Recommended for Practice

Methylnaltrexone

for Constipation

Methylnaltrexone injection is used to treat constipation caused by opioid pain medications. Methylnaltrexone injection is in a class of medications called peripherally acting mu-opioid receptor antagonists. It works by protecting the bowel from the effects of opioid medications at receptor sites in the bowel. Methylnaltrexone injection comes as a solution to inject subcutaneously.

Systematic Review/Meta-Analysis

Ahmedzai, S.H., & Boland, J. (2010, April). Constipation in people prescribed opioids. Clinical Evidence, 2407.

Purpose

To answer the following questions: What are the effects of oral laxatives, rectal preparations, and opioid antagonists for constipation in people prescribed opioids?

Search Strategy

Databases searched were MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Library, NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment, TRIP, and the National Institute for Health and Clinical Excellence (NICE) up to August 2009. Alerts from the U.S. Food and Drug Administration and the U.K. Medicines and Healthcare Products Regulatory Agency were included to identify any adverse effects.

Search keyword were constipation and opioids, Lactulose, macrogols, senna, bisacodyl, co-danthrusate/co-danthramer, docusate, ispaghula husk, liquid paraffin, magnesium salts, methylcellulose, arachis oil enema, glycerol suppository, phosphate enema, sodium citrate enema, and opioid antagonists.

Studies were included in the review if they

  • Were randomized controlled trials (RCTs), observational studies, or systematic reviews
  • Had a study sample of at least 20 participants
  • Had a maximum loss to follow-up of 30% per year in longitudinal studies.

Literature Evaluated

The GRADE System was used to evaluate study quality. Full information is available online with a subscription.

Sample Characteristics

The final sample comprised 23 systematic reviews, RCTs, or observational studies. This was an update of a previous review that added 1 systematic review and 5 RCTs, with no change in overall recommendations provided.

Results

Oral Laxatives

  • Lactulose, polyethylene glycols (PEGs) plus electrolytes, and senna were identified as beneficial in this systematic review. Evidence in this area was graded as low-to-moderate quality. Lactulose appears to be as effective as PEG in reducing the number of hard stools, and as effective as senna in reducing the number of days without defecation.
  • Preparations identified as unknown effectiveness included bisacodyl, co-danthrusate and co-danthramer, docusate, ispaghula husk, liquid paraffin, magnesium salts, and methylcellulose.
  • Some oral laxatives such as bisacodyl often are prescribed in combination with other agents or rectal suppositories, but no evidence supports this use, particularly in people taking opioids.
  • Liquid paraffin may be harmful in patients who have difficulty swallowing.

Rectal Preparations

  • All of the rectal preparations studied were categorized as unknown effectiveness. The preparations included arachis oil enema, glycerol suppository, phosphate enema, and sodium citrate micro-enema.

Opioid Antagonists

  • Opioid antagonists, including alvimopan, methylnaltrexone, and naloxone, were categorized as beneficial.  Categorization was based on studies comparing those agents to no treatment or placebo.  The most common side effects reported were abdominal pain, nausea, and diarrhea, particularly with higher doses. 
  • A concern with these agents is the potential for use to reverse the therapeutic action of opioids.  Alvimopan and methylnaltrexone are considered safer than naloxone in this regard, as neither of those agents can cross the blood-brain barrier and a few small studies of acute pain have shown success in blocking the constipating effect of opioids without compromising pain relief.

Limitations

  • Although various combinations of oral laxatives and rectal agents may be used clinically, their effectiveness for constipation in people taking opioids has not been evaluated. This area can benefit from continued well-designed study.
  • Opioid antagonists are considered effective for reducing constipation in people prescribed opioids. However, only a few studies with small groups of patients have examined the effect of these agents on pain relief with opioids. Use of opioid antagonists may also have implications for which type of opioid should be used for pain control.  Long-term use with chronic pain managed by opioids is not well researched.

Nursing Implications

Nurses should be aware of potential implications related to the use of opioid antagonists in controlling constipation for opioid interactions and changes in pain control. In addition, nurses should routinely assess for pain relief, as well as symptoms of constipation, in this patient population.

Print

Becker, G., Galandi, D., & Blum, H.E. (2007). Peripherally acting opioid antagonists in the treatment of opiate-related constipation: A systematic review. Journal of Pain and Symptom Management, 34, 547-565.

Purpose

To evaluate evidence on the effectiveness of the peripherally acting mu-receptor antagonists alvimopan and methylnaltrexone in the management of opioid-induced constipation.

Search Strategy

Databases searched were Ovid MEDLINE, Biological Abstracts, BIOSIS Previews, CINAHL, Evidence-Based Medicine Reviews (EBMR) (Cochrane Database of Systematic Reviews, ACP [American College of Physicians] Journal Club, Database of Abstracts of Reviews of Effectiveness [DARE], and the Cochrane Central Register of Controlled Trials [1966-May 2005]), PubMed (1996-May 2005), CancerLit (1963-June 2005), and Embase (1980-May 2002). A hand search also was conducted on bibliographies of books about palliative care.  From that hand search, reference citations concerning constipation were identified to find additional clinical trials to include in the review.

Search keywords were constipation, intestinal obstruction, opioid bowel dysfunction, opioid related constipation, opioid-related disorders, peripherally acting opioid antagonist, opioid antagonist, opioid mu receptors, narcotic antagonists/naltrexone, methylnaltrexone, and alvimopan.

Studies were included in the review if

  • The trial population comprised adults with opioid-related constipation who (a) had chronic pain and were being treated with an opioid regimen, (b) were on methadone maintenance programs, or (c) were healthy volunteers used as models to reproduce the condition of real patients.
  • The sample size was at least 10 participants.
  • The intervention treatment was with methylnaltrexone or alvimopan.
  • The outcome measures of prevention or reduction of constipation and the incidence of adverse events were addressed.

Studies were excluded if they had a small sample size (fewer than 10 participants) or used the Rome Diagnostic Criteria to define constipation.

Literature Evaluated

Ten studies were appropriate for this review. However, four of the 10 had two or three parts performed in different populations or using different dosing regimens. The differing parts were treated as different studies and assessed individually, yielding 15 studies (10 randomized controlled trials and five phase II studies addressing dose and toxicity).

