Horizon Scanning Centre July 2014

Methylnaltrexone bromide (Relistor) for opioid-induced constipation in adult patients with chronic non-malignant pain

SUMMARY NIHR HSC ID: 2644

Methylnaltrexone bromide (Relistor) is administered subcutaneously (SC) and intended for use as a first or subsequent line therapy for the treatment of opioid-induced constipation in adult patients with chronic non-malignant pain. This briefing is If licensed, methylnaltrexone bromide will offer an additional treatment option based on for such patients. Methylnaltrexone bromide is a selective peripherally acting information opioid mu-receptor antagonist. As a quaternary amine it has a restricted available at the time ability to cross the blood-brain barrier, and this allows it to function as a of research and a peripherally acting mu-opioid antagonist in tissues such as the limited literature gastrointestinal tract, without impacting opioid-mediated analgesic effects on search. It is not the central nervous system. Methylnaltrexone bromide (as SC formulation) is intended to be a currently licenced in the EU for treatment of adult patients with opioid- definitive statement induced constipation in advanced illness who are receiving palliative care on the safety, when response to usual laxative therapy has not been sufficient. efficacy or effectiveness of the The prevalence of opioid-induced constipation is not known, however, in health technology England in 2013, there were 21,710,300 prescription opioid analgesic items covered and should dispensed. Research suggests that up to 90% of patients treated with not be used for opioids will experience chronic constipation. Constipation can contribute to commercial secondary complications including abdominal distension, urinary retention, purposes or nausea, vomiting, anorexia, haemorrhoids, anal fissures, perianal commissioning abscesses, and intestinal obstruction which may lead to life-threatening without additional faecal impaction additionally the debilitating symptoms of opioid-induced information. constipation can seriously impair patients’ quality of life.

Management of opioid-induced constipation may involve dietary and lifestyle changes in addition to medication such as bulk-forming laxatives, stimulant laxatives, osmotic laxatives or faecal softeners. When oral laxative therapy is ineffective use of suppositories, enemas, prucalopride, rectal irrigation or manual disimpaction may be appropriate. Methylnaltrexone bromide is currently in one phase III trial comparing its effect on rescue-free bowel movements against treatment with placebo.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Opioid-induced constipation: adult patients with chronic non-malignant (non-cancer) pain – first or subsequent line.

TECHNOLOGY

DESCRIPTION

Methylnaltrexone bromide (Relistor) is a selective peripherally acting opioid mu-receptor antagonist that has an alkyl substituent added to the nitrogen atom of the tertiary opioid antagonist1. As a quaternary amine, the ability of methylnaltrexone bromide to cross the blood-brain barrier is restricted, which allows methylnaltrexone bromide to function as a peripherally acting mu-opioid antagonist in tissues such as the gastrointestinal tract, without impacting opioid-mediated analgesic effects on the central nervous system. In a phase III clinical trial methylnaltrexone bromide was administered by subcutaneous (SC) injection at 12mg every day or every other day2,17.

Methylnaltrexone bromide (as SC formulation only) is currently licenced in the EU for treatment of adult patients with opioid-induced constipation in advanced illness who are receiving palliative care when response to usual laxative therapy has not been sufficient. Very common (>10%) adverse effects (AEs) of methylnaltrexone bromide when used for its licenced indication include abdominal pain, nausea, diarrhoea, and flatulence. Common (≥1% to <10%) AEs include dizziness, hyperhidrosis, and injection site reactions (e.g. stinging, burning, pain, redness, and oedema).

An oral formulation of methylnaltrexone bromide is currently in phase III clinical trials for opioid-induced constipation in adult patients with chronic non-malignant pain.

INNOVATION and/or ADVANTAGES

If licensed, methylnaltrexone bromide will offer an additional treatment option for opioid- induced constipation in adult patients with chronic non-malignant pain.

DEVELOPER

TMC Pharma Services Ltd (EU licence holder); LINK Healthcare; Ono Pharmaceutical; Progenics Pharmaceuticals; Salix Pharmaceuticals.

AVAILABILITY, LAUNCH OR MARKETING

Methylnaltrexone bromide is currently in phase III clinical trials.

PATIENT GROUP

BACKGROUND

Chronic pain is defined as pain that persists beyond normal tissue healing time, which is assumed to be three months. It may arise due to numerous conditions, including back pain, osteoarthritis, fibromyalgia, and headache3. Opioids are increasingly used for the

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management of chronic severe pain of non-malignant origin2. Opioids have been shown to be effective in decreasing pain and improving sleep, functioning, and quality of life in patients with these conditions, but opioid use is also associated with multiple adverse effects, including constipation, which can lead to discontinuation of treatment2. Additionally, research suggests that patients with opioid-induced constipation report significant increases in physician visits and sickness-related absence from work, compared with opioid users who do not experience constipation4. The effects of opioids on the gut are primarily mediated by mu-opioid receptors in the gastrointestinal tract. Opioid binding to these receptors decreases enteric nerve activity and gastrointestinal propulsive motor activity, inhibits ion and fluid secretion, and increases resorption of water, leading to constipation2.

