Do Diuretics have Antinociceptive Actions: Studies of Spironolactone, Eplerenone, Furosemide and Chlorothiazide, Individually and with Oxycodone and Morphine

Abstract

Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co-administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)-and morphine (3 mg/kg, s.c.)-induced antinociception using tail-flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system. Strong opioids are an established choice for moderate to severe acute and cancer pain [1]. Spironolactone, eplerenone, furosemide and chlorothiazide are diuretics used to treat hypertension and heart failure. Recently, these drugs have also become of interest in the treatment of pain. Spironolactone [2,3] and eplerenone [4,5] have been shown to have antinociceptive effects in experimental neuropathic and back pain in the rat. Furosemide has been shown to reduce nociceptive behaviour in experimental inflammatory pain in the rat [6] and chlorothiazide [7] has been shown to have a weak thermal antinociceptive effect of its own. In addition, spironolactone [8], chlorothiazide [7] and furosemide [9] have been suggested to potentiate the antinociceptive effect of morphine in the rat.Spironolactone and eplerenone are both mineralocorticoid receptor (MR) antagonists. The antagonism of MR has been suggested to reduce pain via gene transcription in the model of back pain [5]. MR receptors also participate in synaptic transmission in hippocampus, amygdala and prefrontal cortex [10], which could contribute in antinociception in other pain models.Diuretics and opioids are both commonly used drugs and they can be co-administered to manage acute heart failure or malignant ascites. For example, patients suffering from malignant ascites use high doses of spironolactone, up to 400 mg/day [11]. Drug interactions ...

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