Sample Characteristics

  • Study groups ranged in size from 11 to 168 participants, for a total of 605 participants in all 15 studies.
  • Seven studies included healthy volunteers, two included members of methadone maintenance programs, and three included both members of methadone maintenance programs and patients with chronic pain.
  • One study looked at patients receiving opioids for acute pain and two included hospice patients.

Results

This systematic review looked mainly at the efficacy of using the peripherally acting opioid antagonists methylnaltrexone (nine studies) and alvimopan (six studies) in managing opioid-induced constipation. Internal validity of the studies was high, indicating methylnaltrexone and alvimopan may be effective in relieving opioid-induced constipation. However, most study participants were healthy volunteers or members of methadone programs.

Limitations

  • The studies in this review addressed the efficacy of methylnaltrexone and alvimopan. However, most study participants were healthy volunteers or members of methadone programs. The question arises as to whether the effectiveness of those drugs would hold true in other populations.
  • Additional research is needed to assess the effectiveness of methylnaltrexone and alvimopan in patients with cancer. Not all of the studies addressed the effects of those peripherally acting antagonists on pain control and withdrawal. Of the 15 studies, five reported no effect on pain and seven reported no withdrawal effects. The effects of those drugs on pain and withdrawal require additional study.
Print

Brick, N. (2013). Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Clinical Journal of Oncology Nursing, 17(1), 91–92. 

Purpose

STUDY PURPOSE: To assess the effectiveness of a laxative versus methylnaltrexone for the management of constipation in palliative care patients
 
TYPE OF STUDY: Meta-analysis and systematic review

Search Strategy

DATABASES USED: Cochrane Library of Systematic Reviews
 
KEYWORDS: Effectiveness of laxatives, methylnaltrexone 
 
INCLUSION CRITERIA: Randomized clinical trials required to have investigated effectiveness of laxatives or methylnaltrexone; published and unpublished studies; adults; cancer and other chronic diseases
 
EXCLUSION CRITERIA: None noted

Literature Evaluated

TOTAL REFERENCES RETRIEVED: Seven randomized controlled trials (RCTs)
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Review of RCTs with data extraction; meta-analysis was used to provide a pooled estimate effect where the data were of sufficient quality

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 7
  • TOTAL PATIENTS INCLUDED IN REVIEW = 616
  • KEY SAMPLE CHARACTERISTICS: Average age = 61–72 years; patients in advanced stage of diseases in palliative care; four studies examined lactulose, senna, co-danthramer, misrakasneham, and magnesium hydroxide with liquid paraffin; three studies evaluated methylnaltrexone

Phase of Care and Clinical Applications

PHASE OF CARE: End of life care
 
APPLICATIONS: Palliative care

Results

All of the studies investigated variables in laxative types, opioid doses, and frequency of stools. Outcome measures included change in frequency of bowel movements, ease of defection, relief of systemic and abdominal symptoms of constipation, change in quality of life, and the use of rescue laxatives. There were no significant cross-findings, except all participants required rescue laxatives despite the initiation of a constipation prevention regimen. In two studies of (288) participants using methylnaltrexone versus a placebo, a statistically significant difference favored the intervention of rescue-free laxation 4 hours and 24 hours after the first dose of methylnaltrexone. Thirty percent of those participants experienced adverse effects. One study of 33 participants with methylnaltrexone showed a statistical difference favoring higher doses. Adverse effects were similar.

Conclusions

There were no recommendations for optimal laxative management of constipation in palliative care patients.

Limitations

There was little concrete evidence and too many variables across the studies. There was no information on how the search was conducted. It was very difficult to follow the evidence summary.

Nursing Implications

The effectiveness of laxatives and the optimum management of constipation in palliative care patients requires further investigation involving the measurement of standardized, clinically relevant outcomes in a clearly defined population.

Print

Candy, B., Jones, L., Goodman, M.L., Drake, R., & Tookman, A. (2011). Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Cochrane Database of Systematic Reviews, 1, CD003448.

Purpose

To update the information available on the effectiveness of laxatives and methylnaltrexone for constipation management in palliative care patients.

Search Strategy

Databases searched were MEDLINE and the Cochrane Central Register of ControlLed Trials (Central).

Search keywords were laxatives, methylnaltrexone, and palliative care.

Studies were included in the review if

  • They reported on adults receiving palliative care.
  • Patients used laxatives or methylnaltrexone for constipation.

Studies were excluded if they reported on healthy volunteers, drug misuse–related constipation, or bowel obstruction.

Literature Evaluated

A total of 186 references were retrieved. If citation screening did not identify whether a study was eligible, the full text was reviewed for acceptability. Two authors independently screened studies and discussed differences of opinion. Randomized controlled clinical trials were evaluated for inclusion.

Sample Characteristics

  • Seven studies comprising a total of 616 patients were included.
  • Key characteristics were use of lactulose, senna, co-danthramer, misrakasneham,  and magnesium hydroxide with liquid paraffin.

Phase of Care and Clinical Applications

  • Patients were undergoing the end-of-life phase of care.
  • The study has clinical applicability for palliative care.

Results

  • The best laxative for this patient population is unclear.
  • Methylnaltrexone is effective in patients with opioid-induced constipation.

Conclusions

Well-designed clinical trials are needed to help identify which laxatives are most effective for palliative care patients with constipation.

Limitations

Very few clinical trials effectively evaluated the use of laxatives in this patient population.

Print

Siemens, W., Gaertner, J., & Becker, G. (2015). Advances in pharmacotherapy for opioid-induced constipation–A systematic review. Expert Opinion on Pharmacotherapy, 16, 515–532. 

Purpose

STUDY PURPOSE: To evaluate the efficacy and safety of drugs reported in randomized controlled trial for the management of opioid-induced constipation

TYPE OF STUDY: Systematic review

Search Strategy

DATABASES USED: Medline; Medline In-Process and Other Non-Indexed Citations; Cochrane Central Register of Controlled Trials; PubMed; EMBASE
 
KEYWORDS: constipation, gastrointestinal transit, bowel dysfunction, opiate alkaloids, analgesics, opioid
 
INCLUSION CRITERIA: Primary study aim was improvement of opiod-induced constipation (OIC). Study type: Phase II and III RCTs and randomized dose-ranging studies. Full text. Primary intervention: Pharmacological interventions against OIC. Objective outcome measures, bowel movement (BM) within four hours, time to first BM.
 
