Opioids and the gut Job bag number: NP-EU-NAL-0059 Date of preparation: September 2017 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

Opioids are an essential treatment for the management of chronic pain, as recognised by global guidelines1–5 “Opioids are highly effective and safe analgesics and their appropriate use by competent clinicians is a crucial element in modern pain management.” “If pain occurs, there should be prompt oral administration of drugs in the following order: nonopioids; then, as necessary, mild opioids; then strong opioids, until the patient is free of pain.” “Analgesic treatment should start with drugs indicated by the WHO analgesic ladder. Strong opioids are the mainstay of analgesic therapy in treating moderate–severe cancer-related pain.” “Chronic opioid therapy can be an effective therapy for carefully selected and monitored patients with chronic non-cancer pain.” EFIC, European pain federation; ESMO, European Society for Medical Oncology; WHO, World Health Organization. 1. O'Brien T, et al. Eur J Pain 2017;21:3–19; 2. World Health Organization. WHO's cancer pain ladder for adults. Available at: http://www.who.int/cancer/palliative/painladder/en/. Accessed: June 2017 3. Ripamonti CI, et al. Ann Oncol 2012;23 Suppl 7:vii139–54 4. Paice JA, et al. J Clin Oncol 2016;34:3325–45 5. Chou R, et al. J Pain 2009;10:113–30; 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

Opioids bind to opioid receptors causing a reduction in neuronal excitability and inhibition of neurotransmitter release1–3 Opioid receptors are present on the cell surface of neurons involved in pain transmission/control3 Opioids exert their analgesic effect through binding and activating opioid receptors in the central and peripheral nervous system3 Once bound to the opioid receptors, opioids block the release of pain neurotransmitters resulting in the desired analgesic effect3 AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; Ca, calcium; G, g-protein coupled receptor; K, potassium. 1. Chahl LA. Aust Prescr 1996;19:63–5 2. Bell TJ, et al. Pain Med 2009;10:35–42 3. Trescot AM, et al. Pain Phys 2008;11:S133–53 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

Opioid receptors are predominantly located in the central nervous system but are also present in peripheral tissues1 Opioids exert their effect via three main types of opioid receptors which are found throughout the body:1 mu (µ), kappa (κ) and delta (δ) The most commonly used opioids for pain management act on the μ opioid receptor1 There is a high density of µ-receptors within the central nervous system responsible for analgesia1,2 µ-receptors are also widely distributed throughout the peripheral nervous system, including the gastrointestinal system3,4 1. Trescot AM, et al. Pain Phys 2008;11:S133–53 2. Chahl LA. Aust Prescr 1996;19:63–5 3. Bell TJ, et al. Pain Med 2009;10:35–42 4. Benyamin R, et al. Pain Physician 2008;11:S105–20. 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

Opioid receptors are predominantly located in the central nervous system but are also present in peripheral tissues1 Decreased intestinal mucosal secretion Increased fluid reabsorption, resulting in dry, hard, difficult-to- pass stools Disordered ileocecal and anal sphincter function Activation of the µ-receptors enteric system leads to a changes in the gastrointestinal tract:1,2 A reduction in longitudinal gut muscle contractions and stronger contractions of the circular muscle The suppression of generating a peristaltic wave to propel digested food through the gut Reduced bowel tone and contractility 1. Panchal SJ, et al. Int J Clin Pract 2007;61:1181–7 2. Holzer P. Neurosci Lett 2004;361:192–5. 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

Opioid receptors are predominantly located in the central nervous system but are also present in peripheral tissues1 Flatulence Hard, lumpy and dry stools Straining Bloating Abdominal cramping/spasms Sensation of incomplete evacuation or anorectal blockage In the latest Rome IV criteria, OIC is defined as: “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”1 Reflux/heartburn Nausea/vomiting Infrequent bowel movements Pain when going to the toilet Feeling full or heavy Constipation OIC, opioid-induced constipation. 1. Simren M, et al. Curr Gastroenterol Rep 2017;19:15 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

Laxatives provide no or partial relief for patients with chronic OIC, as they don’t target the underlying pathophysiology1–3 The ultimate goal of OIC treatment is to alleviate constipation while maintaining analgesia1 Targeted therapies which specifically act on the pathophysiology, rather than the symptoms, may help offer patients greater relief from OIC2,4 Treatment pathway for OIC5 OIC, opioid-induced constipation; PAMORAs, peripherally acting μ- opioid receptor antagonists. 1. Bell TJ, et al. Pain Med 2009;10:35–42 2. Rumman A, et al. Exp Rev Quality Life Cancer Care 2016;1:25–35 3. Coyne KS, et al. Clinicoecon Outcomes Res 2014;6:269–81 4. Simren M, et al. Curr Gastroenterol Rep 2017;19:15 5. Kumar L, et al. Gastroenterol Res Pract 2014;141737. doi:10.1155/2014/141737. 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.