Opioids are a large family of synthetically active peptides commonly and successfully used for the treatment of both acute and chronic pain. 

Chronic pain is an extremely common condition affecting up to one-third of the general population and leading to a reduction in patient quality of life, socioeconomic morbidity and increased access to and expenditure by the healthcare system.^1,4 

A large-scale computer-assisted telephone survey was recently undertaken to explore the prevalence, severity, treatment and impact of chronic pain. 

The survey, conducted in 15 European countries and Israel, found that chronic pain of moderate-to-severe intensity occurred in 19% of adults, seriously affecting the quality of their social and working lives. 

Approximately 60% of those reporting moderate-to-severe pain had experienced the problem for 2-15 years, and 70% were under the care of their family doctors/GPs for pain management. More than half (52%) of chronic pain sufferers were taking some form of prescription analgesic; strong opioids were used by 5% of the 46,394 patients surveyed.¹

Given the extent of the problem, it is unsurprising to learn that opioid prescription and usage remains extremely common: figures from the US show that opioids have become the most commonly prescribed drug category, with one to four million Americans per year prescribed a long-acting opioid.⁶

Side-effects of opioid use

Opioids, like all medications, produce side-effects. Owing to the presence of opiate receptors within the gastrointestinal (GI) tract, they may produce a constellation of GI symptoms, the most common of which is constipation. Others include decreased gastric emptying (leading to gastro-oesophageal reflux/heartburn), abdominal cramping, spasm, bloating, delayed GI transit and the formation of hard dry stools. 

In turn, this can cause straining, painful defecation, incomplete evacuation and a sensation of anorectal bowel obstruction.^3,8 This group of GI symptoms is often referred to as opiate-induced bowel dysfunction (OBD).^3,4 The most common and debilitating feature of this condition is opioid-induced constipation (OIC). Constipation should be defined as a symptom, that is a subjective phenomenon characterised by decreased frequency of defecation associated with difficulty or discomfort. In the case of OIC it is precipitated or exacerbated by the use of opioids. 

Signs and symptoms of OIC shared in common with functional constipation include: dry hard stools, straining during evacuation, incomplete evacuation, bloating, abdominal distension and retention of contents of the gut. 

Unlike functional constipation, OIC also can include cramping, nausea and vomiting, and gastric reflux.^1,2,3,4 

It should be noted that while tolerance may occur with chronic opioid ingestion, patients rarely develop tolerance to OIC. 

The reported prevalence of OIC varies among studies ranging from 15-90%.¹ This may in part reflect the use of differing definitions for constipation and OIC, as well as the inclusion/exclusion of weak opioids from some studies. 

A meta-analysis reviewed 11 studies including patients with chronic, non-cancer pain in whom the effects of oral therapy with potent opioids such as morphine, methadone, hydromorphone or fentanyl were compared with those of placebo. Constipation was the most common adverse event, experienced by 41% of the 1,025 patients in the study.⁷

It is particularly challenging to obtain accurate estimates of the prevalence of OIC in cancer patients because of numerous other factors that may also induce the condition. 

These include physiological causes such as dehydration, metabolic disturbances, mechanical causes such as tumour and psychological factors. However, it is clear that cancer patients experience constipation relating to opioid use, and that existing disease-related constipation can be exacerbated by opioid therapy.³

Pathophysiology of opioid-induced constipation

The causes of OIC are multifactorial,⁵ and are mediated by activation of enterally located opiate receptors. There are three major classes of opiate receptors present in the enteral mucosa and submucosa: delta, kappa and mu.^6,7 

Under normal conditions, endogenous opiates (leu-enkephalin, met-enkephalin, beta endorphin and dynorphin)⁸ act upon the opiate receptors to co-ordinate the contractile process and suppress intestinal activity where required (eg. stress, inflammation, trauma).⁸

Of these, mu receptors are the principal mediators of analgesia action (and therefore the main target for exogenous opioids). They are also the principal mediators of many of the opiate-related side-effects, including constipation.⁹

Physiological changes

There are three main physiological changes produced via the opiate receptors resulting in constipation:

• Decreased peristalsis
• Increased electrolyte and water reabsorption 
• Increased sphincter tone.^1,9,10

Decreased propulsive peristalsis leads to a decreased transit time, allowing for increased water and electrolyte absorption from stool leading to hardening and drying. 

Increased tone of the circular muscles causes non-propulsive kneading and churning, also leading to increased fluid absorption and stool drying. In addition to these effects, anal sphincter tone is increased, so reflexive relaxation in response to rectal distension is reduced, making defecation more difficult.^1,9,10

Awareness of the risk of OIC, particularly in high-risk patients, and initiating prophylactic laxative therapy when opioid regimens are introduced may decrease the morbidity in this patient cohort. 