EXCLUSION CRITERIA: Open-label (extension) phases with single- or double-blind phase

Literature Evaluated

TOTAL REFERENCES RETRIEVED: N = 869 retrieved, 540 screened 
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two independent reviewers screened abstracts. Items extracted: study ID, author, publication year, article type, study aim, population, inclusion criteria, exclusion criteria, intervention, control group, primary outcome, secondary outcome, results for objective outcome measures (OOM), dropouts adverse events and comments. Risk: fixed effects model with Mantel-Haenszel method

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 21 studies included in qualitative synthesis, 14 analyzed in quantitative synthesis 
  • TOTAL PATIENTS INCLUDED IN REVIEW: methylnaltexone: 1760, naloxone: 798, alvimopan: 1525, naloxegol: 1545, lubiprostone: 877, CB-5945: 131, prucalopride: 196
  • KEY SAMPLE CHARACTERISTICS: Opioid constipation

Phase of Care and Clinical Applications

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Palliative care

Results

Efficacy: Methylnaltrexone OOM were examined in seven studies. Averaged over all the studies, responder rated reached 30%. Median time to rescue-free bowel movement (RFBM) was shortest for doses 0.15 mg/kg and 0.3 mg/kg compared to placebo. Naloxone: Four studies' group differences were significant, but the mean difference of less than or equal to 0.5 and the one-week and four-week comparison was small.  Noloxegel: Three studies with responder rates after 12 weeks of treatment were significantly higher for the 25 mg group, and there was no difference between noloxegel and the placebo group at 12.5 mg. Lubiprostone: Two RCTs showed results not consistent across studies. CB-5945: One study and statistical significant results for all BM frequency only in 0.25 mg bid versus placebo group. Pruclopride: One study with little statistical significance.  Alvimopan: Three studies; after 12 weeks there were spontaneous bowel movement (SBM) in both intervention groups with statistical significance and improvement also.

Conclusions

Seven novel drugs for OIC were reviewed. Effectiveness was shown for all drugs, but BM frequency measures hindered comparison of the studies and the drugs.

Limitations

The authors used different terms in their inclusion criteria for outcome analysis. Seven drugs were included in the review. Comparing seven drugs made comparisons difficult and conclusions limited.

Nursing Implications

Improvement in management of OIC could improve patient experience, reduce hospital stays, and decrease patient suffering. Nurses should ensure preventive and proactice measure for their patients on opioids.

Print

Research Evidence Summaries

Bull, J., Wellman, C.V., Israel, R., Barrett, A.C., Paterson, C., & Forbes, W.P. (2015). Fixed-dose subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation: Results of a randomized, placebo-controlled study and open-label extension. Journal of Palliative Medicine, 18, 593–600. 

Study Purpose

To determine safety and efficacy of fixed doses of methylnaltrexone (MNTX) in patients with advanced disease

Intervention Characteristics/Basic Study Process

After participation in a two-week placebo randomized controlled trial (RCT), patients were eligible to enroll in a 10-week open-label extension study to evaluate the use of MNTX at a fixed dose based on weight using as-needed dosing. Patients were dosed at 8 mg SC for weight of 38 kg to less than 62 kg or, if 62 kg or greater, at a dose of 12 mg. Doses were administered as needed but not more often than daily. Rescue doses of other bowel medications were permitted if the MNTX was not effective. Patients were taking stable laxative regimens and a stable dose of opioids.

Sample Characteristics

  • N = 230  
  • MEAN AGE = 65.9 years
  • MALES: 50.9%-51.7%, FEMALES: 48.3%-49.1%
  • KEY DISEASE CHARACTERISTICS: Advanced illness, with 57%-66% having a cancer diagnosis

Setting

  • SITE: Multi-site    
  • SETTING TYPE: Multiple settings  
  • LOCATION: United States

Phase of Care and Clinical Applications

  • PHASE OF CARE: End-of-life care
  • APPLICATIONS: Palliative care 

Study Design

  • Open-label extension study following a prior clinical trial using MNTX for the management of opioid-induced constipation

Measurement Instruments/Methods

  • Diary of bowel function
  • Clinic visits

Results

MNTX was effective in the management of opioid-induced constipation in both the RCT and the open-label extension study. The results were based on rescue free bowel movements after doses of MNTX. For the MNTX arm in the RCT component, 62.9% of patients had bowel function compared with 9.6% of the placebo control group (p < 0.0001). Weight did not have an effect on outcome. Secondary end points were all in favor of MNTX, including time to bowel function after first dose. The most common side effects were abdominal pain and nausea.

Conclusions

A fixed dose of MNTX is safe and effective in the management of opioid-induced constipation in patients with advanced disease.

Limitations

  • Risk of bias (no blinding)
  • Patients under 38 kg were not eligible
  • Short study duration

Nursing Implications

This study adds support to the data that MNTX is safe and effective for opioid-induced constipation.

Print

Chamberlain, B.H., Cross, K., Winston, J.L., Thomas, J., Wang, W., Su, C., & Israel, R.J. (2009). Methylnaltrexone treatment of opioid-induced constipation in patients with advanced illness. Journal of Pain and Symptom Management, 38, 683-690.

Study Purpose

To describe laxative response to subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation.

Intervention Characteristics/Basic Study Process

Patients were randomly assigned to receive either methylnaltrexone 0.15 mg/kg or placebo subcutaneously every other day for two weeks. Patients were permitted to continue their baseline laxatives. By day 8, the study drug dose (methylnaltrexone or placebo) could be doubled if patients had fewer than three rescue-free bowel movements (BMs).

Sample Characteristics

  • The study reported on a sample of 134 patients.
  • Median age was 72 years (range 34-93) for the methylnaltrexone group and 70 years (range 39-98) for the placebo group.
  • The sample was 57% female (n = 36) and 43% male (n = 27) in the methylnaltrexone group, and 56% female (n = 40) and 44% male (n = 31) in the placebo group.
  • Patients had advanced illness, such as terminal cancer or other end-stage diseases with a life expectancy of at least one month, and opioid-induced constipation.
  • More than 50% of the study participants had a diagnosis of terminal cancer.

