To date,the minimum dose of lactose causing symptoms has not been unequivocally established.It is thought that most lactose maldigesters can tolerate lactose amounts below12g(i.e.the amount present in a cup of milk).8,9However,gastrointestinal symp-toms have been reported after ingestion of smaller doses of lactose.10,11Furthermore,in clinical prac-tice,it is very common to?nd lactose maldigesters who believe that the ingestion of a minimal amount of sugar(e.g.white coffee)can produce gastrointesti-nal symptoms.Frequently encouraged by news media or advised by their family physicians,they start a restrictive lactose-free diet,also avoiding the use of a number of sugar containing pharmaceutical prod-ucts.In fact,lactose,being stable,readily dissolved, not expensive and with a slightly sweet taste,is very frequently used in drug industry as?ller or bulking agent for many oral formulations.12It has been esti-mated that lactose is a component of about20%of prescriptions and6%of over-the-counter medica-tions.13In the Italian Physician’s Desk Reference,we have found at least950of about2900available oral drugs(about33%)containing lactose as an excipi-ent.In particular,among these,capsule?tablet formu-lations contain,when speci?ed,no more than 400mg of lactose.Sometimes,labels of these medi-cations warn that their administration is not recom-mended in lactase de?cient people.Moreover,in some recent scienti?c publications,authors suggest caution with these medications or even warn not to use them.14–16

The onset of gastrointestinal symptoms after inges-tion of a lactose containing drug in lactose maldigest-ers has been described only in a limited number of case reports,17–20and population studies are lacking. The aim of our study was to assess if the adminis-tration of a capsule containing400mg of lactose could be responsible for changes in H2excretion and for intolerance symptoms with respect to placebo. METHODS

Patients and study design

Between September2006and December2007,a total of875subjects,referred to the Day Hospital of Inter-nal Medicine and Gastroenterology of The Catholic University of Rome because of gastrointestinal symp-toms compatible with lactose malabsorption,entered the study.All subjects underwent a20-g lactose H2 breath test(LBT)to identify lactose maldigesters.Those with a positive LBT subsequently underwent a glucose H2breath test(GBT)to exclude small intestinal bacte-rial overgrowth.We considered for the study only sub-jects with positive LBT and negative GBT.Exclusion criteria were:absence of intolerance symptoms at LBT; well-known causes of secondary hypolactasia such as coeliac disease,chronic in?ammatory bowel diseases, chemotherapy,colchicine,radiation enteritis,HIV enteropathy,severe gastroenteritis,intestinal allergies and intestinal parasitosis,other major illness,history of gastrointestinal surgery;recent(<2months)antibi-otic,laxative or prokinetic treatment;age<18and >75years.

The presence of coexisting irritable bowel syndrome (IBS)was evaluated on the basis of Rome III criteria.21 Finally,patients were asked if they believed that,in the past,ingestion of drugs known to contain lactose had produced gastrointestinal symptoms.Such patients were considered lactose-containing drug intolerants (LCDIs).

In a double-blind,cross-over trial,all the enrolled subjects underwent two H2breath tests after ingestion at random of a capsule containing400mg of lactose (test A)and a capsule containing400mg of placebo (test B).Clinical evaluation was performed by inviting all subjects to record in a questionnaire possible symptoms occurring after ingestion of the different substrates.All tests were performed at least21days

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apart,to prevent the effect of colonic acidi?cation. During the whole period of the study,all patients were instructed not to modify their dietary habits and life style.

All subjects gave their written informed consent to participate in the study.

The study was approved by the Ethical Committee of the Faculty of Medicine,The Catholic University of Rome.

Methods

Hydrogen breath test.The evening before each test, all subjects consumed a meal of only rice,meat and olive oil to avoid the possible in?uence,on basal H2 values,of prolonged gas production due to the pres-ence of non-absorbable or slowly fermentable material in the colonic lumen.After an overnight fast,and a mouthwash with clorhexidine to eliminate the possible early hydrogen peak due to the fermentation of the ingested sugar by oropharyngeal bacteria,the patients took the substrate.Smoking and physical exercise were forbidden an hour before and throughout the test.Sampling of alveolar air was performed with a commercial device,which allows the?rst500mL of dead space air to be separated and discarded,while the remaining700mL of end-alveolar air are collected in a gas-tight bag(Gasampler;Quintron Instrument, Milwaukee,WI,USA).Subjects were instructed to avoid deep inspiration and not to hyperventilate before exhalation.For the analysis of H2concentration in air samples,a dedicated gas chromatograph(Model DP12;Quintron Instrument)was used.For LBT and H2 breath test with400mg of lactose?placebo,we evalu-ated maximum H2concentration,as parts per million (ppm)and cumulative H2excretion,as ppm per min-ute,the latter obtained using the formula for the sum of areas of consecutive trapezoids,in accordance with Kotler.22