Risk factors include:

• Advanced age
• Immobility
• Poor diet
• Intra-abdominal pathology
• Neuropathy
• Hypercalcaemia
• Concurrent use of other constipating drugs.

Management of opioid-induced constipation

Management should begin with a full evaluation. This should aim to assess the severity of the problem, while outruling any other potential causes of the patient’s constipation. 

A clinical history should focus on other potential causes of constipation in the patient. Important points to elicit in the history include the presence/absence of ‘red flag’ GI symptoms (loss of appetite, abdominal pain, weight loss, peri-rectal (PR) bleeding, tenesmus), a past medical history or family history of malignancy (if the patient has chronic non-cancer pain). Other medications currently being taken should also be elicited. 

Clinical examination should focus on assessment of the patient’s hydration status, as well as an abdominal examination to elicit for signs of peritonitis (guarding, rigidity) or palpation of a faecal mass. A digital rectal examination must be performed to outrule impaction. 

Further blood tests and/or radiological evaluation will depend on the patient’s history and clinical findings. Once OIC has been diagnosed, a full management plan can be instigated. Non-pharmacological measures should be included in the management plan, if possible. 

Non-pharmacological treatment

These include increasing exercise and dietary modifications, including increased consumption of fluids and dietary fibre.²

Fibre may improve gut motility by increasing intraluminal volume, in the cancer patient empiric therapy involves an increase in fibre intake to at least 10g per day. 

Patients who increase fibre consumption must also increase fluid intake, and those who are unable to increase fluids may experience a paradoxical worsening of their constipation. 

Patients with partial obstruction should not be given fibre because of the risk of increased obstructive symptoms and those who are anorectic should be given fibre cautiously lest the satiety produced worsen malnutrition. 

Patients with OIC should also be encouraged to increase fluid intake, irrespective of fibre consumption. Anecdotally an intake of two to three litres of water per day is recommended.² Immobility has been shown to reduce colonic motility, therefore, if possible, physical activity also should be increased.

Pharmacological treatment

Pharmacological management can be broadly categorised into laxatives, enemas and opioid receptor antagonists, introduced in a step-wise fashion. Unfortunately, there are currently no detailed and widely accepted guidelines for the management of OIC. 

A well recognised source of guidance is the European Association of Palliative Care Research Network (EAPC), which has published recommendations for treating adverse effects associated with opioids. 

The EAPC recommends: reducing opioid dose, rotating opioids, changing the route of administration and symptomatic management. Unfortunately, each of these strategies appears to have limited benefit for most patients with OIC. The obvious disadvantage of reducing opioid dose is that analgesia may be compromised. 

Switching opioids is not supported by randomised trials and, again, may compromise analgesia. Similarly, while there is some evidence that transdermal administration of opiates may cause less constipation than orally administered opioids, contradictory data also exist. 

Symptomatic relief often begins (once impaction is outruled) with the prescription of a laxative. There are numerous options for laxative therapy and no data to suggest that any one approach is superior to any other. In a Cochrane systematic review of management of constipation in palliative care patients, four randomised trials comparing different kinds of laxatives showed no significant differences among them. 

Other pharmacological agents 

Opioid receptor antagonists: naloxone

The main problem in using opioid antagonists for reversing  the gastrointestinal side-effects of opioids is that the dose efficaciousness in reversing OIC may inhibit the analgesic effect of opioids, causing either opiate withdrawal symptoms or reversal of desirable analgesia. 

Naloxone is a competitive antagonist at opioid receptors and it blocks opioid intestinal receptors and has low systemic bioavailability due to marked hepatic first-pass effect. 

The dose of naloxone that reverses gut symptoms can often cause a reversal also of the analgesia. Despite this, naloxone has been used in a prolonged-release formulation with oxycodone for moderate-to-severe pain and much improved bowel function as compared to oxycodone use alone.

Combined opioid agonist and antagonist: oxycodone/naloxone (Targin)

The aim of this formulation is to counteract opioid-induced constipation development through naloxone’s local antagonist effect on the opioid receptors in the gut wall while maintaining analgesia due to high systemic oxycodone availability after oral administration.

Other agents used include:

• Methylnaltrexone
• Alvimopan
• NKTR-118, an oral PEGylated naloxol conjugate that blocks peripheral opioid receptors in the gut
• The new selective 5-HT 4 receptor agonist, prucalopride
• Lubiprostone, a chloride channel  activator that induces intestinal secretion.

Conclusion

The management of patients with OIC is an increasingly important problem with the extensive use of opioids for the relief of chronic pain, often associated with benign conditions. The use of non-pharmacological agents has been widely advocated and several new approaches and use of novel therapies are equally promising in combating this ever-recurring problem of OIC. High-quality clinical trials will support the use of new-generation drugs.   

References

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