Setting

  • Multi-site
  • Inpatient
  • 27 nursing homes, hospice sites, and palliative care centers
  • United States and Canada

Phase of Care and Clinical Applications

The study has clinical applicability for the end-of-life and palliative phases of care.

Study Design

This was a post-hoc analysis of a two-week double-blind, randomized, placebo-controlled study.

Measurement Instruments/Methods

  • Global Clinical Impression of Change (GCIC)
  • National Cancer Institute common toxicity criteria (NCI CTC), version 2.0
  • Numeric pain rating scale (0 = no pain and 10 = worst possible)
  • Modified Himmelsbach Withdrawal Scale

Results

  • Median time to BM was 0.5 hours in the methylnaltrexone group and 2 hours in the placebo group (p = 0.013).
  • More patients in the methylnaltrexone group (75%) than the placebo group (29%) had a laxation response to at least one of the doses (p < 0.0001).
  • In the methylnaltrexone group, 73.5% of patients on day 7 and 67.9% on day 14 rated their bowel status as better on the GCIC scale.
  • During the study, fewer patients in the methylnaltrexone group than the placebo group reported use of some major classes of laxatives.
  • The most common adverse events (AEs) among methylnaltrexone users were abdominal pain, flatulence, and vomiting. Most AEs were Grade 1 or Grade 2 on the NCI CTC.
  • Mean total opioid withdrawal scores were unchanged.

Conclusions

Methylnaltrexone 0.15 mg/kg administered subcutaneously every other day was effective in relieving opioid-induced constipation.

Limitations

Sixteen percent of patients (10 of 62) in the methylnaltrexone group and 24% (17 of 71) in the placebo group did not complete the study.

Nursing Implications

Subcutaneous methylnaltrexone 0.15 mg/kg appears to be effective in relieving opioid-induced constipation in a timely and predictable manner without reducing pain control or producing symptoms of opioid withdrawal. If an individual does not respond to the first dose, they may still receive some benefit with additional doses. However, the response rate decreased to 25% for individuals receiving a third dose in this study. Reasons for constipation other than opioid use may need to be looked for in nonresponders.

Print

Flerlage, J.E., & Baker, J.N. (2015). Methylnaltrexone for opioid-induced constipation in children and adolescents and young adults with progressive incurable cancer at the end of life. Journal of Palliative Medicine, 18, 631–633. 

Study Purpose

To describe the use of methylnaltrexone (MNTX) in pediatric patients with cancer in both inpatient and outpatient settings

Intervention Characteristics/Basic Study Process

A retrospective chart review was conducted on all children, adolescents, and young adults with incurable cancer treated at St. Jude Hospital from May 2008 to June 2013. Pharmacy data and chart data were reviewed for inclusion data. Patients had documented OIC and the administration of enteral preparations and/or suppositories to treat OIC. After standard therapy for OIC was not successful, MNTX was administered subcutaneously at 0.15 mg/kg per dose.

Sample Characteristics

  • N = 9  
  • AGE RANGE = 17 months-21 years
  • MALES: 44%, FEMALES: 56%
  • KEY DISEASE CHARACTERISTICS: Progressive, incurable cancer
  • OTHER KEY SAMPLE CHARACTERISTICS: Children, adolescent, and young adult

Setting

  • SITE: Single site  
  • SETTING TYPE: Multiple settings    
  • LOCATION: Memphis, TN

Phase of Care and Clinical Applications

  • PHASE OF CARE: End-of-life care
  • APPLICATIONS: Pediatrics and palliative care 

Study Design

  • Retrospective chart review (RCR)

Measurement Instruments/Methods

  • Data collection tool specific to this study was used.

Results

MNTX administration produced bowel function in seven (78%) of the patients in one hour and with five (71%) of the patients having a response to first dose. With repeated dosing, 71% had continued response. There were no side effects documented. Two patients responded to repeated doses. The drug was effective in four of five patients with intra-abdominal disease.

Conclusions

The study revealed that MNTX can be safe and effective in children, adolescents, and young adults with OIC and end-of-life disease.

Limitations

  • Small sample (less than 30)
  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment) 
  • Risk of bias (no appropriate attentional control condition)
  • Measurement/methods not well described
  • Measurement validity/reliability questionable
  • Findings not generalizable

Nursing Implications

OIC is a distressing side effect of opioid pain management. The use of MNTX in pediatric patients with cancer with progressive disease appears to be an effective and safe in this retrospective audit, but prospective randomized clinical trials are required.

Print

Lipman, A.G., Karver, S., Cooney, G.A., Stambler, N., & Israel, R.J. (2011). Methylnaltrexone for opioid-induced constipation in patients with advanced illness: A 3-month open-label treatment extension study. Journal of Pain and Palliative Care Pharmacotherapy, 25, 136-145.

Study Purpose

To provide access to methylnaltrexone for patients who participated in a prior study of the agent, and to continue to evaluate the safety and efficacy of methylnaltrexone in patients with opioid-induced constipation.

 

Intervention Characteristics/Basic Study Process

This open-label drug extension study recruited participants from both the control and active treatment groups of a prior methylnaltrexone study. All patients were at the end of life, were not pregnant, and were using birth control. Patient received methylnaltrexone 0.15 mg/kg subcutaneously as needed once per day. The dose was increased to 0.3 mg/kg if the agent was not effective in four hours.  The dose was reduced to 0.075 mg/kg if the patient had adverse events. 

Sample Characteristics

  • The study reported on a sample of 89 participants (39% male and 61% female).
  • Mean age was older than 65 years (range 66.9–68.9).
  • Most participants (55.9%) were diagnosed with cancer.

Setting

  • Multi-site
  • Inpatient and outpatient
  • United States
     

Phase of Care and Clinical Applications

  • Patients were undergoing the end-of-life phase of care.
  • The study has clinical applicability for end-of-life and palliative care.

Study Design

This was a nonrandomized, single-arm, drug continuation study.

Measurement Instruments/Methods

  • Rescue-free laxation time period    
  • Efficacy endpoints identified by the research team
  • Modified Himmelsbach Scale
  • Global Clinical Impression of Change
     

Results

All patients (control group and active treatment group, as defined in the prior study) received a minimum of one drug dose. Patient laxation effect was similar between the active treatment (45.3%) and control (48.3%) groups. Most patients had an effect in less than one hour. Side effects included abdominal pain, nausea, and vomiting. Serious adverse events considered drug related were muscle spasms, abdominal pain, and pain exacerbation. The effect on patient pain levels was minimal. Opioid withdrawal symptoms ranged from none to mild.  

