Constipation

Author and Year

Characteristics of the Intervention

Sample Characteristics,

Setting Characteristics,

Study Design, and Conceptual Model

Measures

Results and

Conclusions

Limitations, Major and Minor Flaws, Cautions and/or

Contraindications, Special Training Needs, and Costs

ONS Levels of Evidence and Comments

Opioid-Induced Constipation: Proactive Approach to Prevent Constipation: ONS PEP Weight-of-Evidence Category: Likely to be Effective

Bennett, M. & Cresswell, H. (2003)24

No intervention was evaluated

Bowel-care protocol used by the hospital was as follows:

All constipated patients and/or those on opioids were started on the following combination laxative:

Codanthramer strong capsules (Napp Pharmaceuticals, Cambridge, United Kingdom, contains 37.5 mg dantron per capsule) titrated from 1 capsule/day up to three capsules twice a day. If no response, polyethylene glycol (MovicolTM, Norgine, Middlesex, United Kingdom) was added starting with 1 packet BID and titrated up to 8 packets/day. Rectal measures (glycerin or bisacodyl suppositories or a stimulant enema) were used if stool was present in the rectum.

Purpose: To test the relationship between opioid dose, bowel function, and ADLs in patients with advanced cancer admitted to a hospice.

Sample Characteristics: N=50 (24 males, 26 females). Mean age =71.4 years. Median MBI was 54.8; 15 patients were not on opioids; 35 were.

Exclusions: Patients with duration of admission less than one week, patients with communication difficulties, or patients with a lack of supporting information in the clinical notes.

Setting Characteristics: St. Gemma's Hospice, Leeds, England.

Study Design: Prospective study. Over a two-month period, all patients with advanced cancer admitted to St, Gemma's Hospice, Leeds, and who had been inpatients for at least one week were interviewed about their bowel movements.

Purpose: Authors challenged the idea of a dose-dependent relationship between opioids and constipation and suggested that some patients may become tolerant to the constipating effects of these drugs.

Measures:

1. Mean daily opioid dose in prior 3 days (calculated as equivalent daily dose of morphine. Transdermal fentanyl 1:150, hydromorphone .1:7.5, SQ diamorphone 1:2, codeine 10:1)

2. Mean daily dose of dantron in prior three days,

3. Modified Barthel Index (MBI) measures 10 ADL with five levels of dependence; maximum score is 100 points, representing independence in daily living

4. Bowel score (number of times bowels open and stool consistency) over prior three days.

Calculated as follows: A= # times bowels opened in last 3 days

B=Stool consistency (1=hard, 2=normal, 3=soft)

Bowel score = A+B; Constipation = <3

Results: Reduced bowel score (particularly stool frequency) in patients taking opiods but not dose-dependent relationship.

No relationship between bowel score & physical functioning. For any given dose of opioid, fitter patients were treated with larger doses of laxatives.

Conclusions: The authors concluded that it is likely that constipation in patients with advanced cancer is more strongly related to other variables (i.e., food, fluid intake, abdominal tumor involvement, depression, cognitive impairment, use of antimuscarinic drugs.)

Clinicians should not base laxative prescribing on opioid dose per se nor degree of dependency but should titrate laxatives according to bowel function.

Lower doses of opioids or weaker opioids are just as likely to cause constipation as higher doses, and increasing opioid dose may not cause more constipation.

Limitations:

1. Small sample size; not randomized; short follow-up time

2. Patients on opiods (compared to those off opiods) are 10 years younger

3. Study assessed patients. after they had been titrated on laxatives

4. Overflow diarrhea might have been inaccurately assessed against the bowel score used in the study

5. Pain severity and prevalence of uncontrolled pain were not examined independently.

ONS Level: II (6)

Comments: The United States and several other countries do not allow dantron because it has been associated with rodent cancer. (This information was provided by the National Cancer Institutes Pharmacy Department.)

Opioid Induced Constipation: Opioid Rotation: ONS PEP Weight-of-Evidence Category: Likely to be Effective

Ahmedzai S., & Brooks, D. (1997)5

This is a comparison of transdermal fentanyl and sustained-released morphine in patients with cancer receiving palliative care, designed to measure efficacy, tolerance, and quality of life.

Sample Characteristics:

Adult patients with cancer receiving palliative care with a life expectancy greater than one month and who are receiving a strong stable dose of opioids. N=202; 110 completed the study, mean age of 61.5 years, 55% male.

