Skip to main content
SpringerLink
Log in

Methylnaltrexon

Ein neuer Ansatz zur Therapie der opioidinduzierten Obstipation

Methylnaltrexone

A new approach for therapy of opioid-induced obstipation

  • Übersichten
  • Published:
Der Schmerz Aims and scope Submit manuscript

Zusammenfassung

Schmerzpatienten unter Therapie mit Opioiden leiden häufig an einer ihr Wohlbefinden sehr beeinträchtigenden Obstipation. Eine entsprechende opioidinduzierte Obstipation kann als gastrointestinale Komplikation regelmäßig auch in der Palliativmedizin sowie bei analgosedierten Patienten auf Intensivstation oder während prolongierter perioperativer Schmerztherapie auftreten. Unbehagen und Unwohlsein bei den betroffenen Patienten sind zum Teil so stark ausgeprägt, dass lieber vermehrt Schmerzen in Kauf genommen werden, als diese Nebenwirkung der Therapie mit Opioiden zu ertragen. Konventionelle Therapieansätze sind vielfach nicht in der Lage diese Obstipation zufriedenstellend zu behandeln: Die opioidinduzierte Darmträgheit ist vielmehr sehr resistent gegenüber den üblichen Laxanzien. Zudem schwindet die Obstipation nicht mit zunehmender Dauer der Therapie, wie dies mit anderen Nebenwirkungen der Opioide der Fall ist. Es ist gut belegt, dass die opioidinduzierte Obstipation über eine Aktivierung von µ-Opioidrezeptoren im Magen-Darm-Trakt vermittelt wird. Selektiv periphere µ-Rezeptorantagonisten (wie Methylnaltrexoniumbromid, Relistor®) können somit eine opioidinduzierte Obstipation effizient therapieren. Eine Interferenz mit der zentralen Analgesie findet dabei nicht statt, da die Blut-Hirn-Schranke aufgrund des Ladungszustandes der Moleküle nicht passiert wird. Eine verringerte Effizienz der Therapie mit Opioiden oder die Entstehung von Entzugssymptomen können hierdurch vermieden werden. Studien haben zudem gezeigt, dass Methylnaltrexon nicht nur sicher und effektiv bei chronisch obstipierten Patienten in der Palliativmedizin eingesetzt werden kann, es bietet auch weitere vielversprechende therapeutische Optionen für zusätzliche Patientengruppen.

Abstract

Chronic pain patients using opioids frequently suffer from constipation which compromises well-being. Such an opioid-induced gastro-intestinal complication can occur regularly in patients in palliative care as well as in analgesic sedated intensive care patients or during prolonged perioperative pain therapy. Discomfort and distress in the affected patients can be so severely pronounced that they would rather suffer from the pain than from the side effect of constipation. Conventional therapy can be insufficient in providing satisfactory relief of constipation, mostly because this opioid-induced bowel hypomotility can be laxative-resistant. Moreover, constipation does not decrease during the course of therapy as do other side effects. It is well known that opioid-induced constipation is mediated via activation of µ-opioid receptors in the gastrointestinal tract. Selective peripheral µ-receptor antagonists (such as methylnaltrexone, Relistor®) can effectively treat opioid-induced constipation. An interference with central analgesia does not occur as the molecules cannot pass the blood-brain barrier due to their charged states. A reduction of opioid therapy or the development of withdrawal symptoms can be avoided. Studies have shown that methylnaltrexone is not only safe and efficient for chronically constipated palliative care patients but offers promising therapeutic options for further patient collectives.

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

Literatur

  1. Agra Y, Sacristan A, Gonzalez M et al (1998) Efficacy of senna versus lactulose in terminal cancer patients treated with opioids. J Pain Symptom Manage 15:1–7

    Article  PubMed  CAS  Google Scholar 

  2. Ahmedzai SH, Boland J (2007) Opioids for chronic pain: molecular and genomic basis of actions and adverse effects. Curr Opin Support Palliat Care 1:117–125

    Article  PubMed  Google Scholar 

  3. Allan L, Hays H, Jensen NH et al (2001) Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ 322:1154–1158

    Article  PubMed  CAS  Google Scholar 

  4. Blunk JA, Schmelz M, Zeck S et al (2004) Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analg 98:364–370

    Article  PubMed  CAS  Google Scholar 

  5. Boland J, Ahmedzai SH (2008) Targeted management of opioid-induced constipation: the role of the novel, peripherally acting, mu-opioid receptor antagonist methylnaltrexone bromide. Eur J Pall Care (Suppl):6–11

    Google Scholar 

  6. Brescia FJ, Portenoy RK, Ryan M et al (1992) Pain, opioid use, and survival in hospitalized patients with advanced cancer. J Clin Oncol 10:149–155