Conclusions

Patients obtained benefit from methylnaltrexone for up to three months, and the agent was well tolerated.

Limitations

  •  The sample size was small (less than 100).
  •  The study had no true control group, as control patients also received methylnaltrexone in this extension study.
     

Nursing Implications

Patients at the end of life who have an ongoing need for methylnaltrexone may continue to receive an effect from the drug for up to three months when it is used as needed.

Print

Nalamachu, S.R., Pergolizzi, J., Taylor, R., Slatkin, N.E., Barrett, A.C., Yu, J., . . . Forbes, W.P. (2015). Efficacy and tolerability of subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation: A responder analysis of 2 randomized, placebo-controlled trials. Pain Practice, 15, 564–571.

Study Purpose

To examine the influence of demographic and baseline characteristics on the efficacy and tolerability of methylnaltrexone (MNTX) in patients with advanced illness and opioid-induced constipation

Intervention Characteristics/Basic Study Process

Data were pooled from two multicenter, randomized, double-blinded, placebo-controlled, phase 3 clinical studies of subcutaneous MNTX (0.15 and 0.03 mg/kg). The primary outcome analyzed was the percentage of patients with rescue medication-free bowel movement (RFBM) within four hours of the first dose.

Sample Characteristics

  • N = 287  
  • AGE = Younger than 65 years (38.2%-49.6%) and 65 years and older (50.4%-61.8%)
  • MALES: 47.3%-56.4%, FEMALES: 43.6%-52.7%
  • KEY DISEASE CHARACTERISTICS: Advanced illness
  • OTHER KEY SAMPLE CHARACTERISTICS: Age, gender, primary diagnosis, baseline constipation-related distress score, baseline oral morphine equivalent dose

Setting

  • SITE: Multi-site

Phase of Care and Clinical Applications

  • PHASE OF CARE: Mutliple phases of care
  • APPLICATIONS: Palliative care

Study Design

  • Randomized and double-blinded study with placebo controlled arm

Measurement Instruments/Methods

  • Chi-squared test to explore the effects of MNTX versus placebo treatment

Results

More than 50% of 165 patients treated with MNTX dose experienced a rescue-free bowel movement (RFBM) within four hours versus 14.6% of the placebo-treated patients. The largest difference was observed in patients taking the MNTX 0.3 mg/kg without cancer versus the placebo group.

Conclusions

Subcutaneous MNTX provides a rapid and robust and consistent RFBM response in patients with advance illness and OIC. MNTX 0.3 mg/kg may have a more favorable response in selected patient populations.

Limitations

  • Baseline sample/group differences of import
  • Unintended interventions or applicable interventions not described that would influence results 

Nursing Implications

MNTX continues to show efficacy for opioid-induced constipation for various types of patients. Additional work is warranted to determine most effective doses.

Print

Portenoy, R.K., Thomas, J., Moehl Boatwright, M.L., Tran, D., Galasso, F.L., Stambler, N., . . . Israel, R.J. (2008). Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: A double-blind, randomized, parallel group, dose-ranging study. Journal of Pain and Symptom Management, 35, 458-468.

Study Purpose

To assess the efficacy and safety of subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation (OIC), and to clarify whether a dose-response relationship could be identified.

Intervention Characteristics/Basic Study Process

Methylnaltrexone was administered in doses of 1 mg, 5 mg, or 12.5 mg subcutaneously; patients were randomized to those dose groups in a ratio of 1:1:1. After 22 patients, the dose range was extended to 20 mg; patients were randomized in a ratio of 1:1:3 to 1-mg, 12.5-mg, or 20-mg dose groups. Patients received study medication if they had no bowel movement for at least two days and had a score of 3 or higher on a 5-point scale assessing constipation-related distress. Patients receiving laxatives had to be on a stable regimen for at least four days and remain on regimen during the study.

During the first week of the study, subcutaneous injections were administered on days 1, 3, and 5. Following the first week of double-blind study, patients received the option for open-label study for a maximum of three weeks. The initial dose was 5 mg subcutaneously as often as every other day. The maximum dose was 15 mg in the first 22 patients and 20 mg for the remaining 11 patients. Dose could be increased or decreased by the investigator.

Sample Characteristics

  • The study reported on a sample of 33 adult men and women (39 screened) with advanced illness, including patients with cancer receiving palliative care and chronic opioid therapy for pain.
  • Mean patient age was 61 years (range 20-87). 
  • Mean body weight was 64 kg.
  • Seventy-nine percent of patients were Caucasian.
  • Eighty-five percent of patients had a primary diagnosis of cancer.
  • Eighty-five percent of patients used laxatives at baseline, 33% used stool softeners or emollients, and 27% used osmotic agents. 
  • Patients were included in the study if they were receiving opioids, were stable for two weeks, and remained stable for four weeks; had no bowel movements despite conventional laxative therapy; had a life expectancy of at least four weeks; and had stable vital signs.

 

Setting

Multi-center

Study Design

This randomized controlled, parallel-group, repeated-dose, dose-ranging trial included a double-blind phase for one week followed by an open-labeled phase for a maximum of three weeks.

Measurement Instruments/Methods

  • The primary endpoint, laxation response, was a bowel movement within four hours of the initial dose.
  • Subjective outcomes were obtained prior to each dose and approximately three hours postdose.
  • Constipation severity and distress were graded on a five-point categorical scale.
  • The Opioid Withdrawal Scale was a modified Himmelsbach scale.
  • Patient satisfaction was assessed on a seven-point scale.
  • The severity of opioid adverse events were graded on a four-point categorical scale.

Results

Twenty-two patients completed the blinded phase, and 14 completed the open-label phase.

In the blinded phase, laxation occurred within four hours on day 1 for 1 of 10 patients (10%) in the 1-mg dose group, 3 of 7 patients (43%) in the 5-mg dose group, 6 of 10 patients (60%) in the 12.5-mg dose group, and 2 of 6 patients (33%) in the 20-mg dose group. On day 2, for all dose groups higher than 1 mg, 11 of 23 patients (48%) responded (p = 0.05). There was no dose-response relationship across the three highest doses compared to the 1-mg dose.

