Quantifying the 'Hidden' Lactose in Drugs Used for the Treatment of Gastrointestinal Conditions

P. Eadala; J.P. Waud; S.B. Matthews; J.T. Green; A.K. Campbell


Aliment Pharmacol Ther. 2009;29(6):677-687. 

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These results clearly show that lactose is present in medications prescribed for the treatment of a wide range of GI disorders and this could lead to symptoms of LI in susceptible individuals. We also have identified that the ingestion of certain medications either alone or in combination may result in a patient consuming over 10 g of lactose a day in addition to that taken in the diet. Doctors may not know that the medicines they prescribe contain lactose as the details of the excipients in medicines are not available in the BNF (the most trusted guide used by doctors in UK).[24] Although the European Commission guidelines of 2003 state that by law manufacturers must list the excipient in the patient leaflets, they are not required to quantify the amount present. A summary of the product characteristics of drugs is listed in the MC; this is used by pharmacists to find information about excipients, but all versions of the drug are not listed in MC or ECM (electronic version of the compendium of medicine). It should also be noted that neither the MC nor the ECM are widely used by doctors and allied health professionals and many of are not even aware of them. We believe that the presence and quantity of lactose should be displayed in a prominent place to alert both the prescriber and the patient, e.g. in the BNF or the drug packet.

The primary form of therapy for LI is to identify a patient's lactose sensitivity and adjust the amount of lactose containing foods in the diet accordingly. Our results show that patients on a clinically restricted diet may inappropriately take medications that contain lactose in amounts that could cause symptoms. The details of excipients in medications are not readily accessible by doctors and other health professionals. They may also be unaware that lactose-free alternatives are available. It has been widely reported that most individuals tolerate up to 11.8 g of lactose per day (250 mL of milk).[25] Clinicians may not feel that the amount of lactose present in drug formulation is enough to contribute towards the symptoms of a patient. However, sensitivity to lactose varies widely in the severity of symptoms it causes. In highly sensitive individuals, it has been reported that the symptoms may occur after ingestion of as little as 200 mg of lactose and different types of medications have been shown to cause LI and in addition affect compliance.[13,26,27,28,29,30,31] This could easily be ingested by taking just a single dosage of several drug preparations. An example which is available in the UK is Budenofalk (Dr Falk) in which each 3 mg tablet contains 600 mg of lactose.

Although primary LI has been increasingly recognized as a clinically significant entity, the importance of secondary LI in patients with established GI diseases is unclear. IBS is a very common diagnosis, with a prevalence of up to 25% in the western world and patients present with at least one of the following symptoms: abdominal pain, bloating, constipation and/or diarrhoea. IBS symptoms are often indistinguishable from those of LI and it should be noted that LI does not lead to the development of IBS.[32] Lactose maldigestion affected 24-27% of patients with IBS;[33,34] 45% of IBS patients have LI, but only 30% related their symptoms to milk and dairy products while dietary exclusion only improved symptoms in 52% of patients. Some IBS patients without lactose maldigestion describe symptoms of LI.[35] A large number of IBS patients showed a clinically unrecognized lactose malabsorption, which could not be discriminated by symptoms and dietary history and which may be treated with a lactose-restricted diet. LI has to be excluded before the diagnosis of IBS is made.[33,36]

Coeliac disease is a life-long inflammatory condition of the GI tract that affects the small intestine in genetically susceptible individuals, which improves morphologically when gluten, the causative agent, is removed from the diet. It is much more common than previously suspected; recent studies show a prevalence of up to one in 100 of the UK population.[37] The inflammation of the small bowel leads to an alteration in the brush border with a reduction in the activity of the lactase enzyme. It is well known that patients affected by coeliac disease have a higher incidence of lactose malabsorption and the breath hydrogen excretion reflects the histological changes in the small bowel mucosa. Lactose malabsorption in many patients with untreated coeliac disease gives rise to more frequent and more watery stools. In well-treated coeliac disease, lactose malabsorption is not more common than in the general population.[38] In addition, a high prevalence of coeliac disease was observed in patients with a positive hydrogen lactose breath test compared to healthy controls where lactase deficiency seems to be the only manifestation of coeliac disease. Serologic screening for coeliac disease in all patients with a positive H2-lactose breath test should be carried out before beginning a milk-exclusion diet.[39]

