Premedication with Mirtazapine Reduces Preoperative Anxiety and Postoperative Nausea and Vomiting : Anesthesia & Analgesia

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Ambulatory Anesthesiology: Research Report

Premedication with Mirtazapine Reduces Preoperative Anxiety and Postoperative Nausea and Vomiting

Chen, Chien-Chuan MD*‡; Lin, Chia-Shiang MD*‡; Ko, Yuan-Pi MD; Hung, Yu-Chun MD*‡; Lao, Hsuan-Chih MD*; Hsu, Yung-Wei MD*‡

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Anesthesia & Analgesia 106(1):p 109-113, January 2008. | DOI: 10.1213/01.ane.0000289636.09841.bc
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Preoperative anxiety and postoperative nausea and vomiting (PONV) are among the most unpleasant experiences associated with surgery. Although anxiolytic premedication may attenuate the stress response to anesthesia,1 practitioners may be reluctant to provide sedative medication because of a concern that it may delay tracheal extubation or prolong discharge from the postanesthesia care unit.

There are still challenges to reduce the incidence of PONV despite the introduction of new antiemetic drugs, short-acting anesthetics, and minimally invasive surgical techniques.2,3 For the prevention of PONV, identifying individual risk factors and using prophylactic antiemetics for patients at high risk is recommended.4

Mirtazapine is a noradrenergic and specific serotonergic antidepressant. It is a potent antagonist of central α2-autoreceptors and α2-heteroreceptors, as well as an antagonist of 5-HT2 and 5-HT3 receptors. The 5-HT2 blocking effects contribute to its anxiolytic effects and enhance sleep. The 5-HT3 blockade by mirtazapine may help to prevent nausea and vomiting.5–7

There have been several reports of successful treatment of nausea and vomiting due to pregnancy, chemotherapy, and nonmechanical vomiting after gastric bypass by mirtazapine.8–10 However, the effects of mirtazapine premedication on PONV have not been studied. The goal of this study was to test the hypothesis that premedication with mirtazapine can reduce preoperative anxiety and the risk of PONV.

METHODS

After obtaining the approval of IRB (Mackay Memorial Hospital, Taipei, Taiwan) and signed informed patient consent, female patients with ASA physical status I or II and aged 20–60 yr were enrolled in this double-blind, randomized, placebo-controlled study. Patients undergoing gynecological procedures, including abdominal total hysterectomy, myomectomy, laparoscopic myomectomy, and laparoscopic oophorectomy, were recruited.

Apfel et al.'s11 simplified score for predicting PONV (female gender, nonsmoking status, history of PONV or motion sickness, and postoperative opioids) was used to identify appropriate patients for enrollment in this study. Only patients who had at least two risk factors were enrolled. Dexamethasone 8 mg was used as an active-control. Patients with a history of peptic ulcer, diabetes mellitus, severe hypertension, Cushing's syndrome, known hypersensitivity to mirtazapine or dexamethasone, taking any other antidepressant drugs or steroids, or taking any medications with antiemetic properties within 24 h of surgery were excluded from this study. Also, patients receiving monoamine oxidase inhibitors or within 2 wk of stopping monoamine oxidase inhibitors were excluded. Patients were randomly assigned to group M + D (mirtazapine 30 mg plus dexamethasone 8 mg) or group D (placebo plus dexamethasone 8 mg).

An oral disintegrating mirtazapine (Remeron® SolTab) 30 mg or placebo tablet was given 1 h before surgery in the holding area of the operating room. The placebo tablets were manufactured by the drug company for training purposes. Except for the labels, the appearance was similar to mirtazapine. Before the study, the labels of mirtazapine and placebo tablets were covered to make them look exactly the same. Preoperative anxiety levels (using a 10-cm visual analog scale (VAS) with one end-labeled “not anxious at all” whereas the other “extremely anxious” were assessed before taking the study drug and 1 h after. When patients entered the operating room, standard monitoring, including noninvasive arterial blood pressure monitoring, electrocardiography, pulse oximetry, and capnography, was begun. An auditory evoked potentials index (AAI) monitor was used to titrate sevoflurane administration. Before induction of anesthesia, 500 mL of a lactated Ringer's solution was infused and dexamethasone 8 mg was given IV. General anesthesia was induced with fentanyl 2 μg/kg, xylocaine 0.5 mg/kg, and propofol. Propofol was infused at the rate of 200 mL/h. Once patients were unable to follow verbal commands to open their eyes, the eyelash reflex was checked at 10-s intervals. The induction dose of propofol was defined as the amount of propofol required for loss of eyelash reflex. Rocuronium 0.8 mg/kg was given to facilitate tracheal intubation. General anesthesia was maintained with sevoflurane in oxygen and air (FiO2 0.6). The sevoflurane concentration was titrated in 1%–2% increments to maintain an AAI value of 15 to 20 and no more fentanyl was added during surgery. Sevoflurane was turned off at the end of surgery.