The median time to laxation was higher than 48 hours for the 1-mg dose group and 1.72, 0.48, and 6.75 hours in the 5-, 12.5-, and 20-mg dose groups, respectively. The median time to laxation was 1.26 hours for all patients dosed 5 mg or higher, and was statistically significant compared to the 1-mg group (p < 0.0003). The 1-mg dose group required laxative rescue approximately twice as often as other groups. There was no trend in worsening pain control over time.

In the open-label phase, the response rate was from 49% to 64% for patients in dose groups from 5 mg to 12.5 mg. Secondary outcomes were not evaluated because of the small sample size.

Conclusions

Methylnaltrexone doses of 5 mg or higher in patients with advanced illness relieved OIC without decreased analgesia or withdrawal symptoms.

Limitations

  • The sample size was small (fewer than 100 patients).
  • The drop-out rate was high: 11 of 22 patients withdrew during the double-blind phase, 4 declined the open-label phase, and 4 withdrew from the open-label phase.
Print

Rodrigues, A., Wong, C., Mattiussi, A., Alexander, S., Lau, E., & Dupuis, L.L. (2013). Methylnaltrexone for opioid-induced constipation in pediatric oncology patients. Pediatric Blood & Cancer, 60(10), 1667–1670. 

Study Purpose

To determine if methylnaltrexone is an effective treatment for opioid-induced constipation in pediatric patients with cancer

Intervention Characteristics/Basic Study Process

Data were collected from pharmacy records and medical chart reviews. They included demographic data, history of constipation, history of vinca alkaloid use, history of abdominal surgery, history of laxative use and dose, duration of opioid use prior to methylnaltrexone administration, the dose and frequency of methylnaltrexone administration, and the patients' responses to the intervention. Opioid doses were converted to oral morphine equivalents. Bowel regimens were compared to pediatric practice guidelines to determine if the bowel regimen had been optimized prior to administration of methylnaltrexone. Patients were given methylnaltrexone in a single subcutaneous injection. The mean dose was 0.15 ± 0.02 mg/kg per dose (range = 3–12 mg per dose).

Sample Characteristics

  • N = 15  
  • MEDIAN AGE = 14 years (range = 4–17)
  • MALES: 33%, FEMALES: 67%
  • KEY DISEASE CHARACTERISTICS: Sarcoma, lymphoma, and neuroblastoma

Setting

  • SITE: Single-site    
  • SETTING TYPE: Inpatient    
  • LOCATION: Canada

Phase of Care and Clinical Applications

  • APPLICATIONS: Pediatrics

Study Design

Retrospective chart review

Measurement Instruments/Methods

  • Naranjo Adverse Drug Reaction Probability Scale (Naranjo Scale)

Results

Ten patients had a bowel movement within 30 minutes of receiving methylnaltrexone. Four patients had a bowel movement between 30 minutes and 4 hours of administration. Four patients were noted to have decreased abdominal girth and active bowel sounds after the intervention. No patients reported a decrease in pain control.

Conclusions

Methylnaltrexone is one effective intervention to treat opioid-induced constipation for pediatric patients after other interventions have failed. The use of methylnaltrexone to relieve constipation did not lead to an increase in pain for the patients in this study.

Limitations

  • Small sample (< 30)
  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment) 
  • Risk of bias (no appropriate attentional control condition) 
  • Measurement/methods not well described
  • Other limitations/explanation: Very small sample size; retrospective review

Nursing Implications

Methylnaltrexone should be considered for pediatric patients when other interventions have failed to relieve opioid-induced constipation.

Print

Slatkin, N., Thomas, J., Lipman, A.G., Wilson, G., Boatwright, M., Wellman, C., . . . Israel, R. (2009). Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. Journal of Supportive Oncology, 7, 39-46.

Study Purpose

To determine the safety and efficacy of subcutaneous (SC) methylnaltrexone in opioid-induced constipation (OIC).

Intervention Characteristics/Basic Study Process

Double-Blind Phase

Patients were randomized to a single dose of study drug or placebo administered SC.  Groups were 0.15 mg/kg, 0.3 mg/kg, or placebo. Patients were randomly assigned in a 1:1:1 ratio to each study group. Baseline laxative regimens could be continued. Rescue laxatives (laxatives administered on an as needed [PRN] basis) were allowed, except within four hours before or after dose administration.

Open-Label Phase

This phase was 28 days with 1 dose per 24 hours PRN. The initial dose of 0.15 mg/kg could be decreased to 0.075 mg/kg or increased to 0.3 mg/kg, based on response.

Protocol Extension

Patients completing the open-label phase could enter a three-month extension. The initial dose was the same as in the open-label phase, with dosing adjusted to 0.075 mg/kg, 0.15 mg/kg, or 0.3 mg/kg by investigator discretion.

Sample Characteristics

  • Of the 154 patients initially randomized, the median age was 66 years, 81.2% had a cancer diagnosis, more than 65% had World Health Organization (WHO) performance status of 3 or 4, and 95% had baseline laxative use.
  • Patients were included in the study if they had advanced illness with a life expectancy of one to six months, were on a stable opioid regimen at least three days prior to study entry, had no significant laxation 48 hours prior, and had stable vital signs.
  • Patients were excluded if they had previously used methylnaltrexone, naltrexone, or naloxone; process suggestive of gastrointestinal obstruction; or nonopioid constipation, diverticular disease, fecal impaction, acute abdomen, or peritoneal catheter.

Double-Blind Phase

  • The age range was 21 to 100 years, with similar median ages across all groups.
  • The sample comprised 54.5% men and 45.5% women, with a similar distribution across groups.
  • Sixty-seven percent had a WHO performance status of 3 or higher.
  • Oral morphine equivalents were 207 mg/day in the 0.15-mg/kg group, 188 mg/day in the 0.3 mg/kg group, and 150 mg/day in the placebo group.
  • No significant differences existed in age, constipation distress, or mean pain score across study groups.
  • At baseline, 95% used laxatives, 83% used stimulants, 56% used osmotic laxatives, and 27% used stool softener.

