Naloxone

Naloxone

PEP Topic 
Constipation
Description 

Naloxone, an opioid antagonist, reverses the effects of opioids and has been used to reverse opioid overdose. Naloxone in combination with opioids for pain management has been examined in patients with cancer for its effects on opioid-induced constipation.

Effectiveness Not Established

Systematic Review/Meta-Analysis

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

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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.

Research Evidence Summaries

Meissner, W., Schmidt, U., Hartmann, M., Kath, R., & Reinhart, K. (2000). Oral naloxone reverses opioid-associated constipation. Pain, 84, 105–109.

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Study Purpose:

To evaluate the use of oral naloxone for the management of opiate-associated constipation in patients with cancer.

Intervention Characteristics/Basic Study Process:

Patients were observed for six days without intervention. Afterward, oral naloxone was titrated as follows: 3 mg TID (day 1), 6 mg TID (day 2), 9 mg TID (day 3), 12 mg TID (day 4; maximum). Titration was stopped with laxation or increased peristalsis.

Sample Characteristics:

  • The study reported on a sample of 22 patients.
  • The final sample included 17 patients.

Setting:

Hospital in Germany

Study Design:

This was a controlled study with a control period, but not a control group.

Measurement Instruments/Methods:

  • Himmelsbach Withdrawal Scale was used to monitor possible systemic withdrawal signs such as shivering or piloerection, yawning, perspiration, nausea or vomiting, tremor or restlessness, and lacrimation or rhinorrhea. Each sign was quantified as 0 (none), 1 (mild), 2 (moderate), or 3 (severe).
  • Laxation frequency
  • Pain intensity on an 11-step numerical rating scale
  • Laxatives received
  • Ratio of morphine dose to naloxone dose

Results:

  • Nausea, restlessness, and sweating were the most common side effects.
  • Laxation increased in 14 of 17 patients, whereas laxative use decreased in 9 of 17 patients.
  • No difference existed in pain rating between study periods.
  • Other laxatives used were lactulose, paraffin, raglan, glycerol, castor oil, and sodium picosulfate.
  • Naloxone dose was based on opioid-tolerance level rather than morphine dose.

Conclusions:

Starting with a low dose of naloxone and titrating up is recommended.

Limitations:

  • Only six days were allocated for measurement periods.
  • A subjective Likert-type scale from 0 to 3 was used.
  • No control group existed for other laxative use (all participants were on at least one).
  • Overdosed patients (via medication error) were kept on the study.
  • The study did not control for diet, exercise, and fluid intake.
  • The p-value was not tested.

Tofil, N.M., Benner, K.W., Faro, S.J., & Winkler, M.K. (2006). The use of enteral naloxone to treat opioid-induced constipation in a pediatric intensive care unit. Pediatric Critical Care Medicine, 7, 252–254.

doi: 10.1097/01.PCC.0000216421.72002.09
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Study Purpose:

To describe the effects of enteral naloxone for the treatment opioid-induced constipation.

Intervention Characteristics/Basic Study Process:

Patients in the treatment group received opioids and enteral naloxone for suspected opioid-induced constipation. Patients in the control group received opioids and were randomly chosen from patients receiving opioids during the study period.

Sample Characteristics:

  • The study reported on a sample of 46 pediatric patients (23 in the treatment group and 23 in the member-matched control group).
  • Mean patient age was 6.4 years (range 5 months to 18 years) in the treatment group and 6.1 years (range 4 months to 17 years) in the control group.
  • The sample comprised 14 boys (61%) in the treatment group and 14 boys (61%) in the control group.
  • The morphine equivalent was 86 mg per day (SD = 83, range 9–197) in the treatment group and 20 mg per day (SD = 17, range 1.3–59) in the control group.
  • Mean length of stay in the pediatric intensive care unit was 15 days (SD = 8, range 7–43) in the treatment group and 10 days (SD = 7, range 3–31) in the control group.
  • Mean length of stay in the pediatric intensive care unit five days before enteral naloxone initiation ranged from 0 to 13 days.

Setting:

Pediatric intensive care unit of a children’s hospital in Alabama

Study Design:

This was a retrospective study conducted from January 2003 to February 2004.

Measurement Instruments/Methods:

  • Daily stool output and opiate usage
  • Nutrition
  • Adjuvant laxative use
  • Side effects

Results:

  • In the treatment group, mean stool output before enteral naloxone was 0.14 (SD = 0.38) stools per day. After initiation, mean stool output was 1.6 (SD = 1.14) stools per day (p < 0.001).
  • In the control group, mean stool output was 0.53 (SD = 1.21) stools per day.
  • Eighteen patients in the treatment group (78%) received other bowel agents in addition to enteral naloxone (13 Miralax®, 7 bisacodyl, 4 glycerin suppositories, and 1 milk-and-molasses enema).
  • Eight patients in the control group (35%) received other bowel agents (4 Miralax, 4 bisacodyl, 1 glycerin suppository, and 1 milk-and-molasses enema).
  • A significant inverse relationship existed between opioid dose and increase in stool output after naloxone initiation (r2 = 0.17; p < 0.05).
  • Two patients experienced withdrawal symptoms. One was caused by medication error.

Conclusions:

Enteral naloxone may be effective for increasing stool output in opioid-induced constipation but carries risk of withdrawal symptoms. Additional study is needed.

Limitations:

  • The study was retrospective.
  • The study was not able to control several variables that could be confounders (e.g., dose, duration, and type of opioids; use of additional bowel stimulants; amount of nutrition).
  • Other patients may have had unrecognized mild withdrawal symptoms.
  • Stool size or weight would have been a more objective outcome measure, but was not available.
  • A significant difference existed in morphine equivalent per day between the treatment and control groups (p = 0.01).

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