Lactose intolerance in IBD was thought to be a cofactor that predisposed to a clinical attack or it is a consequence or accompanying phenomenon of the disease. Several studies have shown variable prevalence of LI in IBD. The prevalence of lactose malabsorption appears to be greater in IBD than in the general population. It is much more common in patients with Crohn's disease (40-46%) when compared with ulcerative colitis (13-16%).[40,41] In addition, lactose malabsorption is more common in Crohn's disease involving the small bowel (68%) when compared with the large bowel (43%).[41] It is also thought that the lactose malabsorption in Crohn's disease may be determined by factors other than lactase enzyme activity, such as bacterial overgrowth and/or accelerated small bowel transit time.[41] IBD patients avoid dairy products more often than they may need based on the prevalence of lactose malabsorption and/or milk intolerance, possibly because of incorrect patient perceptions and arbitrary advice from physicians.[41,42,43,44] The two SNPs C/C(-13910) and G/G(-22018) on chromosome 2 have been associated with the adult-type hypolactasia and it has been shown that these are not associated with susceptibility to the pathogenesis of Crohn's and ulcerative colitis.[45] These results suggest that mucosal damage of the small bowel leads to lactase deficiency which then causes lactose malabsorption.

Lactose malabsorption occurs as a result of acute infection like rotavirus, causing small intestinal injury with loss of the lactase-containing epithelial cells from the villi. The immature epithelial cells that replace these are often lactase deficient, leading to secondary lactose deficiency and lactose malabsorption. Giardiasis, cryptosporidiosis and other parasites that infect the proximal small intestine often lead to lactose malabsorption from direct injury to the epithelial cells by the parasite.

Approximately four out of 10 people with cancer will have radiotherapy as part of their treatment. During their 6-week course of radiotherapy, partly because of mucosal damage, 80% of patients will develop GI problems such as diarrhoea, abdominal cramps, tenesmus or faecal incontinence.[46] Small bowel bacterial overgrowth and LI (15%) may occur during radical pelvic radiotherapy and are likely to contribute to GI symptoms in some patients.[47] In the Finnish population, low lactase enzyme activity, defined by genotyping of the C/T (13910) variant (LI) may increase the risk of colorectal cancer.[48]

The drugs used in treatment of IBD like 5-ASA preparations and Budesonide are formulated to deliver the active ingredients topically to the distal small bowel and colon after oral ingestion. This is achieved by a pH-dependent release mechanism or through bacterial degradation. We have shown that some of these preparations contain lactose and as they remain intact in the upper GI tract, they will also deliver undigested lactose to the colon where they could give the symptoms of LI.

The clinical management of LI has been confused by not taking into account 'hidden' lactose in foods and medications as symptoms may occur after consumption of less than 250 mL of milk which is because of 'hidden' lactose and this is often overlooked by healthcare professionals.[49] Assessment of lactose derived from medications should be considered in addition to dietary sources for both primary and secondary hypolactasic patients. In such patients, the use of alternative 'lactose-free' medications may avoid exacerbating symptoms in GI disorders such as IBD or IBS. It should be noted that liquid preparations of most drugs are lactose-free and provide another alternative form of treatment in those with known lactose sensitivity. We believe that lactose-free medications should be prescribed in patients with high risk of LI due to ethnicity, in those whose symptoms worsen with no objective evidence of disease deterioration and in those who develop new LI symptoms after commencing medications. Ideally, in these groups of patients, tests to diagnose lactose intolerance should be carried out to aid both dietary advice and the prescription of medications.[19]

This work focuses on a selection of formulations available in the UK for the treatment of GI diseases; however, we are aware that certain drugs, for example, Pentasa, Nexium, Asacol and Omeprazole are manufactured with similar constituents in the US and Australia. Adult-type hypolactasia is a global problem, with varying severity based on ethnic origin. Migration and changing dietary habits and increasing use of lactose in food products will lead to increasing incidence of lactose intolerance. The significance of the presence of lactose in the medications needs to be further ascertained in a randomized control trial but in the meanwhile, observational data should be collected from patients with LI and GI conditions to see if they have symptomatic benefit from using lactose-free alternatives.