The term constipation describes the subjective impression that the contents of the intestine are not evacuated at adequate frequency, in adequate volumes, the consistency of the stool is too hard, and/or the stool is passed with discomfort5. Constipation can also contribute to secondary complications including abdominal distension, urinary retention, nausea, vomiting, anorexia, haemorrhoids, anal fissures, perianal abscesses, and intestinal obstruction which may lead to life-threatening faecal impaction5. The debilitating symptoms of opioid-induced constipation can seriously impair patients’ quality of life comparable even to pain, up to a point where some prefer inadequate pain control to avoid these side effects6.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving quality of life for people with long term conditions (2013).

CLINICAL NEED and BURDEN OF DISEASE

Reported prevalence rates of constipation in the UK vary widely between studies, with figures ranging from 4% to 20%7. In 2012, there were 60,567 admissions for constipation (ICD-10 K59.0) in England, resulting in 151,319 bed days and 72,567 finished consultant episodes8; in the same year there were 58 deaths registered in England and Wales due to constipation9. The prevalence of opioid-induced constipation is not known10, however, in England in 2013, there were 21,710,300 prescription opioid analgesic items dispensed with a total net cost of £289,751,80011. Research suggests that up to 90% of patients treated with opioids will experience chronic constipation and of those receiving standard laxative treatments, over half will remain dissatisfied with the outcome5. The population likely to be eligible to receive methylnaltrexone bromide could not be estimated from available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Naloxegol for the treatment of opioid- induced constipation. (ID674). Expected July 2015. • NICE technology appraisal in development. Lubiprostone for the treatment of chronic idiopathic constipation. (ID725). Expected October 2014. • NICE technology appraisal. Prucalopride for the treatment of chronic constipation in women (TA211). December 2010.

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• NICE clinical guideline. Opioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adults (CG140). May 2012.

Other Guidance

• The British Pain Society. Opioids for persistent pain: Good practice. 201012. • The Journal of Pain. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. 20093.

CURRENT TREATMENT OPTIONS

The first step in the management of constipation should be appropriate dietary and lifestyle changes13. Patients should be advised on adequate fluid intake and consuming adequate amounts of food with a high fibre content (such as fruit, vegetables, high-fibre bread, baked beans and wholegrain breakfast cereals)14. A short course of laxatives may relieve symptoms and restore normal bowel function. There are several laxatives available for this purpose, including12,15:

• Bulk-forming laxatives such as methylcellulose, ispaghula (psyllium) husk, sterculia, • Stimulant laxatives such as bisacodyl, senna, sodium picosulfate. • Faecal softeners such as liquid paraffin and docusate sodium. • Osmotic laxatives such as macrogols (polyethylene glycols), lactulose, and magnesium salts (magnesium hydroxide or magnesium sulphate).

Long-term laxative use should be avoided where possible. When oral laxative therapy is ineffective at producing a bowel movement, a suppository (such as glycerol or sodium phosphate) or enema may be appropriate12,14. For women in whom treatment has failed to provide adequate relief after use of two laxatives, the prokinetic treatment prucalopride may also be used. Rectal irrigation and manual disimpaction are alternative treatment options for those who continue to have rectal emptying difficulties14.

EFFICACY and SAFETY

Trial NCT00529087, methylnaltrexone bromide (SC) vs. placebo; phase III. Sponsor Salix Pharmaceuticals. Status Published. Source of Publication2,16, trial registry17. information Location USA and Canada. Design Randomised, placebo-controlled. Participants n=460; 18 years and older; opioid-induced constipation and chronic non-malignant pain; taking oral, transdermal, intravenous, or subcutaneous opioids for chronic non- malignant pain. Schedule Randomised to methylnaltrexone bromide 12mg/day SC; methylnaltrexone bromide 12mg/every other day SC; or SC placebo daily. Follow-up Active treatment for 4 weeks, then an 8 week open-label as-needed dosing phase, follow-up 2 weeks. Primary Percentage of patients having a rescue-free bowel movement (RFBM)a within 4 hours outcome/s of the first dose and percentage of active injections resulting in any RFBM within 4 hours of injection during the double-blind period.

a A rescue-free bowel movement was defined as a bowel movement where no laxatives were used during the prior 24 hours.

