REVIEW ARTICLE
LACTULOSE IN THE MANAGEMENT OF CONSTIPATION: A CURRENT REVIEW Theresa V. Kot and Ngaire A. Pettit-Young
OBJECTIVE: To review the current published clinical studies evaluating the clinical efficacy and safety of lactulose compared with other laxatives or placebo. Adverse effects associated with lactulose are also reported.
Information was retrieved by searching the MEDLINE and EMBASE databases for clinical trials, abstracts, conference proceedings, and review articles dealing with lactulose. DATA SOURCES:
Emphasis was placed on clinical trials where lactulose was compared with other laxatives or placebo in patient populations where the diagnosis of constipation was reasonably established.
STUDY SELECTION:
DATA EXTRAcnON: The methodology and results from clinical studies were evaluated. Assessment of the studies was made based on diagnosis of constipation, prior management of patients, followup of patients, dosage, and adverse effects. DATA SYNTHESIS: Clinical trials in geriatric patients, terminally ill patients, children, and normal and constipated subjects were reviewed. In most instances, lactulose was compared with a placebo, without incorporating the current education on dietary techniques for improving defecation.
Generally, clinical trials have demonstrated a beneficial response compared with placebo, although sometimes that response has been only marginally better, from a clinical point of view. CONCLUSIONS:
AnnPharmacother 1992;26: 1277-82. in the management of constipation is often overshadowed by several factors, including its cost and clinical effectiveness. The cost of lactulose compared with other laxatives is relevant in hospital settings where endeavors are being made to contain drug expenditure. Consequently, prescribers cite published opinions and information from studies and review articles to support the limited prescribing of lactulose. This article evaluates some of the information on lactulose that has been published in the last decade. There was no intention to summarize all other laxatives unless such agents were compared with lactulose and would therefore provide further information. This review may be perceived
THE USE OF LAcruLOSE
THERESA V. KOT, B.Pharm., at the time of writing, was the Director, New South Wales Therapeutic Medicines Information Centre, Darlinghurst, NSW Australia; she is now with the Institute of Drug Research and Control, 30/34 Chelmska St., 00725 Warsaw, Poland; and NGAIRE A. PETTIT·YOUNG, B.A.Dip.Lib., is a Medical Librarian, New South Wales Therapeutic Medicines Information Centre. Reprints: The Annals of Pharmacotherapy, P.O. Box 42696, Cincinnati, OU 45242.
as deficient because certain disease states and age groups are mentioned and others are omitted. This should be viewed as a reflection of the research being undertaken and what has been published in the literature. Other authors have reviewed the pharmacology and use of laxatives, providing information and recommendations on the choice of agent. l -4 No review of lactulose has been published in recent years that summarizes the current knowledge of the management of constipation as studied and reported from clinical trials, open studies, or case reports.
Diagnosis ofConstipation The definition of constipation is variable, as the physician and the patient may use different measurements to diagnose the condition. Although there is no agreed definition of constipation, two aspects generally are stressed: difficulty when passing stools and stools that are infrequent.' Patients may also define constipation as straining with bowel movements, irregular defecation, and other gastrointestinal symptoms. Ninety-nine percent of the population have a bowel frequency ranging from three bowel movements per day to three per week.' Daily bowel movements are believed by some patients to be necessary to prevent absorption of toxic substances.' Therefore, the diagnosis of constipation should be based on a careful patient history including bowel frequency, stool consistency, the presence of blood or mucus, and the ease of evacuation. The onset of symptoms of constipation may assist in its diagnosis.' The patient can frequently present with a selfdiagnosis of constipation because of a decline in frequency of defecation, prolonged and difficult evacuation, or a sensation of incomplete evacuation; these signs may be indicative of an underlying cause of constipation.
Classification ofConstipation The classification of constipation is reasonably consistent and is divided into primary and secondary groups. I Secondary constipation may occur as a result of a disease or drug therapy. Primary or simple constipation may be associated with inadequate dietary fiber, dehydration, poor mobility, withholding of fecal matter evacuation, and reduced muscle tone. Barnes differentiated the primary classification of constipation in adults into the first subgroup, where there is an organic disease of the anus, rectum, and colon;
The Annals ofPharmacotherapy • Downloaded from aop.sagepub.com at CORNELL UNIV on September 5, 2016
1992 October.Volume 26 •
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and the second subgroup, where there is no structural or systemic disease.'