Setting Characteristics: 38 different palliative care centers in the UK.

Study Design: Randomized, open, two-period, crossover study. Patients received two different treatments for 15 days each to compare which provided the greatest efficacy, QOL, and the fewest side effects.

Quality-of-Life assessment, according to the World Health Organization (WHO) – a performance status scale (measured pre, post, and daily during the study) and the European Organization for Research and Treatment Center (EORTC) – measuring side effects, convenience, and effects on ADLs/careers (measured after each arm of the study). Constipation and diarrhea were reported through the EORTC pre study, and days 8, 16, 23, 31. These tools have been validated for patients with advanced cancer. Daily diaries recorded estimated sleep length, night awakening, daytime drowsiness, and use of rescue medications. Memorial Pain Assessment card was used BID for assessment of pain and mood. Skin assessed when removing patches.

Null hypothesis was 50% would prefer fentanyl and 50% would prefer morphine.

The number one reason patients withdrew from the study was adverse events.

Bowel Function: Fentanyl was associated with significantly less constipation than morphine (p< 0.001). This was confirmed through multiple assessment mechanisms.

Patients were allowed short- acting morphine for breakthrough pain, which could alter the results for fentanyl, but the results still were significant.

Unethical to have a “washout” period. Some of the dropouts may have been due to morphine withdrawal

Not blinded, therefore, bias may exist according to preference-of-delivery mechanism.

Fentanyl and morphine doses varied among individuals and were titrated, as needed, throughout the study.

ONS Level I (2)

Allan L., Hays H., Jenson N.H., LePolain de Waroux, B., Bolt, M., Donald , R., Kalso, E. (2001)6

Purpose: To compare patients' preference for transdermal fentanyl or sustained-release oral morphine, their level of pain control, and their quality of life after treatment.

Interventions:

Sustained-release oral formulation of morphine 10, 30, 60, 100, or 200 mg tablets (MS Contin, Napp Laboratories, Cambridge, UK).

Fentanyl, a lipid soluble synthetic opioid, delivered in a transdermal controlled-release formulation 25, 50, 75, or 100 mcg/hour patches (Durogesic, JANSSEN PHARMACEUTICA,, Toronto, Ontario, Canada).

Sample characteristics: N = 256 patients (aged 26-82 years, mean of 51 years) with chronic non-cancer pain (mean duration of chronic pain was 9.3 years) who had been treated with opioids. 64% of patients had nociceptive pain; 33% had neuropathic pain; and 31% had a combination of the two. More than 70% of patients had used morphine prior to the study.

Setting Characteristics: 35 specialty pain clinics in Belgium, Canada, Denmark, Finland, the United Kingdom, the Netherlands, and South Africa.

Study Design: randomized crossover study. Patients were randomized to treatment groups using the central randomization minimization technique. There were no significant differences between the sample characteristics of the two treatment groups. One group was randomized to four weeks of treatment with sustained-release oral morphine followed by transdermal fentanyl for four weeks. The second group received the same treatments but in reverse order.

Outcome measures: Patient preference for transdermal fentanyl or sustained-release oral morphine; pain control; quality of life; and safety assessments (adverse effects).

Tools: Pain control was assessed at each visit using a global treatment assessment at the end of each treatment period.

QOL assessment (SF-36) and pain intensity (0 being low -100 being high) were assessed at baseline and at the end of each treatment period.

Bowel function questionnaire (no details provided)

Safety evaluation ((physical exam, vital signs and disease progression) was performed on the first visit, crossover, and end of study.

Statistical analysis: Primary efficacy variable was analyzed with a binomial test; Differences in personal variables was analyzed with the Van Elteren test and the Cochran-Mantel Haensxel test. The other variables were compared with the Koch non-parametric paired analysis for crossover designs

Final n=212; 39 could not be assessed. The first treatment group (fentanyl) had a 16% withdrawal rate compared with 9% in the morphine group. This was attributed to the fact that most patients (76%) had taken morphine for six weeks before the study and were accustomed to its side effects and the possibility of incomplete cross-tolerance leading to greater-than-anticipated potency of the fentanyl. This incomplete cross-tolerance also may explain the perceived improved pain control with fentanyl. More patients withdrew from the fentanyl treatment (11%) because of adverse events than the morphine treatment (4%), however in patients who had not taken either drug before the study showed similar rates of withdrawal related to adverse events (11% versus 9.8%).

Preference: 7% (15) expressed no preference; 65% (135) preferred fentanyl versus 28% (59) who preferred morphine (p<0.001).

