Methylnaltrexone used in opioid-induced urinary retention. Two cases report. Authors: Malagón Solana B.1, Perpiñá Fortea C.2, Ortega Morell A.3, Romero Sánchez E.1, Garcia Garcia J.4, Díaz Vivas E.5

Institutes:1.- Servicio Andaluz de Salud, Unidad Docente de Medicina Familiar y Comunitaria de Málaga, Torre del Mar, Spain2.- Servicio Andaluz de Salud, Medicina Familiar y Comunitaria, Torre del Mar, Spain3.- Servicio Andaluz de Salud, Equipo de Soporte de Cuidados Paliativos, Antequera, Spain4.- Servicio Andaluz de Salud, Equipo de Soporte de Cuidados Paliativos, Granada, Spain5.- Boots Pharmacy & Health, Pharmacy, Macclesfield, United Kingdom

INTRODUCTION: In April 2008, the FDA approved methylnaltrexone (Relistor) as the first peripheral micro-opioid-receptor antagonist for the treatment of opioid-induced constipation in advanced-illness patients receiving palliative care. and for whom other laxative therapies failed to achieve adequate results. Methylnaltrexone, a quaternary derivative of naltrexone, introduces a novel mechanism of action that selectively antagonizes the peripheral micro-receptors in the GI tract without affecting the Central Nervous System. Clinical and laboratory studies performed during the development of these drugs have indicated that peripheral receptors mediate other opioid effects, including decreased gastric emptying, nausea and vomiting, pruritus, and urinary retention. Methylnaltrexone's mechanism of action suggests it could be beneficial for other peripheral, opioid-induced adverse effects, such as opioid-related nausea, vomiting, urinary retention, pruritus or postoperative ileus.

FIRST CASE: Male patient, 67 years old, with the following medical history: hypertension, nephrosclerosis and chronic kidney desease IV, Hyperlipoproteinemia, sensorimotor polyneurophaty ; ex-smoker; ex-heavy drinker. No prostate problems.Standard Treatment: clopidogrel, duloxetin, folic acid, omeprazole, oxcarbazepine, paracetamol, chlorpromazine, lecardipino, furosemide, valsartan, lactitol ,paracalcitol, B12 supplementation.Lung cancer diagnosed in December 2009; no chemotherapy nor radiotherapy possible because of a big left hilium mass ( 6 x 5 cm ) involving a pulmonary aortic window and invading the mediastinum in the left paratracheal space. The SUV ( standar uptake value ) is 28.60, which suggests bronchogenic carcinoma. Also bone lesions in vertebral body, brain metastases and chronic lacunar stroke in right corona radiate. Both patient and family refused continuation of the study and opted for Palliative Care. The Palliative Care Support Team (PCST) contacted the patient in January 2010.The target clinical manifestations were dry cough and dyspnea. PCST started with codeine 30 mgr q.d.s and laxative as required. An antiemetic was prescribed too.Codeine got control of the cough and dyspnea, but the patient discontinued medication (first time) because with the increase in codeine dosage urinary retention and constipation appeared. At that time, cough and dyspnea went worst, but urinary retention and constipation disappeared. The patient told us he could manage the constipation but not the urinary retention. PCST suggested morphine 10 mgr b.d and an increase to 25-50% every 24- 48 hours if needed. The PCST made sure the patient had access to immediate release morphine for breakthrough cough, dyspnea or pain, and explained to patient how important was to increase the medication as needed in order to obtain good control of cough and dyspnea. The PCST intensified the laxatives used (a combination); dietary and care measures were also implemented on the patient. This symptoms (cough and dyspnea ) began to improve, but there was a sudden occurrence of vertebral pain and left chest wall pain (increased if touched or pressed), headache, haemoptysis, bronchorrhoea and dysphagia. The PCST added dexametasone, hyoscine butylbromide, paracetamol, tranexamic acid, and immediate release liquid morphine. Unfortunately urinary retention appeared again and the patient decided to stop the treatment one more time (2º time). The PCST had tested if any prostate or bladder organic pathology was involved and at point stage offered the use of a urinary catheter. Patient refused and although he perceived the medication was effective in the control of cough and dyspnea, he refused to take a catheter.The PCST proposed then subcutaneous Methylnaltrexone, which finally relieved the urinary retention. There was the need for one dosis (12 mgr) every 48 hours for a week until the symptoms were reasonably well controlled and didn´t need for an increase in morphine administration. The Patient did not have any bladder nor urinary problem if morphine delivery was not rapidly increased. The patient died on March 2010 (3 months later) at home and with sedation pump because of the refractory dyspnea, and with a vesical catheter to cope with resumed urinary retention (reason was the rapid risings in morphine in order to control the dyspnea).

SECOND CASE: Male, 54 years old, no previous deseases. No prostate nor bladder problems. Esophagogastric Junction cancer was diagnosed in September 2008. Metastases in liver, lung and retroperitoneum were found. The treatment was surgical resection ( distal esophaguectomy + gasthrecthomy + resection of liver metastase ) and chemotherapy + liver radioembolisatiom. Palliative Chemotherapy since abril 2010 and died in July 2010. Treatment: fentanyl patch; immediate-release (IR) fentanyl oral tablets used to treat breakthrough pain; clorazepateçç dipotassium; spironolactone; furosemide; dexamethasone; domperidone; paracetamol, lactulose, omeprazole, pregabalin, morphine clorohydratheçç, modified morphine release tablets 12 h.The most important symptom was always the pain (epigastric and abdominal pain) and the patient needed frequent increases of the dosis of stronger opioids for pain control. Every time opioid dosage increased, constipation and urinary retention reappeared. Even if the constipation could be managed with laxatives, urinary retention would only be relieved with Methylnaltrexone.

CONCLUSION: Urinary retention is a very important peripheral opioid-induced adverse effect because of the complications associated to it (urinary infection, hydronephrosis and post renal failure; laxative refractory constipation; agitation, confusion; post-catheterization diuresis). Maybe we underestimated the real frequency in our patients because those presenting with retention often have a prior history of urological disorders or risk factors for the retention of drugs ( such as opioids, anticholinergics) , constipation, poor mobility, etc . We needed to detect when the urinary retention was caused to to opioids use, and which would be the reason for its occurrence (if there were any factors involved regarding management, titration, dosage, type of opioids chosen, etc). The use of methylnaltrexone to relieve this symptom could be beneficial, and there is the need for further studies along this line.