Opioids and the gut

Computer generated image of the human gut

Image for illustrative purposes only. Posed by model.

Chronic pain is thought to affect between 10–43% of the general adult population and can make even commonplace activities such as walking, household activities, socialising and sleeping a challenge.1–6 The World Health Organization’s pain relief ladder recommends that patients with moderate to severe chronic pain, opioids are an essential and recommended component of the pain management strategy, reducing pain and enabling patients to resume their lives.7

Opioids exert their analgesic effect through binding and activating opioid receptors present on the cell surface of neurons in regions of the central nervous system (CNS) that are involved in pain transmission and control.8 There are three types of opioid receptor mu [µ], kappa [κ] and delta [δ]; the majority of clinically available opioids target the mu receptor. Once activated, opioid receptors cause a reduction in neuronal excitability and an inhibition of neurotransmitter release in order to provide pain relief.8,9

Despite their proven analgesic action, opioid use is sometimes limited due to associated adverse events, the most common of which is opioid-induced constipation.10,11 Although most abundant within the CNS, opioid receptors can also be found throughout the peripheral organs, including the gastrointestinal tract.12

Inhibition of activity in these peripheral neurons through activation of the µ-receptors leads to reduced longitudinal muscle contractions combined with stronger contractions of the circular muscles. This means that instead of generating a peristaltic wave to propel digested food through the gut, the contents are shuffled back and forth.14 The longer transit time allows for greater reabsorption of fluids, resulting in difficult-to-pass, hard, dry stools.14 In addition, the high density of µ-receptors in the enteric systems is thought to drive the decreased intestinal mucosal secretion, disordered ileocecal and anal sphincter function and reduced bowel tone and contractility present in OIC.13,14

For patients, this means experiencing infrequent bowel movements, as well as symptoms such as straining, lumpy or hard stools, a sensation of incomplete evacuation, and a sensation of anorectal blockage – all of which may result in the use of manual manoeuvres to facilitate defecation.15

While symptomatically this is similar to functional constipation, the underlying causes of OIC and functional constipation are distinct. Functional constipation is a complex multi-factorial condition but commonly occurs due to low intake of fibre and fluid, while OIC has an established receptor based pathophysiology.12,16 This difference was reflected within the recently released Rome IV criteria, which recognises OIC as a clinical condition linked to opioid usage, defined by new or worsening symptoms of constipation when initiating, changing or increasing opioid therapy, that must include two or more of the symptoms defining functional constipation.15

Laxatives are recommended as the first-line pharmacological treatment for OIC, although there is currently only limited evidence supporting their efficacy.10,17 While the use of laxatives can offer relief to some patients, they do not target its underlying cause, with high rates of inadequate response being reported being by patients.10,17,18

Given the distinct pathophysiology of OIC, treatment approaches that specifically target the cause rather than the symptoms, could help offer patients greater relief from OIC.15,17 Unlike other treatment options,

peripherally acting μ-opioid receptor antagonists (PAMORAs) bind to µ-opioid receptors within the gastrointestinal tract, blocking and antagonising opioid activity at these receptors and so helping to restore gut physiological function.17 Because PAMORAs have been developed to have reduced ability to cross the blood brain barrier, they can directly target the underlying mechanism of OIC without significantly affecting central opioid receptors and associated pain relief.17

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