Results related to constipation showed overall incidence of treatment-related adverse events was similar in both groups (70%-74%), Fentanyl was associated with more nausea (26% versus 18%) than morphine but less constipation (16% vs.22%). Reduced constipation was confirmed by the bowel function questionnaire (29% fentanyl versus 48% morphine; p<0.001)

Limitations:

• The majority of subjects were white.

• No discussion of strategies used for dose conversion

• Lack of placebo control and open-label nature of study was discussed at length. The study was not blinded (i.e., the study could have been improved by having patients use a placebo of the other drug simultaneously to remove bias.)

This study was not designed to evaluate the effect of opioid rotation on constipation. Although there is reference to a bowel function questionnaire, results describing/ comparing laxative use, frequency of bowel movements etc. were not reported.

ONS Level: II (6)

Radbruch L., Sabatowski R., Loick, G., Kulbe, C., Kasper, M., et al. (2000)4

Purpose: Investigated constipation and the use of laxatives in patients with chronic cancer pain treated with oral morphine and transdermal fentanyl

Intervention: Patients would take oral morphine for at least 6 days or until their pain was controlled at a 4 out of 10 pain level or lower. The patient would then be switched to transdermal fentanyl according to a dosing rate of 100:1 (oral morphine: fentanyl equivalent). If the fentanyl dose was greater than 270 mg/day slow-release morphine, more than one fentanyl patch was used.

Sample Characteristics: N=46 (29 males, 17 females); median age 57.5 years (31-83 years.); median weight. 62.5 kg; median height. 172 cm. Sites of primary cancer included GI, head and neck, GU, respiratory, breast, and hematological cancers.

Setting Characteristics: June 1995-January 1996, Germany (unclear if inpatient. or outpatient). Researcher based at University of Cologne.

Study Design: Open sequential, multi-center study. Patients were treated with oral slow-release morphine for at least six days (morphine phase) until they reported stable pain intensity scores of 40 or less on a VAS (0=no pain, 100= worst pain imaginable) for at least two days. Analgesic therapy then was switched from oral morphine to transdermal fentanyl (fentanyl phase). Fentanyl patches were changed regularly after 3 days. Fentanyl doses were increased when patients reported inadequate pain relief or had to take more than six rescue medications per day. Study terminated after 30 days of transdermal therapy.

Patients who completed the study until day 17 or longer were included in an intra-individual comparison of laxative intake using the Wilcoxon rank test

1. Patient diary recording: intensity on a 0-10 visual analogue scale 3 x day; frequency of breakthrough pain and use of PRN medications; use of laxatives; self-assessment of frequency and consistency of defecation.

2. 30-item quality-of-life questionnaire of the European Organization for Research and Treatment of Cancer (EORTC-QOL-C30). Assesses nine symptoms and six dimensions of QOL.

3. BP, HR, RR, and skin reaction at the site of fentanyl application was documented by the treating physician on day 0, 6,12,18,24 and 30.

Results: 46 patients treated with slow-release morphine (7 excluded in morphine phase because stable analgesia could not be achieved); 39 switched to transdermal fentanyl. Twenty-three completed the study; two patients died from basic disease, 12 excluded for various reasons, and not enough data for evaluation was available for two patients.

The frequency of bowel movements did not change significantly but the use of laxatives was reduced in 23 of 28 patients on transdermal fentanyl and increased in 2 of 28 patients on transdermal fentanyl.

No significant changes in vital signs noted.

Mild-to-moderate skin reaction noted in five patients.

The EORTC quality-of-life questionnaire symptom scores showed significant decrease for constipation only.

Conclusions: Transdermal fentanyl significantly reduced the laxatives used.

Open study, so prejudices from staff or patients may have biased the results.

The site of primary tumor was situated in the GI tract for a quarter of the patients, and in these patients constipation may easily have been caused by tumor growth.

It may be questioned whether the conversion from morphine to fentanyl really was equianalgesic. Thus, less constipation may have been the consequence of lower equianalgesic opioid dosage.

Results may have been influenced by the high number of patients who dropped out of the study.

The difference in the degree of constipation between the two analgesics regimens should be confirmed in a randomized double-blind study that takes into account both constipation and use of laxatives.

Short acting morphine was used for breakthrough pain in both arms of the study, and as a result the pts on fentanyl also had morphine on board.

No standardization of the laxative used, so it is unclear whether this influenced the results.

