Abstract
Introduction
Constipation is a common adverse effect of opioids. As an example, constipation is reported in 52% of people with advanced malignancy, and this figure rises to 87% in people who are terminally ill and taking opioids. There is no reason to believe that people with chronic non-malignant disease who are prescribed opioids will be any less troubled by this adverse effect.
Methods and outcomes
We conducted a systematic overview and aimed to answer the following clinical question: What are the effects of opioid antagonists for constipation in people prescribed opioids? The population we studied included people with any condition, although most studies were in people with cancer pain. We searched Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).
Results
At this update, searching of electronic databases retrieved 162 studies. After deduplication and removal of conference abstracts, 84 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 37 full publications. Of the 37 full articles evaluated, two systematic reviews and one RCT were included at this update. We performed a GRADE evaluation for three PICO combinations.
Conclusions
In this systematic overview we categorised the efficacy for three interventions based on information relating to the effectiveness of alvimopan, methylnaltrexone, and naloxone.
Key Points
Constipation is one of the most common and persistent effects of opioids. As an example, constipation is reported in 52% of people with advanced malignancy, and this figure rises to 87% in people who are terminally ill and taking opioids. Although most of the data on opioid-induced constipation comes from studies on cancer patients, there is no reason to believe that people with chronic non-malignant disease who take opioids will be any less troubled by this adverse effect.
Traditionally, laxatives have been used to try and manage constipation when it occurs as a side-effect of opioid therapy. These act by relieving the symptoms and effects of opioid-induced constipation (i.e., palliation) by stimulating bowel movement or softening the stools. They do not address the cause of opioid-induced constipation, and the evidence base for their efficacy is poor (see previous version of this topic). The relatively new use of opioid antagonists represents a targeted approach to stopping the cause of opioid-induced constipation at the bowel opioid receptor level.
There is consensus that the opioid antagonists alvimopan, methylnaltrexone, and naloxone can reverse not only the constipation but, potentially, the other gastrointestinal symptoms induced by opioids.
Naloxone, given as a normal-release drug, may provoke reversal of opioid analgesia, but this is less likely with prolonged-release naloxone, alvimopan, or methylnaltrexone. Normal-release naloxone may also cause opioid withdrawal, but this has not been reported with methylnaltrexone, alvimopan, or prolonged-release naloxone when combined with prolonged-release oxycodone.
We searched for RCTs and systematic reviews of RCTs of methylnatrexone, naloxone alone (and in combination with oxycodone), or alvimopam compared with placebo or with each other in people with opioid-induced constipation.
We included RCTs of the listed interventions prescribed by any route. In the case of naloxone, we included any type (e.g., pegylated), and the combination product prolonged-release naloxone plus oxycodone.
So far, the new peripherally acting opioid antagonists have only been compared with placebo.
The RCTs found that alvimopan, methylnaltrexone, and naloxone may be more effective than placebo at improving bowel function in people with opioid-induced constipation.
There was considerable variation in terms of the characteristics of participants, indications for opioid therapy (e.g., cancer versus non-cancer pain), and type of setting (primary, secondary, and tertiary care).
Further RCTs comparing these preparations with each other and with conventional laxative therapies are needed.
Clinical context
General background
Constipation is a common, debilitating, and sometimes dose-limiting side effect from opioids when prescribed for pain control. Opioids cause constipation because they act on peripheral opioid receptors in the gastrointestinal (GI) tract, as well as in the nervous system where their desired analgesic benefits arise. These gastrointestinal opioid receptors are involved in the normal regulation of bowel motility and fluid absorption by the endogenous opioid system. These functions are disturbed when pharmacological doses of therapeutic opioids are presented to the bowel lumen. It, therefore, makes good sense to try to block the action of opioids on these peripheral GI receptors.
Focus of the review
This overview focuses on the use of opioid antagonists for managing constipation in people prescribed opioids. Traditionally, laxatives have been used to try and manage constipation when it occurs as a side effect of opioid therapy. These act by relieving the symptoms and effects of opioid-induced constipation (i.e., palliation) by stimulating bowel movement or softening the stools. They do not address the cause of opioid-induced constipation, and the evidence base for their efficacy is poor (see previous version of this topic). The relatively new use of opioid antagonists, on the other hand, represents a targeted approach to stopping the cause of opioid-induced constipation at the bowel opioid receptor level.
Comments on evidence
So far, the new peripherally-acting opioid antagonists have only been compared with placebo. There was considerable variation in terms of the characteristics of participants, indications for opioid therapy (e.g., cancer versus non-cancer pain), and type of setting (primary, secondary, and tertiary care). Further RCTs comparing these preparations with each other and with conventional laxative therapies are needed.
