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Perioperative Duloxetine to Improve Postoperative Recovery After Abdominal Hysterectomy: A Prospective, Randomized, Double-Blinded, Placebo-Controlled Study

Castro-Alves, Lucas J. MD*; Oliveira de Medeiros, Andrea Cristina Pereira MD*; Neves, Saulo Pimentel MD*; Carneiro de Albuquerque, Camila Lucena MD*; Modolo, Norma Sueli MD; De Azevedo, Vera Lucia*; De Oliveira, Gildasio S. Jr. MD, MSCI

doi: 10.1213/ANE.0000000000000971
Anesthetic Pharmacology: Research Report

BACKGROUND: Postsurgical quality of recovery is worse in female than that in male patients. Duloxetine has been used successfully for the treatment of chronic pain conditions, but its use for preventing acute postoperative pain has been limited to a single previous study. More importantly, the effect of preoperative duloxetine on global postoperative quality of recovery has yet to be evaluated. The main objective of the current investigation was to evaluate the effect of perioperative duloxetine on postoperative quality of recovery in women undergoing abdominal hysterectomy.

METHODS: The study was a prospective, randomized, placebo-controlled, double-blinded trial. Female patients undergoing abdominal hysterectomy were randomized to receive duloxetine (60 mg orally 2 hours before surgery and 24 hours after surgery) or an identical placebo pill. The primary outcome was the quality of recovery-40 score at 24 hours. Secondary outcomes included opioid consumption and postoperative pain scores. A P value <0.05 was used to reject type I error.

RESULTS: Seventy patients were recruited, and 63 completed the study. The median difference (95% confidence interval) in global recovery scores (quality of recovery-40) at 24 hours after surgery between the duloxetine and the placebo group was 9 (4–20) (P < 0.001). Total opioid consumption was reduced at 24 hours in the duloxetine group compared with the placebo group, median (interquartile range) of 1 (0–5) mg IV morphine compared with 5.5 (0.5–9) mg IV morphine (P = 0.004). Nausea, vomiting, and time to postanesthesia care unit discharge were not significantly reduced in the duloxetine group compared with placebo.

CONCLUSIONS: Duloxetine improves postoperative quality of recovery after abdominal hysterectomy. In addition, duloxetine reduces postoperative opioid consumption, even in the presence of a robust multimodal analgesic strategy. Duloxetine seems to be a viable pharmacologic strategy to improve postoperative quality of recovery in female patients undergoing abdominal hysterectomy.

Published ahead of print September 29, 2015

From the *Department of Anesthesiology, Santo Antonio Hospital, Salvador, Bahia, Brazil; Botucatu Medical School, Botucatu, Sao Paulo, Brazil; and Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Accepted for publication June 16, 2015.

Published ahead of print September 29, 2015

Funding: Institutional.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Gildasio S. De Oliveira, Jr., MD, MSCI, Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, 241 East Huron St., F5-704, Chicago, IL 60611. Address e-mail to g-jr@northwestern.edu.

Female patients have worse quality of recovery after surgery than male patients.1 The greater propensity for pain and opioid-related side effects are likely contributing factors for poor postsurgical recovery in women.2–6 Abdominal hysterectomy is a commonly performed surgical procedure in women, and it often results in significant pain and slow recovery.7–9 Nevertheless, pharmacologic strategies to improve global quality of recovery after abdominal hysterectomy have yet to be examined.

Duloxetine is a serotonin-norepinephrine reuptake inhibitor commonly prescribed for the treatment of major depression and anxiety.10 Duloxetine also has been used in the treatment of chronic pain conditions, such as osteoarthritis and musculoskeletal pain.11 In contrast, studies examining its use to ameliorate acute postoperative pain are limited to a single trial.12 More importantly, it remains to be determined whether perioperative duloxetine can improve global quality of recovery after surgery.

There several reasons why duloxetine might improve postsurgical quality of recovery. First, systemic duloxetine seems to have perioperative analgesic effects.12 In addition, as a serotonin-norepinephrine reuptake inhibitor, it is possible that the drug may prevent transient emotional problems that are common during the perioperative period.13,14 Lastly, the combination of less pain and better emotional status can result in better physical independence scores after surgery.