The study was supported by a research grant from a pharmaceutical company.

ONS Level: II (6)

Comments: Excellent discussion of the studies looking at constipation associated with fentanyl vs. other opiates.

Pharmacologic Intervention: Peripheral Opioid Antagonists: ONS PEP Weight-of-Evidence Category: Benefits Balanced with Harms

Meissner, W., Schmidt, U., Hartmann, M., Kath, R., & Reinhart, K. (2000)9

Purpose: To evaluate the use of oral naloxone to treat opiate-associated constipation in patients with cancer.

Intervention: Naloxone is a competitive agonist of opiod receptors inside and outside the CNS. After systemic administration, it reverses both centrally and peripherally mediated opiod effects.

Sample Characteristics: N=22

Setting Characteristics: Hospital in Germany

Study Design: Controlled study with a control period not a control group. Patients were observed for six days without intervention then oral naloxone was titrated as follows:

3 mg x 3 – day 1

6 mg x 3 – day 2

9 mg x 3 – day 3

12 mg x 3 – day 4 – max

Titration stopped with laxation or increased peristalsis.

Measures:

1. Himmelsbach withdrawal scale was used to monitor possible systemic withdrawal signs as shivering/ piloreaction, yawning, perspiration, nausea/vomiting, tremor/ restlessness, and lacrimation/ rhinorhea. Each of these signs was quantified with 0 (none), 1 (mild), 2 (moderate), or 3 (severe).

2. Laxation frequency

3. Pain intensity on 11- step pain scale

4. Laxatives received

5. Ratio of morphine dose to naloxone dose

Results: Final N = 17.

1. Nausea, restlessness, & sweating were most common side effects.

2. Laxation increased in 14/17; laxative use decreased in 9/17.

3. No difference in pain rating between the periods.

4. Other laxatives used: lactulose, paraffin, raglan, glycerol, castor oil, natruimpicosulfate

5. Naloxone dose was not based on morphine dose, but on opiod tolerance level

Conclusion: Start with low- dose naloxone and titrate up..

Limitations:

1. Only six days were allocated for measurement periods,.

2. Subjective Likert scale 0-3 used.

3. No control for other laxative use (all participants were on at least one).

4. Study kept overdosed (via medication error) patient in study.

5. Diet, exercise, fluid intake were not controlled in the study

6. P value was not tested.

ONS Level: II (6)

Pharmacologic Intervention: Osmotic Laxatives: ONS PEP Weight-of-Evidence Category: Effectiveness Not Established

Agra et. al. (1998)7

Purpose: Compare senna versus lactulose in relation to efficacy and adverse events in terminal cancer patients.

Interventions:

Lactulose - an osmotic laxative, a synthetic disaccharide

Senna - stimulates intestinal peristalsis, acts mainly in the large intestine, directly stimulating the myenteric plexus and increasing water and electrolyte secretions, thus stimulating peristaltic activity. Their action extends over 6-12 hours. Side effects are described as abdominal pain, nausea, vomiting, and diarrhea.

Group A = treated with senna BID starting at 0.4 ml (12 mg)

Group B = treated with lactulose BID starting at 15 ml

Based on clinical response, doses were increased in increments of 0.4 ml and 15 ml respectively, every three days.

Maximum doses were 1.6 ml (48 mg) for senna and 60 ml (40 g) for lactulose.

When a patient reached the ceiling of his respective laxative and had three days without defecation, he was maintained on that dose and, in absence of side effects, he was started on an initial dose of other laxative, which then could be increased at three-day intervals until reaching the experimental maximum.

Enema and/or mechanical bowel evacuation was prescribed after three-day period without defecation (for ethical reasons), and this was recorded as a failure with increase in laxative dose. If no results from mechanical evacuation in six hours, the patient was held on stand-by outside the study until he defecated.

Sample Characteristics: 91 patients with terminal cancer; > 18-years-old, in palliative care program between July 1, 1993, and July 1, 1995. All had clearly documented terminal disease with a life expectancy of < 6 mo. (30% lung cancer, 11% breast cancer, 8.8 % stomach cancer, etc.) and had caregivers in the home. Mean age 67.8 yrs. (41-93 years old.) Exclusions: all patients with contraindications to the experimental laxatives were excluded, including those with colectomy, steatorrhea, or aphagia; Karnofsy <10%; patients who had taken opioids or laxatives during the 72 hours prior to the initiation of the study. Patients on opioids were on codeine or morphine.

