Perioperative psychological distress is associated with preoperative anxiety, depression, and postoperative pain. Mirtazapine is effective as an antidepressant, anxiolytic agent, and sleep enhancer. Moreover, mirtazapine can be made as orodispersible tablets with a fast onset for patients in nil per os status. This study is to determine whether mirtazapine can help psychologically distressed patients reduce perioperative anxiety, depression, and postoperative pain.
Materials and methods
Patients with preoperative psychological distress, undergoing major abdominal surgery, were inquired and assigned to two groups according to their own choice. In the treatment group, patients could choose to take orodispersible mirtazapine 30 mg at each night from Preoperative Day 0 to Postoperative Day 3. There was no other intervention in the nontreatment group. Hospital Anxiety and Depression Scale (HADS), Athens Insomnia Scale (AIS), and pain scores were accessed on the day before
From September 2007 to December 2008, 86 patients agreed to be enrolled and 79 of them completed the study. Propensity scores and multivariate analysis showed that mirtazapine reduced HADS scores of patients in 2 days. Trial results indicated that mirtazapine lowered the AIS day index and tended to decrease night index as well. Mirtazapine may reduce patients' morphine consumption, but this effect was not statistically significant (p = 0.2).
Mirtazapine helps reduce anxiety, depression, and insomnia scores for patients with perioperative psychological distress.
antidepressantinsomniamirtazapineperioperative anxietyperioperative depression;
Patients struggle with anticipation of postoperative pain, separation from family, incapacitation, loss of independence, and fear of surgery and death, which are triggers of anxiety throughout the perioperative period. Psychological distress is a broad array of psychological symptoms including depression, poor coping skills, anxiety, and somatization.1 According to previous studies, the incidence of preoperative anxiety is between 60% and 92% in unselective surgical types.2 Anxiety increases in the distress experienced by patients and leads to higher intraoperative anesthetic requirement, which makes management of postoperative pain difficult and also produces a lower level of patient satisfaction.3 In some susceptible patients, moderate to severe depressive symptoms may occur simultaneously, and identified depressive symptoms are significant predictors of anxiety. Feeling of depression can lead to transient suppression of immune function, increase postoperative complications, and increase acute infections.3 Adequate management of anxiety may facilitate smoother induction and even a better outcome of surgery.4 Yet, in our clinical practice, perioperative caregivers usually focus on advanced surgical techniques and intensive care rather than on the quality of life of perioperative patients or those with symptoms of preop psychological distress.
In present clinical practice, benzodiazepine is the most widely used premedication for patients with anxiety,5 but there is no evidence that it can attenuate patients' psychological distress (i.e., anxiety and depression) in the perioperative period. Therefore, we attempt to find a drug that possesses anxiolytic, antidepressant, sleep-promoting, and pain-reducing effects for patients with perioperative psychological distress. This needs to be effective without affecting perioperative vital signs, in order to eliminate their discomfort during perioperative period and hopefully to improve short- and long-term outcomes.
Mirtazapine is a unique antidepressant that can be formulated as orodispersible tablets for patients in nil per os status or those with difficulty swallowing conditions. It is the only member of the noradrenergic and specific serotonergic antidepressant class. Mirtazapine blocks central α2 auto- and heteroreceptors, and it also antagonizes several subtypes of serotonin (5-HT) receptors, such as 5-HT2 and 5-HT3 receptors. The overall effects of the drug are antidepressant, anxiolytic, and sleep-enhancing effects.6 In clinical use, mirtazapine has potential beneficial effects in the treatment of patients with pain and concomitant depression. Mirtazapine also improves the quality of life of advanced cancer patients with multiple distressing symptoms,7, 8, 9and has been proved to enhance sleep quality in cancer patients and patients with chronic pain combined with sleep disturbance.10 Moreover, Chen et al4found that a 30 mg tablet of mirtazapine ingested 1 hour before surgery reduced preoperative anxiety as well as the incidence of late postoperative nausea and vomiting. It seems that mirtazapine's unique properties meet the need of patients with perioperative psychological distress and may improve their life quality in the perioperative period.
