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Aims: The purpose of the present paper was to evaluate the effectiveness of mirtazapine orally disintegrating tablets for nausea and sleep disturbance, which are common and distressing symptoms of cancer.
Methods: This was a 4-week, prospective, open-labeled study of cancer patients. Assessments were performed at baseline and on days 1, 3, 5, 7, 14, and 28. Primary outcome measures were the Clinical Global Impression scale for nausea/vomiting and the Chonnam National University Hospital–Leeds Sleep Evaluation Questionnaire (C-LSEQ) including total amount of night sleep time. The secondary outcome measures consisted of pain items in the 36-item Short Form Health Survey, the Montgomery–Asberg Depression Rating Scale (MADRS), and the EuroQoL (EQ)-5D. Forty-two cancer patients were enrolled.
Results: Those with nausea (n = 28) improved significantly from day 1. The total night sleep time and each item on the C-LSEQ improved from days 1–5. The scores on the MADRS and the depression/anxiety dimension and visual analog scale of EQ-5D improved significantly from the first week. Pain measures also improved from day 1. Exacerbation of sleepiness developed in approximately one-third of subjects during the initial few days, but disappeared gradually.
Conclusion: In the present study mirtazapine rapidly improved nausea, sleep disturbance, pain and quality of life, as well as depression in cancer patients. Mirtazapine may be an effective treatment option in managing cancer patients with multiple distressing symptoms, including nausea and sleep disturbance.
NAUSEA, SLEEP DISTURBANCE, and depression are common and distressing symptoms in cancer patients,1 and the prevalence of depressive spectrum disorders in these patients is higher than in the general population, ranging up to 58%.2 Sleep disturbance has been reported to be one of the most frequent symptoms in cancer patients,1,3 and factors that are likely to precipitate sleep problems in these patients include not only psychiatric problems such as depression, anxiety, and emotional stress, but also pain and treatment side-effects such as nausea, vomiting, or urinary frequency.4
Selective serotonin re-uptake inhibitors (SSRI) and serotonin norepinephrine re-uptake inhibitors (SNRI) have been commonly used for the treatment of depression but they can induce sleep disturbance and nausea, associated with the pharmacologic stimulation of 5-HT2 and 5-HT3 receptors.5 Therefore, SSRI and SNRI are somewhat limited in their use for cancer patients who suffer from insomnia and nausea. In contrast, mirtazapine is a noradrenergic and specific serotonergic antidepressant with antagonistic effects on 5-HT2 and 5-HT3 receptors.6 Mirtazapine has been reported to be effective in controlling nausea and vomiting under various conditions7–10 and to facilitate sleep continuity.11 In addition, weight gain associated with increasing appetite, which is a common side-effect of mirtazapine, can be advantageous in patients with anorexia.
In clinical practice with cancer patients in consultation–liaison psychiatry, mirtazapine is often used as an antidepressant based on the aforementioned characteristics, but insufficient evidence exists to support its effectiveness in treating nausea, sleep disturbance, or depression in cancer patients. Specifically, to our knowledge, a study has not been performed with mirtazapine in a population of Asian cancer patients. We therefore evaluated the effectiveness of mirtazapine comprehensively on various cancer-related symptoms, including nausea and sleep disturbance.
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Mirtazapine has been recommended for use in cancer patients with nausea because of its unique characteristic of antagonizing 5-HT3 receptors, which is the same as that of ondansetron, a conventional anti-emetic frequently used in cancer patients.19 However, few data existed on the effectiveness of mirtazapine for nausea in cancer patients: a serial case report with positive results20 and a small open-label trial with negative results.21 In the present study mirtazapine was shown to be effective at improving nausea, and its effectiveness was greater for nausea related to chemotherapy than for that caused by other factors. Cautious interpretation is required because nausea induced by chemotherapy can be time-limited, usually persisting for approximately 7–10 days after chemotherapy. However, in the present study mirtazapine was immediately effective in ameliorating nausea, and in some patients the improvement was maintained at the next cycle of chemotherapy. These findings suggest that mirtazapine may be useful for controlling nausea or vomiting in cancer patients. Moreover, mirtazapine orally disintegrating tablets, which dissolve on the tongue, are helpful in patients who become nauseous when swallowing. In addition, mirtazapine, which is a potent blocker of the histamine H1 receptor and a 5-HT2C antagonist, also has potential as an appetite stimulant.