Setting Characteristics: Palliative Care Unit (PCU) in Madrid Health Care District #4, Madrid, Spain. The PCU assists patients released from the local hospital and is in charge of the home care follow-up protocols.

Study Design: comparative study - randomized open, parallel group design. Randomization schedule stratified for age and gender (limit 8 per stratum). 43 patients assigned to senna arm and 48 to lactulose arm.

Study period: 7 days to assess laxative efficacy on defecation days and at variable opioid dosage and 27 days to assess mean morphine dose at which a laxative was necessary. Both laxative and opioid treatment was initiated simultaneously.

Prescribers were blinded (single doses of identical volume in closed opaque flasks).

Outcome measures: Defecation-free intervals of 72 hours; number of days with defecation events; and general state of health (5-pt Likert scale).

Defecation days as a function of opioid dose and treatment cost were also examined.

Results:

Of the 91 subjects, 75 completed the study for at least 7 days and were evaluated in the analysis.

16 subjects dropped from study within four days and were not included in analysis (one because of diarrhea, four because of non-compliance, four died within the first 24 hours, five because of permanent hospitalization, and two moved out of the jurisdiction of the home care area).

Laxative efficacy was analyzed by t-test and analysis of variance.

Conclusions:

1. No difference between senna and lactulose in efficacy as measured by defecation-free intervals; days with defecation; or in adverse effects. Recommend use of senna based on lower cost.

2. Opioid dose did not determine laxative efficacy.

3. 37.5% of patients required both laxatives by the end of the study.

Limitations:

1. Patients could differentiate medications by taste and texture.

2. Data based on self-report, which is not considered very reliable.

3. Study done in Spain so results may not be transferable to a U.S. population.

4. N < 100 in final analysis

5. Baseline effect of diet, age, tumor type, mobility not discussed in relation to study results

Strengths:

Very precise, detailed description of study design

ONS Level: I (2)

Harris, A.C. & Jackson, J.M. (1977)38

Purpose: This study measured the efficacy of lactulose in patients with cancer receiving vincristine, as a treatment for vincristine-induced intractable constipation or for prevention of vincristine-associated constipation.

Intervention: Lactulose was given 20 ml BID to 25 ml TID

Sample Characteristics: N=8 patients ages 22-67 with. lymphoma and leukemia

Six patients had protracted problems with constipation; five females and one male

Two male patients received prophylactic treatment with lactulose immediately after vincristine therapy was initiated.

Setting Characteristics: Inpatient at Royal Perth Hospital in Perth, Western Australia.

Study Design: Descriptive study

Measures: time to first bowel movement after vincristine treatment and lactulose therapy started.

Results:

All patients obtained relief of constipation within two days of initiating lactulose.

Limitations: Small sample size, no randomization, no mention of side effects, or duration of use.

ONS Level: II (6)

Comments: The myenteric plexus neurons are damaged by the vincristine, causing this type of constipation, and lactulose is not dependent on the functioning of these neurons to stimulate a bowel movement.

Lederle, F.A., Busch, D.L., et al. (1990)16

Purpose: To evaluate the use of sorbitol as an inexpensive alternative to lactulose for treating constipation in older adults.

Intervention: Lactulose (ChronulacR, Hoechst, Marion, Roussel, Kansas City, MO) and 70% sorbitol (0 to 60 ml daily) were given for four weeks. During the treatment period, patients were instructed to begin taking 30 ml of the study laxative at bedtime, thereafter adjusting the dose as needed between 0 & 60ml. Patients were instructed to maintain high dietary fiber and to avoid sources of free fructose, such as apples and pears.

Lactulose: nonabsorbable sugar that has an osmotic laxative effect

Sorbitol: nonabsorbable sugar that has an osmotic laxative effect

Length of wash-in and washout periods were based on previous studies showing that up to 3-4 days are required for lactulose to take effect and that the carry-over effect after cessation of lactulose is about 6-7 days.

Sample Characteristics: 40 ambulatory men (see setting characteristics below only 30 patients accounted for), aged 65-86 (mean 72) with a history of constipation of at least one year's duration were eligible. Designed to recruit the most severely constipated ambulatory patients not taking narcotics. Twenty-one took bulk-forming agents throughout the study (psyllium in all cases).

Setting Characteristics: Minneapolis Veterans Affairs Medical Center from September 1988 to July 1989. Five patients were residents of Minnesota Veterans Home and the other 25 were outpatients.

