Mirtazapine: A Drug with Many Palliative Uses #314

Abstract

P atients referred to palliative care services often have between three and seven distressing symptoms and may require multiple medications for effective symptom reduction. 1 Due to its effects on multiple receptors, mirtazapine has the potential to target several common symptoms in serious illness with one medication. This Fast Fact provides an overview of the pharmacology and potential uses of mirtazapine in palliative care beyond its FDA indication as an antidepressant. PharmacologyMirtazapine is a tetracyclic antidepressant that antagonizes noradrenergic, histamine (H1), 5-HT2, and 5-HT3 receptors, thereby enhancing central norepinephrine and serotonergic transmission. 2,3 It has a relatively high oral bioavailability (50%) for its medication class. It is absorbed relatively quickly reaching peak plasma concentrations within two hours and its absorption is not affected by food. 3,4 The half-life is long and variable, between 20 and 40 hours, with the longest half-lives seen in elderly women. Consequently, steady-state levels of the medication may not be achieved for a week. 4 Dose reductions are necessary in liver and renal failure, as it is metabolized in the liver mainly by the cytochrome (CYP) P450 isoenzymes and >75% is excreted in the urine. 2,3 Utility in Symptom Management Mood DisordersMirtazapine has been shown to be effective in moderatesevere major depression in short-term and long-term (up to 72 weeks) studies of otherwise healthy adults. 8 It is not considered to be any more or less effective than other modern antidepressants, although it may have a faster onset of antidepressant action with reductions in affective symptoms described in just one to two weeks. 9 Refer to Fast Fact #309 for more information on pharmacotherapy for depression. PruritusIn case reports, mirtazapine has been shown to be effective for chronic pruritus related to inflammatory skin disease, cancer, cholestasis, and renal failure at doses of 15-30 mg/day. 5,6 AnorexiaMirtazapine is associated with short-and long-term weight gain in otherwise healthy depressed children and adults likely due to appetite stimulation through effects on H1 and 5-HT2 receptors. 7,8 This has led to an interest in using mirtazapine for anorexia related to cancer and other advanced illnesses. No well-designed studies have confirmed mirtazapine's effectiveness for this indication. A small open-label study demonstrated weight gain of >1 kg after four weeks of therapy in only 4 of 17 (24%) cancer patients. Secondary endpoints of improvements in appetite and health-related quality of life (QOL) were noted in only 24% and 6% of patients, respectively. 10

Nausea and Vomiting Not Related to Cancer Therapy: Intractable Problem or Clinical Challenge?

“…Prices from goodrx.com . Information from Allen et al, 2016 ; Collis & Mather, 2015 ; Digges et al, 2018 ; Harder et al, 2019b ; Hendren et al, 2015 ; Hernandez et al, 2015 ; Jaward et al, 2019 ; Kaneishi et al, 2016 ; Khanna et al, 2019 ; Khoo & Quinlan, 2016 ; Langley-DeGroot et al, 2015 ; Lovell et al, 2018 ; MacKintosh, 2016 ; Prohotsky et al, 2014 ; Prommer, 2012 ; Riordan et al, 2019 ; van der Meer et al, 2014 ; Wiebe, 2012 . …”

“…Medical records were reviewed, and there was documented improvement in nausea, sleep, pain, and appetite (37.0%, 37.7%, 36.4%, and 23.5%, respectively) in mirtazapine-treated patients. These may have been underestimates of symptom improvement, because 229 patients had no follow-up documentation and were counted as “no improvement.” Antidepressant effects are not seen for weeks, but gastric stasis, anorexia, chronic pruritus, dyspnea, and anxiety with advanced lung disease may improve with the first dose ( Cangemi & Kuo, 2019 ; Khanna, Boozalis, Belzberg, Zampella, & Kwatra, 2019 ; Khoo & Quinlan, 2016 ; Lovell, Bajwah, Maddocks, Wilcock, & Higginson, 2018 ). Mirtazapine has a long half-life (20–40 hours), so antiemetic doses (7.5 to 15 mg) are given at bedtime ( Khoo & Quinlan, 2016 ).…”