Opioid constipation

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Classification according to ICD-10
K59.02 Drug-induced constipation
ICD-10 online (WHO version 2019)

Opioid-induced constipation , opioid-induced constipation ( English opioid-induced constipation , OIC ) or opioid-induced bowel dysfunction (English opioid-induced bowel dysfunction , OIBD is) a functional disorder of the gastrointestinal tract (gastrointestinal tract), by the taking of opioids or opiates the WHO step II / III arises such. B. morphine , oxycodone or tapentadol . If opioids are taken regularly, tolerance to the adverse effects of the opioid may develop, so that some symptoms - such as: B. Drowsiness , nausea, and vomiting - ease up. The blockage on the other hand remains generally over the entire period of opioid use.

Definition of OIC

Opioid-induced constipation (OIC) or opioid-induced intestinal dysfunction (OIBD) are symptoms of constipation caused by the use of opioids. For the development of an OIC / OIBD, both opioids of WHO level II, such as z. B. Tramadol , as well as stage III opioids such. B. morphine , oxycodone , hydromorphone , tapentadol , polamidon , into consideration. The form in which the opioids are administered is irrelevant. Even with the transdermal administration of opioids, such as. B. with fentanyl or buprenorphine , an OIC / OIPBD can develop.

OIC encompasses a wide range of symptoms, as constipation can cause further complications. These include B. pain, flatulence, loss of appetite, anorexia (weight loss), paradoxical diarrhea (diarrhea), aggravation of hemorrhoids complaints and other unpleasant effects, such as bloating, nausea and reflux symptoms . In contrast to most of the other side effects of opioids, there is no habituation with a reduction in the respective side effect, but rather the constipation persists. The OIC leads to a reduction in quality of life, a reduction in the ability to work and an increased use of the health care system.

background

Over 20 million people in Germany suffer from chronic pain. Around 6 million people are severely impaired in their everyday coping.

Only about a third of the patients with severe impairment from chronic pain use professional pain therapy. In drug pain therapy, a distinction is made between non-opioid drugs and opioids. In the WHO grading scheme , non-opioids are classified as non- steroidal anti-inflammatory drugs , coxibs , metamizole and paracetamol in level 1, while opioids are listed in levels 2 and 3. The risks of WHO-1 painkillers of the nonsteroidal anti-inflammatory drug and coxib type lie in side effects or damage to the cardiovascular system or kidney function. Paracetamol can damage liver function. In the case of opioids, according to the current state of knowledge, these possibilities for damage are not seen; opioids lead to various side effects, such as a. Nausea, vomiting, constipation, tiredness, changes in nature. Other disadvantages are the potential for abuse and the development of tolerance.

How does an OIC come about?

Opioid receptors are found in almost all tissues in the body, not just in the brain and spinal cord, but also in the gastrointestinal area. Opioids inhibit mobility in the gastrointestinal area.

In the stomach, the movement of the stomach contents is reduced and gastric emptying is delayed. Mobility in the small intestine is also restricted, which can lead to pain. In the large intestine, the decreased intestinal mobility leads to a prolonged passage time and increased fluid absorption from the intestine. It also reduces the production of secretions, resulting in dry and hard stools. In the anus there may be difficult defecation. An OIC can be defined as a change in bowel habits and defecation after starting opioid therapy.

It comes to

  • a decreased frequency of spontaneous bowel movements,
  • new or increased straining to defecate
  • the feeling of incomplete defecation and
  • harder chair texture.