Study Design: a randomized, double-blind, crossover study. Study began with a two-week lead- in period during which patients were given lactulose in a single-blind fashion. This was followed sequentially by a washout period A (two weeks), treatment period A (four weeks) washout period B (two weeks), and treatment period B (four weeks). The purpose of the lead-in period was to ensure (1) that the patient tolerated lactulose, (2) that the patient understood how to complete the diary, and (3) that the conditions preceding the two treatment periods were similar. At the end of washout period A, patients were randomly assigned to receive one of the two study laxatives in treatment period A, with the other laxative being used in treatment period B.

The primary endpoints of the study were the average number of bowel movements per week and the average number of days per week on which bowel movements occurred.

Patient diary was used to record bowel consistency (hard, soft, loose); daily dose of study laxative; use of any other laxative or enema; and occurrence and severity of seven symptom categories (bloating, cramping, excessive flatulence, nausea, diarrhea, fecal incontinence and other).

Statistical analysis: t-test method for cross-over trials (2-sided a)

Results: 30 patients completed the study; nine withdrew prior to randomization because of intolerance of lactulose. One patient dropped out after randomization.

There were no significant differences between sorbitol and lactulose in any outcome measured except nausea, which increased with lactulose (p<0.05).

The average # of bowel movements per week was 6.71 with sorbitol and 7.02 with lactulose (95% confidence interval of the difference ranged from -0.43 to 1.06) and the average number of days per week with bowel movements was 5.23 with sorbitol and 5.31 with lactulose (95% confidence interval of the difference ranged from -0.32 to 0.48)

Conclusions: These results support the hypothesis that sorbitol and lactulose have no clinically or statistically significant difference in laxative effect. Sorbitol can be recommended as a cost effective alternative to lactulose for the treatment of constipation in elderly men.

Study had a short duration and was confined to ambulatory older men. Caution should be used in extrapolating these findings to women, younger patients or those who are bedridden. The withdrawal of patients because they did not tolerate lactulose may have biased the study.

Sample size smaller than the 32 required to provide sufficient power for statistical significance of the results.

Participants dropped out related to intolerance to lactulose

ONS Level: II (6)

Comments: based on sample <100 and sample size smaller than required for sufficient power.

Pharmacologic Intervention: Tegaserod for General Constipation: ONS PEP Weight of Evidence Category: Effectiveness Not Established

Tegaserod maleate (Zelnorm) for IBS with constipation. (2002) 53

FDA approval for use of Tegaserod for IBS was based on results of three studies (only one published), three randomized, double-blind trials of 2470 women taking tegaserod 6 mg bid or placebo for 12 weeks.

Sample Characteristics: 2470 woman with IBS

Study Design: Combination of three double-blind, randomized clinical trials

Patients: Rated well-being and relief of abdominal discomfort, pain, and altered bowel habits. Tegaserod may improve constipation, abdominal discomfort, and bloating in some women with constipation—predominant IBS but results not impressive Long- term efficacy and safety have not been established, and IBS is a chronic disease.

Comments: This was a letter announcing the FDA approval for tegaserod. No detailed information regarding the studies or the results was included.

ONS Level not assigned because of the nature of the publication.

Johanson J. (2004)18

This article was a summary and review of two, double-blind, randomized, placebo-controlled trials of identical design (same duration, efficacy endpoints, and patient population) reported in the literature: one in Europe and Asia and the other in North and South America.

Purpose: to review the efficacy of tegaserod in the management of chronic constipation.

“Tegaserod, a 5 HT4 receptor partial agonist which stimulates GI motility and intestinal secretion (p. 21)” has demonstrated efficacy in relieving constipation in patients with irritable bowel syndrome.

Sample characteristics: Across both studies the total n= 2,612 with the majority being white females. All subjects were > 18 years of age with a minimum six-month history of constipation, defined as < 3 complete spontaneous bowel movements (CSBM)/week. Patients with constipation caused by other primary colon disease, pelvic floor dysfunction, metabolic or neurological disturbances, or concomitant medication were excluded.

Setting characteristics: Europe and Asia (study #1, n=1264); North and South America (study #2, n=1348)

Study Design: Combination of two double-blind, randomized, placebo-controlled, three-armed trials of identical design (same duration, efficacy endpoints, and patient population). After a two week baseline period, patients were randomized to treatment with Tegaserod 2 mg BID, Tegaserod 6 mg BID, or placebo for 12 weeks.

