Intended for healthcare professionals

Practice Therapeutics

Pharmacological therapies for opioid induced constipation in adults with cancer

BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3313 (Published 02 August 2017) Cite this as: BMJ 2017;358:j3313
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Infographic available

Click here for a visual overview of the management of opioid induced constipation

  1. Jason W Boland, senior clinical lecturer and honorary consultant in palliative medicine1,
  2. Elaine G Boland, consultant and honorary senior lecturer in palliative medicine1 2
  1. 1Wolfson Palliative Care Research Centre, Hull York Medical School, University of Hull, Hull HU6 7RX, UK
  2. 2Hull and East Yorkshire NHS Trust, Hull, UK
  1. Correspondence to: J W Boland jason.boland{at}hyms.ac.uk

What you need to know

  • Prescribe a laxative to patients starting treatment with opioids to prevent constipation

  • If constipation is bothersome and does not respond to laxatives, discuss the option of starting peripherally acting μ-opioid receptor antagonists

  • These drugs reverse the effect of opioids on bowels without affecting the analgesic effect of opioids

A 75 year old woman with metastatic breast cancer complains of constipation for two weeks. She has been taking regular modified release oral morphine for pain for three weeks. Despite using laxatives, she now opens her bowels with difficulty once or twice a week and complains of abdominal discomfort; these are so severe that she is considering stopping morphine. She has come to discuss treatment options.

Opioids are commonly prescribed for cancer pain. Constipation reportedly affects around 52% of patients with advanced cancer and 87% of terminally ill patients taking opioids.123 Constipation is often multifactorial in patients with cancer, and opioids may be one cause. The infographic outlines possible contributory factors. Consider opioid induced constipation in people who describe a change in bowel habit after starting opioid therapy that is characterised by reduced frequency, development or worsening of straining, a sense of incomplete rectal evacuation, or harder stool consistency.4Figure 1 illustrates the effects of opioids on the bowel mediated through opioid receptors that can lead to constipation, and in some cases limit opioid use.56

Figure1

Fig 1 Effect of opioids on the bowel and clinical manifestations. Opioids act on opioid receptors in the gastrointestinal tract, leading to decreased small and large bowel motility with increased intestinal fluid absorption, increased anal sphincter tone, and reduced anorectal sensitivity to distension. These factors together cause dry, hard stools and reduced bowel movements

The infographic shows an approach to assessment and management options. The remainder of this article will focus on pharmacological options. Continue non-pharmacological options alongside pharmacological management.

What treatments are available for opioid induced constipation in patients with cancer?

Laxatives

The National Institute for Health and Care Excellence (NICE) guidelines recommend prescribing laxatives to prevent constipation for all patients starting strong opioids such as buprenorphine, diamorphine, fentanyl, morphine, and oxycodone.7 The infographic lists the different types of laxative available.2 Oral laxatives are used as first line pharmacological therapy to relieve constipation in people with cancer.289

Peripheral acting μ-opioid receptor antagonists

If laxative therapy fails, targeted therapy to antagonise the peripheral effect of opioids on μ-opioid receptors in the gut may be considered. Drugs include:

  • Methylnaltrexone bromide

  • Prolonged-release formulation of oxycodone in fixed dose combination with naloxone

  • Naloxegol oxalate.

Table 1 summarises how these drugs work, dosing, indications, and precautions.

Table 1

Peripherally acting μ-opioid receptor antagonists: posology, indications, precautions, and drug interactions.

View this table:

The oxycodone-naloxone combination may be used in patients requiring oxycodone for pain relief for a long duration, as naloxone can potentially counteract the peripheral effects on the bowels.

NICE technology appraisal guidance recommends oral naloxegol in patients with opioid induced constipation that has not adequately responded to laxatives and non-pharmacological management.8 The US Food and Drug Administration (FDA) has also licensed the use of naloxegol for this indication.15 Methylnaltrexone as subcutaneous injection is licensed by the FDA for treatment of opioid induced constipation in patients with advanced illness in palliative care.10

Clinicians might worry about the possibility of these drugs reversing the pain relief action of opioids. However, the naloxone present in the oxycodone-naloxone combination undergoes extensive first pass metabolism and has low systemic availability. Methylnaltrexone and naloxegol cross the blood-brain barrier poorly. Instances of reducing analgesic effect of opioids or causing opioid withdrawal are rare.1317

How well do they work?

There is limited, mostly low quality, evidence on effectiveness of laxatives in opioid induced constipation. This represents a large gap in the evidence base, and more studies, especially in patients with cancer, are needed.