Frequency of occurrence of the OIC

In meta-analyzes of therapy studies, the frequency of OIC was up to 41%, in individual observational studies in patients with an increased risk of constipation, it was up to 81%. The OIC occurs in all forms of administration of the opioids. Since tolerance does not develop in the course of therapy, OIC is often the most distressing symptom for patients. It is of great importance for pain therapy that the OIC leads some of the patients to limit their opioid pain therapy or to discontinue it completely. In an online survey, more than half of patients with chronic pain, opioid therapy, and OIC said the OIC affects their pain management.

diagnosis

In principle, the diagnosis of OIC is simple: A newly developed constipation under opioid therapy with one or more criteria allows this diagnosis. The contribution of comorbidity, comedication and patient behavior to constipation must be examined individually. The multitude of accompanying symptoms makes the diagnosis of OIC difficult. An extreme example in this regard is what is known as paradoxical diarrhea . Here, above stool retention, the stool can become liquefied due to bacterial decomposition with explosive emptying in the further course. The diagnosis is also difficult because constipation is an "embarrassing" topic for many patients, which is not openly addressed. As a result, the treating doctor often does not even notice an OIC, so that treatment is not started. It is therefore important that patients are informed about the possible occurrence of an OIC when prescribing opioids and that they are regularly asked about it during the course of treatment.

An international online survey by Robert Epstein provided information on how patients imagine a relevant improvement in their OIC. 80% of the 513 patients with chronic pain, opioid therapy and OIC each stated the following therapy goals: regular bowel movements, bowel movements without rectal pain, loose stools, less pressing, no flatulence, less concern about adhering to opioid therapy, less worry around the bowel movement and less pain in the upper abdomen. For 90% of the patients an additional weekly bowel movement was important, for 70% it was very important. The therapeutic goal of increasing their low stool frequency with fewer than three bowel movements per week was just as important for the patients as pain relief.

Prevention and treatment (prophylaxis and therapy) of OIC

When starting opioid therapy, preventive measures should be taken with the aim of preventing OIC. The standard approach to the OIC improves the effectiveness and safety of treatment with opioids. These should be carried out schematically according to a fixed step-by-step plan: the prophylaxis and therapy of an OIC were summarized in a step-by-step scheme.

General measures

First of all, general measures such as adequate mobilization, hydration, and changing eating habits in favor of an increased intake of fiber are suggested. On the other hand, dietary fiber should be used with caution in OIC / OIPBD, as the increase in stool volume caused by dietary fiber can exacerbate the symptoms. Since the general measures z. B. are not always sufficiently feasible for bedridden patients or patients with dysphagia, early is prophylaxis with laxatives ( laxative ) is recommended.

Level I.

In stage I a single laxative (laxative) or intestinal motility ( prokinetic ) is used. There are laxatives with different mechanisms of action. A group of so-called osmotically active laxatives increases the water content in the intestine, so that the stool becomes more voluminous and thus stimulates the inner wall of the intestine to move. It also makes the chair less hard and easier to transport. The group of so-called propulsive laxatives causes an increased bowel movement by stimulating the inner wall of the intestine. The use of prokinetic substances that promote bowel motility, such as B. metoclopramide is possible. Possible restrictions on applicability, such as B. Parkinson's disease should be observed. Another supplement could be prucalopride , which is only approved for the symptomatic treatment of chronic constipation in adults, i.e. not specifically for the OIC, if laxatives are not sufficiently effective. There have been many studies of laxatives and prokinetics for use in constipation in the general sense, but only a few OICs. However, there is a great deal of experience in practical application and this is common practice and described in the guidelines.

Naloxone in fixed combination with oxycodone . The use of naloxone in combination with the opioid oxycodone in a fixed dose ratio of 1: 2 shows fewer symptoms of constipation than with oxycodone without the addition of naloxone. Naloxone is a so-called opioid antagonist that blocks the effects of opioids on the opioid receptor. This blockage can occur in central structures, such as the brain or spinal cord, or in the gastrointestinal area. The mixing ratio of 1: 2 is specific for the opioid oxycodone and is selected in such a way that naloxone unfolds its blocking effect as far as possible in the gastrointestinal area without leading to a general abolition of the pain relieving effect of oxycodone. This mixing ratio probably differs specifically for all opioids. The naloxone addition to the opioid tilidine has not yet been investigated with regard to its effect on OIC.

Stage II

If level I is insufficient and the laxative treatment does not work, a peripherally active opioid receptor antagonist (e.g. naloxegol , naldemedine , methylnaltrexone ) can be used. According to the approval, there is a corresponding indication in the case of insufficient effectiveness of a laxative use. The non-absorbable peripheral µ-opioid receptor antagonists (PAMORA) can be used to treat the cause of opioid-related constipation (OIC), as they neutralize the effect of opioids on the intestine. A specific dose-mixing ratio to the pain reliever opioid does not need to be taken into account, as absorption into the central structures (brain or spinal cord) is negligible. Thus there is a predominantly selective blockade of the opioid effect on the opioid receptors of the gastrointestinal area, so that PAMORA can in principle be used with all opioids. A combination of PAMORA and mixed preparations (opioids with naloxone) has not yet been investigated and should not be used.

In stage II, a combination of laxatives with different mechanisms of action can be used.

Stage III

In stage III, further measures are recommended, such as B. a local use of suppositories in the rectum or enemas in the form of enemas . Further treatment options include certain medications that, after medical consideration, can be used outside of the original intended use and can be effective against constipation even without appropriate approval ( off-label ).

Examples

  • Laxatives: osmotic (e.g. macrogol), stimulating laxative (e.g. sodium picosulfate or bisacodyl)
  • Prokinetics: prucalopride, metoclopramide
  • Opioid receptor antagonists:
    • PAMORA oral : naloxegol, naldemedine (not available in Germany) in any opioid combination
    • PAMORA subcutaneous : methylnaltrexone
  • Naloxone in fixed combination with oxycodone (mixing ratio 2: 1)
  • Supplementary measures: Laxative suppositories (e.g. CO 2 formers or glycerine), enemas, other off-label measures