The main objective of the current investigation was to examine the effect of perioperative duloxetine on global postoperative quality of recovery after abdominal hysterectomy. We hypothesized that subjects receiving perioperative duloxetine would have a better global quality of recovery at 24 hours after surgery scores than those receiving placebo. In addition, we sought to evaluate whether perioperative duloxetine had opioid-sparing properties when given as part of a multimodal pain strategy.

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METHODS

The study was a prospective, randomized, double-blinded, placebo-controlled trial. IRB approval was obtained from Santo Antonio Hospital. The study is described in accordance with the Consolidated Standards of Reporting Trials (i.e., CONSORT) statement. Written informed consent was obtained from all participating subjects. Clinical trial registration was performed at http://aplicacao.saude.gov.br/plataformabrasil (identifier: 03127512.4.0000.0047). Patients were included if they were female, 18 to 64 years old, and undergoing abdominal hysterectomy for benign (noncancerous) diseases (ASA physical class I–III). Subjects were excluded if they were allergic to duloxetine, pregnant, unable to understand the informed consent, had renal and/or liver disease, were taking chronic opioids and/or antidepressants, and had contraindications to neuraxial anesthesia. Reasons for exclusion after randomization were protocol violations or patient request. Subjects were randomized by the use of a computer-generated table of random numbers to receive duloxetine 60 mg orally 2 hours before the surgical procedure and at 24 hours after the surgical procedure or a placebo pill following the same time schedule. Group assignments were sealed in sequentially numbered opaque envelopes that were opened after patient inclusion in the study. The placebo pill was assembled by the hospital pharmacy to ensure that the placebo and the duloxetine pills appeared to be identical.

All subjects were premedicated with 0.02 mg/kg IV midazolam and 1 μg/kg of IV fentanyl. After arrival in the operating room, standard American Society of Anesthesiologists monitors were applied. Patients received 10 mL/kg of a lactate Ringer’s solution IV and were placed in the sitting position. After the lumbar region was prepared and draped in a sterile fashion, topical 1% lidocaine was given for skin analgesia. The spinal block was achieved at the L3-4 or L4-5 interspace by the use of a spinal introducer and a 27-G Pencan spinal needle (B. Braun Medical Inc., Bethlehem, PA) and using 17.5 mg of 0.5% hyperbaric bupivacaine. The correct placement of the needle was confirmed by aspiration of clear cerebral spinal fluid before and after the injection. After confirmation of an appropriate dermatomal level of blockage (T4 level), the surgeon was allowed to proceed.

Subjects received ephedrine 5 mg titrated to keep blood pressure within 20% of the baseline value. All subjects received 4 mg ondansetron to prevent postoperative nausea and/or vomiting (PONV). In the postanesthesia care unit (PACU), subjects were asked to rate their pain upon arrival and at regular 15-minute intervals on a 0 to 10 pain Numeric Rating Scale (NRS), where 0 means no pain and 10 is the worst pain imaginable. The scores were assessed with patients at rest and after asking them to cough. Morphine sulfate 1 to 2 mg IV was administered every 15 minutes to maintain an NRS pain score <4 (1 mg for pain <7/10 and 2 mg for pain ≥7/10). Nausea was assessed at the same intervals and recorded as present or absent. Number of vomiting episodes also was recorded. Discharge readiness from PACU was assessed by using the modified Aldrete score every 15 minutes until patients met discharge criteria (score ≥9). PONV was treated with 4 mg IV ondansetron. Postoperative pain was prevented by using IV ketoprofen 100 mg every 8 hours and metamizol 50 mg every 6 hours. Additional morphine sulfate 1 to 2 mg IV was administered by the nurse taking care of patient every 15 minutes to maintain an NRS pain score of <4 (1 mg for pain <7/10 and 2 mg for pain ≥7/10). Pain assessments in the ward were performed by nurses every 4 hours.

