Mechanism of Action of Lactulose
Lactulose is a synthetic disaccharide that is not digested in the small intestine and exerts its therapeutic effect through osmotic action in the colon, drawing water into the intestinal lumen to promote peristalsis and soften stool. 1, 2
Primary Mechanisms
Osmotic Laxative Effect
- Lactulose remains unabsorbed in the small intestine and reaches the colon essentially unchanged, where it exerts an osmotic effect by retaining water in the colonic lumen 1, 2
- Urinary excretion is only 3% or less, confirming minimal systemic absorption, with excretion essentially complete within 24 hours 2
- When incubated with human small intestinal mucosa extracts, lactulose was not hydrolyzed during a 24-hour period and did not inhibit lactase activity 2
Colonic Bacterial Fermentation
- Once in the colon, lactulose is metabolized by colonic bacteria into low molecular weight acids (primarily lactic acid and short-chain fatty acids), which acidify the colonic contents 1, 2
- This bacterial degradation promotes the growth and activity of beneficial lactic acid bacteria (Bifidobacterium and Lactobacillus species) while counteracting detrimental species such as clostridia 3
- The acidification process converts ammonia (NH3) to the ammonium ion (NH4+), trapping it in the colon and preventing absorption—this is the basis for its use in hepatic encephalopathy 2
Prokinetic Action
- The metabolites of lactulose stimulate colonic peristalsis, expelling trapped contents and promoting bowel movements 2
- The osmotic gradient created by lactulose increases small bowel water content, which is more pronounced in IBS patients compared to healthy controls 4
Special Considerations in IBS Patients
Abnormal Intestinal Response
- IBS patients demonstrate abnormal accumulation of fluid in the small bowel following lactulose ingestion, with significantly greater increases in small bowel water content compared to healthy controls (p = 0.0005) 4
- This may result from impaired motor activity of the small intestine or impaired function of the ileocecal segment 4
Symptom Provocation
- Lactulose provokes significantly more symptoms in IBS patients than in healthy controls (p < 0.0001), despite similar mechanisms of action 4
- The intensity of symptoms following lactulose challenge correlates with visceral hypersensitivity measured by rectal barostat (p < 0.05-0.001), making it a potential noninvasive marker of visceral sensitivity 5
- Patients with high-intensity GI symptoms after lactulose challenge have more severe IBS (p < 0.0001), higher somatization (p < 0.01), and lower quality of life (p < 0.05-0.01) 5
Gas Production and Symptoms
- Lactulose fermentation by colonic bacteria produces hydrogen and methane gas, which can be measured via breath testing 1, 6
- Subjects with positive lactulose breath tests have significantly greater gas volume scores and more gas-related symptoms (bloating frequency p = 0.02, flatulence severity p = 0.02) 6
- However, symptom intensity does not correlate with the amount of gas produced or fecal microbiota composition, suggesting visceral hypersensitivity rather than excessive gas production drives symptoms in IBS 5
Clinical Implications for IBS
Dosing Considerations
- The FDA-approved dose for constipation is 10-20 g (15-30 mL or 1-2 packets) daily, which may be increased to 40 g (60 mL or 2-4 packets) daily if needed 1
- Bloating and flatulence are dose-dependent side effects occurring in approximately 20% of patients, which particularly limit use in IBS patients who already experience these symptoms 1, 7
Positioning in IBS Management
- Lactulose can be considered if IBS-C symptoms have failed to improve with fiber and over-the-counter laxatives, but only in individuals who do not experience significant bloating or abdominal pain with lactulose use 1
- The mechanism of lactulose—promoting fermentation and gas production—may exacerbate the core pathophysiologic features of IBS, including visceral hypersensitivity and abnormal gut-brain signaling 1