Evaluating dexmedetomidine’s opioid-sparing effect with ropivacaine in ultrasound-guided erector spinae block during mastectomy – A randomized clinical trial

Abstract

Background:

Mastectomy is associated with postoperative pain that can become chronic if left untreated. While opioids are commonly used, their adverse effects on recovery highlight the need for alternative methods. This study investigates the opioid-sparing effects of adding dexmedetomidine to ropivacaine, compared to ropivacaine without dexmedetomidine, in erector spinae plane block for patients undergoing mastectomy.

Methods:

This is a prospective, randomized controlled trial conducted at a tertiary University Hospital. Forty-four patients undergoing mastectomy with axillary lymph node dissection under general anesthesia were enrolled and randomized to receive erector spinae block with dexmedetomidine added to ropivacaine (intervention) or without dexmedetomidine (control). The primary outcome was total opioid consumption in the post-anesthesia care unit (PACU) and up to 24 hours postoperatively. Secondary outcomes included intraoperative hemodynamics, vitals, medications, and complications, as well as pain medications and levels, and side effects during the first 24 hours postoperatively.

Results:

PACU opioid consumption was significantly lower in patients who received the intervention compared to those who underwent the routine procedural protocol (3.14 ± 2.85 vs 5.86 ± 4.52, P = 0.021). Median survival time to opioid provision in the PACU and total morphine consumption up to 24 hours were not statistically significantly different between the two groups. Pain levels remained statistically significantly lower in the experimental group up to 12 hours postoperatively, after which no significant difference was observed. No significant side effects were reported.

Conclusions:

Dexmedetomidine, in safe doses, with ropivacaine in erector spinae block reduces immediate opioid consumption and postoperative pain in mastectomy patients.

Introduction

Breast cancer, the most common cancer in women, requires vital surgical intervention. Postoperative pain often accompanies breast cancer surgeries, potentially originating from neuroma formation or nerve injuries during the procedure. If left untreated, acute postmastectomy pain can progress to chronic pain, significantly impacting daily life and increasing healthcare costs.[1,2] Preventing postoperative pain is crucial; however, opioids, commonly used for pain management, can adversely affect recovery quality.[3]

Peripheral nerve blocks, especially with ultrasound guidance, have surged, and among them is the erector spinae plane (ESP) block – a novel thoracic analgesia method.[4,5] Several studies highlight ESP blocks’ efficacy in managing postoperative pain in breast surgery patients.[5,6,7,8] Oksuz et al.[9] compared tumescent anesthesia with ESP block for breast reduction surgery patients, finding that ESP block resulted in lower tramadol use, lower pain scores, reduced need for extra pain relief, and higher patient satisfaction compared to tumescent anesthesia, indicating ESP block as a more effective postoperative analgesia method.

Local anesthetics used in ESP, particularly ropivacaine – an amide-based local anesthetic – provide prolonged action with reduced cardiac toxicity and sensory-motor effects. However, its limited efficacy in nerve blocks and postoperative pain management often leads to pain during the critical initial postoperative period, sometimes requiring additional opioid use.[10,11] Dexmedetomidine, a selective α2-adrenergic receptor agonist, shows promise as an adjunct in peripheral nerve blocks to extend the duration of local anesthetics.[12] It stimulates the vagus nerve, reducing plasma catecholamine levels, resulting in stable hemodynamics and decreased blood pressure and heart rate.[13] A recent meta-analysis conducted by Dai et al.[10] underscored the efficacy of dexmedetomidine in prolonging sensory block duration, motor block duration, and analgesia when added as an adjunct to ropivacaine in brachial plexus blocks. To the best of the author’s knowledge, studies that compared the effectiveness of adding dexmedetomidine to ropivacaine in ESP in mastectomy patients are scarce, and most studies have investigated its use in paravertebral and pectoral nerve blocks.[14] In this study, we hypothesize that combining dexmedetomidine with ropivacaine in ESP reduces postmastectomy opioid consumption. We aim to assess this combination’s efficacy compared to ropivacaine alone on opioid consumption and pain scores after mastectomy with lymph node dissection. Our primary outcome includes total opioid consumption during the postoperative care unit (PACU) stay and 24 hours after surgery, with secondary objectives including monitoring intraoperative hemodynamics, postoperative pain, opioid requirements, and occurrences of hypotension, bradycardia, and postoperative nausea and vomiting (PONV) until discharge.

Materials and Methods

Design and patients

This is a double-blind, prospective, parallel, randomized controlled trial conducted at a tertiary referral hospital, “Lebanese American University Medical Center – Rizk Hospital” in Lebanon. This study was reviewed and approved by the LAU Institutional Review Board (LAUMCRH.YJ1.16/Jul/2019), and all subjects signed a written informed consent before undergoing the study interventions. The study procedures were registered with clinicaltrials.gov before the initiation of the study (NCT04029467). This study conforms with the CONSORT reporting guidelines for clinical trials. The patients were identified through the Medical Center’s surgical list admitted to the preadmission unit between August 6, 2019 and January 14, 2022.