The aim of our study is to prove that the perioperative use of oral disintegrating mirtazapine (30 mg/tablet) can decrease the degree of anxiety and depression, improve sleep quality, and reduce postoperative pain and morphine consumption in patients with perioperative psychological distress.
2.1. Study design
This study was approved by the Institutional Review Board of National Taiwan University Hospital. It was an open-labeled, quasiexperimental clinical follow-up study conducted in a single medical center. Participants were recruited from those who received major abdominal surgery, including subtotal gastrectomy, hepatectomy, open cholecystectomy, Whipple's operation, hemicolectomy, and anterior resection colectomy. The treatment period is from 1 day before the operation (Day 0) until 2 days after the operation (Day 3). Patients would be discharged on Day 4. Thus, the total treatment period was 4 days and the outcome assessments were performed according to the schedule described in the following subsection.
Being able to sign the consent form
Females of childbearing potential willingly using effective birth control
Receiving upper or lower abdominal operation under general anesthesia in the American Society of Anesthesiologists Physical Status classification system (ASA) I, II, and III confirmed by an anesthesiologist
Brief Symptom Rating Scale (BSRS-5) total score of ≥6
Between 18 years and 65 years old
Physical examination and brief neurological examination showing clinically significant abnormal findings
Significant abnormal laboratory findings during screening
BSRS-5 total score of <5
A history of psychiatric disorder (except depression and anxiety)
A history of epilepsy or seizures
Alcohol or substance abuse categorized by the Diagnostic and Statistical Manual of Mental Disorders, 4th. Edition (DSM-IV) during the last 6 months prior to baseline
Any unstable chronic physical disease
Actual risk of committing suicide according to the investigator
Participation in other clinical trials in the last 30 days
Eligible patients were approached the day before the surgery (Day 0). Preanesthesia evaluation was completed by the same anesthesiologist. Patients were asked if they agreed to use patient-controlled analgesia (PCA) postoperatively. Those patients were then visited by our study members. Upon their agreement, the patients were asked to complete BSRS-5. If the BSRS-5 total score was ≥6, the patient was considered to have “preoperative psychological distress.” After a detailed and complete verbal explanation of the study was provided, those patients were free to sign the informed consents. Baseline data on age, gender, weight, height, ASA classification, receiving cancer surgery or not, and postoperative use of PCA were recorded.
Then, these participants could choose to be in the treatment or nontreatment group: patients of the treatment group received mirtazapine (Remeron) 30 mg before sleep from the day before surgery until 2 days after the surgery (from Day 0 to Day 3). On each day of this study period, patients in the treatment group could decide on their own to take mirtazapine or not. Patients in the nontreatment group received no drug therapy. During this the period, all participants were not allowed to receive any other tranquilizers. All participants completed questionnaires of Hospital Anxiety and Depression Scale (HADS) and Athens Insomnia Scale (AIS) in the afternoon of Day 0 and the mornings of Days 2 and 4. Numeric pain score was accessed by a trained nurse 1 hour after the surgery and in the morning of Days 2–4. The amounts of morphine consumption of PCA were recorded daily. The degree of nausea/vomiting, side effects of mirtazapine, and/or the reason why patients did not take mirtazapine were also recorded.
All patients received endotracheal intubation general anesthesia with standard intraoperative care (including electrocardiogram, arterial blood pressure, and pulse oximetry). Patients' vital signs were maintained within 20% of baseline. Intraoperative inhalation gas concentrations were kept around 1.0–1.3 minimum alveolar concentration, and fentanyl was given according to patients' vital signs of pain or surgical stimulation (e.g., increasing heart rate or blood pressure intraoperatively).
