1. Prim. mag. Marija Cesar Komar dr.med. 1st Congress of the Slovenian Association for Pain Therapy and Symposium on Clinical Neurophysiology of Pain Bled, 9-10 October 2009 OPIOID-INDUCED CONSTIPATION IN PALLIATIVE CARE AND NEW TREATMENT OPTIONS

2. Causes of opioid-induced constipation  Opioids: agonists of mu-receptors, desired analgesic effect  Mu-receptors: in CNS, on periphery and in GI tract  Opioid binding on mu-receptors in GIT: decreased propulsion, decreased peristalsis, decreased intestinal secretions, increased water absorption...  Constipation - dependent of opioid dose and opioid type: very unpleasant, stressful adverse event  Prevalence up to 90 % - in oncology patients and other advanced chronic diseases which require palliative care and opioid therapy  A number of different causes: inactivity, unsufficient fluid intake, bad nutrition-not enough fibres, metabolic and endocrine changes, sedation, depression, neurological dissorders...  Constipation is often resistant to usual standard laxatives

3. Persistent constipation:  strongly worsens QoL  interferes with efficient pain therapy (need for lowering effective doses, rotation and change of opioids)  hospitalizations  increase of health care costs  stress and troubles – for patient and families, as well as for doctors and nurses Opioid-induced constipation– few considerations

7. Ideal new treatment option?  targeted effect  mu-receptor antagonist  effective only in GIT  analgesic effect of opioids must remain unaffected  good profile of undesired effects and drug interactions

9. 1)Thomas J. et al., 2008 – placebo controled, multicentric, double-blind, randomized study; 133 patients – methylnaltrexone for opioid-induced constipation in advanced illness Thomas, J. et al. 2008. Methylnaltrexone for Opioid-Induced Constipation in Advanced Illness. The New England Journal of Medicine 358(22):2332-2343. 2)Slatkin N. et al., 2009 – single dose, multicentric, double- blind, randomized study; Advanced illness and opioid therapy, 154 patients Slatkin, N. et al., 2009. Methylnaltrexone for Treatment of Opioid-Induced Constipation in Advanced Illness Patients. The Journal of Supportive Oncology 7(1):39–46. RELISTOR – main clinical studies

10. RELISTOR – clinical studies results Thomas, J. et al. 2008. Methylnaltrexone for Opioid-Induced Constipation in Advanced Illness. NEJM 358(22):2332-2343. Slatkin, N. et al., 2009. Methylnaltrexone for Treatment of Opioid-Induced Constipation in Advanced Illness Patients. J Support Oncol 7(1):39–46. RELISTOR – SmPC

11. RELISTOR – indicated for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient  RELISTOR is available in single-use vials for subcutaneous injection (upper arm, abdomen or thigh). It is added to usual laxatives therapy.  The most common adverse reactions with RELISTOR in clinical trials were abdominal pain, flatulence, and nausea (in placebo-controlled trials, the discontinuation rate due to AE was 1.2% for RELISTOR and 2.4% for placebo).  No dose adjustment required in elderly patients. No dose adjustment required in patients with mild or moderate renal or hepatic impairment. Dose lowering is recommended in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

12. PRECAUTIONS (1) RELISTOR is effective ONLY if opioids are the reason of constipation! (2) RELISTOR is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction or acute abdomen! (3) RELISTOR may work within a few minutes to a few hours of the injection. Therefore, it is important to be near toilet facilities soon after receiving your dose with assistanceavailable if necessary.

13. Probing for suspected constipation

14. Clinical practice recommendations for prophylaxis, ongoing assessment and treatment of constipation in palliative care

15. Clinical practice recommendations for management of opioid-induced constipation in palliative care Larkin, P., 2009. Clinical practice recommendations for the management of constipation in palliative care: what do they mean for opioid-induced constipation?European Journal of Palliative Care, Supplement: 1-8.