Due to complex symptomatology in opioid-induced bowel dysfunction, laxatives are rarely sufficient and peripheral opioid antagonists could be considered as additional treatment in these patients
Anne Estrup Olesen PhD
Christina Brock PhD
Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Asbjørn Mohr Drewes MD
Mech-Sense, Department of
Gastroenterology & Hepatology, Aalborg
University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg
University, Aalborg, Denmark
Patients who receive opioid treatment will most likely experience adverse effects on the gastrointestinal system. This opioid-induced bowel dysfunction (OIBD) is problematic and is often misinterpreted as constipation as this is the most frequently reported symptom of OIBD. However, OIBD actually affects the whole gut with symptoms such as nausea, reflux, vomiting, delayed gastric emptying, bloating and anorexia being very prevalent.1
The prevalence of OIBD is high and in a group of cancer patients it was estimated to be 61.7%. Moreover, according to the physician’s subjective assessment 85.7% were considered constipated, despite the use of laxatives. Quality of life is significantly reduced in constipated versus non-constipated patients.2 Unfortunately, the negative impact of OIBD is often overlooked and is often the main reason for patients discontinuing their therapy.1
As well as relieving pain, opioids also produce substantial negative gastrointestinal (GI) side effects, which can affect quality of life. In evaluation of adverse effects of opioids on the gut, valid tools to assess the complexity of OIBD should be used.3,4
Opioid pharmacology
Opioid receptors are activated by endogenous ligands, but also by exogenous opioids used in the clinic. Localisation of opioid receptors of the µ-, δ- and k-subtype has been demonstrated in the GI tract in rodents and humans.5 In the human gut, µ-opioid receptors are mainly localised on myenteric and submucosal neurons. Thus, opioid treatment leads to modified GI function via decreased neuronal activity and less neurotransmitter release.
OIBD pathophysiology
The complex innervations of the GI tract comprise sensory neurons (extrinsic afferents) and their own integrated enteric nervous system (ENS). This rich network of neurons and interneurons has a structural complexity and functional heterogeneity similar to that of the central nervous system (CNS). Hence, the ENS is considered the “brain” of the gut.
Opioids mainly exert effects in the CNS; however they also bind to peripheral opioid receptors in the ENS. In humans the activation of peripheral opioid receptors in the gut will decrease gastrointestinal neural activity. Three factors of the modified GI function will affect symptoms: gut motility, gut secretion and sphincter tone.
Gut motility: Gut motility is controlled from the myenteric plexus and is largely dependent on neurotransmitters released from the enteric neurons (mainly acetylcholine and serotonin). Opioid receptor activation will inhibit the neurotransmitter release, increase resting tone in the circular muscle, reduce propulsive activity and delay transit of contents through the small and large bowel. The reduced transit time may also enhance absorption of fluids.5,6
Gut secretion: Intestinal fluid secretion is essential in the establishment of an ideal environment favouring effective enzymatic digestion, nutrient absorption and stool movements. Chloride secretion is the major determinant in gut hydration. Opioids inhibit acetylcholine release and chloride secretion and thus intestinal fluid secretion.7 Additionally, when opioids act on µ-receptors within the ENS, it will lead to increased activity in the sympathetic nervous system, leading to inhibited vasoactive intestinal peptide release and hence decreases gut secretion in an indirect manner.3
Sphincter tone: Sphincters throughout the GI tract control the forward movement of the contents through propulsive movements and prevents reflux, for example. Sphincters normally exert a delicate balance between relaxation and contraction and any disturbance will lead to dysfunction. Opioids affect the sphincter tones in the GI tract. An example is the influence on the sphincter of Oddi, which is a muscular valve that controls the flow of bile and pancreatic juice. Any disturbance results in decreased emptying of digestive juices leading to poor digestion. Finally the anal sphincter is especially relevant, as constriction will result in straining, haemorrhoids and incomplete evacuation.
