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Lubiprostone (Amitiza) for opioid-induced constipation in patients with chronic non-cancer pain

Source agency:
NIHR-HSC
Date of Submission:
25/07/2012
Date of Printing:
18/04/2014
Disclaimer:
This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:
Lubiprostone (Amitiza)
Technology - description:
Lubiprostone (Amitiza; RU-0211; SPI-0211) is a bicyclic fatty acid that specifically activates the CIC-2 chloride ion channel located in the apical intestinal membrane. Activation of the chloride channel enhances the intestinal secretion of a chloride-rich fluid, without altering electrolyte concentrations in the serum. This increase in intestinal fluid secretion results in softening of the stool, promotion of spontaneous bowel movements, and a reduction in abdominal discomfort/pain and bloating. Lubiprostone does not instigate opioid withdrawal or compromise analgesia.
Company or developer:
Sucampo Pharamceuticals, Inc.
Reason for database entry:
If licensed, lubiprostone may provide an additional treatment option for this patient group.
Technology - stage in early warning process:
Assessment in progress
Technology - stage of development:
Investigational - phase III
Licensing, reimbursement and other approval:
No information available.
Technology - type(s):
Drug
Technology - use(s):
Therapeutic

Patient Indication & Setting

Patient indications:
Opioid-induced constipation (OIC) and associated signs and symptoms: chronic non-cancer pain.
Disease description and associated mortality and morbidity:
Prevalence estimates for chronic non-cancer pain, which includes neuropathic pain and musculoskeletal pain (1), vary widely and typically range from 10 to 30% (2). In recent years there has been a large increase in the use of opioids for the treatment of chronic non-cancer pain, and patients are commonly treated with opioids for months or even years (3). A meta-analysis of randomised, placebo-controlled trials of non-cancer patients receiving opioid treatment revealed that 80% experienced at least one adverse event, with constipation (41%) and nausea (32%) being the most common (4). A survey in the US found that 80% of patients taking opioid therapy for non-cancer pain required laxative therapy, and of these only 46% reported achieving the desired treatment result >50% of the time (3,5).

In England in 2010 there were 17,689,000 prescription opioid items dispensed in the community with a total net cost of £265,503,100 (6).
Number of Patients:
It is estimated that OIC is experienced by around 40% of patients treated with opioids for non-cancer pain (3).
Technology - specialities(s):
Gastrointestinal, pancreatic and liver disease
Technology - setting(s):
General hospital and ambulatory care
Setting - further information:
 

Impact

Alternative and/or complementary technology:
Substitution technology
Current Technology:
Current approaches to the management of OIC include (1,4,7):
• Laxatives:
o Stimulant laxatives - bisacodyl, senna.
o Softening laxatives - arachis oil (enema), docusate sodium.
o Osmotic laxatives - lactulose, macrogols, phosphates, magnesium salts (rarely used ).
• Opioid-receptor antagonists - naloxone, naltrexone and nalmefene (can reverse analgesia and provoke opioid withdrawal symptoms in some patients).
• Peripheral opioid-receptor antagonists - methylnaltrexone.
• Prokinetic agents - prucalopride (chronic constipation in women, where other treatments have failed to provide adequate relief).
Health Impact:
No information available.
Diffusion:
No information available.
Cost, infrastructure and economic consequences:
The cost of lubiprostone is not yet known. The cost of selected comparator treatments for OIC are summarised below (8):

Bisacodyl - 10mg, orally, once daily - £6.54
Lactulose - 15ml, orally, twice daily - £13.68
Methylnaltrexone - 12mg, SC, every other day - £884.10
Ethical, social, legal, political and cultural impact:
No information available.

