Skip to main content

Advertisement

SpringerLink
Log in

Phase II trial of subcutaneous methylnaltrexone in the treatment of severe opioid-induced constipation (OIC) in cancer patients: an exploratory study

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Methylnaltrexone is a peripherally acting mu-opioid receptor antagonist that has been shown to relieve severe opioid-induced constipation (OIC) in patients with advanced disease receiving palliative care. Its efficacy remains unknown in cancer patients who are not terminally ill. The primary aim of this study was to evaluate the efficacy of methylnaltrexone over 48 h in cancer patients who were not terminally ill.

Methods

In this single-dose phase II trial, cancer patients with a prognosis of ≥3 months and OIC with <3 laxations during the preceding week were eligible. The primary endpoint was a rescue-free laxation ≤4 h after a single dose of methylnaltrexone. Friedman’s two-way analysis of variance was conducted for the number of laxations, pain and withdrawal scales, and laxation- and constipation-related symptoms. Univariate/bivariate Cox proportional hazard models for laxation times were employed.

Results

Twelve patients received methylnaltrexone. Eleven patients had an ECOG performance status of 1 or 2. Four (33.3 %) and 5 (41.7 %) patients had rescue-free laxation within 4 and 24 h, respectively, and 10 (83.3 %) had laxation within 48 h (p = 0.006). Difficulty passing a stool improved significantly over 48 h (p = 0.029). The bivariate Cox models revealed that a shorter time to laxation was associated with a higher baseline morphine equivalent daily dose (hazard ratio, 1.02 per 1 mg; p = 0.018) and a smaller number of laxations in the preceding week (hazard ratio, 0.13 per one laxation; p = 0.035). Patients tolerated methylnaltrexone well without opioid withdrawal.

Conclusions

Methylnaltrexone may relieve severe OIC in cancer patients who are not terminally ill. A larger prospective study is justified in this population. (NCT01004393, https://clinicaltrials.gov/show/NCT01004393).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Goudas LC, Bloch R, Gialeli-Goudas M, Lau J, Carr DB (2005) The epidemiology of cancer pain. Cancer Invest 23(2):182–190

    Article  PubMed  Google Scholar 

  2. Walsh TD (1990) Prevention of opioid side effects. J Pain Symptom Manage 5(6):362–367

    Article  CAS  PubMed  Google Scholar 

  3. Cherny N, Ripamonti C, Pereira J, Davis C, Fallon M, McQuay H, Mercadante S, Pasternak G, Ventafridda V, Expert Working Group of the European Association of Palliative Care N (2001) Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 19(9):2542–2554

  4. Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R (2009) The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med 10(1):35–42. doi:10.1111/j.1526-4637.2008.00495.x

    Article  PubMed  Google Scholar 

  5. Pappagallo M (2001) Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 182(5A Suppl):11S–18S

    Article  CAS  PubMed  Google Scholar 

  6. Kaufman PN, Krevsky B, Malmud LS, Maurer AH, Somers MB, Siegel JA, Fisher RS (1988) Role of opiate receptors in the regulation of colonic transit. Gastroenterology 94(6):1351–1356

    Article  CAS  PubMed  Google Scholar 

  7. McNicol ED, Boyce D, Schumann R, Carr DB (2008) Mu-opioid antagonists for opioid-induced bowel dysfunction. Cochrane Database Systematic Rev 2:CD006332. doi:10.1002/14651858.CD006332.pub2

    Google Scholar 

  8. Moss J, Rosow CE (2008) Development of peripheral opioid antagonists’ new insights into opioid effects. Mayo Clin Proc 83(10):1116–1130. doi:10.4065/83.10.1116

    Article  CAS  PubMed  Google Scholar 

  9. Thomas J, Karver S, Cooney GA, Chamberlain BH, Watt CK, Slatkin NE, Stambler N, Kremer AB, Israel RJ (2008) Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 358(22):2332–2343. doi:10.1056/NEJMoa0707377

    Article  CAS  PubMed  Google Scholar 

  10. Slatkin N, Thomas J, Lipman AG, Wilson G, Boatwright ML, Wellman C, Zhukovsky DS, Stephenson R, Portenoy R, Stambler N, Israel R (2009) Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol 7(1):39–46

    CAS  PubMed  Google Scholar 

  11. Chamberlain BH, Cross K, Winston JL, Thomas J, Wang W, Su C, Israel RJ (2009) Methylnaltrexone treatment of opioid-induced constipation in patients with advanced illness. J Pain Symptom Manage 38(5):683–690. doi:10.1016/j.jpainsymman.2009.02.234

    Article  CAS  PubMed  Google Scholar 

  12. Candy B, Jones L, Goodman ML, Drake R, Tookman A (2011) Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Cochrane Database Systematic Rev 1:CD003448. doi:10.1002/14651858.CD003448.pub3

    Google Scholar 

  13. Bell T, Annunziata K, Leslie JB (2009) Opioid-induced constipation negatively impacts pain management, productivity, and health-related quality of life: findings from the National Health and Wellness Survey. J Opioid Manag 5(3):137–144

    PubMed  Google Scholar 

  14. Michna E, Blonsky ER, Schulman S, Tzanis E, Manley A, Zhang H, Iyer S, Randazzo B (2011) Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain 12(5):554–562. doi:10.1016/j.jpain.2010.11.008