2.4. Assessment of investigational treatment
2.4.1. Brief Symptom Rating Scale
The five-item BSRS-5 is a screening instrument developed to screen psychiatric illnesses in nonpsychiatric health settings.11 The total score ranges from 0 to 20, and the best cutoff point determined for psychiatric disorder is 6+.12
2.4.2. Hospital Anxiety and Depression Scale
This is a self-screening questionnaire for depression and anxiety consisting of 14 questions, seven for anxiety and seven for depression, with each question being rated from 0 to 3. Higher scores of HADS indicate higher anxiety and depression levels; HADS scores can predict psychosocial and possibly physical outcome.13
2.4.3. Athens Insomnia Scale
It is a self-assessment psychometric instrument designed for quantifying sleep difficulty based on the International Classification of Diseases 10th Revision (ICD-10) criteria. It consists of eight items, including pertaining to sleep induction, awakenings during the night, final awakening, total sleep duration, sleep quality, well-being, functioning capacity, and sleepiness during the day. All items are rated from 0 to 3. The high measures of consistency, reliability, and validity of the AIS make it an invaluable tool in sleep research and clinical practice.14, 15
2.4.4. Pain score (Numerical Rating Scale)
Pain intensity is scored on a 0–10 scale by patients themselves. A score of 0 indicated no pain at all and a score of 10 the worst pain imaginable. A score of >7 points is considered as severe pain.
2.5. Statistical analysis
Statistical analyses were performed using the SAS statistical software (version 9.1.3; SAS Institute Inc., Cary, NC, USA). Two-sided p ≤ 0.05 was considered statistically significant. Background characteristics, scores of baseline assessments, operation time, and the dosage of intraoperative fentanyl of the two groups were compared by two-sample t test, two-sample Wilcoxon rank-sum test, Pearson chi-square test, or Fisher's exact test, as appropriate. We used paired t test to compare daily HADS, AIS, and pain scores, and morphine consumptions within each group and two-sample t test between two groups.
Because participants of the treatment group could decide which group they would enroll into and choose daily whether to take mirtazapine or not, we used the propensity score method to adjust the self-selection bias. The propensity score of each patient for taking mirtazapine on Day t (t = 0, 1, 2, and 3) was the estimated probability of taking mirtazapine on Day t, conditioning on individual's covariate values. The propensity scores are estimated from our data by fitting four separate multiple logistic regression models to the mirtazapine usage, using a more liberal significant criterion of p < 0.2, on Day 0 and on each of the following 3 days as the dependent variables respectively. Specifically, for each patient of the treatment and nontreatment groups, propensity scores are generated on Day 0 by the background characteristics only, but on Days 1–3 by the background characteristics as well as the outcome variables and side effects of the previous day(s). In particular, we set two “lag” variables, Lag 1 and Lag 2, to represent mirtazapine taking 1 night and 2 nights ago based on the sequence of time.
Marginal regression models are fitted to our correlated longitudinal data using the generalized estimating equations (GEE) method to evaluate the population average effects of time-varying mirtazapine usage on the mean values of HADS, AIS, and pain scores, and morphine consumptions. We incorporated the estimated four time-dependent propensity scores as the fixed covariates in our marginal regression analyses of longitudinal data using the GEE method to balance the distributions of the confounding variables between the time-varying treatment and nontreatment groups, i.e., the mirtazapine takers and mirtazapine nontakers of each day.
As shown in Figure 1, 539 patients prepared to receive major abdominal surgery from September 2007 to December 2008 were eligible for this study. The incidence of preoperative anxiety and depression was 27.8% (150/539). A total of 86 patients agreed to be enrolled in the study and 79 patients finally completed it.
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Figure 1. Patient enrollment and allocation. A total of 53 patients chose to be in the treatment group and the other 33 in the nontreatment group. Yet, three and four patients in these two groups could not complete the trial owing to unplanned postoperative ICU care. BSRS = Brief Symptom Rating Scale; ICU = Intensive Care Unit.