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Secondary Time to first RFBM after injection, change in weekly number of RFBMs, outcome/s improvements in Bristol Stool Form Scale scores, Straining Scale scores, Sense of Complete Evacuation Scale scores, use of rescue laxatives, pain intensity scores, Subjective Opiate Withdrawal Scale scores, Objective Opiate Withdrawal Scale scores, QoL measured using the Patient Assessment of Constipation–Qualify of Life (PAC-QOL) questionnaire. Key results In the methylnaltrexone bromide daily, every other day, and placebo groups, respectively: percentage having a RFBM within 4 hours or first dose, 33.3%, 35.1%, 9.9%; percentage of active injections resulting in any RFBM within 4 hours of injection, 28.9%, 30.2%, 9.3%; adjusted mean change from baseline in weekly number of RFBMs, 3.1, 2.1, 1.5. Adverse Very common (>10%) AEs in methylnaltrexone bromide daily group and every other effects (AEs) day group respectively: abdominal pain 19.3%; abdominal pain 15.5%, diarrhoea 11.5%, nausea 11.5%.

ESTIMATED COST and IMPACT

COST

Methylnaltrexone bromide (SC) is already marketed in the UK for the treatment of adult patients with opioid-induced constipation in advanced illness, receiving palliative care with an insufficient response to usual laxative therapy; a 0.6mL vial (20mg/mL) costs £21.0518.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: wider societal benefits - earlier return  No impact identified to normal activities, including employment.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services: reduced complications of opioid therapy.

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs: reduced complications of opioid therapy.

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified

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REFERENCES

1 Earnshaw S, Klok M, Iyer S, et al. Methylnaltrexone bromide for the treatment of opioid-induced constipation in patients with advanced illness–a cost effectiveness analysis. Alimentary pharmacology & therapeutics, 2010;31(8):911-921. 2 Michna E, Weil A, Duerden M, et al. Efficacy of subcutaneous methylnaltrexone in the treatment of opioid-induced constipation: A responder post hoc analysis. Pain Medicine 2011;12(8):1223- 1230. 3 Chou R, Fanciullo G, Fine P et al. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. The Journal of Pain 2009;10(2):113-130. 4 Ford A, Brenner D, Schoenfeld P. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: Systematic review and meta-analysis. The American journal of gastroenterology 2013;108(10):1566-1574. 5 Clemens K, and Klaschik E. Managing opioid-induced constipation in advanced illness: focus on methylnaltrexone bromide. Therapeutics and clinical risk management 2010;(6):77-82. 6 Bader S, Jaroslawski K, Blum H, et al. Opioid-induced constipation in advanced illness: safety and efficacy of methylnaltrexone bromide. Clinical Medicine Insights. Oncology 2011;(5):201-211. 7 National Institute for Health and Care Excellence. Constipation (chronic idiopathic) - lubiprostone: final scope. Technology appraisal in development ID725. London: NICE; November 2013. 8 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2012-13. www.hscic.gov.uk 9 Office for National Statistics. Mortality statistics: deaths registered in England and Wales, series DR, 2012. http://www.ons.gov.uk 10 National Institute for Health and Care Excellence. Constipation (opioid induced) - lubiprostone: final scope. Technology appraisal in development ID646. London: NICE; November 2013. 11 Health and Social Care Information Centre. Prescription Cost Analysis England 2013. http://www.hscic.gov.uk/catalogue/PUB13887/pres-cost-anal-eng-2013-rep.pdf 12 The British Pain Society. Opioids for persistent pain: Good practice. London: January 2010. 13 National Institute for Health and Clinical Excellence. Constipation (women) – prucalopride: final scope. Technology appraisal ID211. London: NICE; December 2010. 14 National Institute for Health and Care Excellence. Pathways. Clinical management of idiopathic constipation in children and young people. http://pathways.nice.org.uk/pathways/constipation-in- children-and-young-people/constipation-in-children-and-young-people-overview Accessed 10 June 2014. 15 Map of Medicine. Chronic constipation management. http://app.mapofmedicine.com/mom/1/page.html?department-id=4&specialty-id=1016&pathway- id=3143&page-id=7563&pathway-prov-cert=/attachments/15324_provcert.pdf Accessed 10 June 2014. 16 Michna E, Blonsky E, Schulma S, et al. Subcutaneous methylnaltrexone for treatment of opioid- induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. The Journal of Pain 2011;12(5):554-562. 17 Study evaluating subcutaneous MOA-728 for the treatment of opioid-induced constipation (oic) in subjects with chronic non-malignant pain http://www.clinicaltrials.gov/ct2/show/NCT00529087?term=Methylnaltrexone+bromide&rank=14 Accessed 11 June 2014. 18 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF June 2014. http://www.bnf.org/

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