Indicationsfor Lactulose In reviewing the literature, the indications for a laxative need to be established, especially for a product that has been on the market for many years. The indications in the Australian product information for lactulose are portal-systemic encephalopathy and the treatment of chronic and habitual constipation. The American Hospital Formulary Service details the approved indications and those uses not currently approved by the US Food and Drug Administration," Below are listed the indications and uses of lactulose: 1. portal-systemic encephalopathy where it is used as an adjunct to protein restriction and supportive thera-
py6.7; 2. constipation, especially chronic constipation in adults and elderly patients"; 3. to restore regular bowel movements after hemor-
rhoidectomy"; 4. to induce bowel evacuation in elderly patients with colonic retention after a barium meal examination and severe constipation'; 5. constipation in the proximal colon in patients with distal colitis'; 6. when patients are investigated for underlying causes of constipation, an osmotic agent with bulk-forming agents may be required'; 7. constipation in the presence of normal bowel transit times and normal barium enemas'; 8. in bedridden or institutionalized patients on bulkforming agents, a stimulant or osmotic agent is prescribed to prevent impaction.' Many authors have expressed reservations about the cost-effectiveness of lactulose treatment for constipation. Thompson, after discussing the pharmacology and adverse effects associated with lactulose, states that "its cost and its relative lack of potency, make lactulose unsuitable for the routine treatment of constipation.?" One reference text states that the superiority of lactulose to conventional laxatives has not been established in the treatment of chronic constipation." The cost of lactulose is mentioned by other authors, with the recommendation that it should be used only in patients needing its specific effects or who do not respond to other agents.P Tedesco and DiPiro suggest lactulose in bedridden or institutionalized patients receiving daily bulk-forming laxatives, but only after other agents have proven ineffective.'
PharmacologyofLactulose Lactulose, a synthetic disaccharide, is classified as an osmotic laxative. It is metabolized by bacteria in the colon and the metabolites then acidify the contents of the colon. This has an irritant, as well as an osmotic effect, on the distal colon and rectum.Y After metabolism in the colon, the short-chain organic acid metabolites are absorbed so that the osmotic effect does not continue throughout the colon? However, this fact is at variance with published data stating that negligible amounts of lactulose and its metabolites are absorbed from the colon." This difference in information on the absorption of the metabolites cannot be easily resolved as both statements are unreferenced. However, 1278
•
the caution and warning for the use of lactulose in diabetic patients would lead to the assumption that there is some absorption of galactose and lactose. Lactulose usually requires 24-48 hours for its onset of action.P?
Adverse Reactions with Lactulose GASTROINTESTINAL REACTIONS
Abdominal cramps, gaseous distention, belching, flatulence, bowel distention, unpleasant taste, diarrhea, and borborygmi have been reported with lactulose.Pe" Wright reported five observations of colonic dilation in elderly patients using lactulose for constipation. These patients received broad-spectrum antibiotics, ceased the use of lactulose, and symptoms resolved. Wright suggested that these cases of "nontoxic megacolon" are related to gas production by the bacterial metabolism of lactulose," METABOLIC OR ELECTROLYTE DISORDERS
Electrolyte imbalance in long-term use I and severe hypernatremia secondary to fluid depletion" have been reported. The manufacturer responded that the daily dose in the latter reaction was 720 mL, more than 20 times the normal starting dose for the treatment of constipation." In 1984, Nanji and Lauener described a case of hypernatremia in a 72-year-old woman with a history of hypertension, congestive heart failure, and positive serologic tests for hepatitis. This patient also received lactulose 720 mL/d for suspected hepatic encephalopathy," TOLERANCE OR DEPENDENCE POTENTIAL
Some authors mention that tolerance may develop with continued use l ,7,12; however, the manufacturer refuted this suggestion." Perkin contended that tolerance does not occur with lactulose and that stopping therapy does not cause rebound constipation or problems of withdrawal." Because there is some disagreement about the occurrence of tolerance with continued use of lactulose, this point was further evaluated by referring to the original articles. Wesselius-De Casparis et al. studied lactulose in elderly patients who regularly used laxatives for chronic constipation." Florent et al. used healthy human volunteers to study the intracolonic metabolism of lactulose. IS Although these studies were not designed to evaluate tolerance to lactulose, they are cited as supporting such claims. The relevant points of each study and the results are summarized, and opinions by Bateman and Smith" and the manufacturer are expressed. 10 Wesselius-De Casparis et al. studied 103 elderly patients who were regularly taking laxatives for chronic constipation. The study was arranged into three phases: a two-week observation period where frequency of defecation and pattern oflaxative use were determined; a three-week treatment phase where patients were randomly assigned to receive lactulose 50% or glucose syrup; and a two-week observation, posttreatment period. The criterion used to assess the effectiveness of lactulose was the need for additional laxatives during the treatment period (i.e., successful management was defmed as no requirement for additional laxatives). The study showed a statistically significant difference for the use of laxatives between the lactulose and glucose treatment groups (86 vs. 60 percent, respectively,
The Annals ofPharmacotherapy • 1992 October, Volume 26 Downloaded from aop.sagepub.com at CORNELL UNIV on September 5, 2016
Lactulose in Constipation
p
LACTULOSE IN THE MANAGEMENT OF CONSTIPATION: A CURRENT REVIEW Theresa V. Kot and Ngaire A. Pettit-Young
OBJECTIVE: To review the current published clinical studies evaluating the clinical efficacy and safety of lactulose compared with other laxatives or placebo. Adverse effects associated with lactulose are also reported.