3.1. Univariate analysis
Background characteristics, baseline assessment scores of Day 0, operation time, and the amount of intraoperative fentanyl consumption are listed in Table 1. There were statistically significant mean differences in height (p = 0.037) and AIS scores on Day 0 (p = 0.03) between the two groups.
In the treatment group, the trend of HADS scores decreased daily. The mean value of HADS scores on Day 4 was significantly lower than that on Day 0 (20.14 ± 5.54 vs. 16.42 ± 5.82, p < 0.001). In the nontreatment group, changes of HADS scores on Day t did not reach statistical significance (Figure 2A).
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Figure 2. Group mean plots of (A) HADS, (B) AIS, (C) NRS, and (D) daily morphine consumption over time. AIS = Athens Insomnia Scale; HADS = Hospital Anxiety and Depression Scale; NRS = Numerical Rating Scale.
The mean of AIS on Day 0 is significantly different between the two treatment groups (p = 0.03). In the treatment group, the mean value of AIS on Day-2 is higher than that on Day 4, and the AIS on Day 4 is borderline significantly lower than that on Day 0 (p = 0.057). Yet, in the nontreatment group, the changes of AIS on Day t are not statistically significant (Figure 2B).
In our findings, the postoperative pain score decreased significantly. No difference is noted between the two treatment groups (Figure 2C). In both groups, the dosage of daily morphine also decreased from Postoperative Day 1 to Day 3 in patients using postoperative PCA, but there were no significant differences in daily morphine consumption between the two groups (Figure 2D).
3.2. Multivariate analysis
3.2.1. Stage 1: propensity score models
We obtained the estimated time-dependent propensity scores of mirtazapine daily use for all participants with the fitted multivariate logistic regression models (Table 2). The propensity score of Day 1 was estimated from an exact logistic regression model due to the separation (or high discrimination) problem occurring in the original logistic regression analysis. The patients who had a higher AIS score on Day 0 and were in ASA Class III had higher tendencies to take mirtazapine. On Day 1, the patients who had side effects were not willing to take mirtazapine. However, those who experienced vomiting or felt more pain preferred to take mirtazapine. The patients who had taken mirtazapine on Day 1 preferred to take mirtazapine on Day 2, and those who had side effects such as dry mouth did not take mirtazapine. On Day 3, the patients who took mirtazapine in the past 2 days, used PCA for postoperative pain control, and had higher HADS scores on Day 2 were more likely to take mirtazapine.
Table 2. Logistic regression analysis for estimating propensity scores of mirtazapine use on Days 0, 1, 2, and 3.
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3.2.2. Stage 2: marginal regression models (using the GEE method) adjusted by the estimated time-dependent propensity scores
The correlated longitudinal data are analyzed by multiple marginal regression models using the GEE method to assess the effect of mirtazapine, conditioning on the estimated time-dependent propensity scores of mirtazapine use (as a covariate) for reducing self-selection bias. In the GEE analysis, we specified the AR(1) (first-order autoregressive process) correlation structure for the repeated-measures data, and then reported the model-based standard error estimates of the estimated regression coefficient because the model-based and empirical estimates of the standard errors were compatible.
First, we found that the mean HADS score decreased significantly daily. As shown in Table 3, after adjusting for the effects of the other covariates, the patients who had a higher HADS score at the baseline or a longer operation time would have a higher mean HADS score postoperatively. However, mirtazapine, PCA usage, or use of more opioid (fentanyl) intraoperatively decreased the mean value of HADS scores postoperatively. Moreover, we further divided HADS into anxiety and depression indexes in the post hocanalysis. The patients who had a higher anxiety index on Day 0 would have higher mean scores of anxiety index postoperatively, but those who took diphenhydramine (Venan) as an antiemetic would have a lower anxiety index. After adjusting for the effects of the other covariates, mirtazapine was found to decrease the mean scores of depression index in 2 days. The patients who took dyphenhadramine or used more fentanyl intraoperatively would have lower mean scores of depression index postoperatively. By contrast, in the treatment group, patients with higher scores of depression index on Day 0 or with higher BSRS-5 scores had higher mean scores of depression index postoperatively (Table 4).