Conceptual model: None

Note: For details of study #1, refer to Kamm et al. below.

Symptoms were recorded in a patient diary throughout the study as follows:

1. Time of bowel movements and associated characteristics: completeness of evacuation (yes/no); straining (3 point scale); and stool form (Bristol Stool Form seven- point scale) were recorded on a daily basis

2. Use of other medications, including laxatives, were recorded daily

3. Satisfaction with bowel habits & “bothersomness” of constipation were each evaluated weekly using a five-point ordinal scale

4. Duration & severity of adverse events reported by the patient or discovered on history and physical were recorded.

5. Safety evaluations included standard laboratory tests, measurement of vital signs, physical exam, and electrocardiogram evaluation.

The primary efficacy variable was the response rate of CSBM during the first four weeks of treatment, defined as a mean increase of one or more CSBM per week compared to baseline after a minimum of seven days exposure to the study medication.

The secondary efficacy variable was the increase in CSBMs over the entire 12-week treatment period; patient evaluation of symptoms associated with constipation and bowel habits.

Results: The study populations were similar with regards to demographic distribution.

Primary efficacy variable: Both studies showed a significantly greater frequency of CSBM during weeks one to four for the tegaserod groups compared with placebo (p< 0.05 vs. placebo).

Secondary efficacy variables: A similar trend was seen over weeks 12, however, the 2 mg dose of Tegaserod did not achieve a statistical significance in Study #1. Similarly, when responder rates in study #2 were defined using more stringent efficacy criteria (>3 CSBMs per week) responder ratings remained significant for tegaserod 6 mg during the first four weeks as well as the entire 12-week study period. In addition, the quality of bowel movements as measured by diverse secondary efficacy variables, significantly favored tegaserod. Of note, no rebound effect was observed following treatment withdrawal among patients who participated in the second study.

Overall, the effect of tegaserod on bowel movements was rapid and predictable. In both studies, patients treated with tegaserod experienced their first SBM and first CSBM statistically significantly faster than patients receiving placebo for both doses of tegaserod.

Safety and tolerability: No consistent difference in the frequency of adverse events was noted between both tegaserod doses and placebo. Mild to moderate diarrhea was reported as follows: placebo 3.8%, tegaserod 2 mg 4.5% and 6 mg 7.3%.

Of note, the median number of spontaneous bowel movements per week by patient history was significantly different from the median number per week recorded in diaries, suggesting that patients do not always accurately recall the number of weekly spontaneous bowel movements.

Conclusions: Tegaserod is an effective treatment for chronic constipation. Tegaserod provides more rapid, predictable, and consistent improvement in bowel frequency when compared to placebo in patients with a history of chronic constipation. In addition, tegaserod provided relief of accompanying symptoms of chronic constipation, including straining, incomplete evacuation etc. It also was safe and well- tolerated in this population.

Both studies were well-designed outcome studies.

Implications: Unclear what, if any, implications this has in the oncology population since patients with co-morbidities, such as cancer, organic disease, GI surgery, and ano-rectal malformations were excluded from the study.

ONS Level: I (2)

Comments: This study excluded patients with many of the characteristics of patients with cancer.

Kamm, M.A., Muller-Lissner, S., et al. (2005)19

Tegaserod: Selective agonist that acts at 5-HT4 receptors to increase small bowel transit, stimulate intestinal secretion, and inhibit visceral afferent responses.

Intervention: During 12-week treatment phase, patients received tabs of tegaserod 2 mg, tegaserod 6 mg, or placebo, each taken BID within 30 min. of morning and evening meals.

The 2 mg and 6 mg tegaserod tablets were different sizes; to maintain blinding of the study, two sizes of placebo were made. Patients took one large and one small tablet for each dose (i.e., 6 mg tegaserod with small placebo)

Purpose: evaluate the efficacy, safety and tolerability of tegaserod in patients with chronic constipation

Sample Characteristics: N=1246, >18 years (19 years in Australia), men and women with constipation for six months or more. Patients with primary organic disease of the colon or pelvic floor dysfunction, metabolic disorders, neurologic disorders, or other significant disease were excluded. Majority of patients were female (86%), Caucasian (98%); mean age 46. 85% of patients. had previously used at least one treatment for constipation in the six months prior to the study.

Setting characteristics: study conducted between July 2001 – June 2002 across 128 centers in Europe, South Africa, and Australia.