Information was retrieved by searching the MEDLINE and EMBASE databases for clinical trials, abstracts, conference proceedings, and review articles dealing with lactulose. DATA SOURCES:
Emphasis was placed on clinical trials where lactulose was compared with other laxatives or placebo in patient populations where the diagnosis of constipation was reasonably established.
STUDY SELECTION:
DATA EXTRAcnON: The methodology and results from clinical studies were evaluated. Assessment of the studies was made based on diagnosis of constipation, prior management of patients, followup of patients, dosage, and adverse effects. DATA SYNTHESIS: Clinical trials in geriatric patients, terminally ill patients, children, and normal and constipated subjects were reviewed. In most instances, lactulose was compared with a placebo, without incorporating the current education on dietary techniques for improving defecation.
Generally, clinical trials have demonstrated a beneficial response compared with placebo, although sometimes that response has been only marginally better, from a clinical point of view. CONCLUSIONS:
AnnPharmacother 1992;26: 1277-82. in the management of constipation is often overshadowed by several factors, including its cost and clinical effectiveness. The cost of lactulose compared with other laxatives is relevant in hospital settings where endeavors are being made to contain drug expenditure. Consequently, prescribers cite published opinions and information from studies and review articles to support the limited prescribing of lactulose. This article evaluates some of the information on lactulose that has been published in the last decade. There was no intention to summarize all other laxatives unless such agents were compared with lactulose and would therefore provide further information. This review may be perceived
THE USE OF LAcruLOSE
THERESA V. KOT, B.Pharm., at the time of writing, was the Director, New South Wales Therapeutic Medicines Information Centre, Darlinghurst, NSW Australia; she is now with the Institute of Drug Research and Control, 30/34 Chelmska St., 00725 Warsaw, Poland; and NGAIRE A. PETTIT·YOUNG, B.A.Dip.Lib., is a Medical Librarian, New South Wales Therapeutic Medicines Information Centre. Reprints: The Annals of Pharmacotherapy, P.O. Box 42696, Cincinnati, OU 45242.
as deficient because certain disease states and age groups are mentioned and others are omitted. This should be viewed as a reflection of the research being undertaken and what has been published in the literature. Other authors have reviewed the pharmacology and use of laxatives, providing information and recommendations on the choice of agent. l -4 No review of lactulose has been published in recent years that summarizes the current knowledge of the management of constipation as studied and reported from clinical trials, open studies, or case reports.
Diagnosis ofConstipation The definition of constipation is variable, as the physician and the patient may use different measurements to diagnose the condition. Although there is no agreed definition of constipation, two aspects generally are stressed: difficulty when passing stools and stools that are infrequent.' Patients may also define constipation as straining with bowel movements, irregular defecation, and other gastrointestinal symptoms. Ninety-nine percent of the population have a bowel frequency ranging from three bowel movements per day to three per week.' Daily bowel movements are believed by some patients to be necessary to prevent absorption of toxic substances.' Therefore, the diagnosis of constipation should be based on a careful patient history including bowel frequency, stool consistency, the presence of blood or mucus, and the ease of evacuation. The onset of symptoms of constipation may assist in its diagnosis.' The patient can frequently present with a selfdiagnosis of constipation because of a decline in frequency of defecation, prolonged and difficult evacuation, or a sensation of incomplete evacuation; these signs may be indicative of an underlying cause of constipation.
Classification ofConstipation The classification of constipation is reasonably consistent and is divided into primary and secondary groups. I Secondary constipation may occur as a result of a disease or drug therapy. Primary or simple constipation may be associated with inadequate dietary fiber, dehydration, poor mobility, withholding of fecal matter evacuation, and reduced muscle tone. Barnes differentiated the primary classification of constipation in adults into the first subgroup, where there is an organic disease of the anus, rectum, and colon;
The Annals ofPharmacotherapy • Downloaded from aop.sagepub.com at CORNELL UNIV on September 5, 2016
1992 October.Volume 26 •
1277
and the second subgroup, where there is no structural or systemic disease.'