Open-Label Phase

  • Of the 147 patients who elected the open-label phase, 72 completed the phase.
  • Of the remaining 75 patients, 36 withdrew and 39 died.

Extension Phase

  • Twenty-seven patients elected extension.
  • Nine patients completed extension.

Setting

  • Patients were recruited from hospice and palliative care settings.
  • 17 treatment sites

Study Design

This was a double-blind, randomized, placebo-controlled, single-dose study, followed by an open-label phase, and then an open-label extension phase.

Measurement Instruments/Methods

Efficacy/Primary Outcomes

  • Percent of patients who defecated within four hours of dose
  • Twenty-four–hour rescue-free laxation rates
  • Median time to rescue-free laxation
  • Global Clinical Impression of Change (GCIC) scale (seven-point rating scale from “much worse” to “much better”)
  • Improvement in stool consistency (patient report, 1 = very hard to 6 = watery)
  • Constipation distress (five-point scale from 1= none to 5 = very much)

Secondary Outcomes

  • Pain, as measured on a 10-point scale from 0 (none) to 10 (worst possible)
  • Modified Himmelsbach opioid withdrawal scale (composite summed score for seven symptoms, each scored on a four-point scale from 1 = none to 4 = severe)
  • National Cancer Institute common toxicity criteria, version 2
  • WHO performance status

Results

  • In the methylnaltrexone 0.15 mg/kg group, 61.7% had laxation within four hours, 64.4% reported improvement in constipation distress, and 58.7% reported improvement in GCIC.
  • In the methylnaltrexone 0.3 mg/kg group, 58.2% had laxation within four hours, 63.5% had improvement in constipation distress, and 58.8% had improvement in GCIC.
  • In the placebo group, 13.5% had laxation within four hours, 34% had improvement in constipation distress, and 21.6% had improvement in GCIC.
  • Comparisons between each methylnaltrexone group and placebo were significant (p < 0.00001).
  • In the open-label phase (n = 72), laxation within four hours was experienced by 55.8% in weeks 1 and 2, 61.7% in weeks 3 and 4, and 63.7% at more than 8 weeks.
  • Nineteen patients had AEs. Three patients in the open-label phase reported serious AEs.
  • A few patients experienced abdominal pain and watery stool.
  • No changes were observed in pain or symptoms of opioid withdrawal four hours after dosing.
  • In the open-label phase, the 0.3 mg/kg dose was associated with more abdominal pain than the 0.15 mg/kg dose.

Conclusions

SC methylnaltrexone is effective in the treatment of OIC and generally is well tolerated. No relationship exists between dose and laxation response, suggesting the optimal dose is 0.15 mg/kg.

Limitations

  • Patients who responded to SC dosing often defecated soon after drug administration, with 50% responding within 30 minutes. Average time to defecation or timing in all respondents to the medication were not described.  Timing of response may be important for planning patient care related to toileting.
  • Three patients were reported as having severe AEs. When they occurred in the open-label phase of study and what percentage of cases were affected was unclear. Investigators noted patients were frail and rapid reversal of constipation in such cases can be associated with AEs. Data for AEs in control and study groups were not provided.
  • What impact continued laxative use had on the results was unclear. Many patients were on multiple types of laxatives, as well as the study drug.
  • This study reported on patients with a short life expectancy and advanced disease; therefore, findings may not be applicable to other populations.
Print

Thomas, J., Karver, S., Cooney, G.A., Chamberlain, B.H., Watt, C.K., Slatkin, N.E., . . . Israel, R.J. (2008). Methylnaltrexone for opioid-induced constipation in advanced illness. New England Journal of Medicine, 358, 2332-2343.

Study Purpose

To examine the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness.

Intervention Characteristics/Basic Study Process

Patients were randomly assigned to receive either methylnaltrexone 0.15 mg/kg or placebo subcutaneously every other day for two weeks. Patients were permitted to continue their baseline laxatives and could use rescue laxatives. By day 8, the study drug dose (methylnaltrexone or placebo) could be doubled if patients had fewer than three rescue-free bowel movements. Patients in both groups who completed the two-week study were eligible to enter an open-label extension phase. During the extension trial, methylnaltrexone 0.15 mg/kg was offered as needed every 24 hours for up to three months. Subsequent doses could be increased to 0.3 mg/kg if there was no defecation.

Sample Characteristics

  • The study reported on a sample of 134 patients aged 18 years or older.
  • Median age was 72 years (range 34-93) in the methylnaltrexone group and 70 years (range 39-98) in the placebo group.
  • The sample comprised 27 men (43%) and 36 women (57%) in the methylnaltrexone group, and 31 men (44%) and 40 women (56%) in the placebo group.
  • Patients had advanced illness, such as terminal cancer or other end-stage diseases with a life expectancy of at least one month, as well as opioid-induced constipation. 
  • Patients were receiving a median opioid dose of 100 mg of oral morphine equivalent. 
  • More than 50% of study participants had a diagnosis of terminal cancer.

Setting

  • Multi-site
  • 27 U.S. and Canadian nursing homes, palliative care centers, and hospice centers

Phase of Care and Clinical Applications

The study has clinical applicability for the end-of-life and palliative phases of care.

Study Design

This was a two-week, double-blind, randomized, placebo-controlled phase III study with a subsequent three-month, open-label extension phase.

Measurement Instruments/Methods

  • Global Clinical Impression of Change (GCIC)
  • National Cancer Institute common toxicity criteria (CTC), version 2.0
  • Numeric pain rating scale (0 = no pain and 10 = worst pain possible)
  • Modified Himmelsbach Withdrawal Scale

Results

Efficacy Analysis: Double-Blind Phase

  • Forty-eight percent of patients in the methylnaltrexone group, as compared with 15% of patients in the placebo group, had rescue-free laxation within four hours of receiving the first dose (p < 0.001 for all comparisons).
  • Sixty-eight percent of patients in the methylnaltrexone group, as compared with 45% of patients in the placebo group, had three or more rescue-free laxations per week (p = 0.009).
  • The median time to laxation after the first dose was 6.3 hours in the methylnaltrexone group and 48 hours in the placebo group (p < 0.001).

Pain Scores and Opioid Withdrawal

  • Both groups had stable scores on the Modified Himmelsbach Withdrawal Scale and no change in pain scores. 