Inclusion and exclusion criteria

All patients undergoing an elective partial or radical mastectomy with sentinel lymph node dissection at LAUMC-RH, the American Society of Anesthesiologists classification of Physical Health (ASA) class Ⅰ, Ⅱ, and Ⅲ, and aged between 18 and 80 years were screened for potential consenting and inclusion. Exclusion criteria were pregnant women, women undergoing bilateral mastectomy, women with skin infection at the site of needle puncture, with coagulopathy problems, allergy or contraindication to any of the study drugs, and recent use of opioids. To ensure the participant had no contraindications to the ESP block, initial laboratory results were reviewed in the patient’s chart to determine inclusion/exclusion suitability.

Randomization

After obtaining written informed consent from each eligible patient, randomization into one of two ESP block modalities was performed. The randomization scheme was generated by an online randomizer (website: http://www.jerrydallal.com/random/randomize.htm) using two different-sized blocks to eliminate the possibility of identifying which participant was assigned to which group and avoid the prediction of the next group assignment based on previous assignments.

Blinding and concealment

Blinding of patients, the data collector, and the outcome assessor was achieved by concealing the allocation treatment modality. As for blinding the anesthesiologist in charge, the registered anesthesia nurse or resident not involved in the study allocated the interventions via opaque sealed envelopes marked according to the allocation schedule. Additionally, the anesthesia nurse who prepared the medications was not involved, neither in the study nor in the data collection.

Anesthesia procedures and data collection

Immediately after randomization, demographic data were then reported, including age, weight, and ASA class. In the induction room, the nurse/resident prepared the patient and the medications, after which the patient was handed to the anesthesiologist to perform the ESP block. Once in the induction room, baseline vitals, including noninvasive blood pressure, oxygen saturation, and heart rate, had been recorded until the end of the surgery. After properly placing the patient into Fowler’s position and just before performing the ESP block, all patients received 1 mg of midazolam intravenously. The ESP block modalities were provided to each patient after sterility was maintained, and the skin was prepped at the site of the mastectomy. Patients in the experimental group received ESP block with 20 ml ropivacaine 0.375% and 0.5 µg/kg dexmedetomidine 20 minutes before the operation. Patients allocated to the control group received an ESP block with 20 ml ropivacaine 0.375% 20 minutes before the operation. After being transferred to the operating room, all patients underwent general anesthesia. After preoxygenation using 100% oxygen for 3 minutes, induction using 1–2 mg/kg of propofol, 2 µg/kg of fentanyl, and 0.6 mg/kg of rocuronium was performed. Anesthesia was maintained using the inhaled anesthetic sevoflurane, with 50 µg fentanyl administered as needed to keep hemodynamic parameters within 20% of the baseline. Vagolytics (atropine 0.5 mg or glycopyrrolate 0.1 mg), vasopressors (phenylephrine 0.1 mg or ephedrine 6 mg), and volume infusions (250 ml of normal saline) were used to keep the mean arterial blood pressure and the heart rate within 20% of the baseline. Acetaminophen 1 g was administered intravenously 30 minutes before the end of the surgery. We preferred to refrain from administering nonsteroidal anti-inflammatory drugs given the mean age of the patients in this study, which was 60 years old. Sevoflurane was discontinued when the last skin suture was applied. In the postoperative care unit, opioids were administered when the pain score levels exceeded a Visual Analogue Scale (VAS) score of 4 following the routine practice of our institution and cumulative opioid consumption was reported upon PACU discharge. Pain score was assessed upon PACU discharge using the same routinely used VAS scoring approach. VAS scores range between 0 (indicating no pain) and 10 (indicating worst pain felt). Upon PACU discharge, we collected data on opioid consumption and pain scores up to 24 hours postsurgery. Total opioid consumption represented the total morphine provided in the PACU and the oxycodone morphine equivalent provided on the floor using the formula 1 mg Oxycodone = 1.5 mg morphine. All patients received 1 g of oral acetaminophen every 6 hours after discharge from the PACU. Side effects including sedation, pruritic, respiratory depression, nausea, and vomiting were collected and documented during the follow-up period. Follow-up time points were conducted every 2 hours up to 6 hours and then every 6 hours up to 24 hours post surgery. VAS pain scores at 6, 12, and 24 hours were reported.