Conventional treatment
Treatment of OIBD is a challenge and the current recommended strategies involve the use of different laxatives in combination with non-pharmacological strategies, such as increased dietary fibre and fluid intake, encouraging exercise etc. However, these interventions are rarely sufficient to increase the number of bowel movements, while other presentations of OIBD may persist.
Lifestyle interventional strategy
Changes in lifestyle have never been documented to be effective in constipation and therefore it will hardly be effective in OIBD.
Laxatives
Generally laxatives are recommended as first-line treatment in all patients, to whom opioids are prescribed. Laxatives can be divided into different sub-groups, including osmotic agents (magnesium, lactulose, polyethylene glycol), stimulants (bisacodyl, senna), bulking agents (methylcellulose, psyllium) and stool softeners (anionic surfactants). Although traditional laxatives have proven useful in inducing bowel movements, their efficacy is insufficient overall.3 This may be explained by the fact that the key symptoms related to blockade of opioid receptors in the GI tract (uncoordinated motility, decreased secretion and sphincter dysfunction) are not targeted by laxatives that exert their main effect in the colon only. Additionally, treatment with laxatives is also associated with GI side effects such as bad taste, bloating, gas and reflux.
Novel pharmacological approaches are the 5-HT4 receptor agonist prucalopride and the secretagogue lubiprostone (activator of the type 2 chloride channel). For both drugs, it has been demonstrated that spontaneous complete bowel movements increased in patients with opioid-induced constipation.
Opioid antagonist treatment
Tolerance to OIBD does not evolve over time and conventional treatments are often targeted towards constipation, hence it does not always attenuate the overall problem. Therefore, new treatment modalities such as those based on combinations of opioids and their antagonists with local action on the gut are highly warranted.
Opioid antagonists
Opioid antagonists with restricted peripheral effects target the underlying pathophysiology of OIBD, by blocking the µ-opioid receptors in the gut. The main principle between the different treatment options is mainly the pharmacokinetic properties, rendering them more or less suitable for treatment of OIBD. Opioid antagonists will target the three different factors affected in the modified GI function.
Effect on motility: Opioid antagonists will alleviate the opioid-induced increased resting tone in the circular muscle layer. The outcome of opioid antagonism treatment is diminished segmental contraction along with normalisation of peristaltic propulsion, and consequently decreased transit time. Indirectly this will also counteract the increased passive absorption of fluids.3 Overall, this is likely to reduce typical OIBD symptoms including constipation, gut spasm and abdominal cramps.
Effect on secretion: Opioid antagonists will counteract the opioid-induced inhibition of acetylcholine release and consequently tends to normalise chloride secretion. Additionally, the opioid induced increased activity in the sympathetic nervous system will be antagonised. Collectively, the patient will experience less dry and softer stools.1
Effect on sphincter function: Opioid antagonists will, at least in theory, normalise sphincter coordination. Opioid antagonists may thus prevent opioid-induced sphincter of Oddi dysfunction and thus acute biliary-like type of pain attacks. Finally, opioid antagonists may diminish opioid-induced dysfunction of the anal sphincter.3
Peripherally acting μ-opioid receptor antagonists
Naloxone is a competitive opioid receptor antagonist. It is widely used to treat opioid overdose and administered intravenously or as an intramuscular injection. In this formulation it reverses both centrally and peripherally mediated effects of opioids.3 This has led to the development of a combined oral prolonged release formulation of oxycodone and prolonged release naloxone in a 2:1 ratio. The aim of this formulation has been to counteract OIBD through the local antagonistic effect of naloxone in the gut wall, while maintaining analgesia. Studies have shown promising analgesic efficacy as well as improvement in OIBD-related symptoms.3 As naloxone is primarily metabolised in the liver, there is a potential risk of increased bioavailability in patients with hepatic impairment. The maximum recommended daily dose (which may not be sufficient to relive the pain) may, in some clinical settings, limit its use. Furthermore, the fixed combination to oxycodone makes opioid rotation difficult.