    PubMed  CAS  Google Scholar 

  7. Chappell D, Conzen P (2008) Therapy of opioid-induced constipation. Anaesthesist 57:1011–1014

    Article  Google Scholar 

  8. Chappell D, Rehm M, Conzen P (2008) Opioid-induced constipation in intensive care patients: relief in sight? Crit Care 12:161

    Article  PubMed  Google Scholar 

  9. Cherny N, Ripamonti C, Pereira J et al (2001) Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 19:2542–2554

    PubMed  CAS  Google Scholar 

  10. Droney J, Ross J, Gretton S et al (2008) Constipation in cancer patients on morphine. Support Care Cancer 16:453–459

    Article  PubMed  Google Scholar 

  11. Fainsinger R, Miller MJ, Bruera E et al (1991) Symptom control during the last week of life on a palliative care unit. J Palliat Care 7:5–11

    Google Scholar 

  12. Jiang Q, Sheldon RJ, Porreca F (1990) Opioid modulation of basal intestinal fluid transport in the mouse: actions at central, but not intestinal, sites. J Pharmacol Exp Ther 253:784–790

    PubMed  CAS  Google Scholar 

  13. Klaschik E, Nauck F, Ostgathe C (2003) Constipation – modern laxative therapy. Support Care Cancer 11:679–685

    Article  PubMed  CAS  Google Scholar 

  14. Klepstad P, Borchgrevink PC, Kaasa S (2000) Effects on cancer patients‘ health-related quality of life after the start of morphine therapy. J Pain Symptom Manage 20:19–26

    Article  PubMed  CAS  Google Scholar 

  15. Kurz A, Sessler DI (2003) Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs 63:649–671

    Article  PubMed  CAS  Google Scholar 

  16. Liu M, Wittbrodt E (2002) Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage 23:48–53

    Article  PubMed  Google Scholar 

  17. Liu SS, Hodgson PS, Carpenter RL, Fricke JR Jr (2001) ADL 8-2698, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia. Clin Pharmacol Ther 69:66–71

    Article  PubMed  CAS  Google Scholar 

  18. Meissner W, Leyendecker P, Mueller-Lissner S et al (2008) A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain 13:56–64

    Article  PubMed  CAS  Google Scholar 

  19. Moore RA, McQuay HJ (2005) Prevalence of opioid adverse events in chronic nonmalignant pain: systematic review of randomised trials of oral opioids. Arthritis Res Ther 7:R1046–R1051

    Article  PubMed  CAS  Google Scholar 

  20. Mostafa SM, Bhandari S, Ritchie G et al (2003) Constipation and its implications in the critically ill patient. Br J Anaesth 91:815–819

    Article  PubMed  CAS  Google Scholar 

  21. Oeltjenbruns J, Schäfer N (2005) Anwendungsmöglichkeiten und Stellenwert der peripheren Opioidanalgesie. Schmerz 19:447–455

    Article  PubMed  CAS  Google Scholar 

  22. Osterbrink J, Haas U (2008) Die opioidinduzierte Obstipation und ihre Behandlungsmöglichkeiten. Klinikarzt 37:527–530

    Google Scholar 

  23. Osterbrink J, Haas U (2008) Opioid-induced bowel dysfunction: a literature analysis on pathophysiology and treatment. Wien Med Wochenschr 158:621–626

    Article  PubMed  Google Scholar 

  24. Panchal SJ, Muller-Schwefe P, Wurzelmann JI (2007) Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract 61:1181–1187

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. Radbruch L, Sabatowski R, Loick G et al (2000) Constipation and the use of laxatives: a comparison between transdermal fentanyl and oral morphine. Palliat Med 14:111–119

    Article  PubMed  CAS  Google Scholar 

  27. Ramesh PR, Kumar KS, Rajagopal MR et al (1998) Managing morphine-induced constipation: a controlled comparison of an Ayurvedic formulation and senna. J Pain Symptom Manage 16:240–244

    Article  PubMed  CAS  Google Scholar 

  28. Reintam A, Parm P, Redlich U et al (2006) Gastrointestinal failure in intensive care: a retrospective clinical study in three different intensive care units in Germany and Estonia. BMC Gastroenterol 6:19

    Article  PubMed  Google Scholar 

  29. Ruan X (2007) Drug-related side effects of long-term intrathecal morphine therapy. Pain Physician 10:357–366

    PubMed  Google Scholar 

  30. Schwarzer A, Nauck F, Klaschik E (2005) Strong opioids and constipation. Schmerz 19:214–219

    Article  PubMed  CAS  Google Scholar 

  31. Slatkin N, Thomas J, Lipman AG et al (2009) Methylnaltrexone for treatment of opioidinduced constipation in advanced illness patients. J Support Oncol 7:39–46

