Skip to main content

Advertisement

SpringerLink
Log in

Prolonged-Release Oxycodone/Naloxone Improves Anal Sphincter Relaxation Compared to Oxycodone Plus Macrogol 3350

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Opioid analgesics inhibit anal sphincter function and contribute to opioid-induced bowel dysfunction (OIBD). However, it is unknown whether the inhibition can be reduced by opioid antagonism with prolonged-release (PR) naloxone and how this compares to laxative treatment.

Aims

To compare the effects of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350 on anal sphincter function and gastrointestinal symptoms.

Methods

A randomized, double-blind, crossover trial was conducted in 20 healthy men. Participants were treated for 5 days with combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Resting anal pressure, anal canal distensibility, and relaxation of the internal sphincter to rectal distension were evaluated before treatment (baseline) and on day 5. The Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire, stool frequency, and stool consistency were assessed daily.

Results

Both PR oxycodone/naloxone and PR oxycodone plus macrogol treatment decreased sphincter relaxation compared to baseline (− 27.5%; P < 0.001 and − 14.7%; P = 0.01). However, sphincter relaxation was increased after PR naloxone/oxycodone treatment compared to macrogol (difference = + 17.6%; P < 0.001). Resting anal pressure and anal canal distensibility did not differ between treatments. PAC-SYM abdominal symptoms score was lower during PR naloxone compared to macrogol (0.2 vs. 3.2; P = 0.002). The number of bowel movements was lower during PR naloxone versus macrogol (4.2 vs. 5.4; P = 0.035).

Conclusion

Relaxation of the internal anal sphincter was significantly better after PR oxycodone/naloxone treatment compared to PR oxycodone plus macrogol 3350. These findings highlight that OIBD may require specific therapy against the complex, pan-intestinal effects of opioids.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gilson AM, Maurer MA, Ryan KM, Rathouz PJ, Cleary JF. Using a morphine equivalence metric to quantify opioid consumption: examining the capacity to provide effective treatment of debilitating pain at the global, regional, and country levels. J Pain Symptom Manag. 2013;45:681–700.

    Article  Google Scholar 

  2. Bell TJ, Panchal SJ, Miaskowski C, et al. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med. 2009;10:35–42.

    Article  PubMed  Google Scholar 

  3. Müller-Lissner S, Bassotti G, Coffin B, et al. Opioid-induced constipation and bowel dysfunction: a clinical guideline. Pain Med. 2016;7:121–134.

    Google Scholar 

  4. Brock C, Olesen SS, Olesen AE, et al. Opioid-induced bowel dysfunction: pathophysiology and management. Drugs. 2012;72:1847–1865.

    Article  CAS  PubMed  Google Scholar 

  5. Becker G, Blum HE. Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus. Lancet (London, England). 2009;373:1198–1206.

    Article  CAS  Google Scholar 

  6. Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: Pathophysiology, clinical consequences, and management. Gastroenterol Res Pract. 2014. doi:10.1155/2014/141737.

    PubMed  PubMed Central  Google Scholar 

  7. Camilleri M, Drossman DA, Becker G, et al. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroenterol Motil. 2014;26:1386–1395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2–guidance. Pain Physician. 2012;15:S67–S116.

    PubMed  Google Scholar 

  9. Rao SSC, Rattanakovit K, Patcharatrakul T. Diagnosis and management of chronic constipation in adults. Nat Rev Gastroenterol Hepatol. 2016;13:295–305.

    Article  CAS  PubMed  Google Scholar 

  10. Lee AA, Hasler WL. Opioids and GI motility-friend or foe? Curr Treat Options Gastroenterol. 2016;14:478–494.

    Article  PubMed  Google Scholar 

  11. Galligan JJ, Akbarali HI. Molecular physiology of enteric opioid receptors. Am J Gastroenterol. 2014;2:17–21.

    Article  CAS  Google Scholar 

  12. Gaertner J, Siemens W, Camilleri M, et al. Definitions and outcome measures of clinical trials regarding opioid-induced constipation: a systematic review. J Clin Gastroenterol. 2015;49:9–16.