Arterial blood pressure, heart rate, and end-tidal concentrations of sevoflurane were recorded every 15 min. SEVOawake was defined as the end-tidal concentration of sevoflurane when the patient could open her eyes on command. Recovery time was defined as the time from turning off sevoflurane to when patients could grasp their hands on command. Neuromuscular blockade was antagonized with IV atropine 0.02 mg/kg and neostigmine 0.05 mg/kg. IV morphine patient-controlled analgesia (PCA) (bolus 1 mg, lockout 5 min, 4-h limit 25 mg) or IM meperidine (50 mg, every 4 h as needed) was ordered for postoperative pain management.

Postoperative pain and sedation level were assessed by a VAS and the Ramsay Sedation Score. The incidence of PONV, the use of rescue antiemetic, postoperative Ramsay Sedation Score, and VAS pain scale were assessed 1 h (at postanesthesia care unit), 2, and 24 h (on the floor) after surgery. The severity of nausea was assessed using a verbal numerical rating scale from 0 to 10. Patients verbally rated their level of perceived nausea, with zero representing one extreme (e.g., no nausea) and the 10 representing the other extreme (e.g., “the worst nausea possible”). All episodes of vomiting were recorded. Either vomiting or retching was considered as vomiting. IM metoclopramide 10 mg was given as rescue antiemetic if two or more emetic episodes occurred or nausea persisted for more than 10 min. Complete response was defined as no PONV and no administration of rescue antiemetic during the first 24 h after anesthesia. Any side effects that patients reported during the study were recorded.

Statistical analysis was performed with SPSS software (version 11.5; SPSS Inc., Chicago, IL). The demographic characteristics of patients were summarized using descriptive statistics. The frequency of PONV, rescue treatment, and complete response were analyzed using the χ2 test. The preoperative VAS anxiety scale, AAI, severity of nausea, and Ramsay Sedation Score were analyzed using Mann-Whitney U-test. A two-sided P value of <0.05 was considered to be of statistical significance.

RESULTS

Eighty patients were enrolled and completed the study. There were no differences in age, ASA status, duration of anesthesia, and PONV risk factors between the two groups (Table 1). The number of patients with nonsmoking status, history of PONV or motion sickness, and postoperative use of opioids was comparable. Postoperative opioid use, with either IV PCA morphine (37.5% vs 35%) or IM meperidine (52.5% vs 45%) was similar in group M + D and group D, respectively. An average of 29 ± 9 and 32 ± 8 mg of morphine was used over 24 h in the two groups (P > 0.05).

T1-21
Table 1:
Patient Demographics

The effects of mirtazapine on preoperative anxiety are shown in Figure 1. We found significantly lower anxiety levels in group M + D at 1 h after mirtazapine administration compared with group D (65 ± 11 vs 44 ± 10, P < 0.05). The effects of mirtazapine on dosing required for general anesthesia are illustrated in Table 2. There were no significant differences between the two groups in baseline AAI, propofol induction dose, the concentrations of sevoflurane for maintenance and on arousal, arousal AAI, or recovery times. However, the AAI at loss of consciousness during induction in group M + D was less than group D (42 ± 18 vs 60 ± 23, P < 0.05). There were no differences of Ramsay Sedation Score and VAS pain scores at 1, 2, 24 h after surgery in the two groups.

F1-21
Figure 1.:
Mirtazapine premedication reduces preoperative anxiety. The error bar charts represent the mean, standard deviation of mean, and range. *P < 0.05.
T2-21
Table 2:
The Effect of Mirtazapine on General Anesthesia

The effects of mirtazapine on PONV are shown in Table 3. The incidence of vomiting over 0–24 h was less in group M + D (7.5% vs 30%, P < 0.01) Also, the complete response rate was higher (80% vs 50%, P < 0.01) and the requirement for rescue antiemetic was less in group M + D (5% vs 27.5%, P < 0.01).

T3-21
Table 3:
The Effect of Mirtazapine on Postoperative Nausea and Vomiting

There were no serious adverse events associated with this study. Eighteen (45%) patients in group M + D and one patient in group D (2.5%) complained of somnolence (P < 0.05). Dry mouth occurred in eight (20%) patients in group M + D and four (10%) patients in group D (P = 0.21). During anesthesia, there were no significant differences in hemodynamics (arterial blood pressure and heart rate) between groups.

DISCUSSION

In this study, we found that for women at moderate-to-high risk for PONV undergoing gynecologic surgery, premedication with an oral disintegrating 30 mg tablet of mirtazapine 1 h before surgery reduced preoperative anxiety as well as the incidence of late PONV.