Evidence & Policy

Clinical evidence and safety:
Trial: NCT01298219, OBD1033; lubiprostone vs placebo; phase III.
Sponsor: Sucampo Pharmaceuticals, Inc.
Status: Complete and published in abstract.
Source of information: Trial registry (9), abstract (10), manufacturer.
Location: EU (inc UK) and USA.
Design: Randomised, placebo-controlled.
Participants and schedule: n=447 (planned); adults; OBD; treatment for chronic, non-cancer related pain with any full opioid agonist other than methadone, methadone HCl, or a congener of methadone, for ≥30 days.
Randomised to lubiprostone 24µg, oral twice daily or placebo, oral twice daily.
Follow-up: Active treatment period 12 weeks.
Primary outcome: Overall spontaneous bowel movement (SBM) response .
Secondary outcomes: Change from baseline in SBM frequency at week 8; SBM frequency; first post-dose SBM; responder rate; straining, stool consistency, constipation severity, abdominal bloating, abdominal discomfort, and bowel habit regularity; health related quality of life.
Key results: For lubiprostone vs placebo: overall SBM responders, 26.9% vs 18.6% (p=0.035); median time to first SBM, 24.3 vs 38.5 hours (p=0.019). Straining, stool consistency and constipation severity were improved to a greater extent for lubiprostone vs placebo (all p<0.05).
Adverse effects (AEs): Most common treatment-related AEs reported for lubiprostone were diarrhoea (9.6%), nausea (8.2%) and abdominal pain (5.5%). There were no treatment-related serious AEs (SAE) reported.

Trial: OPAL, NCT00595946, OBD0631; lubiprostone vs placebo; phase III.
Sponsor: Sucampo Pharmaceuticals, Inc.
Status: Complete and published in abstract.
Source of information: Trial registry (11), abstract (12), manufacturer.
Location: USA and Canada.
Design: Randomised, placebo-controlled.
Participants and schedule: n=443; adults; OBD; treatment for chronic, non-cancer related pain with any full agonist opioid for ≥30 days.
Randomised to lubiprostone 24µg, oral twice daily or placebo, oral twice daily.
Follow-up: Active treatment period 12 weeks.
Primary outcome: Change from baseline in SBM frequency at week 8.
Secondary outcomes: First post-dose SBM; responder rate; straining, stool consistency, constipation severity, abdominal bloating, abdominal discomfort, and bowel habit regularity.
Key results: Change from baseline SBM frequency at week 8, overall SBM frequency, first SBM within 24 and 48 hours, constipation severity, stool consistency, abdominal discomfort, and straining associated with SBMs were all improved to a greater extent for lubiprostone vs placebo (all p<0.05). Patients receiving lubiprostone who were on methadone treatment regimens showed a lower SBM response.
Adverse effects (AEs): Most common AEs reported were nausea, diarrhoea and abdominal distension.

Trial: OPAL, NCT00597428, OBD0632; lubiprostone vs placebo; phase III.
Sponsor: Sucampo Pharmaceuticals, Inc.
Status: Complete but unpublished.
Source of information: Trial registry (13), manufacturer (14).
Location: USA and Canada.
Design: Randomised, placebo-controlled.
Participants and schedule: n=420 (planned); adults; OBD; treatment for chronic, non-cancer related pain with any full opioid agonist for ≥30 days.
Randomised to lubiprostone 24µg, oral twice daily or placebo, oral twice daily.
Follow-up: Active treatment period 12 weeks.
Primary outcome: Change from baseline in SBM frequency at week 8.
Secondary outcomes: First post-dose SBM; responder rate; straining, stool consistency, constipation severity, abdominal bloating, abdominal discomfort, and bowel habit regularity; treatment effectiveness.
Key results: Lubiprostone was not stastically significantly different from placebo for the primary endpoint. Statistical significance vs placebo was achieved for improvement in stool consistency, abdominal discomfort, constipation severity and straining associated with SBMs. Patients receiving lubiprostone who were on methadone treatment regimens showed a lower SBM response.
Adverse effects (AEs): Most common treatment-emergent AEs were nausea and diarrhoea.

Trial: NCT00620061, OBD06S1; lubiprostone; phase III extension.
Sponsor: Sucampo Pharmaceuticals, Inc.
Status: Complete but unpublished.
Source of information: Trial registry (15), manufacturer (16).
Location: USA.
Design: Non-randomised, single arm.
Participants and schedule: n=439; adults; OBD; previously completed 12 weeks of blinded treatment in studies NCT00595946 or NCT00597428.
Lubiprostone, oral, 24µg twice daily.
Follow-up: Active treatment period 36 weeks.
Primary outcome: Overall safety.
Secondary outcomes: SBM and bowel movement frequency; responder rates; straining associated with SBMs, stool consistency, constipation severity, treatment effectiveness, abdominal bloating, abdominal discomfort and bowel habit regularity.
Key results: Treatment with lubiprostone demonstrated consistent improvements over baseline with respect to SBM and other OBD-related symptoms compared to baseline.
Adverse effects (AEs): Most common treatment-related AEs were nausea (5.0%) and diarrhoea (4.6%). Most common AEs reported during trial were diarrhoea (9.6%), nausea (8.9%), upper respiratory tract infection (6.4%) and back pain (5.2%). Severe events of nausea and diarrhoea each occurred in 0.5% patients. No treatment-related SAEs were reported.
Economic evaluation:
No information availavble.
Ongoing research:
No information available.
Ongoing or planned HTA:
No information available.
Web link:
 