Lactose H2breath test.A hydrogen breath test using 20g of lactose was performed for the diagnosis of lactose malabsorption.Breath samples were taken at fasting and every30min for4h after ingestion of lactose dissolved in250mL of water.An increase in H2concentration of at least20ppm above the basal value was considered indicative of lactose malabsorption.Glucose H2breath test.Breath samples were taken at fasting and every10min for2h after ingestion of75g of glucose.An increase in H2concentration of at least12ppm above the basal value was con-sidered indicative of small intestinal bacterial over-growth.23

Hydrogen breath test after ingestion of capsules. Breath samples were taken at fasting and every 30min for4h after ingestion of a capsule containing 400mg of lactose(test A)and a capsule containing 400mg of placebo(test B).

Capsule composition.Capsules were produced by Galeno s.r.l.,Prato,Italy.Capsules used in test A (capsule A)contained400mg of monohydrate lactose, as a water-soluble,alcohol-insoluble,inodorous and crystalline white dust.Capsules used for test B(capsule B)contained placebo consisting of400mg of malto-dextrines formed by a water-soluble,alcohol-insoluble mixture of glucose,disaccharides and polysaccharides, obtained by partial starch hydrolysis.

The two types of capsules were indistinguishable in colour and form;they were packed in two identical boxes stored at room temperature(<30°C)and relative humidity(<50%).Each box was labelled with codes(A or B)kept undisclosed until all data were collected.A blinded investigator administered the capsules and the enrolled subjects did not receive any information about the content of the capsules.

Clinical evaluation.On the test day,for8h after sub-strate ingestion in LBT,tests A and B,all subjects recorded according to the visual-analogue scale (VAS),the severity of four intolerance symptoms (abdominal bloating,abdominal pain,?atulence,bor-borygmi).The VAS was represented by a10-cm line, anchored with two verbal descriptors to the extremi-ties,indicating‘no pain’(0cm)and‘worst imaginable pain’(10cm)respectively.The patients were asked to mark the10-cm line to indicate pain intensity.The score was measured from the zero anchor to the patient’s mark.24We calculated the VAS for each symptoms and the cumulative VAS by summing the single symptom VAS.In the same observation period, diarrhoea,de?ned as watery defecation,was evaluated as present?absent.

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Statistical analysis.Maximum H2concentration, cumulative H2excretion,clinical parameters(cumula-tive VAS,abdominal bloating VAS,abdominal pain VAS,?atulence VAS,borborygmi VAS)were reported after ingestion of lactose20g(LBT),lactose400mg (test A)or placebo400mg(test B).Differences among groups were analysed by means of one-way analysis of variance.The post hoc effect was assessed by Bon-ferroni t-test.t-Test for unpaired data was used when comparison was restricted to only two groups.The sta-tistical analysis of categorical parameters was per-formed with the Chi-square test.Correlation analysis was assessed by Pearson’s test.

All values were assessed as mean?standard deviation.A P-value of0.05or less was regarded as signi?cant.

RESULTS

Demographic data of the whole study group and dif-ferent subgroups are summarized in Table1.

Out of the875subjects with suspected lactose mal-absorption,495(56.5%)were LBT positive.Among these,192(38.8%)were excluded because they did not experience symptoms during LBT,134(27.1%)were not considered because of GBT positivity and28 (5.6%)were ruled out based on the other above men-tioned exclusion criteria.

Out of the141eligible patients,77Caucasians gave their informed consent to participate in the study. Twenty-seven of77subjects(35.1%)were consid-ered IBS positive on the basis of the Rome III criteria. Twenty-seven of77subjects(35.1%)were in the LCDI subgroup.

Results of the considered parameters in the whole study group are summarized in Table 2.Results as regards gender,IBS and LCDI status are summarized in Table3.