Search and appraisal summary
The updated literature search for this overview was carried out from the date of the last search, July 2009, to May 2014. A back search from 1966 was performed for the new options added to the scope at this update. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 162 studies. After deduplication and removal of conference abstracts, 84 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 37 full publications. Of the 37 full articles evaluated, two systematic reviews and one RCT were included at this update.
About this condition
Definition
Constipation is infrequent defecation with increased difficulty or discomfort and with reduced number of bowel movements, which may or may not be abnormally hard. It can have many causes, one of which is opioid use. The broader concept of opioid-induced bowel dysfunction (OBD) encompasses a wide range of associated symptoms, including constipation, abdominal distension, colicky pain, gastric fullness, nausea, vomiting, anorexia, confusion, and overflow diarrhoea. It should be noted that these symptoms may also be associated with constipation from other causes, including other drugs. This overview focuses only on constipation in people prescribed opioids. Although most of the data on opioid-induced constipation comes from studies on cancer patients, there is no reason to believe that people with chronic non-malignant disease who take opioids will be any less troubled by this adverse effect. In the past, opioids were used in cancer for pain (and increasingly for breathlessness) relatively late in the disease process (advanced and terminal cancer), and were prescribed especially by palliative care services. The WHO definition of palliative care is as follows: "Palliative care is an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual". Although this definition of palliative care does not specify incurable or terminal illness, conventionally palliative care applies to people approaching the end of life; that is, people with a prognosis of less than 1 year. There is recognition that, for many people being treated for cancer, good symptom control needs to 'upstream' to those with earlier stages of cancer. Furthermore, cancer survivors are living longer after treatment but may continue to need opioids for a longer period. The management of earlier-stage cancer patients and long-term survivors is now regarded as part of 'supportive care'. The UK National Institute for Health and Care Excellence (NICE) definition of supportive care is as follows: supportive care "helps the patient and their family to cope with cancer and treatment of it — from pre-diagnosis, through the process of diagnosis and treatment, to cure, continuing illness, or death, and into bereavement. It helps the patient to maximise the benefits of treatment and to live as well as possible with the effects of the disease. It is given equal priority alongside diagnosis and treatment". Both supportive and palliative care embrace the same priorities of maximising quality of life; but supportive care aims to do this in people who may live longer, become cured, or who are living in remission from their disease. The NICE definition of supportive care was written in relation to people with cancer but is applicable to all people with chronic or terminal illness; for example, those with heart failure, neurological disease, or lung disease. There are other BMJ Clinical Evidence overviews on Constipation in adults and Constipation in children.
Incidence/ Prevalence
In one prospective cohort study (1000 people with advanced cancer), constipation was reported to occur in 52% of people. In another prospective cohort study (498 people in hospice with advanced cancer) this figure rose to 87% in people who were terminally ill and taking opioids. A survey (76 people) carried out by the American Pain Society found that, in people with chronic pain of non-cancer origin treated with opioids, the incidence of constipation was five times higher than in another US survey of 10,018 US controls (health status of controls not defined). A British cohort study (274 people with cancer attending a tertiary referral cancer hospital) found that 72% of patients taking oral morphine for pain had mild to severe constipation. The prevalence of constipation is not the same with all opioids. One RCT (212 people with cancer), assessing people who were taking opioids for 14 days or less, found that constipation affected significantly more people taking modified-release oral morphine than taking transdermal fentanyl (45% with modified-release oral morphine v 27% with transdermal fentanyl; P <0.001). One further systematic review (search date 2004, 6 RCTs, 1220 people, 657 with cancer, 563 with chronic painful diseases taking opioids for 28 days or more) found that significantly more people had constipation when taking modified-release oral morphine than taking transdermal fentanyl (37% with modified-release oral morphine v 16% with transdermal fentanyl; P <0.001).Another systematic review (search date 2007, 4 RCTs, 425 people with moderate-severe cancer pain) comparing oral morphine with transdermal opioids (fentanyl or buprenorphine) found that both transdermal drugs were associated with a significantly reduced incidence of constipation (31/214 [14%] with transdermal opioids v 62 /211[29%] with oral morphine).