    PubMed  CAS  Google Scholar 

  32. Stefano GB, Goumon Y, Casares F et al (2000) Endogenous morphine. Trends Neurosci 23:436–442

    Article  PubMed  CAS  Google Scholar 

  33. Stefano GB, Zhu W, Cadet P et al (2004) Morphine enhances nitric oxide release in the mammalian gastrointestinal tract via the micro (3) opiate receptor subtype: a hormonal role for endogenous morphine. J Physiol Pharmacol 55(3):279–288

    PubMed  CAS  Google Scholar 

  34. Stein C, Schäfer M, Machelska H (2003) Attacking pain at its source: new perspectives on opioids. Nat Med 9:1003–1008

    Article  PubMed  CAS  Google Scholar 

  35. Suzuki R, Chapman V, Dickenson AH (1999) The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain. Pain 80:215–228

    Article  PubMed  CAS  Google Scholar 

  36. Sykes N (1990) Methods of assessment of bowel function in patients with advanced cancer. Palliat Med 4:287–292

    Article  Google Scholar 

  37. Sykes N (2008) Opioid induced constipation. Eur J Pall Care (Suppl):1–5

    Google Scholar 

  38. Sykes NP (1998) The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med 12:375–382

    Article  PubMed  CAS  Google Scholar 

  39. The European Pain in Cancer survey (2009) http://www.paineurope.com/index.php?q=en/book_page/epic_survey

  40. Thomas J (2008) Opioid-induced bowel dysfunction. J Pain Symptom Manage 35:103–113

    Article  PubMed  CAS  Google Scholar 

  41. Thomas J, Karver S, Cooney GA et al (2008) Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 358:2332–2343

    Article  PubMed  CAS  Google Scholar 

  42. Thompson WG, Longstreth GF, Drossman DA et al (1999) Functional bowel disorders and functional abdominal pain. Gut 45 (Suppl 2):II43–II47

    Article  PubMed  Google Scholar 

  43. Twycross RG, McNamara P, Schuijt C et al (2006) Sodium picosulfate in opioid-induced constipation: results of an open-label, prospective, dose-ranging study. Palliat Med 20:419–423

    Article  PubMed  Google Scholar 

  44. van der Spoel JI, Schultz MJ, van der Voort PH, de Jonge E (2006) Influence of severity of illness, medication and selective decontamination on defecation. Intensive Care Med 32:875–880

    Article  Google Scholar 

  45. Wellmann C, Wilson G, Israel R (2008) Methylnaltrexone in the treatment of opioidinduced constipation in patients with advanced illness: results of two Phase 3 trials. Palliative Medicine 12th International Symposium. Scotsdale, AZ, USA (Poster)

  46. Wigzell FW (1969) The health of nonagenarians. Gerontol Clin (Basel) 11:137–144

    Google Scholar 

  47. Wirz S, Klaschik E (2005) Management of constipation in palliative care patients undergoing opioid therapy: is polyethylene glycol an option? Am J Hosp Palliat Care 22:375–381

    Article  PubMed  Google Scholar 

  48. Yuan CS (2007) Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother 41:984–993

    Article  PubMed  CAS  Google Scholar 

  49. Yuan CS, Doshan H, Charney MR et al (2005) Tolerability, gut effects, and pharmacokinetics of methylnaltrexone following repeated intravenous administration in humans. J Clin Pharmacol 45:538–546

    Article  PubMed  CAS  Google Scholar 

  50. Yuan CS, Foss JF (1999) Gastric effects of methylnaltrexone on mu, kappa, and delta opioid agonists induced brainstem unitary responses. Neuropharmacology 38:425–432

    Article  PubMed  CAS  Google Scholar 

  51. Yuan CS, Foss JF (2000) Oral methylnaltrexone for opioid-induced constipation. JAMA 284:1383–1384

    Article  PubMed  CAS  Google Scholar 

  52. Yuan CS, Israel RJ (2006) Methylnaltrexone, a novel peripheral opioid receptor antagonist for the treatment of opioid side effects. Expert Opin Investig Drugs 15:541–552

    Article  PubMed  CAS  Google Scholar 

  53. Zhukovsky D, Slatkin N, Thomas J et al (2007) Methylnaltrexone for the treament of opioid-induced constipation in patients with advanced illness: evaluating the risk of central opioid antagonism in patients with CNS metastases. Support Care Cancer 15:715

    Google Scholar 

  54. Zubieta JK, Smith YR, Bueller JA et al (2001) Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 293:311–315

    Article  PubMed  CAS  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehung hin: Mit Unterstützung der Wyeth Pharma GmbH.

Author information

Authors and Affiliations

  1. Klinik für Anaesthesiologie, Ludwig-Maximilians-Universität, Nussbaumstr. 20, 80336, München, Deutschland

    D. Chappell & P. Conzen

Authors
  1. D. Chappell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Conzen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. Chappell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chappell, D., Conzen, P. Methylnaltrexon. Schmerz 23, 471–478 (2009). https://doi.org/10.1007/s00482-009-0824-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00482-009-0824-3

Schlüsselwörter

Keywords

Search

Navigation