Adverse Events

  • Similar percentages of patients in both groups had at least one adverse event (AE), of which abdominal pain and flatulence were the most common.
  • Most AEs were rated by investigators as being mild or moderate. 

Open-Label Extension

  • Eighty-nine patients entered the open-label extension phase.
  • Response rates to methylnaltrexone were consistent during the extension.

Conclusions

Methylnaltrexone as administered in this study was effective in inducing laxation in patients with advanced illness and opioid-induced constipation, without compromising analgesia or triggering withdrawal symptoms.

Limitations

Calculations showed that a total of 130 patients (65 in each group) would allow detection of a difference of 30% to 35% in the proportion of patients having a laxation response. However, only 106 patients (52 in the methylnaltrexone group and 54 in the placebo group) completed the study.

Nursing Implications

Subcutaneous methylnaltrexone seems effective in treating constipation in patients with advanced illness and opioid-induced constipation without compromising analgesia or causing withdrawal symptoms. In this study, more than 50% of patients had a diagnosis of cancer; therefore, conclusions can likely be extended to patients with cancer. In addition, patients in this study were receiving a median opioid dose of approximately 100 mg of oral morphine equivalent. Many patients with cancer receive a larger dose; therefore, further study with increased doses of morphine equivalent is warranted.

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Guideline / Expert Opinion

Librach, S.L., Bouvette, M., De Angelis, C., Farley, J., Oneschuk, D., Pereira, J.L., . . . Canadian Consensus Development Group for Constipation in Patients With Advanced Progressive Illness. (2010). Consensus recommendations for the management of constipation in patients with advanced, progressive illness. Journal of Pain and Symptom Management, 40, 761-773.

Purpose & Patient Population

To identify best practices for the management of constipation in patients with advanced progressive disease.

Type of Resource/Evidence-Based Process

In this consensus-based guideline, the literature was reviewed and a multidisciplinary group met to develop the consensus statement. The guideline was revised and reviewed several times prior to publication.

Databases searched were PubMed and the Cochrane Library.

Search keywords were constipation, palliative care, advanced illness, laxatives, management, guidelines, and recommendations.

Inclusion and exclusion criteria were not provided.

 

Phase of Care and Clinical Applications

  • Patients were undergoing the end-of-life or palliative phase of care.
  • The study has clinical applicability for palliative care.

Results Provided in the Reference

This information was not provided. The consensus statement included only 20 references.

Guidelines & Recommendations

The consensus statement included information on the components of patient assessment, history, rectal and abdominal examination, management, goal development, and pharmacologic and nonpharmacologic interventions, as well as a best practice summary. Nonpharmacologic recommendations included maintaining adequate fluid and fiber intake, mobility, optimizing toileting with privacy, and positioning. Pharmacologic recommendations included selection of laxatives based on patient symptoms and preferences, as well as use of methylnaltrexone with opioid-induced constipation for patients who fail to respond to optimal laxative therapy. Osmotic laxatives, polyethylene glycol (PEG), and lactulose are supported by high-level evidence. Docusates and mineral oil should not be used.

Limitations

  • Patients with cancer were not identified as a specific target of the review.
  • The number of articles reviewed to develop the consensus statement was not provided.

Nursing Implications

The consensus statement included a summary in outline format that reviewed the information provided in the body of the article. The summary is the most useful section of the document as the information is concise but contains adequate detail. No new information is provided. In addition, a decision tree was included that may be useful. Regular assessment is needed for the management of patients with constipation.

Print

National Comprehensive Cancer Network. (2011). NCCN Clinical Practice Guidelines in Oncology: Adult cancer pain [v. 2.2011]. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf

Guidelines & Recommendations

The guidelines recommend the following for management of opioid-induced constipation.

Preventive Measures:

  • Take polyethylene glycol or a combination of stool softener and stimulant laxative daily.
  • Maintain adequate fluid intake.
  • Maintain adequate fiber intake. Compounds such as psyllium are not recommended because they are unlikely to control opioid-induced constipation.

If Constipation Occurs:

  • Rule out other causes and begin treating.
  • Titrate stool softeners and laxatives as needed.
  • Consider coanalgesics to enable opioid dose reduction.

Persistent Constipation:

  • Consider the addition of agents such as magnesium hydroxide, bisacodyl, rectal suppository, lactulose, and sorbitol.
  • Use enemas.
  • Consider methylnaltrexone 0.15 mg/kg subcutaneously daily.

Limitations

Recommendations were identified as having low-level evidence and uniform consensus.

Print

National Comprehensive Cancer Network. (2015). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Palliative care [v.1.2016]. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf

Purpose & Patient Population

PURPOSE: To provide guidance to clinicians regarding the provision of palliative care
 
TYPES OF PATIENTS ADDRESSED: Patients with cancer

Type of Resource/Evidence-Based Process

RESOURCE TYPE: Consensus-based guideline

PROCESS OF DEVELOPMENT: Guidelines were developed by a panel

Phase of Care and Clinical Applications

PHASE OF CARE: Multiple phases of care
 
APPLICATIONS: Palliative care 

Results Provided in the Reference

These guidelines did not provide a specific search strategy or information about literature search results.

Guidelines & Recommendations

  • Dyspnea: Use fans, cooler temperatures, stress management, and relaxation therapy; use morphine if the patient is opioid-naïve, and add benzodiazepines symptoms are not relieved by opioids; give oxygen for subjective relief; reduce excessive secretions with scopolamine, atropine ophthalmic solution, or glcopyrrolate.
  • Anorexia: Consider an appetite stimulant such as megestrol acetate, olanzapine, dexamethasone, or a cannabinoid.
  • Constipation: Use senna with or without docusate; add other laxatives as needed; consider methylnaltrexone for opioid-induced constipation.
  • Diarrhea: Administer loperamide; recommend the Bananas, Rice, Applesauce and Toast (BRAT) diet; consider atropine, corticosteroids, infliximab, or octreotide.

Limitations

These recommendations were made mainly by consensus, and the guidelines provided no information about literature search results and appeared to use only one database for searching. All suggestions were based on low-level evidence and uniform consensus.

Nursing Implications

These guidelines provided numerous suggestions for the management of various symptoms, but they were not truly evidence-based. In those aspects for which there was no research evidence, the guidelines provided expert opinion suggestions for management.

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