Aetiology/ Risk factors
The constipating effect of opioids is through their action on mu opioid receptors in the submucosal and myenteric plexus of the gastrointestinal tract. This decreases gastrointestinal motility by decreasing coordinated propulsive peristalsis (at the same time increasing circular contractions), decreases secretions (pancreatic and biliary), and increases intestinal fluid absorption. The opioid-induced increase in circular muscle contractions causes colicky pain. There is also a centrally-mediated effect of opioids on the GI tract so that even spinally administered opioids cause decreased gastric emptying and prolonged oral-caecal transit time. There is good evidence from RCTs and animal studies that, compared with water-soluble opioids such as morphine and oxycodone, the more lipid-soluble opioids such as fentanyl and buprenorphine are less likely to cause constipation while maintaining the same degree of analgesic effect. This may be because they are given by a transdermal route, which avoids the gastrointestinal tract. It may also be due to their much reduced time in the systemic circulation. Other risk factors for constipation and bowel dysfunction in people taking opioids for advanced cancer include hypercalcaemia, reduced mobility, reduced fluid and food intake, dehydration, anal fissures, and mechanical obstruction, as well as positional problems (e.g., with bedpan use). Lack of privacy for defecation may also play a part for people in hospital. Drugs that can cause or exacerbate constipation include anticholinergics. In the treatment of cancer, thalidomide, vinca alkaloids, and 5HT3 antagonists can all cause constipation. Additionally there is an increased risk of constipation in people with autonomic neuropathy caused by diabetes mellitus, for example, and in people with neuromuscular problems such as spinal cord compression.
Prognosis
One single-centre observational study (50 people) found a correlation between persistent constipation and poorer performance status (94% of people with Eastern Cooperative Oncology Group [ECOG] score 3 or 4 were constipated). This study found no relationship between total opioid dose and degree of constipation. However, a more recent single-centre observational study (50 people with advanced cancer) found increased constipation in people taking opioids, but found no relationship between constipation and a more sensitive measure of physical functioning using the Barthel Index.
Aims of intervention
To reduce constipation in people prescribed opioids, with minimal adverse effects of treatment.
Outcomes
Bowel movements/laxation frequency; completeness of evacuation; adverse effects, including abdominal pain and discomfort, reversal of opioid analgesia, and opioid withdrawal symptoms.
Methods
Search strategy BMJ Clinical Evidence search and appraisal date May 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to May 2014, Embase 1980 to May 2014, The Cochrane Database of Systematic Reviews 2014, issue 4 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, including open-label trials, and containing more than 20 individuals (10 in each arm), of whom more than 30% were followed up. There was no minimum length of follow-up. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributor. In consultation with the expert contributor, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' sections. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributor may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported questions: What are the effects of oral laxatives for constipation in people prescribed opioids? What are the effects of rectally applied medications for constipation in people prescribed opioids? Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Constipation: opioid antagonists in people prescribed opioids.
| Important outcomes | Frequency of bowel movements | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of opioid antagonists for constipation in people prescribed opioids? | |||||||||
| 4 (1693) | Frequency of bowel movements | Alvimopan versus placebo or no treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for weak methods (1 of 4 RCTs at low risk of bias, diverse response criteria in analysis); directness point deducted for unclear generalisability (all based in secondary/tertiary care, all in chronic non-malignant pain) |
| 6 (1610) | Frequency of bowel movements | Methylnaltrexone versus placebo/no treatment | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for weak methods (3 of 6 RCTs at low risk of bias, diverse response criteria in analysis); consistency point deducted for significant heterogeneity |
| 5 (955) | Frequency of bowel movements | Naloxone versus placebo/no treatment | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for weak methods (2 of 4 RCTs at low risk of bias, diverse response criteria in analysis, no ITT analysis in 1 RCT) and incomplete reporting of results |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Barthel index
The Barthel scale or Barthel ADL index is a scale used to measure performance in basic activities of daily living (ADL). It uses 10 variables describing ADLs and mobility. A higher number is associated with a greater likelihood of being able to live with a degree of independence.
- Brief Pain Inventory
The Brief Pain Inventory is a questionnaire used to assess the severity and the impact of pain on daily functions. It asks about the severity of pain, impact of pain on daily function, location of pain, pain medications, and amount of pain relief in the past 24 hours or the past week.
- EORTC QLQ-C30
The European Organisation for Research and Treatment Quality of Life Questionnaire consists of five functioning scales (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, nausea/vomiting, and pain), six single time scales (dyspnoea, sleep disturbances, appetite loss, constipation, diarrhoea, and financial impact), and the global quality-of-life scale.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Sam H. Ahmedzai, Department of Oncology, The University of Sheffield, Sheffield, UK.
Jason W. Boland, Medical School, University of Hull, Hull, UK.
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