  15. Iyer SS, Randazzo BP, Tzanis EL, Schulman SL, Zhang H, Wang W, Manley AL (2011) Effect of subcutaneous methylnaltrexone on patient-reported constipation symptoms. Value Health 14(1):177–183. doi:10.1016/j.jval.2010.11.003

  16. Sawh SB, Selvaraj IP, Danga A, Cotton AL, Moss J, Patel PB (2012) Use of methylnaltrexone for the treatment of opioid-induced constipation in critical care patients. Mayo Clin Proc 87(3):255–259. doi:10.1016/j.mayocp.2011.11.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yuan CS, Foss JF, O’Connor M, Osinski J, Roizen MF, Moss J (1999) Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study. Pain 83(3):631–635

    Article  CAS  PubMed  Google Scholar 

  18. Yuan CS, Foss JF, O’Connor M, Karrison T, Osinski J, Roizen MF, Moss J (2000) Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time. Clin Pharmacol Ther 67(4):398–404. doi:10.1067/mcp.2000.105037

    Article  CAS  PubMed  Google Scholar 

  19. Yuan CS, Foss JF, O’Connor M, Osinski J, Karrison T, Moss J, Roizen MF (2000) Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA 283(3):367–372

  20. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ (2010) Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363(8):733–742. doi:10.1056/NEJMoa1000678

  21. Zimmermann C, Swami N, Krzyzanowska M, Hannon B, Leighl N, Oza A, Moore M, Rydall A, Rodin G, Tannock I, Donner A, Lo C (2014) Early palliative care for patients with advanced cancer: a cluster-randomised controlled trial. Lancet 383(9930):1721–1730. doi:10.1016/S0140-6736(13)62416-2

    Article  PubMed  Google Scholar 

  22. Smith TJ, Temin S, Alesi ER, Abernethy AP, Balboni TA, Basch EM, Ferrell BR, Loscalzo M, Meier DE, Paice JA, Peppercorn JM, Somerfield M, Stovall E, Von Roenn JH (2012) American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol 30(8):880–887. doi:10.1200/JCO.2011.38.5161

  23. Slatkin NE, Lynn R, Su C, Wang W, Israel RJ (2011) Characterization of abdominal pain during methylnaltrexone treatment of opioid-induced constipation in advanced illness: a post hoc analysis of two clinical trials. J Pain Symptom Manage 42(5):754–760. doi:10.1016/j.jpainsymman.2011.02.015

    Article  PubMed  Google Scholar 

  24. Nalamachu SR, Pergolizzi J, Taylor R Jr, Slatkin NE, Barrett AC, Yu J, Bortey E, Paterson C, Forbes WP (2015) Efficacy and tolerability of subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation: a responder analysis of 2 randomized placebo-controlled trials. Pain Pract 15(6):564–571. doi:10.1111/papr.12218

  25. Lennon FE, Mirzapoiazova T, Mambetsariev B, Poroyko VA, Salgia R, Moss J, Singleton PA (2014) The mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and epithelial mesenchymal transition (EMT) in human lung cancer. PLoS ONE 9(3):e91577. doi:10.1371/journal.pone.0091577

  26. Singleton PA, Mirzapoiazova T, Hasina R, Salgia R, Moss J (2014) Increased mu-opioid receptor expression in metastatic lung cancer. Br J Anaesth 113(Suppl 1):i103–i108. doi:10.1093/bja/aeu165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mathew B, Lennon FE, Siegler J, Mirzapoiazova T, Mambetsariev N, Sammani S, Gerhold LM, LaRiviere PJ, Chen CT, Garcia JG, Salgia R, Moss J, Singleton PA (2011) The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg 112(3):558–567. doi:10.1213/ANE.0b013e31820568af

    Article  CAS  PubMed  Google Scholar 

  28. Vanhoff D, Hesser T, Kelly KP, Freyer D, Stork S, Sung L (2013) Facilitating accrual to cancer control and supportive care trials: the clinical research associate perspective. BMC Med Res Methodol 13:154. doi:10.1186/1471-2288-13-154

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We express our special appreciation to Dr. Steven Grunberg for his mentorship in this study, Dr. Mansoor Alam and the staff of the oncology ward and clinic for their efforts to accrue patients, and Vermont Cancer Center for its administrative support.

Author information

Authors and Affiliations

  1. Palliative Care Team, Seirei Mikatahara General Hospital, 3453, Mikatahara-cho, Kita-ku, Hamamatsu, Shizuoka, 433-8558, Japan

    Masanori Mori

  2. Division of Hematology/Oncology, Massachusetts General Hospital, Center for Cancer Care at Exeter Hospital, 5 Alumni Drive, Exeter, NH, 03833, USA

    Yongli Ji

  3. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA

    Santosh Kumar

  4. Department of Medical Biostatistics, University of Vermont College of Medicine, 27 Hills Building, 105 Carrigan Drive, Burlington, VT, 05405, USA

    Takamaru Ashikaga

  5. Division of Hematology and Oncology, University of Vermont Cancer Center, Given E-214-UVM363, 89 Beaumont Avenue, Burlington, VT, 05405, USA

    Steven Ades

Authors
  1. Masanori Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongli Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Santosh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takamaru Ashikaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven Ades
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masanori Mori.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mori, M., Ji, Y., Kumar, S. et al. Phase II trial of subcutaneous methylnaltrexone in the treatment of severe opioid-induced constipation (OIC) in cancer patients: an exploratory study. Int J Clin Oncol 22, 397–404 (2017). https://doi.org/10.1007/s10147-016-1041-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-016-1041-6

Keywords

Search

Navigation