H2excretion

No signi?cant differences were found in both maxi-mum H2concentration and mean cumulative H2 excretion between tests A and B.The same parameters were signi?cantly lower in both tests A and B when compared to LBT(Figure1).

No signi?cant differences in either maximum H2 concentration or mean cumulative H2excretion were found,in all three tests,between men and women,IBS and non-IBS and LCDI and non-LCDI subjects.In all of these subgroups,comparison between tests A and B showed no signi?cant differences for H2parameters, while a signi?cant difference was found between LBT and both tests A and B.

In all three tests,no correlation was found between either mean cumulative H2excretion or mean maximum H2concentration and age(P=ns for all correlations).

Clinical evaluation

In the entire study group,all single symptom VAS and mean cumulative VAS scores did not differ sig-ni?cantly between tests A and B,while they were signi?cantly lower in both these tests when compared to LBT(Figure2).As regards the presence of diar-rhoea,no statistical difference was found among the three tests.

No statistical differences were found in single symp-tom VAS values and diarrhoea,between men and women in tests A and B;in LBT all single symptom VAS values were signi?cantly higher in women than in men.As regards the mean cumulative VAS,no sig-ni?cant differences were found between men and women in test A,while this parameter was signi?-cantly higher in women in test B and LBT.When women were analysed separately,no signi?cant differ-ences were found in all evaluated clinical parameters between tests A and B.

In all three tests,a trend to a higher clinical score (single symptom VAS values and mean cumulative VAS)was found for IBS subjects compared with non-IBS subjects,this difference statistical being signi?cant only for some of the considered parameters,as shown

Table1.Demographic data of the population study

Male Female Total Mean age?s.d.;range (years)

Whole study

group

22557743.75?12.97;25–72

Subgroups

IBS3242743.33?12.46;25–62

non-IBS19315043.98?13.35;25–72

LCDI3242737.04?11.46;25–60

non-LCDI19315047.38?12.36;27–72

LCDI,lactose-containing drug intolerant.

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in Table3.In all the three tests,there was no signi?-cant difference as regards diarrhoea between IBS and non-IBS subjects.When IBS subjects were considered separately,no signi?cant differences were found in all evaluated clinical parameters between tests A and B. No signi?cant differences in all three tests were found between LCDI and non-LCDI subjects for all VAS scores considered and diarrhoea.If LCDI subjects were analysed separately,no signi?cant differences were found in all evaluated clinical parameters between tests A and B.

No correlation was found,in both tests A and B, between age and all clinical parameters(P=N.S.for all correlations),while in LBT an inverse correlation was shown only between age and abdominal bloating VAS(P<0.01).

DISCUSSION

Our study shows that the ingestion of400mg of lac-tose does not cause signi?cant differences in breath H2 excretion and severity of gastrointestinal symptoms compared to placebo.

In clinical practice,as well as in daily life,tolerance to lactose in drugs is debated and is still an open question.No population studies have been performed as yet and only a few case reports have been described.Lieb et al.17described two patients with lac-tose malabsorption in whom abdominal cramps and diarrhoea developed,after a medication with lithium carbonate and?urazepam hydrochloride(both of them containing unspeci?ed dosages of lactose)was started. Petrini et al.19observed two lactase-de?cient women with Graves’disease who experienced severe diarrhoea after ingestion of propylthiouracil(amount of lactose not speci?ed)and methimazole(about60mg of lactose).Previously,Brandstetter et al.described the case of a young woman with lactase de?ciency who complained of gastrointestinal symptoms after inhala-tion of a capsule of cromolyn sodium containing 20mg of lactose.The authors supposed that lactose intolerance was related to the oral or pharyngeal deposition of inhaled mixture and subsequent gastro-intestinal passage.20In all these case reports,the authors have hypothesized a possible cause–effect link between ingestion of lactose-containing medications and occurrence of gastrointestinal symptoms on the basis of a strictly temporal relationship and the absence of clinical symptoms after challenge with the same drug deprived of lactose.Our randomized, double-blind,cross-over,controlled trial represents the?rst study aimed at evaluating tolerance to the amount of lactose present in medications.