Evidence on effectiveness of peripherally acting μ-opioid receptor antagonists for opioid induced constipation is largely limited to studies in patients using opioids for chronic, non-cancer pain. A systematic review and meta-analyses (14 randomised controlled trials, 4101 patients with opioid induced constipation) found better response with methylnaltrexone and naloxone compared with placebo.13 The number needed to treat (NNT) with μ-opioid receptor antagonists (pooled across drugs) to prevent one patient with opioid induced constipation failing to respond to therapy was 4 (95% confidence interval 3 to 6). The studies vary in treatment regimens used and outcomes measured, and only reported short term outcomes (<12 weeks).

Naloxegol has not been studied in patients with cancer. Evidence from two phase III trials in patients with non-cancer pain and opioid induced constipation suggests significantly better response with naloxegol in spontaneous bowel movements compared with placebo.18

Laxatives

There is limited evidence for the superiority of one laxative over another. A crossover randomised controlled trial (RCT) in 57 people on a methadone maintenance programme with opioid induced constipation found no difference between osmotic laxatives polyethylene glycol (PEG) electrolyte solution and lactulose, though both were significantly better than placebo.19 An open label, randomised controlled trial in 91 people with advanced cancer taking opioids found no difference in defecation-free intervals and days with defecation between lactulose and stimulant laxative senna.20

Peripherally acting μ-opioid receptor antagonists

A Cochrane review published in 2008 examined the efficacy of peripherally acting opioid antagonists for opioid induced constipation.21 Twenty three placebo controlled trials were included and provided data on 2871 participants treated with opioid antagonists, which included patients receiving opioids for cancer or non-cancer pain and healthy volunteers. Methylnaltrexone was evaluated in six studies and naloxone in seven studies. Methylnaltrexone was effective in reducing gastrointestinal transit time and opioid induced constipation, though this is based on limited data, and information on safety and adverse events is lacking. There was insufficient evidence on the safety or efficacy of naloxone.21

Subsequently, a well conducted systematic review and meta-analysis (14 randomised controlled trials, 4101 patients) evaluated the effectiveness of μ-opioid receptor antagonists for opioid induced constipation.13 Methylnaltrexone (six randomised controlled trials, 1610 patients, relative risk of failure to respond to therapy 0.66 (95% CI 0.54 to 0.84)) and naloxone (four trials, 798 patients, relative risk 0.64 (0.56 to 0.72)) were both superior to placebo. Of the included studies on naloxone, two trials used oral, normal release naloxone, while two randomised controlled trials used an oral fixed-dose combination of prolonged release oxycodone and naloxone (2:1 ratio). There was considerable heterogeneity between studies (I2=72%, P=0.003).13 Most of these studies included patients with chronic non-cancer pain, and findings may not directly apply to patients with cancer.

An additional double blind, randomised controlled trial (185 patients) compared the oxycodone-naloxone combination with oxycodone alone for constipation in people with chronic cancer pain. Oxycodone-naloxone provided superior bowel function, measured as a composite of ease of defecation, feeling of incomplete bowel evacuation, and personal judgment of constipation.22

A retrospective propensity analysis of consecutive opioid-naïve patients with cancer who started with either oxycodone (73 patients) or oxycodone-naloxone (73-matched patients) also showed improved bowel function in the oxycodone-naloxone group.23 However, the combination did not completely eliminate the need for laxatives, with 34-70% of patients presenting with opioid induced constipation requiring adjunct therapy after four weeks of treatment.2223

Naloxegol has not been studied in people with cancer. Two phase III, double blind trials randomised patients with non-cancer pain and opioid induced constipation received naloxegol (12.5mg or 25mg) or placebo (study 04: 652 participants; study 05: 700 participants). Patients taking naloxegol reported significantly better response measured as spontaneous bowel movements compared with placebo without reducing opioid-mediated analgesia.18

How safe are they?

Laxatives may cause gastrointestinal side effects such as diarrhoea, vomiting, and cramps, but studies have generally shown them to be safe.2

In the systematic review discussed above, the number needed to harm (NNH) with peripheral μ-opioid receptor antagonists (pooled across drugs) was 14 (95% CI 9 to 33). Adverse events (including diarrhoea, abdominal pain, and headache) were more common with these drugs than with placebo.13

The oxycodone-naloxone combination can produce opioid side effects including respiratory depression and dependence,14 which must be watched for especially in patients taking a high dose combination. A higher incidence of diarrhoea has been observed with the combination in patients with chronic non-cancer pain.242526

Local site reactions can occur with methylnaltrexone injections, so injection sites should be rotated.11

Reversal of analgesia and opioid withdrawal symptoms have not been observed to be more common with the peripherally acting μ-opioid receptor antagonists.13172427 However, caution is advised, especially in patients with extensive liver metastases or disruptions to the blood-brain barrier such as with malignancies or metastases in the central nervous system or who have had brain radiotherapy. There is little evidence on effectiveness and safety in these patients.11141627

How are they taken?

