OIC and opioid adherence Job bag number: NP-EU-NAL-0058 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.

OIC is the most common and bothersome adverse event affecting patients on long-term opioid treatment1 OIC is characterised by infrequent bowel movements and incomplete bowel evacuation, along with other GI symptoms including abdominal pain and bloating, straining and gastric reflux2 GI, gastrointestinal; OIC, opioid-induced constipation. *Experienced by ≥30% of patients.1 1. Bell TJ, et al. Pain Med 2009;10:35–42 2. Drossman DA, Hasler WL. Rome IV-functional GI disorders: disorders of gut-brain interaction. Gastroenterology 2016;150:1257-1261. 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

OIC is seen as the most debilitating and distressing adverse event by patients1–3 “I am on and off the toilet straining to go…I look pregnant all the time, so I am self-conscious all of the time”6 “I’d much rather live with pain than the side effect of severe constipation”1 Alongside their physical OIC symptoms, patients also report psychological distress from OIC1–6 “No movement at all will lead to an impaction which will be painful to solve, possibly requiring a trip to the emergency room. So I worry a lot about not having a bowel movement”5 OIC, opioid-induced constipation 1. Bell TJ, et al. Pain Med 2009;10:35–42 2. Coyne KS, et al Clinicoecon Outcome Res 2014;6:269–81 3. Veterans' MATES. Therapeutic brief 27. Opioid-induced constipation - a preventable problem. Available at: https://www.veteransmates.net.au/documents/10184/23464/ M27_TherBrief-RefList_Merge.pdf. Accessed: July 2017 4. Gudin J, et al. Practice pain management 2015 update. Available at: https://www.practicalpainmanagement.com/treatments/phar macological/opioids/opioid-induced-constipation-new- emerging-therapies-update-2015. Accessed: June 2017 5. Dhingra L, et al. Pal Med 2012;27:447–56; 6. Epstein RS et al. Adv Ther 2017;34:726–31. 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

Patients report that OIC impacts significantly on their quality of life, and interferes with daily functioning and wellbeing In an online survey of opioid-treated chronic pain patients (n=489) 50% of patients reported that OIC impaired at least one part of their daily living 40% of patients also reported an impact on their work productivity and ability OIC, opioid-induced constipation References: Rauck RL, Pain Pract 2017;17:329–35. Patients were asked “How has OIC impacted your quality of life?” and chose feelings that they felt applied. 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

OIC interferes with patients’ pain management and their adherence to opioid treatment1,2 OIC can be so severe that patients will reduce, miss or completely stop taking their pain medication, even at the expense of the pain returning2–5 Approximately half of patients on chronic opioid treatment reported that the constipation moderately or completely interfered with their ability to control pain5,6 GI, gastrointestinal; OIC, opioid-induced constipation. 1. Hjalte F, et al. J Pain Sympt Manag 2010;40:696–703 2. Kurz A, Sessler DI. Drugs 2003;63:649–71 3. Dhingra L, et al. Pal Med 2012;27:447–56 4. LoCasale RJ, et al. Int J Clin Pract 2015;69:1448–56 5. LoCasale RJ, et al. J Manag Care Spec Pharm 2016;22:236–45 6. Coyne KS, et al Clinicoecon Outcome Res 2014;6:269–81. OIC interference with pain management, % 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.

Common laxatives may offer some symptomatic relief, but have limited efficacy as they do not target the underlying pathophysiology of OIC1–3 PROBE 1, a multinational online survey (n=322), assessed the prevalence, frequency, severity and impact of opioid-induced GI side effects of patients currently taking laxatives for their OIC1 GI, gastrointestinal; OIC, opioid-induced constipation. 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. Nelson AD, Camilleri M. Therap Adv Gastroenterol 2015;8:206–20. Of these patients:1 28% used a lower dose of their opioids 33% skipped, decreased or stopped their opioids in the hope to facilitate a bowel movement 05/09/2017 © Shionogi Limited. 33 Kingsway. London WC2B 6UF, UK Registered in England and Wales No. 07945432.