    Article  CAS  PubMed  Google Scholar 

  13. Mearin F, Lacy BE, Chang L, et al. Bowel disorders. Gastroenterology. 2016;150:e5.

    Google Scholar 

  14. Wu S-D, Zhang Z-H, Jin J-Z, et al. Effects of narcotic analgesic drugs on human Oddi’s sphincter motility. World J Gastroenterol. 2004;10:2901–2904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Helm JF, Venu RP, Geenen JE, et al. Effects of morphine on the human sphincter of Oddi. Gut. 1988;29:1402–1407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rattan S, Culver PJ. Influence of loperamide on the internal anal sphincter in the opossum. Gastroenterology. 1987;93:121–128.

    Article  CAS  PubMed  Google Scholar 

  17. Chowdhury AR, Lorber SH. Effects of glucagon and secretin on food- or morphine-induced motor activity of the distal colon, rectum, and anal sphincter. Am J Dig Dis. 1977;22:775–780.

    Article  CAS  PubMed  Google Scholar 

  18. Göke M, Ewe K, Donner K, et al. Influence of loperamide and loperamide oxide on the anal sphincter: a manometric study. Dis Colon Rectum. 1992;35:857–861.

    Article  PubMed  Google Scholar 

  19. Wilder-Smith CH, Bettiga A. The analgesic tramadol has minimal effect on gastrointestinal motor function. Br J Clin Pharmacol. 1997;43:71–75.

    Article  CAS  PubMed  Google Scholar 

  20. Read M, Read NW, Barber DC, Duthie HL. Effects of loperamide on anal sphincter function in patients complaining of chronic diarrhea with fecal incontinence and urgency. Dig Dis Sci. 1982;27:807–814.

    Article  CAS  PubMed  Google Scholar 

  21. Bouvier M, Kirschner G, Gonella J. Actions of morphine and enkephalins on the internal anal sphincter of the cat: relevance for the physiological role of opiates. J Auton Nerv Syst. 1986;16:219–232.

    Article  CAS  PubMed  Google Scholar 

  22. Bouchoucha M, Faye A, Arsac M, Rocaries F. Anal sphincter response to distension. Int J Colorectal Dis. 2001;16:119–125.

    Article  CAS  PubMed  Google Scholar 

  23. Lottrup C, Gregersen H, Liao D, et al. Functional lumen imaging of the gastrointestinal tract. J Gastroenterol. 2015;50:1005–1016.

    Article  PubMed  Google Scholar 

  24. Musial F, Enck P, Kalveram KT, Erckenbrecht JF. The effect of loperamide on anorectal function in normal healthy men. J Clin Gastroenterol. 1992;15:321–324.

    Article  CAS  PubMed  Google Scholar 

  25. Gregersen T, Grønbæk H, Worsøe J, et al. Effects of Sandostatin LAR on gastrointestinal motility in patients with neuroendocrine tumors. Scand J Gastroenterol. 2011;46:895–902.

    Article  CAS  PubMed  Google Scholar 

  26. Dipalma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol. 2007;102:1436–1441.

    Article  CAS  PubMed  Google Scholar 

  27. Harris ML, Hobson AR, Hamdy S, et al. Neurophysiological evaluation of healthy human anorectal sensation. Am J Physiol Gastrointest Liver Physiol. 2006;291:G950–G958.

    Article  CAS  PubMed  Google Scholar 

  28. Krogh K, Mosdal C, Gregersen H, Laurberg S. Rectal wall properties in patients with acute and chronic spinal cord lesions. Dis Colon Rectum. 2002;45:641–649.

    Article  CAS  PubMed  Google Scholar 

  29. Alqudah MM, Gregersen H, Drewes AM, McMahon BP. Evaluation of anal sphincter resistance and distensibility in healthy controls using EndoFLIP ©. Neurogastroenterol Motil. 2012;24:e591–e599.