The British National Formulary advises prescribing a regular stimulant laxative (such as senna or bisacodyl) at first opioid prescription rather than waiting until constipation is established.28

In patients with constipation, offer laxatives either singly or in combination, for example, a stimulant with a stool softener. Perform a rectal examination to exclude hard faeces in the rectum or impaction. If so, suppositories or enemas may be needed initially. Laxatives need to be individually titrated, and effects may be noted after a few days. Patients with severe constipation may require a higher initial dose, which can lead to diarrhoea.

If constipation is not adequately relieved by laxatives, offer the patient the option of starting oral naloxegol or methylnaltrexone as subcutaneous injection in patients with advanced illness.8101516

Laxative therapy may be halted until the clinical effect of the peripherally acting μ-opioid receptor antagonist is determined.81516 In severe resistant cases and in patients receiving palliative care,11 as well as for maintenance therapy, these antagonists might be continued alongside laxatives. Clear guidance on the place of these drugs in the treatment pathway is lacking, and it is important to discuss treatment with the patient and adapt intensity of treatment to their symptoms. Ask patients to report any side effects which may require stopping the drug.

How cost effective are they?

The burden of opioid induced constipation is large in terms of costs from doctor visits, medications, and hospitalisation, and impact on daily functioning and quality of life.29 A retrospective data analysis of 8836 cancer patients taking opioids suggests that patients with constipation were more likely to receive inpatient care, hospice outpatient care, and emergency care than matched controls, resulting in higher total costs.30

A cost utility analysis for oxycodone-naloxone in patients with moderate to severe non-malignant pain and opioid induced constipation reported higher direct treatment costs than oxycodone alone (£160 for the 301 day average treatment duration). However, patients treated with the combination reported a quality of life gain. The estimated incremental cost effectiveness ratio was less than £6000, below the £20 000 UK threshold set by NICE.31

A technology appraisal of naloxegol (with bisacodyl as a rescue medication) showed incremental cost effectiveness ratios up to £13 000 per quality adjusted life year (QALY) compared with placebo.8 Naloxegol was more effective and less costly than methylnaltrexone and oxycodone-naloxone, except when naloxegol was given with oxycodone and compared with oxycodone-naloxone.8

Tips for patients

  • Opioids are known to cause constipation, which can include reduced frequency of bowel movements; dry, hard stools; straining; a feeling that you still need to open your bowels (even though you have just defecated); and abdominal discomfort

  • Your doctor may discuss with you the option to start a laxative as you commence treatment with opioids to prevent constipation

  • Report any troublesome bowel symptoms to your doctor while taking morphine or other opioids

  • Your doctor may advise changes in your diet and activity. If these do not help, you may be prescribed laxatives and in severe cases an enema

  • If constipation persists, your doctor may discuss the option of starting a “peripherally acting μ-opioid receptor antagonist”. These are a targeted treatment for opioid induced constipation, which only block the effect of opioids outside of the central nervous system

  • Peripherally acting μ-opioid receptor antagonists reverse the action of opioids on the bowels (e.g. constipation), but do not usually affect the pain killing effect of opioids. In some people, they can cause abdominal pain, diarrhoea, nausea, headache, and flatulence

Education into practice

  • How would you assess patients with cancer who have constipation for reversible causes that may be modified?

  • Do you generally advise a laxative to patients when starting treatment with opioids?

  • Can you describe how opioids cause constipation and the role of peripherally acting μ-opioid receptor antagonists?

How patients were involved in the creation of this article

A patient (who is part of our patient and public involvement (PPI) group) reviewed the Tips for patients section.

Footnotes

  • This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Patricia McGettigan, clinical senior lecturer in clinical pharmacology, Queen Mary’s University, London. To suggest a topic, please email us at practice@bmj.com.

  • Contributors: JWB and EGB contributed equally to this article and approved the final version to be published. They agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JWB is the guarantor.

  • Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

  • Provenance and peer review: Commissioned; externally peer reviewed.

  • Transparency: The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

References

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