Previous studies had evaluated tolerance to low quantities of lactose by the administration of the sugar dissolved in chemically lactose-deprived milk or in water.Bedine and Bayless,by giving different amounts of lactose(3,6,12,24,48and96g)in a solution similar to the electrolyte composition of milk, found that after ingestion of3g of lactose,two of

Table2.Results in the entire

study group

LBT Test A Test B

Maximum H2concentration55.25?31.92 2.71?3.58 2.64?3.19

Cumulative H2excretion5019.55?3777.00437.73?498.60429.74?460.76

Bloating VAS 4.03?1.98 1.40?1.90 1.50?2.18

Abdominal pain VAS 3.16?2.060.80?1.420.88?1.58

Flatulence VAS 2.95?1.96 1.23?1.73 1.14?1.50

Borborygmi VAS 2.95?1.99 1.04?1.72 1.16?1.65

Cumulative VAS13.1?6.68 4.46?5.73 4.69?5.70

Diarrhoea7?772?773?77

VAS,visual-analogue scale;LBT,lactose H2breath test.

Maximum hydrogen concentration is expressed in parts per million.Cumulative hydro-

gen excretion is expressed as parts per million per minute.Diarrhoea is expressed as

patients with diarrhoea?total patients.

No statistical difference was found,for all considered parameters,when test A was com-

pared to test B.Signi?cant difference was observed,for all breath H2parameters and

VAS scores,when LBT was compared to both tests A and B(P<0.001).No statistical

difference was found for diarrhoea among LBT,tests A and B.

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a2008The Authors,Aliment Pharmacol Ther28,1003–1012

Journal compilationa2008Blackwell Publishing Ltd

T a b l e 3.R e s u l t s o f c o n s i d e r e d p a r a m e t e r s a s r e g a r d g e n d e r ,I B S a n d l a c t o s e -c o n t a i n i n g d r u g i n t o l e r a n t s t a t u s

L B T T e s t A T e s t B

M a l e –f e m a l e M a x i m u m H 2c o n c e n t r a t i o n 48.14?27.94–58.09?33.181.82?1.87–3.07?4.032.55?2.56–2.67?3.43C u m u l a t i v e H 2e x c r e t i o n 4268.86?2579.57–5319.82?4143.49323.86?273.02–483.27?559.92394.77?314.11–443.73?509.63B l o a t i n g V A S 2.50?1.14–4.64?1.92*0.96?1.47–1.57?2.030.76?1.21–1.80?2.41A b d o m i n a l p a i n V A S 1.79?1.27–3.71?2.07*0.33?0.74–0.99?1.570.33?0.95–1.10?1.73F l a t u l e n c e V A S 1.93?1.51–3.35?1.99*0.86?1.64–1.37?1.760.65?0.97–1.33?1.63B o r b o r y g m i V A S 1.82?1.45–3.41?2.01*0.90?1.69–1.10?1.740.71?1.28–1.35?1.75C u m u l a t i v e V A S 8.05?4.27–15.12?6.42*3.05?4.60–5.03?6.082.45?3.52–5.58?6.17*D i a r r h o e a 2?22–5?55

1?22–1?550?22–

3?55

I B S –n o n -I B S M a x i m u m H 2c o n c e n t r a t i o n 55.89?31.25–54.90?32.583.33?4.47–2.38?3.002.81?3.17–2.54?3.23C u m u l a t i v e H 2e x c r e t i o n 5624.44?4674.44–4692.90?3197.17504.44?586.29–401.70?446.57435.00?344.46–426.90?516.19B l o a t i n g V A S 4.72?2.07–3.66?1.85*2.01?2.46–1.06?1.44*2.62?2.80–0.90?1.47*A b d o m i n a l p a i n V A S 3.93?2.14–2.75?1.91*1.33?1.91–0.51?0.96*1.74?2.04–0.41?1.03*F l a t u l e n c e V A S 3.24?2.19–2.79?1.831.71?2.10–0.97?1.451.61?1.74–0.88?1.30*B o r b o r y g m i V A S 13.57?2.14–2.62?1.841.28?2.05–0.91?1.511.76?2.10–0.84?1.25C u m u l a t i v e V A S 15.46?6.54–11.82?6.46*6.34?7.70–3.45?4.06*7.74?7.15–3.04?3.93*D i a r r h o e a 3?27