    Article  CAS  PubMed  Google Scholar 

  30. Sørensen G, Liao D, Lundby L, et al. Distensibility of the anal canal in patients with idiopathic fecal incontinence: a study with the Functional Lumen Imaging Probe. Neurogastroenterol Motil. 2014;26:255–263.

    Article  PubMed  Google Scholar 

  31. Gregersen H. Biomechanics of the Gastrointestinal Tract: New Perspectives in Motility Research and Diagnostics. London: Springer; 2003.

    Book  Google Scholar 

  32. Haas S, Liao D, Gregersen H, et al. Increased yield pressure in the anal canal during sacral nerve stimulation: a pilot study with the functional lumen imaging probe. Neurogastroenterol Motil. 2016;29:1–9.

    Google Scholar 

  33. Rao SSC, Azpiroz F, Diamant N, et al. Minimum standards of anorectal manometry. Neurogastroenterol Motil. 2002;14:553–559.

    Article  CAS  PubMed  Google Scholar 

  34. Slappendel R, Simpson K, Dubois D, Keininger DL. Validation of the PAC-SYM questionnaire for opioid-induced constipation in patients with chronic low back pain. Eur J Pain. 2006;10:209–217.

    Article  PubMed  Google Scholar 

  35. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32:920–924.

    Article  CAS  PubMed  Google Scholar 

  36. Andresen T, Arendt-Nielsen L, Drewes A, Oksche A, Staahl C. Effect of buprenorphine and fentanyl in experimental induced superficial, deep and hyperalgesic pain. Scand J Pain. 2010;1:174–175.

    Article  Google Scholar 

  37. Cheeney G, Nguyen M, Valestin J, Rao SSC. Topographic and manometric characterization of the recto-anal inhibitory reflex. Neurogastroenterol Motil. 2012;24:e147–e154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rattan S. The internal anal sphincter: regulation of smooth muscle tone and relaxation. Neurogastroenterol Motil. 2005;17:50–59.

    Article  PubMed  Google Scholar 

  39. Bhardwaj R, Vaizey CJ, Boulos PB, Hoyle CH. Neuromyogenic properties of the internal anal sphincter: therapeutic rationale for anal fissures. Gut. 2000;46:861–868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sternini C, Patierno S, Selmer I-S, Kirchgessner A. The opioid system in the gastrointestinal tract. Neurogastroenterol Motil. 2004;16:3–16.

    Article  PubMed  Google Scholar 

  41. Kromer W. Endogenous opioids, the enteric nervous system and gut motility. Dig Dis. 1990;8:361–373.

    Article  CAS  PubMed  Google Scholar 

  42. Rasmussen OO, Colstrup H, Lose G, Christiansen J. A technique for the dynamic assessment of anal sphincter function. Int J Colorectal Dis. 1990;5:135–141.

    Article  CAS  PubMed  Google Scholar 

  43. Luft F, Fynne L, Gregersen H, et al. Functional luminal imaging probe: a new technique for dynamic evaluation of mechanical properties of the anal canal. Tech Coloproctol. 2012;16:451–457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gourcerol G, Granier S, Bridoux V, et al. Do endoflip assessments of anal sphincter distensibility provide more information on patients with fecal incontinence than high-resolution anal manometry? Neurogastroenterol Motil. 2016;28:399–409.

    Article  CAS  PubMed  Google Scholar 

  45. Monteiro FJR, Regadas FSP, Murad-Regadas SM, Rodrigues LV, Leal VM. Comparative evaluation of the effect of sustained inflation and rapid inflation/deflation of the intrarectal balloon upon rectoanal inhibitory reflex parameters in asymptomatic subjects. Tech Coloproctol. 2007;11:323–326.

    Article  CAS  PubMed  Google Scholar 

  46. Burness CB, Keating GM. Oxycodone/naloxone prolonged-release: a review of its use in the management of chronic pain while counteracting opioid-induced constipation. Drugs. 2014;74:353–375.