Indicationsfor Lactulose In reviewing the literature, the indications for a laxative need to be established, especially for a product that has been on the market for many years. The indications in the Australian product information for lactulose are portal-systemic encephalopathy and the treatment of chronic and habitual constipation. The American Hospital Formulary Service details the approved indications and those uses not currently approved by the US Food and Drug Administration," Below are listed the indications and uses of lactulose: 1. portal-systemic encephalopathy where it is used as an adjunct to protein restriction and supportive thera-
py6.7; 2. constipation, especially chronic constipation in adults and elderly patients"; 3. to restore regular bowel movements after hemor-
rhoidectomy"; 4. to induce bowel evacuation in elderly patients with colonic retention after a barium meal examination and severe constipation'; 5. constipation in the proximal colon in patients with distal colitis'; 6. when patients are investigated for underlying causes of constipation, an osmotic agent with bulk-forming agents may be required'; 7. constipation in the presence of normal bowel transit times and normal barium enemas'; 8. in bedridden or institutionalized patients on bulkforming agents, a stimulant or osmotic agent is prescribed to prevent impaction.' Many authors have expressed reservations about the cost-effectiveness of lactulose treatment for constipation. Thompson, after discussing the pharmacology and adverse effects associated with lactulose, states that "its cost and its relative lack of potency, make lactulose unsuitable for the routine treatment of constipation.?" One reference text states that the superiority of lactulose to conventional laxatives has not been established in the treatment of chronic constipation." The cost of lactulose is mentioned by other authors, with the recommendation that it should be used only in patients needing its specific effects or who do not respond to other agents.P Tedesco and DiPiro suggest lactulose in bedridden or institutionalized patients receiving daily bulk-forming laxatives, but only after other agents have proven ineffective.'
PharmacologyofLactulose Lactulose, a synthetic disaccharide, is classified as an osmotic laxative. It is metabolized by bacteria in the colon and the metabolites then acidify the contents of the colon. This has an irritant, as well as an osmotic effect, on the distal colon and rectum.Y After metabolism in the colon, the short-chain organic acid metabolites are absorbed so that the osmotic effect does not continue throughout the colon? However, this fact is at variance with published data stating that negligible amounts of lactulose and its metabolites are absorbed from the colon." This difference in information on the absorption of the metabolites cannot be easily resolved as both statements are unreferenced. However, 1278
•
the caution and warning for the use of lactulose in diabetic patients would lead to the assumption that there is some absorption of galactose and lactose. Lactulose usually requires 24-48 hours for its onset of action.P?
Adverse Reactions with Lactulose GASTROINTESTINAL REACTIONS
Abdominal cramps, gaseous distention, belching, flatulence, bowel distention, unpleasant taste, diarrhea, and borborygmi have been reported with lactulose.Pe" Wright reported five observations of colonic dilation in elderly patients using lactulose for constipation. These patients received broad-spectrum antibiotics, ceased the use of lactulose, and symptoms resolved. Wright suggested that these cases of "nontoxic megacolon" are related to gas production by the bacterial metabolism of lactulose," METABOLIC OR ELECTROLYTE DISORDERS
Electrolyte imbalance in long-term use I and severe hypernatremia secondary to fluid depletion" have been reported. The manufacturer responded that the daily dose in the latter reaction was 720 mL, more than 20 times the normal starting dose for the treatment of constipation." In 1984, Nanji and Lauener described a case of hypernatremia in a 72-year-old woman with a history of hypertension, congestive heart failure, and positive serologic tests for hepatitis. This patient also received lactulose 720 mL/d for suspected hepatic encephalopathy," TOLERANCE OR DEPENDENCE POTENTIAL
Some authors mention that tolerance may develop with continued use l ,7,12; however, the manufacturer refuted this suggestion." Perkin contended that tolerance does not occur with lactulose and that stopping therapy does not cause rebound constipation or problems of withdrawal." Because there is some disagreement about the occurrence of tolerance with continued use of lactulose, this point was further evaluated by referring to the original articles. Wesselius-De Casparis et al. studied lactulose in elderly patients who regularly used laxatives for chronic constipation." Florent et al. used healthy human volunteers to study the intracolonic metabolism of lactulose. IS Although these studies were not designed to evaluate tolerance to lactulose, they are cited as supporting such claims. The relevant points of each study and the results are summarized, and opinions by Bateman and Smith" and the manufacturer are expressed. 10 Wesselius-De Casparis et al. studied 103 elderly patients who were regularly taking laxatives for chronic constipation. The study was arranged into three phases: a two-week observation period where frequency of defecation and pattern oflaxative use were determined; a three-week treatment phase where patients were randomly assigned to receive lactulose 50% or glucose syrup; and a two-week observation, posttreatment period. The criterion used to assess the effectiveness of lactulose was the need for additional laxatives during the treatment period (i.e., successful management was defmed as no requirement for additional laxatives). The study showed a statistically significant difference for the use of laxatives between the lactulose and glucose treatment groups (86 vs. 60 percent, respectively,
The Annals ofPharmacotherapy • 1992 October, Volume 26 Downloaded from aop.sagepub.com at CORNELL UNIV on September 5, 2016
Lactulose in Constipation
p