Table 3. Marginal linear regression analysis of HADS, AIS, and pain scores, and daily morphine consumption using the GEE method adjusted by the estimated time-dependent propensity scores.
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Table 4. Post hoc marginal linear regression analysis of anxiety and depression index of HADS, and day and night index of AIS using the GEE method adjusted by the estimated time-dependent propensity scores.
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Table 3 also shows that patients with higher degrees of sleep disturbance at the baseline or higher BSRS-5 scores would have higher mean scores of AIS postoperatively, but male patients or the patients who used dyphenhadramine as an antiemetic would have lower AIS scores. Nevertheless, conditioning on the values of the other covariates, the effect of mirtazapine was not statistically significant. We also divided the AIS scores into the day and night indices in the post hoc analysis. The AIS day index assessed the function, feelings, and sedation level in daytime, while the AIS night index evaluated the quality of sleep, induction to sleep and wake time, and total sleep time at night. Furthermore, only postoperative PCA usage had a negative influence on the mean score of AIS night index. Conditioning on the postoperative PCA usage, patients who took mirtazapine 1 and 2 days before tended to have lower mean scores of AIS night index (Table 4), but the effects were not statistically significant (mirtazapine Lag 1, p = 0.6254; mirtazapine Lag 2, p = 0.3370). In contrast, after adjusting for the effects of the other covariates, the mean scores of AIS day index dropped significantly on Day 4. We can also see that male, elder patients, PCA users, or those who took mirtazapine 2 days before had lower mean scores of AIS day index, while patients with higher scores of AIS on Day 0 or a longer operative time had higher mean scores of AIS day index (Table 4).
Finally, after adjusting for the effects of the other covariates, the pain score dropped significantly with the sequence of time. Male patients tended to have lower pain scores than female patients. In addition, the amount of daily morphine consumption also decreased with the sequence of time, and older patients used less morphine, but male patients or the patients who used more fentanyl intraoperatively consumed more morphine postoperatively. Mirtazapine had the tendency of decreasing the amount of morphine consumed by patients daily, but it did not reach statistical significance (p = 0.2).
This is a pilot study that reveals that perioperative use of mirtazapine can help decrease patients' HADS scores, having the potential to improve AIS scores and reduce the daily morphine consumption in the postoperative period for psychologically distressed patients. We found that the 1st day after operation (Day 2) is the most uncomfortable day for patients in the perioperative period, with the highest HADS, AIS, and pain scores. Mirtazapine can decrease HADS and AIS day indexes in the postoperative period, and improve patients' quality of life immediately after the operation.
Our results indicated that mirtazapine can decrease HADS scores in 2 days, especially depression scores. Therefore, we are inclined to believe that the response time of mirtazapine's antidepressant effects on our patients is less than 2 days, instead of 1–2 weeks as reported in previous studies.16, 17 Anxiety is a normal response to a stressor and spontaneously disappears as the stressor passes (e.g., surgical operation). Therefore, we focus more on the time element than on mirtazapine's effect while considering the cause of decreasing anxiety index of HADS. Moreover, patients with PCA use also have lower HADS scores, indicating that active coping style and information-seeking behaviors may be related to lower depression and anxiety levels.18, 19
Sleep disturbances in the perioperative period have been published in previous studies.20 Changes in early postoperative sleep are characterized by a decreased sleep time, elimination of rapid eye movement sleep, a marked reduction in slow wave sleep, and increased nonrapid eye movement sleep Stage 2. Sleep quality of subjective feelings decreased markedly during 1–2 nights postoperatively, but the total sleep time and pattern normalize to the preoperative levels within the 1st postoperative week. Depressive symptoms are listed as the major risk factors for insomnia.21 In our study, patients with a higher AIS score are more inclined to join the treatment group, which might be an indicator that the psychologically distressed patients would experience sleep disturbance preoperatively. Mirtazapine has been proved to enhance sleep efficiency and prolong sleep continuity without changing the sleep structure through the blockade of 5-HT2 receptors.10, 22 Our results reveal that mirtazapine can help decrease AIS day scores and showed a tendency to decrease AIS night scores. This may be a result of the more pronounced antidepressant effects of mirtazapine that patients felt better in the daytime. More studies are required to investigate the possible benefits of mirtazapine for patients with perioperative sleep disturbance.