References and sources:
1) Panchal SJ, Muller-Schwefe P and Wurzelmann JI. Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. International Journal of Clinical Practice 2007;61(7):1181-1187.
2) Reid K, Harker J, Bala M et al. Epidemiology of chronic non-cancer pain in Europe: narrative review of prevalence, pain treatments and pain impact. Current Medical Research and Opinion 2011;27:449-462.
3) Camilleri M. Opioid-induced constipation: Challenges and therapeutic opportunities. The American Journal of Gastroenterology 2011;106:835-842.
4) Kalso E, Edwards JE, Moore RA et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004;112:372-380.
5) Pappagallo M. Incidence, prevalence and management of opioid bowel dysfunction. American Journal of Surgical Pathology 2001;182 (5A Suppl):11S-18S.
6) The Information Centre, Prescribing Support Unit. Prescription cost analysis data 2010.
7) Goodheart CR, Leavitt SB. Managing opioid-induced constipation in ambulatory-care patients. Pain Treatment Topics 2006. Available from: http://pain-topics.org/pdf/Managing_Opioid-Induced_Constipation.pdf Accessed 26 March 2012.
8) British Medical Association and Royal Society of Great Britain. British National Formulary. BNF 63. London: BMJ Group and RPS Publishing, March 2012.
9) ClinicalTrials.gov. Opioid-induced bowel dysfunction: pivotal assessment of lubiprostone (OPAL). http://www.clinicaltrials.gov/ct2/show/NCT00595946?term=Lubiprostone+AND+opioid+induced+bowel+dysfunction&rank=3 Accessed 26 June 2012.
10) Jamal M, Mareya S, Woldegeorgis F et al. Lubiprostone significantly improves treatment response in non-methadone opioid-induced bowel dysfunction patients with chronic, non-cancer pain: results from a phase 3, randomised, double-blind, placebo-controlled clinical trial. Gastroenterology 2012;142(5):144-145. Abstract 848a.
11) ClinicalTrials.gov. Opioid-induced bowel dysfunction: pivotal assessment of lubiprostone (OPAL). http://www.clinicaltrials.gov/ct2/show/NCT00595946?term=Lubiprostone+AND+opioid+induced+bowel+dysfunction&rank=3 Accessed 26 June 2012.
12) Cryer B, Katz S, Vallejo R et al. A phase 3, randomised, double-blind, placebo controlled clinical trial of lubiprostone for the treatment of opiod-induced bowel dysfunction in patients with chronic non-cancer pain. Gastroenterology 2010;138(5):129. Abstract 906.
13) ClinicalTrials.gov. Opioid-induced bowel dysfunction pivotal assessment of lubiprostone. http://www.clinicaltrials.gov/ct2/show/NCT00597428?term=NCT00597428&rank=1 Accessed 27 June 2012.
14) Sucampo Pharmaceuticals. New release. Takeda and Sucampo report top-line results of two phase 3 trials of lubiprostone in opioid-induced bowel dysfunction. http://investor.sucampo.com/phoenix.zhtml?c=201197&p=irol-newsArticle&ID=1309679&highlight= Accessed 28 June 2012.
15) ClinicalTrials.gov. Opioid-induced bowel dysfunction: long-term assessment of lubiprostone. http://www.clinicaltrials.gov/ct2/show/NCT00620061?term=NCT00620061&rank=1 Accessed 27 June 2012.
16) Sucampo Pharmaceuticals. News release. Positive top-line results from phase 3 long-term, open-label safety and efficacy trial of lubiprostone in opioid-induced bowel dysfunction patients. http://investor.sucampo.com/phoenix.zhtml?c=201197&p=irol-newsArticle&ID=1680449&highlight= Accessed 28 June 2012.
Notes: