Horizon Scanning Technology Summary. Methylnaltrexone for opioid induced constipation in advanced illness and palliative care

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1 Horizon Scanning Technology Summary National Horizon Scanning Centre Methylnaltrexone for opioid induced constipation in advanced illness and palliative care April 2007 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

2 Methylnaltrexone for opioid induced constipation in advanced illness and palliative care Target group Treatment of opioid induced constipation (OIC) a in patients with advanced illness or receiving palliative care. Technology description Methylnaltrexone (MNTX, MOA-728, Methylnaltrexone bromide) is a peripheral muopioid receptor antagonist that is currently in phase III trials for the treatment of patients with OIC. Methylnaltrexone is administered by subcutaneous injection and is intended to block the negative effects of opioids on the gastrointestinal system without disrupting their analgesic effects. Methylnaltrexone as an iv formulation, is also in phase III trials for patients with postoperative ileus, and as an oral formulation, is in phase II trials for patients with OIC. Alvimopan (Entrareg TM ) GlaxoSmithKline and Adolor Corporation, an oral peripherally selective mu-opioid receptor antagonist in development for OIBD has recently been suspended while findings from a long-term safety study are evaluated 1. Innovation and/or advantages Methylnaltrexone is in a new drug class. Laxatives are the only licensed treatment for constipation. OIC can have a major impact on the quality of life of patients and their carers. Subcutaneous injection may limit it usefulness. Developer Wyeth Pharmaceuticals. Place of use Home care e.g. home dialysis i.e. specialist palliative care at home Secondary care e.g. general, non-specialist hospital General public e.g. over the counter Community or residential care e.g. district nurses, physio Tertiary care e.g. hospices Other: Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care Availability, launch or marketing dates, and licensing plans: Methylnaltrexone is currently pre-registration in the USA. NHS or Government priority area: Cancer Cardiovascular disease Children Diabetes Long term neurological Mental health conditions Older people Public health Renal disease Women s health None identified Other: This topic relates to the NHS Cancer Plan and the National Service Framework for renal services, long-term conditions and coronary heart disease. a Opioid-induced constipation is a specific form of opioid-induced bowel dysfunction (OIBD). OIBD is a gastrointestinal condition characterised by (i) hard, dry stools, (ii) straining, (iii) incomplete evacuation, (iv) bloating, (v) abdominal distension, and (vi) increased gastric reflux. April

3 Relevant guidance Improving supportive and palliative care for adults with cancer, National Institute for Health and Clinical Excellence Control of pain in patients with cancer, Scottish Intercollegiate Guidelines Network Palliative care pain, Prodigy Guidance 4. The use of strong opioids in palliative care, National Prescribing Centre and MeReC Clinical need and burden of disease 70% of patients with advanced cancer and 65% of patients dying from non-malignant disease are estimated to have some pain 6. In 2004, there were approximately 134,590 deaths from cancer in England and Wales 7. In addition there are approximately 35,500 deaths from major non-malignant diseases: chronic lung disease, chronic heart failure and end-stage renal disease 8. Therefore at least 117,200 terminally ill patients in England and Wales are estimated to have some pain. Expert opinion suggests that most of the patients with cancer pain will receive opioid analgesics at some point in their treatment, as will about 10 to 20% of patients with nonmalignant disease. Therefore an estimated 94,400 and 98,800 patients each year may receive opioids as part of their care. Published studies indicate that constipation occurs in between 23% 9 and 70% 10 of patients with cancer and between 15% 11 and 41% 12 of patients with non-malignant pain. Laxative treatment will be adequate to relive symptoms of constipation in a proportion of patients. Expert opinion suggests that methylnaltrexone is likely to be of most benefit in patients with laxative resistant constipation - approximately 4% of patients (an estimated 4,000 patients in England and Wales). Existing comparators and treatments Laxatives ineffective in a proportion of patients. Tertiary opioid receptor antagonists such as naloxone, naltrexane and nalmefene. These reduce primary symptoms, but can also reverse analgesia and provoke opioid withdrawal symptoms or reverse analgesia in some patients, limiting their clinical use 13. Efficacy and safety Participants in trial open-label n=154. Patients with advanced medical illness in palliative care with life expectancy <6 months, no laxation for 48 hours, stable opioid and laxative dose for at least 3 days. In addition to baseline laxatives, patients received for 2 weeks either: Trial name or code 301. Methylnaltrexone (MNTX) vs placebo - single dose then 4 wks 302. MNTX vs placebo 2 weeks Sponsor Wyeth and Progenics Pharmaceuticals Wyeth and Progenics Pharmaceuticals Status Completed, published in abstract 14, 15 Completed, published in abstract 15 Location Multi-centre (16 sites) Multi-centre Design Randomised, placebo-controlled, followed by Randomised, double-blind placebocontrolled n=133. Patients with advanced medical illness in palliative care with life expectancy <6 months, no laxation for 48 hours, stable opioid and laxative dose for at least 3 days. In addition to baseline laxatives, patients received for April