    Article  CAS  PubMed  Google Scholar 

  47. Smith K, Hopp M, Mundin G, et al. Single- and multiple-dose pharmacokinetic evaluation of oxycodone and naloxone in an opioid agonist/antagonist prolonged-release combination in healthy adult volunteers. Clin Ther. 2008;30:2051–2068.

    Article  CAS  PubMed  Google Scholar 

  48. Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016;14:273–287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Olesen AE, Drewes AM. Validated tools for evaluating opioid-induced bowel dysfunction. Adv Ther. 2011;28:279–294.

    Article  PubMed  Google Scholar 

  50. Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001;182:11S–18S.

    Article  CAS  PubMed  Google Scholar 

  51. Moore J, Barlow D, Jewell D, Kennedy S. Do gastrointestinal symptoms vary with the menstrual cycle? Br J Obstet Gynaecol. 1998;105:1322–1325.

    Article  CAS  PubMed  Google Scholar 

  52. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014;6:71–80.

    PubMed  PubMed Central  Google Scholar 

  53. McCrea GL, Miaskowski C, Stotts NA, et al. Gender differences in self-reported constipation characteristics, symptoms, and bowel and dietary habits among patients attending a specialty clinic for constipation. Gend Med. 2009;6:259–271.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Susanne Haas, MD for her assistance in protocol design, pilot studies, and production of the balloons for rectal distension.

Funding

The study was funded in part by Innovation Fund Denmark—Individuals, Disease and Society, Grant Number 10–092786, in part by The A.P. Møller Foundation for the Advancement of Medical Science, Grant Number 14-319, in part by Aage og Johanne Louis-Hansens Fond, in part Svend Andersen Fonden, and in part by an unrestricted grant from Mundipharma Research GmbH & Co. KG.

Author information

Authors and Affiliations

  1. Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Mølleparkvej 4, 9000, Aalborg, Denmark

    Jakob Lykke Poulsen, Christina Brock, Debbie Grønlund & Asbjørn Mohr Drewes

  2. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Christina Brock

  3. GIOME Academia, Department of Clinical Medicine, Aarhus University, Nordre Ringgade 1, 8000, Aarhus, Denmark

    Donghua Liao

  4. GIOME, Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong

    Hans Gregersen

  5. Neurogastroenterology Unit, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, Denmark

    Klaus Krogh

  6. Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, 9000, Aalborg, Denmark

    Asbjørn Mohr Drewes

Authors
  1. Jakob Lykke Poulsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christina Brock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Debbie Grønlund
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Donghua Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hans Gregersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Klaus Krogh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Asbjørn Mohr Drewes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JLP was involved in study design; data acquisition; data interpretation; statistical analysis; drafting of manuscript, submission guarantor. CB contributed to study supervision; study design; data interpretation; drafting of the manuscript. DG, DL, and HG were involved in data acquisition; data interpretation; revision of the manuscript for important intellectual content. KK contributed to study design, data interpretation; revision of the manuscript for important intellectual content. AMD was involved in obtaining funding for the study; study supervision; study design; data interpretation; revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Asbjørn Mohr Drewes.

Ethics declarations

Conflict of interest

Asbjørn Mohr Drewes has received financial support from Mundipharma, AstraZeneca, Shire, Almirall, Grünenthal, and Pfizer. Klaus Krogh has served as an advisory board member for Coloplast, Wellspect, Nordic Health Care, Amirall, and Shire. Hans Gregersen invented the EndoFLIP technology and owns a minority share (< 5%) in Crospon Ltd.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Poulsen, J.L., Brock, C., Grønlund, D. et al. Prolonged-Release Oxycodone/Naloxone Improves Anal Sphincter Relaxation Compared to Oxycodone Plus Macrogol 3350. Dig Dis Sci 62, 3156–3166 (2017). https://doi.org/10.1007/s10620-017-4784-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-017-4784-7

Keywords

Search

Navigation