Another approach is methylnaltrexone, a drug originally designed to shorten the length of postoperative ileus. It is a derivative of the opioid antagonist naltrexone. Due to its ammonium group, the drug does not pass the blood-brain barrier. It has been shown to relieve OIBD and induce laxation.3 However, it is only available in subcutaneous formulation and only approved in palliative care in patients suffering from advanced illness. Hence, it is of limited benefit for the general OIBD population.
Alvimopan is another orally administered peripherally acting µ-opioid receptor antagonist, which does not cross the blood-brain barrier at clinically relevant doses. Moreover, it does not reverse analgesia or cause opioid withdrawal symptoms.3 Alvimopan has been shown to increase spontaneous bowel movements, however, cardiovascular safety concerns (increased risk of myocardial infarction) halted further development. Yet, the FDA approved alvimopan for postoperative ileus following partial small or large bowel resection with primary anastomosis in hospitalised patients registered in the US only, hence it is also of little benefit for the general OIBD population.
Naloxegol is a PEGylated naloxone molecule that cannot cross the blood-brain barrier. Hence, the effects are restricted to the periphery and it has proven to be efficacious in OIBD when compared to placebo. It has an acceptable safety profile and can be used in addition to existing pain treatment so that opioid rotation is not necessary.3 Therefore, it is easier to use as compared to other existing drugs.
However, it was first marketed in 2015 and more clinical experience is still needed.
Other peripherally acting µ-opioid receptor antagonists in earlier stages of development are ADL-5945 and ADL-7445 (Cubist®), and TD-1211 (Theravance®). ADL-5945 and ADL-7445 have proven tolerable and effective in producing spontaneous bowel movements in Phase I trials. TD-1211 has shown to be well tolerated and has a linear pharmacokinetic profile, but is still being evaluated in Phase II trials. It is too early to draw any strong conclusions on these novel drugs. Their place in therapy will depend not only on efficacy and safety but also on convenience of administration, patient preferences and costs.
Conclusions
Patients with OIBD suffer from a myriad of symptoms affecting their quality of life and willingness to remain on the subscribed opioid treatment in order to alleviate pain. Due to the complexity of OIBD and the different mechanisms caused by activation of the peripheral opioid receptors, treatments with laxatives are rarely sufficient. Thus, physicians are challenged by the fact that they have to treat both the underlying pain and OIBD. Peripheral opioid antagonists can improve symptoms of OIBD and could be considered as additional treatment in patients treated with opioids.
Key points
- Opioid-induced bowel dysfunction (OIBD) is a net symptom relating to blockade of three different opioid receptors resulting in decreased gut motility and secretion as well as uncoordinated sphincter function.
- The symptoms are constipation but also anorexia, reflux, abdominal distension and pain, straining, etc.
- The side effects of opioids are often overlooked leading to insufficient treatment.
- A high index of suspicion for any OIBD symptoms should follow administration of opioids.
- Awareness and experience in how to prevent and treat OIBD is highly warranted.
References
- Brock C et al. Opioid-induced bowel dysfunction: Pathophysiology and management. Drugs 2012;72(14):1847–65.
- Abramowitz L et al. Prevalence and impact of constipation and bowel dysfunction induced by strong opioids: A cross-sectional survey of 520 patients with cancer pain: DYONISOS study. J Med Econ 2013;16(12):1423–33.
- Poulsen JL et al. Clinical potential of naloxegol in the management of opioid-induced bowel dysfunction. Clin Exp Gastroenterol 2014;7:345–58.
- Olesen AE, Drewes AM. Validated tools for evaluating opioid-induced bowel dysfunction. Adv Ther 2011;28(4):279–94.
- Kurz A, Sessler DI. Opioid-induced bowel dysfunction: Pathophysiology and potential new therapies. Drugs 2003;63(7):649–71.
- Greenwood-Van MB et al. Preclinical studies of opioids and opioid antagonists on gastrointestinal function. Neurogastroenterol Motil 0910 10;16(S2):46–53.
- Wood JD, Galligan JJ. Function of opioids in the enteric nervous system. Neurogastroenterol Motil 2004;16 (S2):17–28.