–4?501?27–1?50

1?27

–

2?50

L C D I –n o n -L C D I M a x i m u m H 2c o n c e n t r a t i o n 55.85?21.46–54.92?36.542.70?3.77–2.72?3.523.04?2.90–2.42?3.35C u m u l a t i v e H 2e x c r e t i o n 5040.00?2618.10–5008.50?4299.89414.44?456.22–450.30?524.20439.44?283.99–424.50?535.17B l o a t i n g V A S 4.67?2.17–3.69?1.801.24?2.11–1.49?1.811.48?2.41–1.52?2.08A b d o m i n a l p a i n V A S 3.78?2.20–2.83?1.930.78?1.60–0.81?1.331.03?1.98–0.80?1.35F l a t u l e n c e V A S 3.32?2.03–2.75?1.921.20?1.80–1.25?1.721.30?1.84–1.06?1.31B o r b o r y g m i V A S 3.52?2.26–2.65?1.790.98?1.62–1.08?1.791.30?1.86–1.10?1.54C u m u l a t i v e V A S 15.28?6.98–11.92?6.284.19?6.40–4.62?5.415.10?6.81–4.47?5.07D i a r r h o e a

3?27–4?501?27–

1?50

1?27

–

2?50

V A S ,v i s u a l -a n a l o g u e s c a l e ;L C D I ,l a c t o s e -c o n t a i n i n g d r u g i n t o l e r a n t ;L B T ,l a c t o s e H 2b r e a t h t e s t .M a x i m u m h y d r o g e n c o n c e n t r a t i o n i s e x p r e s s e d i n p a r t s p e r m i l l i o n .C u m u l a t i v e h y d r o g e n e x c r e t i o n i s e x p r e s s e d a s p a r t s p e r m i l l i o n p e r m i n u t e .D i a r r h o e a w a s e x p r e s s e d a s p a t i e n t s w i t h d i a r r h o e a ?t o t a l p a t i e n t s .*S i g n i ?c a n t d i f f e r e n c e b e t w e e n m a l e a n d f e m a l e ,I B S a n d n o n -I B S ,L C D I a n d n o n -L C D I ;P <0.05.W h e n m a l e ,f e m a l e ,I B S ,n o n -I B S ,L C D I a n d n o n -L C D I s u b g r o u p s w e r e s e p a r a t e l y a n a l y s e d ,c o m p a r i s o n b e t w e e n t e s t s A a n d B s h o w e d n o s i g n i ?c a n t d i f f e r e n c e s f o r a l l t h e c o n s i d e r e d p a r a m e t e r s ;c o m p a r i s o n b e t w e e n L B T a n d b o t h t e s t s A a n d B s h o w e d s i g n i ?c a n t d i f f e r e n c e f o r a l l t h e c o n s i d e r e d p a r a m e t e r s (P <0.05)e x c e p t f o r B o r -b o r y g m i V A S b e t w e e n L B T a n d t e s t A i n m a l e s u b g r o u p (P =N .S .).

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20lactase-de?cient subjects experienced gastrointes-tinal symptoms.None of them complained of symp-toms after administration of the same doses of a glucose ?galactose control challenge.However,in this study,no attempt was made to match the ?avour or colour of treatments and no statistical evaluation of symptoms response was performed.10Later,Hertzler et al.25in 1996demonstrated that,in 13lactose maldi-gesters receiving ?ve solutions with 0,2,6,12and 20g of lactose dissolved in water (not distinguishable according to a triangle sensory test),symptoms devel-oped only after a 12-g lactose dose or higher,even if a signi?cant H 2breath increase occurred after 6g of sugar.The same year,Vesa et al.26studied 39lactose maldigesters and showed that increasing amounts of lactose (0.5,1.5and 7g)did not cause signi?cant dif-ferences in the severity of gastrointestinal symptoms compared to milk chromatographically deprived of lac-tose.Symptom occurrence after low doses of lactose has been investigated also in lactose containing foods.

In particular,Ja

¨rvinen et al.27examined 27symptom-atic lactose maldigesters,after the administration of milk chocolate samples containing 0,2and 12g of

lactose,and demonstrated no signi?cant differences among different samples.