4 MNTX 0.15 mg/kg every other day (n=47), MNTX 0.30 mg/kg every other day (n=55), or placebo (n=52) 24 hours after a single double-blind dose of MNTX, patients could receive open-label MNTX for 4 weeks 2 weeks either: MNTX 0.15 mg/kg every other day (n=62), or placebo (n=71) Follow-up 4 weeks 2 weeks Primary Laxation within 4 hours Laxation within 4 hours outcome Secondary outcomes Laxation within 24 hours, adverse events, pain score and opioid withdrawal symptoms Key results Major adverse effects Laxation in patients: within 4 hours 0.15 mg/kg MNTX 62% increase; 0.30 mg/kg MNTX 58% increase; placebo 13% increase within 24 hours 0.15 mg/kg MNTX 68% increase; placebo 33% increase (versus placebo p<0.0004); 0.30 mg/kg MNTX 64% increase (versus placebo p<0.0014) median time 0.15 mg/kg MNTX 70 minutes; placebo >24 hours (versus placebo p<0.0001); 0.30 mg/kg MNTX 45 minutes (versus placebo p<0.0001) No significant changes in pain score noted. Median survival 21 days. No reports of systemic opioid withdrawal due to MNTX. Transient abdominal cramping (30-40%) and flatulence (15-20%) were most common adverse events. Estimated cost and cost impact The cost of methylnaltrexone is yet to be determined. Potential or intended impact speculative Laxation occurring within 4 hours over the first 4 doses, adverse events, pain score and opioid withdrawal symptoms Laxation in patients: within 4 hours 0.15 mg/kg MNTX 48% increase; placebo 16% increase occurring within 4 hours over the first 4 doses, 0.15 mg/kg MNTX 52% increase; placebo 9% increase No significant changes in pain score noted. No reports of systemic opioid withdrawal due to MNTX. Transient abdominal cramping and flatulence most common adverse events Patients Reduced morbidity Quicker or more accurate diagnosis Reduced mortality or increased survival Earlier identification of disease Improved quality of life for patients and/or carers Other: Services Increased use e.g. length of stay, Service reorganisation required out-patient visits Decreased use - potential reduced length of stay by Other: speeding up resolution of constipation Staff or training required Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment Increased costs: capital investment needed New costs: Savings: Other: April

5 References 1 Press release - GSK and Adolor announce preliminary results from Phase 3 Safety study of Alvimopan (Entereg/Entrareg ), 9 th April Improving supportive and palliative care for adults with cancer, NICE, March Control of pain in patients with cancer, SIGN, number 44, June Palliative care pain, Prodigy Guidance, (accessed 13/04/2007) 5 The use of strong opioids in palliative care, NPC and MeReC, issue no. 22, June Colvin L, Forbes K, Fallon M. Difficult pain, ABC of palliative care. British Medical Journal : CancerStats Mortality data, Cancer Research UK Traue DC, Ross JR. Palliative care in non-malignant diseases. Journal of the Royal Society of Medicine : Meuser T, Pietruck C. Radbruch L. et al. Symptoms during cancer pain treatment following WHO guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain ; Cherny N, Ripamonti, Pereira J et al. Strategies to manage the adverse effects of oral morphine: an evidencebased report. Journal of Clinical Oncology 2001;19(9): Moore RA. McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. Arthritis Research and Therapy ;5:R Kalso E, Edwards JE, Moore RA et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain : Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. American Journal of Surgery : Thomas J, Lipman A, Slatkin N et al A phase III double-blind placebo-controlled trial of methylnaltrexone (MNTX) for opioid-induced constipation (OIC) in advanced medical illness (AMI). American Society of Clinical Oncology Abstract Thomas J, Karver S, Cooney GA et al Phase III results from two multi-center randomised double-blind placebo-controlled trials of methylnaltrexone for opioid-induced constipation (OIC) in patients with advanced Illness (AI). American Society of Clinical Oncology Annual Gastrointestinal Cancers Symposium. January The is a constituent of the NHS National Institute for Health Research and is managed under contract from the Department of Health's R&D Division. The views expressed in NHSC publications are those of the author(s). They are not necessarily shared by the Department of Health and should not be taken as representing Government policy. The, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0) April