Study design: randomized, double-blind, placebo-controlled study with a parallel-group design. Eligible patients entered a two-week washout period without study medications, followed by a 12- week treatment phase. Patients seen by the investigator on day one, and following 4,8, &12 weeks of treatment for collection of efficacy data and information on adverse events. Patients who did not have a BM for more than 96 hours were instructed to use bisacodyl as a rescue medication with a maximum dose of 15 mg/day.

Number of spontaneous bowel movements; completeness of defecation.

Patients recorded data in a paper diary including:

1. Time of any BM,

2. Whether BM was associated with straining or a feeling of incomplete evacuation,

3. Stool form using the seven-point Bristol Stool Form Scale,

4. Use of bisacodyl as rescue medication;

5. Weekly assessment of patient satisfaction with bowel habits.

Quality of life and general health were evaluated using the short-form 36 questionnaire completed at baseline, 4 weeks and 12 weeks.

Adverse events; labs, ECG, and vital signs and physical exam were completed at baseline and 12 weeks.

Results: N=1048 pts (82.9%) completed the double-blind treatment period. Reasons for discontinuation were adverse events, unsatisfactory efficacy, consent withdrawal, or other.

Responder rates (defined as increase of >1 complete spontaneous BM/wk compared with baseline 14 days prior to study as long as have been on treatment 7 days) during weeks 1-4 was significant for tegaserod over placebo; this effect was sustained over the 12-week treatment period for the 6 mg bid dose.

Onset of action significantly faster for patients receiving tegaserod— the higher dose of tegaserod was associated with faster onset of action (98 hours versus 174 hours for the 2 mg BID group and 286 hours in the placebo group).

Stool form, straining, and other bothersome symptoms all improved with tegaserod. During the double-blind treatment period, the mean number of days/week with additional laxative use was significantly lower (p = 0.01) for both doses of tegaserod versus placebo.

Safety and tolerability: Incidence of diarrhea in tegaserod 6 mg BID compared with placebo was significantly higher; not true of tegaserod 2 mg versus placebo. Adverse effects were the primary reason for discontinuation from the study for all groups.

No clinically relevant changes in hematology, biochemistry, urinalysis, vital signs, or ECG parameters noted.

Conclusions: Tegaserod is safe, well-tolerated, and effective in relieving chronic constipation symptoms. Greater efficacy with the 6 mg BID dose especially in patients with irritable bowel syndrome. Supports study findings of Johanson, J.F. et al. 2003 (clinical trial of tegaserod in chronic constipation conducted in North and South America)

Strengths: large sample size; randomization process; statistical methods, and data analysis

Limitations:

Majority of sample was female and Caucasian.

Compared efficacy of different dosages of tegaserod. Did not compare efficacy versus other drugs

Study funded by Novartis Pharma who makes the drug.

ONS Level: I (2)

Comments: Tegaserod available in United States in 6 mg tabs. Safety and efficacy not established in patients < 18 years of age. Indicated for treatment of abdominal pain/discomfort in female patients with constipation and predominant irritable bowel syndrome. No data regarding its use in patients with cancer.

Pharmacologic Intervention: Polyethylene Glycol (PEG) With or Without Electrolyte: ONS PEP Weight of Evidence Category: Effectiveness Not Established

Attar, A., Lemann, M., Ferguson, A., et al. (1999)17

PEG 3350 is an osmotic laxative, which opposes the colon's normal drying action on the feces, increasing fecal bulk, which causes stretching of the circular muscle fibers in the bowel wall and triggers myogenic peristalsis. PEG plus electrolytes (PEG+E) provides electrolyte depletion and dehydration that can occur with other laxatives.

Lactulose is metabolized to lactic acid by bacteria in the colon. These bacteria exert a local osmotic effect, drawing water and electrolytes into the colon from the surrounding tissues to bulk feces.

Sample Characteristics:

N = 115 Inclusion Criteria: Age 18-90 years;, had at least one of the following two symptoms present for at least three months: (1) fewer than three stools a week and (2) difficult evacuation. Patients with secondary constipation; those taking concomitant medication, which might modify bowel transit; severe liver, renal or cardiac impairment; those not likely to comply with treatment; those not able to give informed consent, and women of childbearing age not using effective contraception were excluded.

Study Design: Single-blind, randomized, multicenter study.

Part A: Patients were randomized to receive either PEG+E (n=60) or lactulose (n=55) for one month.

Part B:

Patients >65 continued on the treatment for another two months.

Patients < 65 received PEG+E irrespective of the laxative they received at the start of part A

Measures: