Startseite Opioids and the gut; not only constipation and laxatives
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Opioids and the gut; not only constipation and laxatives

  • Asbjørn Mohr Drewes EMAIL logo
Veröffentlicht/Copyright: 1. April 2017
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Scandinavian Journal of Pain
Aus der Zeitschrift Scandinavian Journal of Pain Band 15 Heft 1

In this issue of the Scandinavian Journal of Pain, Søndergard et al. studied the impact of opioid induced constipation (OIC) in the Danish population [1]. Due to the epidemiological design the authors could not study OIC as defined in the clinic, but rather used a surrogate based on the available information in different registers. It is therefore not surprising that the prevalence of OIC among opioid users is much lower (15% in non-cancer and 35% in cancer patients) than normally reported in the literature. For example was the prevalence of OIC (despite concomitant use of laxatives) reported to be as high 80% in a multinational, internet-based survey of 322 chronic opioid users [2]. As pointed out by Søndergaard et al. chronic constipation is also prevalent in the general population, varying depending on definition used, but most studies have estimated the prevalence to be around 15% [3]. This will invariable also bias the prevalence estimates of OIC. Despite the limitations, the study by Søndergaard et al. has several interesting findings such as the relationship between OIC and demographics and co-morbidities [1]. Furthermore, the authors documented that patients with OIC have increased healthcare utilization and costs, a finding that supports previous studies in this area [4].

1 The spectrum of opioid induced side effects

The increased focus on side effects to opioid analgesics is important for the treatment of patients with pain. Opioids are the mainstay in treatment of severe pain, but previous studies may not have used the most optimal outcome variables. For example, pain intensity has traditionally been primary outcome. Chronic pain is, however, not only a matter of intensity, but rather a composite feeling of different sensory, affective, and cognitive components. When treatment of pain is evaluated, these different variables should therefore be taken into consideration. Furthermore, most treatments are followed by different side effects and this should be considered as well. Combined outcome measures such as “utility functions” where the balance between effects and side effects are computed may be a more true outcome measure of effect in clinical practice [5]. Therefore, estimation and quantification of side effects is a sine qua non in future research. Opioid treatment may result in many symptoms including nausea, headache, confusion and gastrointestinal-related symptoms [6]. OIC is such a side effect, but as the gut has opioid receptors from the oesophagus to rectum it is only one of many symptoms collectively referred to as opioid-induced bowel dysfunction (OIBD). Opioids affect the gut in different ways. First of all motility is compromised as opioids lead to increased tone of the intestines, slowing of the antegrade motility and dis-coordination of the normal propulsive movements. Opioids also decrease secretion of fluids and increase water absorption leading to dry faeces. As motility is in part dependent of a normal faecal volume that initiates intrinsic reflexes, this further reduces motility and complicates defecation due to the dry and less viscous faeces. Finally, sphincter function is also compromised as opioids increase the tone of smooth muscles. This will potentially also affect the internal anal sphincter and render defecation difficult [7].These different effects lead to symptoms such asgastrooesophageal reflux, vomiting, bloating, abdominal pain, anorexia, hard stools, constipation, and incomplete evacuation. These symptoms can be severe and as consequence it is not uncommon for patients to discontinue treatment, which naturally results in inadequate pain management.

2 Treatment of all symptoms of opioid induced bowel dysfunction with PAMORAs

It is mandatory that the pain clinicians are aware of OIBD and not only ask about constipation, but consider the whole spectrum of symptoms. There are no good studies that have explored the prevalence of OIBD in large cohorts of patient, partly as there are no validated questionnaires that consider all the symptoms. Therefore, most surveys have investigated the prevalence of constipation using bowel movements as key outcome variable even though number of bowel movements only ranks number 5 in a list of the most troublesome symptoms in constipation. Hence, symptoms such as straining, gas, hard consistency of stools, and abdominal discomfort may be more important for the patient [8]. Even though the study by Søndergaard et al. used data from Danish national health registries this is likely biased in the same way [1]. It is, however, important to consider the whole spectrum of disease, as treatment depends on which part of the gut that is mainly affected. OIC can often be alleviated with standard laxatives, but when symptoms are more widespread throughout the gut, the effect of laxatives is often limited as standardized laxative treatment mainly targets the colon. When treatment with laxatives fails, opioid rotation and patch formulations may in some cases improve the balance between analgesia and OIBD. New drugs such as the chloride channel activators lubiprostone and prucalopride, that alters colonic motility via serotonin 5-HT4 receptors, may also be used. Drugs with dual effects on the opioid receptors and noradrenaline reuptake inhibition such as tapentadol can also be used in difficult cases [7,9]. The most promising drugs to treat OIBD, however, are those where the local effects of opioids on the gut is selectively blocked.

Methylnaltrexone-bromide is a derivative of the opioid antagonist naltrexone with a methyl group that restricts its effects to the periphery. Methylnaltrexone-bromide has been shown to relieve OIC and induce laxation [10], and was the first peripherally acting μ-opioid receptor antagonist (PAMORA) to be approved for the treatment of OIC. However, it has until now only been available in subcutaneous formulation. Recent trial of higher oral doses of methylnaltrexone appear to make oral administration as effective as parenteral administration [11]. Alvimopan is another oral peripherally acting μ-opioid receptor antagonist, but due to cardiovascular safety concerns its use is restricted and it is only registered in USA [12]. Another approach has been an oral prolonged release formulation of oxycodone and naloxone combined in a 2:1 ratio. Due to the low bioavailability (<2%) of the prolonged release naloxone there is an analgesic efficacy as well as improvement in OIBD-related symptoms [13]. Finally, naloxegol is a PEGylated naloxone molecule that restricts its functions to the periphery with the key advantage that it can be added to a patient’s existing opioid therapy and thereby also allows for opioid rotation. It has proven efficacious compared to placebo on a number of different outcome measures [14] .

3 Cost of opioid induced side effects on the gut

Some papers have estimated the costs of pain for society, and for example a Swedish study approximated the cost of patients where pain was part of the diagnosis to 32 billion Euro per year [15], although the cost drivers are dependent on which opioids are selected and how they are used [5]. On the other hand there are only few studies that have looked at the costs of OIC. As pointed out by Søndergaard et al. OIC this may add up to 30% of the total costs for patients in opioid therapy [1]. Considering the high prevalence of OIC this may not only be a major burden for the patient, but also for society. It is therefore of outmost importance that clinicians treating pain patients are aware of OIC and OIBD, and that they consider the different treatment options that are available – and take action accordingly!

4 Conclusions and implications

Opioid induced effects on the gut are prevalent, but can normally be treated well if physicians follow the guidelines as recently outlined in, e.g. [7,9]. However, as patients, who are treated with opioids often have a significant burden of co-morbidity in addition to their pain condition, treating opioid-induced bowel dysfunctions may in many cases be rather complex, especially in patients with a pre-existing disease of the gastrointestinal tract. Such complex pain patients will invariably need a multidisciplinary approach where gastroenterologists and pain physicians work together with other specialists.

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2017.01.006.

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  1. Conflict of interest: AMD has received unrestricted funds for research and speaker fees from Mundipharma, AstraZeneca and Kyowa Kirin.

References

[1] Søndergaard J, Nordahl-Christensen H, Ibsen R, Ejg Jarbøl D, Kjellberg J. Healthcare resource use and costs of opioid-induced constipation among non-cancer and cancer patients on opioid therapy: a nationwide register-based cohort study in Denmark. Scand J Pain 2017;15:83–90.Suche in Google Scholar

[2] Bell TJ, Panchal SJ, Miaskowski C, Miaskowski C, Bolge SC, Milanova T, Williamson R. 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.Suche in Google Scholar

[3] Poulsen JL, Brock C, Olesen AE, Nilsson M, Drewes AM. Evolving paradigms in the treatment of opioid-induced bowel dysfunction. Ther Adv Gastroenterol 2015;8:360–72.Suche in Google Scholar

[4] Dunlop W, Uhl R, Khan I, Taylor A, Barton G. Quality of life benefits and cost impact of prolonged release oxycodone/naloxone versus prolonged release oxycodone in patients with moderate-to-severe non-malignant pain and opioid-induced constipation: a UK cost-utility analysis. J Med Econ 2012;15:564–75.Suche in Google Scholar

[5] Drewes AM, Jensen RD, Nielsen LM, Droney J, Christrup LL, Arendt-Nielsen L, Riley J, Dahan A. Differences between opioids. Pharmacological, experimental, clinical and economical perspectives. Br J Clin Pharmacol 2013;75:60–78.Suche in Google Scholar

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[7] Drewes AM, Munkholm P, Simrén M, Breivik H, Kongsgaard UE, Hatlebakk JG, Agreus L, Christrup LL. Definition, diagnosis and treatment strategies for opioid-induced bowel dysfunction—recommendations of the Nordic Working Group. Scand J Pain 2016;11:111–22.Suche in Google Scholar

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[10] Thomas J. Opioid-induced bowel dysfunction. J Pain Symptom Man 2008;35:103–13.Suche in Google Scholar

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[14] Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. NEJM 2014;370:2387–96.Suche in Google Scholar

[15] Gustavsson A, Bjorkman J, Ljungcrantz C, Rhodin A, Rivano-Fischer M, Sjolund KF, Mannheimer C. Socio-economic burden of patients with a diagnosis related to chronic pain – register data of 840,000 Swedish patients. Eur J Pain 2012;16:289–99.Suche in Google Scholar
Published Online: 2017-04-01
Published in Print: 2017-04-01

© 2017 Scandinavian Association for the Study of Pain

Artikel in diesem Heft

  2. Scandinavian Journal of Pain
  3. Editorial comment
  4. Cardiovascular risk reduction as a population strategy for preventing pain?
  5. Observational study
  6. Diabetes mellitus and hyperlipidaemia as risk factors for frequent pain in the back, neck and/or shoulders/arms among adults in Stockholm 2006 to 2010 – Results from the Stockholm Public Health Cohort
  7. Editorial comment
  8. Exercising non-painful muscles can induce hypoalgesia in individuals with chronic pain
  9. Clinical pain research
  10. Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders
  11. Editorial comment
  12. Education of nurses and medical doctors is a sine qua non for improving pain management of hospitalized patients, but not enough
  13. Observational study
  14. Acute pain in the emergency department: Effect of an educational intervention
  15. Editorial comment
  16. Home training in sensorimotor discrimination reduces pain in complex regional pain syndrome (CRPS)
  17. Original experimental
  18. Pain reduction due to novel sensory-motor training in Complex Regional Pain Syndrome I – A pilot study
  19. Editorial comment
  20. How can pain management be improved in hospitalized patients?
  21. Original experimental
  22. Pain and pain management in hospitalized patients before and after an intervention
  23. Editorial comment
  24. Is musculoskeletal pain associated with work engagement?
  25. Clinical pain research
  26. Relationship of musculoskeletal pain and well-being at work – Does pain matter?
  27. Editorial comment
  28. Preoperative quantitative sensory testing (QST) predicting postoperative pain: Image or mirage?
  29. Systematic review
  30. Are preoperative experimental pain assessments correlated with clinical pain outcomes after surgery? A systematic review
  31. Editorial comment
  32. A possible biomarker of low back pain: 18F-FDeoxyGlucose uptake in PETscan and CT of the spinal cord
  33. Observational study
  34. Detection of nociceptive-related metabolic activity in the spinal cord of low back pain patients using 18F-FDG PET/CT
  35. Editorial comment
  36. Patients’ subjective acute pain rating scales (VAS, NRS) are fine; more elaborate evaluations needed for chronic pain, especially in the elderly and demented patients
  37. Clinical pain research
  38. How do medical students use and understand pain rating scales?
  39. Editorial comment
  40. Opioids and the gut; not only constipation and laxatives
  41. Observational study
  42. Healthcare resource use and costs of opioid-induced constipation among non-cancer and cancer patients on opioid therapy: A nationwide register-based cohort study in Denmark
  43. Editorial comment
  44. Relief of phantom limb pain using mirror therapy: A bit more optimism from retrospective analysis of two studies
  45. Clinical pain research
  46. Trajectory of phantom limb pain relief using mirror therapy: Retrospective analysis of two studies
  47. Editorial comment
  48. Qualitative pain research emphasizes that patients need true information and physicians and nurses need more knowledge of complex regional pain syndrome (CRPS)
  49. Clinical pain research
  50. Adolescents’ experience of complex persistent pain
  51. Editorial comment
  52. New knowledge reduces risk of damage to spinal cord from spinal haematoma after epidural- or spinal-analgesia and from spinal cord stimulator leads
  53. Review
  54. Neuraxial blocks and spinal haematoma: Review of 166 case reports published 1994–2015. Part 1: Demographics and risk-factors
  55. Review
  56. Neuraxial blocks and spinal haematoma: Review of 166 cases published 1994 – 2015. Part 2: diagnosis, treatment, and outcome
  57. Editorial comment
  58. CNS–mechanisms contribute to chronification of pain
  59. Topical review
  60. A neurobiologist’s attempt to understand persistent pain
  61. Editorial Comment
  62. The triumvirate of co-morbid chronic pain, depression, and cognitive impairment: Attacking this “chicken-and-egg” in novel ways
  63. Observational study
  64. Pain and major depressive disorder: Associations with cognitive impairment as measured by the THINC-integrated tool (THINC-it)
https://doi.org/10.1016/j.sjpain.2017.01.010

Artikel in diesem Heft

  2. Scandinavian Journal of Pain
  3. Editorial comment
  4. Cardiovascular risk reduction as a population strategy for preventing pain?
  5. Observational study
  6. Diabetes mellitus and hyperlipidaemia as risk factors for frequent pain in the back, neck and/or shoulders/arms among adults in Stockholm 2006 to 2010 – Results from the Stockholm Public Health Cohort
  7. Editorial comment
  8. Exercising non-painful muscles can induce hypoalgesia in individuals with chronic pain
  9. Clinical pain research
  10. Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders
  11. Editorial comment
  12. Education of nurses and medical doctors is a sine qua non for improving pain management of hospitalized patients, but not enough
  13. Observational study
  14. Acute pain in the emergency department: Effect of an educational intervention
  15. Editorial comment
  16. Home training in sensorimotor discrimination reduces pain in complex regional pain syndrome (CRPS)
  17. Original experimental
  18. Pain reduction due to novel sensory-motor training in Complex Regional Pain Syndrome I – A pilot study
  19. Editorial comment
  20. How can pain management be improved in hospitalized patients?
  21. Original experimental
  22. Pain and pain management in hospitalized patients before and after an intervention
  23. Editorial comment
  24. Is musculoskeletal pain associated with work engagement?
  25. Clinical pain research
  26. Relationship of musculoskeletal pain and well-being at work – Does pain matter?
  27. Editorial comment
  28. Preoperative quantitative sensory testing (QST) predicting postoperative pain: Image or mirage?
  29. Systematic review
  30. Are preoperative experimental pain assessments correlated with clinical pain outcomes after surgery? A systematic review
  31. Editorial comment
  32. A possible biomarker of low back pain: 18F-FDeoxyGlucose uptake in PETscan and CT of the spinal cord
  33. Observational study
  34. Detection of nociceptive-related metabolic activity in the spinal cord of low back pain patients using 18F-FDG PET/CT
  35. Editorial comment
  36. Patients’ subjective acute pain rating scales (VAS, NRS) are fine; more elaborate evaluations needed for chronic pain, especially in the elderly and demented patients
  37. Clinical pain research
  38. How do medical students use and understand pain rating scales?
  39. Editorial comment
  40. Opioids and the gut; not only constipation and laxatives
  41. Observational study
  42. Healthcare resource use and costs of opioid-induced constipation among non-cancer and cancer patients on opioid therapy: A nationwide register-based cohort study in Denmark
  43. Editorial comment
  44. Relief of phantom limb pain using mirror therapy: A bit more optimism from retrospective analysis of two studies
  45. Clinical pain research
  46. Trajectory of phantom limb pain relief using mirror therapy: Retrospective analysis of two studies
  47. Editorial comment
  48. Qualitative pain research emphasizes that patients need true information and physicians and nurses need more knowledge of complex regional pain syndrome (CRPS)
  49. Clinical pain research
  50. Adolescents’ experience of complex persistent pain
  51. Editorial comment
  52. New knowledge reduces risk of damage to spinal cord from spinal haematoma after epidural- or spinal-analgesia and from spinal cord stimulator leads
  53. Review
  54. Neuraxial blocks and spinal haematoma: Review of 166 case reports published 1994–2015. Part 1: Demographics and risk-factors
  55. Review
  56. Neuraxial blocks and spinal haematoma: Review of 166 cases published 1994 – 2015. Part 2: diagnosis, treatment, and outcome
  57. Editorial comment
  58. CNS–mechanisms contribute to chronification of pain
  59. Topical review
  60. A neurobiologist’s attempt to understand persistent pain
  61. Editorial Comment
  62. The triumvirate of co-morbid chronic pain, depression, and cognitive impairment: Attacking this “chicken-and-egg” in novel ways
  63. Observational study
  64. Pain and major depressive disorder: Associations with cognitive impairment as measured by the THINC-integrated tool (THINC-it)
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