Perioperative data collected included subject’s age, height, weight, ASA physical class, surgical duration, total IV fluids, pain scores at rest and after coughing, and total amount of morphine in PACU, at 24 and 48 hours. Perioperative data collection was performed by one of the investigators not involved with patient care and blinded to the study group allocation. The Quality of Recovery-40 questionnaire (QoR-40) was completed by the subjects at 24 and 48 hours after the surgical procedure (Appendix 1).15,16 The QoR-40 scoring system was explained to all subjects and reviewed to provide accurate understanding of all questions. The questionnaire evaluates 5 components of patient recovery: physical comfort (12 questions), physical independence (5 questions), emotional state (9 questions), psychological support (7 questions), and pain (7 questions). The sum of the individual components generates an aggregate score. Global QoR-40 scores range from 40 to 200, representing, respectively, very poor to outstanding quality of recovery.17 The instrument was translated to the Portuguese language by one of the investigators fluent in both English and Portuguese. Our group has previously used the QoR-40 in a similar patient population of Portuguese-speaking patients.18 We found a similar relationship between the QoR-40 and other outcomes (pain and opioid consumption) using the Portuguese version of the instrument compared with the English version, which has suggested external validity of the instrument in the Portuguese language. The simple language of the instrument makes changes in semantics during the translation unlikely to alter the instrument’s internal validity, and this fact has justified the use of the instrument in languages different from English, despite a lack of formal validation.19,20

The primary outcome was the QoR-40 aggregate score at 24 hours. A sample size of 31 subjects per group was estimated to achieve 90% power to detect a 10-point difference in the aggregated QoR-40 scores for the 2 study groups to be compared using 12-point SD. A 10-point difference represents a 15% improvement in quality of recovery based on previously reported values on the mean and range of the QoR-40 in patients following anesthesia and surgery.18,21 A12-point SD is consistent with a previous investigation.18 To account for dropouts, 70 subjects were randomized.

The Shapiro-Wilk and Kolmogorov-Smirnov tests were used to test the hypothesis of normal distribution. Normally distributed continuous data are reported as mean (SD) and were evaluated with a 2-sided independent t test for equal variances. Non-normally distributed interval data and ordinal data are reported as median (interquartile range [IQR]) and were evaluated using the Mann-Whiney U test.22,23 Median differences and 95% confidence intervals of the differences in global QoR-40 scores and pain scores were calculated by the use of a 10,000 sample nonparametric bootstrapping method.24 Categorical variables are presented as count (percentages) and were evaluated with the Fisher exact test. A nonparametric correlation between opioid consumption and global quality of recovery was performed with the Spearman rho correlation coefficient. The criterion for rejection of the null hypothesis was a 2-tailed P value <0.05 for the primary outcome. For secondary outcomes, we used a 2-tailed P value <0.001 to reduce type I errors. Statistical analysis was performed using STATA version 13 (StataCorp, College Station, TX).

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RESULTS

The details of the conduct of the study are shown in Figure 1. Patients were enrolled in the study from December 2012 through December 2013. Seventy subjects were randomized, and 63 completed the study. Patients’ baseline characteristics and surgical factors were not different between groups (Table 1).

Table 1

Table 1

Figure 1

Figure 1

Subjects in the duloxetine group had better postoperative quality of recovery than the placebo group. The median difference (95% confidence interval) in global recovery scores (QoR-40) at 24 hours after surgery between the duloxetine and the placebo group was 9 (4–20). The median (IQR) QoR-40 score for the duloxetine group was 196 (192–199) compared with 187 (172–194) in the placebo group (P < 0.001). The differences between individual subcomponents in the QoR-40 are presented in Table 2. The duloxetine group had greater scores than the placebo group in the physical comfort, emotional, independence, and pain subcomponents of the QoR-40 at 24 hours postoperatively (all P < 0.01). The global QoR-40 score was highly correlated to the pain subcomponent of the QoR-40 (Spearman ρ = 0.77, P < 0.001). In contrast, the global QoR-40 at 48 hours was not significantly different between the duloxetine and the placebo groups, with median (IQR) of 200 (198–200) and 199 (197–200), respectively (P = 0.23).