Individual evidence

  1. ↑ F. Petzke, T. Kohlmann: There will be no one number . In: Manual Medicine . tape 52 , no. 6 , December 1, 2014, ISSN  1433-0466 , p. 538-539 , doi : 10.1007 / s00337-014-1151-z .
  2. ↑ Harald Breivik, Beverly Collett, Vittorio Ventafridda, Rob Cohen, Derek Gallacher: Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment . In: European Journal of Pain . tape 10 , no. 4 , 2006, ISSN  1532-2149 , p. 287-287 , doi : 10.1016 / j.ejpain.2005.06.009 (English).
  3. ↑ Karin S. Coyne, Robert J. LoCasale, Catherine J. Datto, Chris C. Sexton, Karen Yeomans: Opioid-induced constipation in patients with chronic noncancer pain in the USA, Canada, Germany, and the UK: descriptive analysis of baseline patient-reported outcomes and retrospective chart review . In: ClinicoEconomics and outcomes research: CEOR . tape 6 , 2014, ISSN  1178-6981 , p. 269–281 , doi : 10.2147 / CEOR.S61602 , PMID 24904217 , PMC 4041290 (free full text) - (English).
  4. ↑ a b c Consensus recommendation on the management of opioid-induced constipation (OIC) (Kyowa Kirin GmbH, Düsseldorf) . In: Thieme Praxis Report . tape 9 , no. 4 , November 2017, ISSN  1611-7891 , p. 1-12 , doi : 10.1055 / s-0038-1657852 .
  5. ↑ Stefan Wirz: side effect management of opioid therapy . In: Journal of Gastroenterology . tape 55 , no. 4 , March 31, 2017, ISSN  0044-2771 , p. 394-400 , doi : 10.1055 / s-0043-103348 .
  6. ↑ Pain therapy opioid-induced constipation (OIC). In: CME-Kurs.de. Retrieved November 20, 2019 .
  7. ^ Robert S. Epstein, Ali Cimen, Hannah Benenson, Ronald E. Aubert, Mona Khalid: Patient Preferences for Change in Symptoms Associated with Opioid-Induced Constipation . In: Advances in Therapy . tape 31 , no. December 12 , 2014, ISSN  0741-238X , p. 1263–1271 , doi : 10.1007 / s12325-014-0169-x , PMID 25414049 , PMC 4271128 (free full text) - (English).
  8. ↑ a b c Stefan Wirz: Symptom control in pain therapy, palliative medicine, anesthesia and intensive care medicine . UNI-MED Verlag, Bremen 2010.
  9. ^ Robert S. Epstein, Ali Cimen, Hannah Benenson, Ronald E. Aubert, Mona Khalid, Mark B. Sostek, Tehseen Salimi: Patient Preferences for Change in Symptoms Associated with Opioid-Induced Constipation . In: Advances in Therapy . tape 31 . Springer, 2014, p. 1263-1271 , PMID 25414049 , PMC 4271128 (free full text) - (English).
  10. ^ Robert S. Epstein, Ali Cimen, Hannah Benenson, Ronald E. Aubert, Mona Khalid: Patient Preferences for Change in Symptoms Associated with Opioid-Induced Constipation . In: Advances in Therapy . tape 31 , no. December 12 , 2014, ISSN  0741-238X , p. 1263–1271 , doi : 10.1007 / s12325-014-0169-x (English).
  11. ^ V. Andresen, P. Enck, T. Frieling, A. Herold, P. Ilgenstein: S2k guidelines for chronic constipation. Definition, pathophysiology, diagnostics and therapy . In: Journal of Gastroenterology . tape 51 , no. 7 , July 9, 2013, ISSN  0044-2771 , p. 651-672 , doi : 10.1055 / s-0033-1335808 .
  12. ↑ a b c Claudia Bausewein, Markus Follmann, Gloria Hanke, Thomas Langer, Susanne König, Kerstin Kremeike, Anne Pralong, Steffen Simon, Raymond Voltz: Guideline report of the expanded S3 guideline on palliative medicine for patients with incurable cancer. (PDF) Working Group of the Scientific Medical Societies in Germany (AWMF) eV, August 2019, accessed on November 20, 2019 (AWMF register number: 128/001-OL).
  13. ^ V. Andresen, P. Enck, T. Frieling, A. Herold, P. Ilgenstein: S2k guidelines for chronic constipation: definition, pathophysiology, diagnostics and therapy . In: Journal of Gastroenterology . tape 51 , no. 7 , July 9, 2013, ISSN  0044-2771 , p. 651-672 , doi : 10.1055 / s-0033-1335808 .
  14. ↑ Eugene R. Viscusi: Clinical Overview and Considerations for the management of opioid-induced constipation in Patients With Chronic noncancer pain: . In: The Clinical Journal of Pain . tape 35 , no. 2 , February 2019, ISSN  0749-8047 , p. 174-188 , doi : 10.1097 / AJP.0000000000000662 (English).
  15. ↑ a b Adam D Farmer, Asbjørn M Drewes, Giuseppe Chiarioni, Roberto De Giorgio, Tony O'Brien: Pathophysiology and management of opioid-induced constipation: European expert consensus statement . In: United European Gastroenterology Journal . tape 7 , no. 1 , February 2019, ISSN  2050-6406 , p. 7–20 , doi : 10.1177 / 2050640618818305 , PMID 30788113 , PMC 6374852 (free full text) - (English).
  16. ↑ Winfried Meissner, Petra Leyendecker, Stefan Mueller-Lissner, Joachim Nadstawek, Michael Hopp: A randomized controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation . In: European Journal of Pain . tape 13 , no. 1 , January 2009, p. 56-64 , doi : 10.1016 / j.ejpain.2008.06.012 (English).
  17. ↑ Sam H Ahmedzai, Friedemann Nauck, Gil Bar-Sela, Björn Bosse, Petra Leyendecker: A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone / naloxone prolonged- release tablets in patients with moderate / severe, chronic cancer pain . In: Palliative Medicine . tape 26 , no. 1 , January 2012, ISSN  0269-2163 , p. 50-60 , doi : 10.1177 / 0269216311418869 , PMID 21937568 , PMC 3255516 (free full text) - (English).
  18. ↑ New drugs: Naldemedine (Rizmoic) , drug regulation in practice, June 22, 2020 (PDF) .