Mirtazapine is rapidly absorbed after oral administration, and peak plasma concentrations are reached within 2 h. The elimination half-life of mirtazapine ranges from 20 to 40 h, and it is recommended to be taken as a single nighttime dose before going to bed.12 Because no water is needed for taking the oral disintegrating mirtazapine tablet, it may become a very useful drug for premedication within 2 h before general anesthesia.

We found that patients became less anxious and that 45% of patients felt somnolent after mirtazapine premedication. These anxiolytic and sleep-enhancing effects are likely a result of the blockade of 5-HT2 receptors by mirtazapine. Although the antidepressant effect of mirtazapine via enhancing noradrenergic and serotonergic neurotransmission can be seen as early as the first week of treatment, our results indicate that the anxiolytic and sleep-improving effects are rapid in onset and seen within an hour of administration. According to a study investigating the effect of mirtazapine on sleep in healthy volunteers, mirtazapine demonstrated sleep-promoting action when given 2 h before bedtime.13 Thus, the onset time of blockade of 5-HT2 receptors is matched with its peak plasma concentration after oral administration of mirtazapine. Moreover, a pharmacokinetic study shows that the peak plasma concentrations is reached within about 1.65 ± 0.7 h for fasting patients versus 2.4 ± 1.2 h for fed patients.12 Our patients were fasted; therefore, they experienced quicker onset of anxiolysis and the sleep-enhancing effects of mirtazapine. Also, our results indicate that a single 30-mg dose of mirtazapine reduces preoperative anxiety but does not affect anesthetic consumption and recovery.

A previous report has shown the antiemetic effect of mirtazapine has an onset within hours when used for the treatment of resistant hyperemesis gravidarum.8 The blockade of 5-HT3 receptors accounts for its lack of serotonergic side effects (i.e., nausea, vomiting, and headache) which are often associated with other antidepressants. Mirtazapine's tolerability profile suggests that the onset of the 5-HT3 receptor blockade is rapid.

We observed no difference in the prevention of PONV during the early postoperative period (0–2 h) in either group. The difference in prevention of PONV was found during the late postoperative period (2–24 h). A previous study has found postoperative opioids to be one of the main predictors of PONV in the late postoperative period (2–24 h).14 Thus, we believe the frequent incidence of PONV in group D for 2–24 h was likely related to the emetic effect of postoperative opioids. A systemic review of the dexamethasone literature for the prevention of PONV shows that dexamethasone is an effective prophylactic antiemetic, and late efficacy seems to be most pronounced.15 This contrasts with our findings that, for the first 24 h postoperatively, a single 8-mg dose of dexamethasone alone was not sufficient for high-risk patients, whereas the combination of mirtazapine plus dexamethasone effectively reduced the PONV risk in the late postoperative period. The combination of dexamethasone with a 5-HT3 receptor antagonist is recommended for high-risk patients in several studies.4,16,17 The reduction of PONV risk in group M + D confirms that mirtazapine (with 5-HT3 blocking properties) similarly reduced the PONV risk as has been shown with other 5-HT3 receptor antagonists.

Patients in our study were moderate and high risk for PONV. According to the prediction of Apfel et al.'s risk score, the PONV risk was 65% if subjects in group D did not receive an antiemetic. A previous study indicated that dexamethasone could reduce the risk by about 26%. Therefore, the average expected risk of PONV was 39% in group D.11,16 However, our results showed the risk to be 50% in group D. The difference might have been because of the inter-individual variability in the antiemetic response to dexamethasone and to the pro-emetic effect of opioids.

In the present study, mirtazapine premedication was associated with less late PONV. However, there are some limitations to the study. First, we did not enroll male subjects. Thus, our results can only be applied in female patients. Second, we did not use the state and trait anxiety inventory (STAI) for anxiety evaluation. STAI is the “gold standard” for anxiety evaluation, but STAI consists of 20 multiple-choice questions for state anxiety alone, which limited its use in our study. The VAS scale allows patients to easily indicate their degree of preoperative anxiety, and correlates well with STAI.18 Another limitation is that we did not control the method of postoperative pain management. Either IV PCA morphine or IM meperidine was allowed. By not controlling postoperative opioids we inevitably decreased the internal validity of the study. However, there was no difference in the ratio of patients using morphine or meperidine in the two groups. In addition, external validity was increased because the design was similar to our daily practice. As this is the first study investigating the effect of mirtazapine on PONV, our post hoc power analysis revealed that 40 patients per group gave this study a power of 85% (for P < 0.05).

In summary, we have shown that premedication with oral disintegrating mirtazapine 30 mg may reduce the level of preoperative anxiety and the incidence of late PONV in moderate and high-risk female patients. Further studies are required to determine the safety and compare the efficacy of mirtazapine as PONV prophylaxis with other serotonin 5-HT3 receptor antagonists.

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