We found that pain scores and morphine consumption decreased gradually after the surgery. Although previous studies proved that mirtazapine can decrease the feeling of pain in healthy participants23 and has antinociceptive effects mediated though κ3-opioid receptor subtypes combined with both serotonergic and noradrenergic receptors,24 we did not find a significant decrease in postop morphine consumption with mirtazapine use. In our study, we noticed that male patients have lower pain scores but more morphine consumption than female patients. Moreover, with the same pain scores, patients who are more active may use more morphine. Thus, in some circumstances, PCA morphine consumption may not be a reliable indicator in evaluating postoperative pain.25
Dizziness and drowsiness at daytime, and dry mouth are the most common side effects observed in this study. These side effects affect participants' willingness to take mirtazapine, as reflected in the analysis of propensity score. Dizziness/drowsiness at daytime and dry mouth influence participants' decision of taking mirtazapine on Days 1 and 2. Dizziness and drowsiness are probably due to mirtazapine's high affinity to the H1 receptor, which causes a powerful sedative effect. However, the H1 receptor tends to desensitize and patients usually compensate for antihistamine-related sedation in 1 week.6, 8Dry mouth is possibly from noradrenergic effects, and its onset is later than H1 receptor effects.
Some methodological issues related to this clinical study should be mentioned. Propensity score analysis is an important statistical method to reduce selection bias in observational or nonrandomized studies, and it has been used widely in many fields recently.26, 27, 28 In practice, well-designed observation studies are important when randomized studies are not always feasible because of ethical, economical, or clinical constraints.29 Restrictions in randomized, double-blind, controlled studies may conflict with clinical situations, and thus patients are reluctant to continue the trial. In the early stage of the study, we encountered great difficulties in obtaining participants' agreements on participating in a randomized trial even after well explaining and communicating the trial details. Many participants did not follow the protocol and only wanted to take mirtazapine as freely as possible. As a result, we modified our study design to a quasiexperiment, and then used the propensity score method not only to analyze participants' drug-taking behaviors, but also to reduce selection bias in the GEE regression analyses. Thus, we can still evaluate mirtazapine effects with the “quasirandomization” feature. Nevertheless, the limitation of propensity score analysis is that it cannot mitigate the selection bias caused by “unobserved” confounding variables.26, 30 For example, we did not have the data on some potentially important factors, such as participants' education levels and economic status; these might still cause selection bias after regression adjustment by the estimated propensity scores.
In summary, mirtazapine can decrease anxiety and depression scores, and the level of insomnia in patients with perioperative psychological distress. Further studies are still required to investigate mirtazapine's effects on perioperative complications and short- and long-term outcomes of those patients.
Conflicts of interest
I certify that all my affiliations with or financial involvement in, within the past 5 years and foreseeable future, any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript are completely disclosed (e.g., employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, royalties).
The authors would like to thank Dr Fu-Chang Hu, National Center of Excellence for General Clinical Trial and Research, National Taiwan University Hospital and College of Medicine, National Taiwan University, for his guidance in regression analysis and Ms Chia-Chi Cheng for her assistance in statistical computing. We would also like to thank Dr Ting-Shan Yen, Cardinal Tien Hospital (Xindian), for her help in design of study and acquisition of data.