Few data are available concerning the effectiveness of mirtazapine for sleep disturbance in cancer patients.22 Our results suggest that mirtazapine may have an effect on sleep quality, as well as sleep quantity, in cancer patients. The mechanism of mirtazapine for promoting sleep seems to be related to its antihistaminic, α-adrenolytic, and 5-HT2 antagonistic actions.6 Compared to benzodiazepines, which are commonly used to induce sleep, mirtazapine does not have the potential for dependence, respiratory suppression, or disturbance of deep-stage sleep.
Mirtazapine exacerbated sleepiness in more than one-third of the present patients during the initial few days, and two patients were not able to tolerate mirtazapine due to excessive sedation. Among items on the C-LSEQ, ease of waking improved last. However, sleepiness was not caused by mirtazapine alone. Sleepiness was reported in nearly half of the present subjects, even before starting mirtazapine. This sleepiness was assumed to be related to the poor quality of night-time sleep, physical condition, and other medication used, including opiates.23 Exacerbation of sleepiness by mirtazapine disappeared gradually. Moreover, mirtazapine ameliorated sleepiness in 60% of the subjects who suffered from it at baseline. Previous studies have also reported that daytime sedation by mirtazapine, which has a half-life of 20–40 h, is prominent during the first week of treatment but appears to diminish after a few days.24 Therefore, information about sleepiness related to the use of mirtazapine, which can develop initially but becomes tolerable within a few days, should be given to patients. In particular, the concomitant use of benzodiazepines with mirtazapine needs to be avoided to prevent over-sedation.25
Antidepressant agents have been used extensively to treat pain.26 Several studies have examined the effect of mirtazapine on pain under various conditions, such as tension headache, fibromyalgia, and chronic pain syndrome,27–29 but the effect of mirtazapine on cancer pain had not been sufficiently studied.21 In the present study the reduction in pain score, including pain magnitude and its interference with daily activities, was statistically significant from day 1. One of the reasons for rapid improvement in pain and pain behavior seemed to be an indirect result of an improvement in sleep and mood. Pain is usually exacerbated at night when sensory stimuli decrease, and depression worsens pain by lowering the pain threshold, while pain also can worsen sleep disturbance and depression.3,30–32 The correlation between pain reduction and improvement in the quality of sleep and depression was significant in the present study.
The mean dose of mirtazapine used in the present study was around 20 mg. However, previous studies performed in Western countries have reported a dosage of ≥30 mg in the treatment of cancer patients.20,25 The pharmacokinetic difference between Caucasian and Asian patients possibly contributed to a lower dose being used in the present study compared to past studies.33 Another study with mirtazapine performed on Korean alcoholic patients reported that low doses of mirtazapine (mean 23 mg/day) were effective.34 Moreover, the effective dose of mirtazapine for sleep disturbance and nausea has been reported to be relatively low (≤30 mg).7–11,24 Finally, the dosage used in the present study might have been influenced by the patients' physical condition because most had advanced cancer.
We acknowledge several limitations of the present study. A possibility exists that the placebo effect influenced the results because this was not a controlled trial. The sample was relatively small in relation to the large number of outcome variables. Furthermore, some confounding factors were present, including concomitant medical treatments, which were not strictly controlled. However, strict prohibition of concomitant medication in patients with advanced cancer would have produced ethical conflicts. To avoid confounding effects, we tried not to increase or add anti-emetics, hypnotics, or analgesics, and in the analysis did not include symptom measures that were taken after commencing or altering the dosages of these drugs. In addition, the dropout rate was high. The physical status of the subjects and the study design requiring frequent assessment seemed to influence the dropout rate. It was difficult to follow up patients with advanced-stage cancer who were discharged from the oncology unit or transferred to another hospital for supportive care. To overcome this limitation, measurements in subjects who dropped out were analyzed using end-point analysis. Although the follow-up period was relatively short for the evaluation of depression, we performed more frequent assessments than previous studies on changes in sleep and nausea, which were primary outcomes of the study. This was one of the strengths of the present study. Finally, all of the present subjects were depressed; therefore, the improvement in nausea, anorexia, insomnia, and pain might have been related to an improvement in depression. Further research is warranted, and studies that include non-depressed patients using a randomized controlled design in a large sample, while focusing on specific symptoms, are needed.
In the present study, nausea, anorexia, sleep disturbance, pain, depression, and quality of life rapidly improved in cancer patients with the use of mirtazapine. The present results suggest that mirtazapine may be an effective treatment option for managing cancer patients with multiple distressing symptoms. A controlled trial is needed to confirm the study results.