Table 2

Table 2

Table 3

Table 3

Table 4

Table 4

The duloxetine group had significantly lower pain scores at rest and after coughing than the placebo group at 24 hours but not at other time points (Table 3). Total opioid consumption was reduced at 24 hours in the duloxetine group compared with the placebo group (Table 4). Nausea, vomiting, and time to PACU discharge were not significantly reduced in the duloxetine group compared with placebo (Table 4). There was no correlation between total opioid consumption in the first 24 hours and QoR-40 score (Spearman ρ = −0.0172, P = 0.86).

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DISCUSSION

The most important finding of the current investigation was the better postoperative quality of recovery after abdominal hysterectomy in patients who received duloxetine compared with those who received placebo. Duloxetine specifically improved physical comfort, independence, emotional, and pain subcomponents in the quality of recovery score. In addition, duloxetine reduced postoperative opioid consumption and pain ratings at 24 hours compared with placebo. Taken together, our results suggest that duloxetine improves postoperative quality of recovery in women undergoing abdominal hysterectomy.

Our results are clinically important because pharmacologic strategies to improve global quality of recovery after abdominal hysterectomy have not been studied. In addition, female patients have poor quality of recovery after surgery compared with male patients.1 Opioid-related side effects, pain, and emotional factors may be factors responsible for poor quality of postsurgical recovery in women.25,26 Duloxetine may improve acute pain and emotional status in female patients undergoing abdominal hysterectomy.

It was interesting that, despite a small reduction in postoperative opioid consumption, we still detected an effect of duloxetine on the global recovery outcome. In contrast, Ho et al.12 observed a much greater opioid-sparing effect of duloxetine. It is likely that specific protocol characteristics of the current study (such as the concurrent use 2 different multimodal analgesics) may have reduced the opioid-sparing properties of duloxetine. Also, in the study by Ho et al., about one-third of the patients had general anesthesia, whereas all patients in the current study had regional anesthesia. We believe that the improvement in recovery by duloxetine observed in the current study, despite the use of aggressive multimodal analgesic strategies, further demonstrates its value as an important adjuvant to improve postoperative quality of recovery.

Our group has demonstrated previously that patients having abdominal hysterectomy under general anesthesia have worse recovery than patients having abdominal hysterectomy under regional anesthesia.18 However, surgeon and patient preference may require the use of general anesthesia for patients undergoing abdominal hysterectomy, which may negatively affect specific recovery items, such as PONV and upper airway morbidity.27–30 Because the effect of a pharmacologic intervention on recovery outcomes may be dependent on the type of anesthesia technique,31,32 future studies should evaluate the effect of duloxetine on patients having abdominal hysterectomy under general anesthesia.

The use of patient-centered outcomes in perioperative medicine is relatively new, and the specific improvement in the quality of recovery score that is clinically significant remains to be determined. Because any difference in the postoperative quality of recovery score directly reflects patients’ values and perception of improvement, it is possible that smaller effect-size differences than the 10 points used in our previous studies may be clinically significant.18 Nevertheless, future studies are needed to establish a more specific effect-size value in the quality of recovery score that are universally accepted as clinically significant.

We did not detect any side effects associated with the perioperative administration of duloxetine in the current study. It is important to note that patients received only 2 dosages of oral duloxetine. Nonetheless, common side effects of the medication include nausea, headache, and dry mouth. Future studies examining the use of perioperative duloxetine to improve postsurgical quality of recovery should also examine the potential side effects of the drug.

High doses of systemic dexamethasone (0.1 mg/kg) have been shown to improve quality of recovery in patients undergoing outpatient surgery under general anesthesia.31 Patients in the current study did not receive systemic dexamethasone, and it is unknown whether the use of systemic dexamethasone in patients having surgery under spinal anesthesia can result in improvements in quality of recovery scores. Nevertheless, it is possible that the concomitant administration of systemic dexamethasone could have resulted in a smaller effect size of duloxetine in postsurgical quality of recovery than the one observed in the current investigation.

We detected greater quality of recovery scores in patients who received a spinal anesthetic in our previous investigation compared with the ones in the current study.18 Subjects in the spinal group of our previous study received intrathecal morphine, but subjects in the spinal group of the current study did not receive it. Intrathecal morphine may have beneficial properties on postoperative quality of recovery in subjects receiving neuraxial anesthesia. Future studies to quantify the effect of intrathecal morphine on quality of postsurgical recovery are therefore warranted.