Despite these ?ndings,many physicians still believe that lactose maldigesters should follow a rigorous lactose-free diet.According to this therapeutic strat-egy,they advise their patients to refrain also from medications containing lactose as an excipient,often encouraged by labels warning that their use is not recommended in lactase-de?cient patients.In addi-tion,numerous articles in the news media and even some recent scienti?c publications promote this attitude.14–16

It is possible that this lack of clarity is because of the complexity of correctly establishing the threshold level for symptom onset,because many variables can impact on it.28,29Psychological factors can also play a pivotal role in lactose intolerance.In clinical practice,it is common to ?nd subjects,who attri-bute the occurrence of symptoms to those foods (for example,lactose or fat)notoriously believed to be responsible for gastrointestinal disorders.In this regard,Suarez reported that a majority of subjects who consider themselves as severely lactose-intolerant

1009080706050403020100

M e a n m a x i m u m H 2 c o n c e n t r a t i o n (p p m )

M e a n c u m u l a t i v e H 2 e x c r e t i o n (p p m )

900080007000600050004000300020001000

LBT

Test A T est B

LBT

Test A Test B

P = N.S.

P < 0.001

Figure 1.Mean maximum H 2concentration and mean cumulative H 2concentration in the three tests.

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may erroneously attribute a variety of abdominal symptoms to lactose maldigestion as they do not show any difference in the severity of gastrointestinal symptoms after the administration of 240mL of milk compared to placebo.9In our study,we evaluated LCDI subjects separately,possibly representing a subgroup of extremely intolerant people.Similarly,in these subjects,no statistical differences were observed in H 2excretion and clinical score between lactose and placebo.Therefore,it is possible that our LCDI subjects mistakenly link the occurrence of intolerance symp-toms to lactose ingestion.

It has been reported that lactose intolerance is more prevalent in IBS subjects because of altered intestinal motility and visceral hypersensitivity.29–31Our IBS subgroup showed more severe scores for some gastro-intestinal symptoms when compared to the non-IBS subgroup after ingestion of 400mg of lactose,despite no signi?cant differences in H 2production,but the same result was observed also after ingestion of 400mg of placebo.Therefore,IBS patients might have reported more signi?cant symptoms irrespective of the administered substrate,probably because of unspeci?c visceral hypersensitivity and psychological factors,known to play a key role in the disease.

Previous studies reported that lactose malabsorp-tion is independent of gender,but this does not seem to apply to lactose intolerance,the latter condition being more prevalent in women.30,31These ?ndings have been related to an increased prevalence of IBS in female subjects.32In agreement with these authors,in our study,we have shown that after ingestion of 20g of lactose,women experienced more severe symptoms than men.However,this difference was missing with 400mg of sugar,supporting the hypothesis that,even in more sensitive individuals,the amount of lactose in drugs does not cause notable symptoms.

In addition,in lactose malabsorbers,no correlation between age and severity of intolerance was described.33We obtained similar ?ndings except for bloating VAS score in LBT,being higher in younger people;no correlation between age and clinical picture was evidenced using 400mg of lactose.

Bloating Abdominal pain Flatulence Cumulative

Borborygmi

LBT

Test A

Test B LBT

T est A Test B LBT T est A Test B

LBT Test A Test B LBT T est A Test B

1086V A S s c o r e

V A S s c o r e

420

1086420

10P < 0.001P < 0.001

P < 0.001

P < 0.001P < 0.001

P = N.S.

P < N.S.

86420

201612840

Figure 2.Single symptom visual-analogue scale (VAS)and cumulative VAS in the three tests.

1010M.MONTALTO et al.

a2008The Authors,Aliment Pharmacol Ther 28,1003–1012Journal compilation a2008Blackwell Publishing Ltd

Finally,we found a high positive glucose test rate (about27%).We suppose that it does not represent a surprising?nding in our study population.In fact, symptoms occuring in our patients can also occur in SIBO,especially after ingestion of fermentable foods as dairy products.34This high prevalence of SIBO could represent an underestimated condition in people complaining of symptoms.

CONCLUSION

In conclusion,we have demonstrated that the adminis-tration of capsules containing400mg of lactose does not produce different changes in H2breath excretion and gastrointestinal symptoms in lactose maldigesters compared to placebo.The same?ndings have been observed in subjects with self reported intolerance of lactose-containing drugs.These results suggest that lactose in drugs can be mistakenly considered respon-sible for gastrointestinal symptoms,thus in?uencing medication compliance or suggesting the use of alternative,not always considered equally effective, therapeutic approaches.According to these?ndings, lactase de?ciency should no longer be considered a contraindication to the use of medications with similar or lower doses of lactose. ACKNOWLEDGEMENTS

We are very grateful to Dr Angelo Montecuollo who prepared the capsules for the study.Declaration of personal and funding interests:None.

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