Constipation in people prescribed opioids

Abstract

Introduction

Constipation is reported in 52% of people with advanced malignancy. This figure rises to 87% in people who are terminally ill and taking opioids. Constipation may be the most common adverse effect of opioids. 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.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: oral laxatives, rectally applied medications, and opioid antagonists for constipation in people prescribed opioids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: arachis oil enemas, bisacodyl, co-danthrusate/co-danthramer, docusate, glycerol suppositories, ispaghula husk, lactulose, liquid paraffin, macrogols plus electrolyte solutions, magnesium salts, methylcellulose, opioid antagonists, phosphate enemas, senna, sodium citrate micro-enema, and sodium picosulfate.

Key Points

Constipation is reported in 52% of people with advanced malignancy. This figure rises to 87% in people who are terminally ill and taking opioids. Constipation may be the most common adverse effect of opioids. 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.

There is some RCT evidence, supported by consensus, that the oral laxatives lactulose, macrogol/electrolyte solutions, and senna are probably of similar efficacy in people with opioid-induced constipation.

• Macrogol/electrolyte solutions may have a better adverse effect profile than the other oral laxatives.

• We found no good-quality studies on other oral laxatives such as ispaghula husk and liquid paraffin. Liquid paraffin is associated with severe adverse effects and is not recommended for long-term use.

• Sodium phosphate enemas have a high incidence of adverse effects. We found no RCT evidence assessing other rectally applied agents (arachis oil enema, glycerol suppository, sodium citrate micro-enema).

We found no RCT evidence assessing rectally applied agents (arachis oil enema, glycerol suppository, phosphate enema, sodium citrate micro-enema).

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 may provoke reversal of opioid analgesia, but this is less likely with alvimopan or methylnaltrexone. Naloxone may also cause mild degrees of opioid withdrawal, but this has not been reported with methylnaltrexone or alvimopan.

Further RCTs assessing all the currently available treatments are needed.

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. Opioid-induced bowel dysfunction (OBD) encompasses a wide range of associated symptoms including abdominal distension and pain, gastric fullness, nausea, vomiting, anorexia, confusion, and overflow diarrhoea. These symptoms may also be associated with constipation from other causes. This review focuses only on constipation in people prescribed opioids. For the purposes of this review, we have used the UK National Institute for Health and Clinical Excellence definition of supportive care 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". This definition was written in relation to people with cancer but is applicable to all people with chronic or terminal illness; for example, heart failure or lung disease. We have used the WHO definition of palliative care 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, there is consensus that palliative care applies to people approaching the end of life; that is, people with a prognosis of less than 1 year. Thus, 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.

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). Fifty-eight percent of people who took opioids regularly required more than two types of treatment for constipation.A British cohort study (274 people with cancer attending a tertiary referral cancer hospital) found that 72% of people taking oral morphine for pain had mild to severe grades of 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 significantly more people taking modified-release oral morphine than taking transdermal fentanyl had constipation (27% with transdermal fentanyl v 45% with modified-release oral morphine; P less than 0.001). One 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 (16% with transdermal fentanyl v 37% with modified-release oral morphine; P less than 0.001).A more recent systematic review (search date 2007, 4 RCTs, 425 people with moderate–severe cancer pain) comparing oral morphine versus transdermal opioids (fentanyl and 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 plexus of the gastrointestinal tract. This decreases gastrointestinal motility by decreasing propulsive peristalsis (at the same time increasing circular contractions), decreases secretions (pancreatic and biliary), and increases intestinal fluid absorption. There is also a central descending opioid-mediated effect so that even spinally administered opioids cause decreased gastric emptying and prolonged oral–caecal transit time. The opioid-induced increase in circular muscle contractions causes colicky pain. 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 is probably caused by 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. 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 sophisticated measure of physical functioning such as 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, stool consistency, abdominal pain and discomfort, cramping, nausea, small bowel (oral–caecal) transit time assessed by hydrogen breath test, adverse effects, including reversal of opioid analgesia and opioid withdrawal symptoms.

Methods

Clinical Evidence search and appraisal July 2009. The following databases were used to identify studies for this review: Medline 1966 to July 2009, Embase 1980 to July 2009, and The Cochrane Library and Cochrane Central Register of Controlled Clinical Trials, Issue 3, 2009. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language. Open or blinded studies were included, containing at least 20 people, with a maximum loss to follow-up of 30% a year. There was no minimum length of follow-up required to include studies. We also included prospective or retrospective comparative cohort studies in any language for harms data. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. To aid readability of the numerical data in our reviews, 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). 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 1.

Constipation in people prescribed opioids

Important outcomes	Bowel movement frequency, stool consistency, abdominal pain, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of oral laxatives for constipation in people prescribed opioids?
1 (57)	Stool consistency	Lactulose v placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (57)	Stool consistency	Macrogol/electrolyte solution v placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (57	Stool consistency	Lactulose v polyethylene glycol 3350/electrolyte solution	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (91)	Frequency of bowel movements	Lactulose v senna	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (22)	Frequency of bowel movements	Docusate sodium v placebo	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for uncertainty about population group
What are the effects of rectally applied medications in people for constipation in people prescribed opioids?
No clinically important studies found
What are the effects of opioid antagonists for constipation in people prescribed opioids?
2 (690)	Frequency of bowel movements	Alvimopan v placebo/no treatment	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 (287)	Frequency of bowel movements	Methylnaltrexone v placebo/no treatment	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 (732)	Frequency of bowel movements	Naloxone v placebo/no treatment	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results

Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes.

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.

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.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

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.