We have noticed greater quality of recovery scores in the current study than what has been reported for patients having intermediate surgery.16 The use of a robust multimodal postsurgical analgesic strategy (e.g., IV ketoprofen 100 mg every 8 hours and metamizol 50 mg every 6 hours) in the current study protocol likely contributed to greater recovery scores. In addition, we examined a population receiving free medical care through a government-funded health care system. Low expectations in our patient population also may have contributed to greater perceived quality of recovery. Nonetheless, the fact that we detected a benefit for duloxetine in this patient population suggests an even more promising effect of the drug in patients with greater expectations or in cases in which multimodal analgesic strategies are not used. Replication of our finding in other patient populations is needed.

The current study should only be interpreted within the context of its limitations. We only studied patients undergoing abdominal hysterectomy and, therefore, cannot generalize our findings to patients undergoing different surgical procedures. In addition, we used the same dose as previous investigators and did not evaluate possible dose-response effects of duloxetine on the examined outcomes.12 Lastly, we did not evaluate a possible effect of duloxetine on chronic postsurgical pain and were likely underpowered to study that effect.33,34

In summary, duloxetine improves postoperative quality of recovery in female patients undergoing abdominal hysterectomy, even in the presence of a robust multimodal analgesic strategy. Specifically, duloxetine resulted in better emotional and physical comfort, independence, and pain subscales scores of the QoR-40 instrument when compared with placebo. Replication of our results in other perioperative populations is warranted. Duloxetine should be considered an effective strategy for improving postoperative quality of recovery in female patients undergoing abdominal hysterectomy.

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APPENDIX 1

Quality of Recovery-40

Pt. Name: _______________________ DOS: ___ / ___ / ___

Table

Table

How have you been feeling in the last day? (Circle one)

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Part B

Have you had any of the following in the last 24 hours?

Table

Table

Please check that all questions have been answered. Thank you for your assistance.

Date: ___ / ___ / ___ Time: ________ AM/PM

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DISCLOSURES

Name: Lucas J. Castro-Alves, MD.

Contribution: This author contributed to design of the study, conduct of the study, and preparation of the manuscript.

Attestation: Lucas J. Castro-Alves approved the final manuscript. Lucas Castro-Alves attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Andrea Cristina Pereira Oliveira de Medeiros, MD.

Contribution: This author contributed to conduct of the study and preparation of the manuscript.

Attestation: Andrea Cristina Pereira Oliveira de Medeiros approved the final manuscript. Andrea Cristina Pereira Oliveira de Medeiros attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Saulo Pimentel Neves, MD.

Contribution: This author contributed to conduct of the study and preparation of the manuscript.

Attestation: Saulo Pimentel Neves approved the final manuscript. Saulo Pimentel Neves attests to the integrity of the original data reported in this manuscript.

Name: Camila Lucena Carneiro de Albuquerque, MD.

Contribution: This author contributed to conduct of the study and preparation of the manuscript.

Attestation: Camila Lucena Carneiro de Albuquerque approved the final manuscript. Camila Lucena Carneiro de Albuquerque attests to the integrity of the original data in this manuscript.

Name: Norma Sueli Modolo, MD.

Contribution: This author contributed to preparation of the manuscript.

Attestation: Norma Sueli Modolo approved the final manuscript.

Name: Vera Lucia De Azevedo.

Contribution: This author contributed to conduct of the study and preparation of the manuscript.

Attestation: Vera Lucia De Azevedo approved the final manuscript. Vera Lucia De Azevedo attests to the integrity of the original data in this manuscript.

Name: Gildasio S. De Oliveira, Jr., MD, MSCI.

Contribution: This author contributed to design of the study, analysis of the data, and preparation of the manuscript.

Attestation: Gildasio S. De Oliveira, Jr., approved the final manuscript. Gildasio S. De Oliveira, Jr. attests to the integrity of the analysis reported in this manuscript.

This manuscript was handled by: Ken B. Johnson, MD.

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