Sample size calculation

Gurkan et al. compared the use of ESP with bupivacaine to a control group, with no intervention, in 50 patients who underwent mastectomy with lymph node dissection.[5] In their study, Gurkan et al. reported that the mean morphine consumption during the first 24 hours after surgery was 5.76 mg ± 3.8 mg in the experimental group versus 16.6 mg ± 6.92 mg in the control group. Considering the experimental group morphine consumption in the Gurkan et al. study as our reference point (similar intervention to our study protocol) and our clinical judgment, a 70% decrease in morphine consumption between the experimental and the control group patients is sought. An a priori power analysis for an independent sample t-test was conducted using G-POWER software to determine the sample size required for this study. Using an alpha of 0.05, a power (β) of 0.80, and a two-tailed test for detecting differences between the two study groups, a sample size of 15 participants per group was determined. Considering a potential attrition bias, a 30% dropout rate was considered. A total sample size of 44 was required (22 in each treatment arm).

Statistical analysis

Variables with data collected on a continuous scale (age, weight, mean systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate, surgery, and anesthesia duration, time till eye-opening, time from the end of the surgery till extubating, time to first analgesic, PACU stay time, and intraoperative and postoperative medications) were reported as mean ± SD for normally distributed data and as median (IQR) for nonparametric data. Categorical data (ASA class and adverse events) were presented as frequencies and percentages. Effect size was reported for baseline characteristics and intraoperative data. An independent samples t-test was used for normally distributed continuous data to determine any statistically significant differences between the experimental and control group patients’ variables. Variables with data that were not normally distributed were analyzed using nonparametric tests. The Pearson χ2 test detected any statistically significant differences in categorical variables between the two study groups. Survival analysis was performed to determine whether there were any significant differences in the variable “time to first opioid administration after the surgery”. The level of significance was considered to be at 0.05. Statistical analyses were conducted using Stata version 18 (StataCorp, College Station, TX, USA).

Results

Study population and intraoperative data

A final sample of 44 participants aged between 36 and 77 years and undergoing mastectomy with axillary lymph node dissection under general anesthesia were enrolled in the study between August 6, 2019 and January 14, 2022. No patients were excluded or withdrawn at any stage of the study. The study consort diagram is illustrated in Figure 1. The sample data were complete; there were no missing values. Baseline characteristics and intraoperative data of the study participants are presented in Table 1. There were no statistically or clinically significant differences between the two groups with respect to baseline characteristics (effect size ≤ 0.5).

Figure 1.

CONSORT diagram of included patients

Table 1.

Baseline characteristics and intraoperative data

	Control group n=22	Experimental group n=22	Effect size
Baseline characteristics
Age, years	59.59±9.49	60.59±11.67	-0.09
Weight, kg	69.68±9.89	69.77±14.90	-0.007
ASA Score
1     2     3	3 17 2	2 18 2	-0.1
Intraoperative vitals and duration
Mean Systolic Blood Pressure, mmHg	111.32±12.82	115.68±14.75	-0.3
Mean Diastolic Blood Pressure, mmHg	61.05±7.38	63.55±8.12	-0.3
Mean of Mean Arterial Blood Pressure, mmHg	77.82±8.68	80.95±9.73	-0.3
Mean Heart Rate, beats per minute	66.41±9.72	71.82±9.98	-0.5
Surgery duration, minutes	125.14±32.40	133.91±28.84	-0.2
Anesthesia duration, minutes	167.55±35.93	169.41±30.94	-0.05
Time till eye-opening, minutes	9.23±4.59	9.00±5.54	0.04
End of surgery till extubation, minutes	13.41±5.66	10.59±5.51	0.5
Intraoperative medications
Intraoperative Antihypertensive (dose)	0.57±1.29	1.07±1.42	-0.3
Intraoperative Antihypertensives (number of patients)	5 (22.73%)	9 (40.91%)	0.4
Intraoperative Vasopressors (dose)	2.39±3.09	0.86±1.28	0.6
Intraoperative Vasopressors (number of patients)	12 (54.54%)	8 (36.36%)	-0.4
Fentanyl, µg	182.95±71.29	205.68±63.59	-0.3

Vital signs were fluctuating within normal ranges and remained stable during the surgery. Intraoperative medication use was not statistically significantly different between the two groups [Table 1]. Nausea occurred in five patients in the control group and two patients in the experimental group, which was not statistically significantly different (P = 0.412). There was no vomiting incidence in any of the patients.

Primary outcomes

PACU opioid consumption was limited to morphine only and was significantly lower in patients belonging to the experimental group compared to the patients in the control group (3.14 ± 2.85 vs 5.86 ± 4.52, P = 0.021). However, the total opioid consumption from 1 hour after arrival in the PACU up to 24 hours postsurgery was not significantly different between the experimental and control groups (0.00 [0–4] vs 0.00 [0–0], P = 0.353).

Secondary outcomes

The duration of stay and pain upon discharge from PACU were not statistically significantly different between the two groups (P = 0.576 and P = 0.392, respectively) [Table 2]. Pain scores were statistically significantly lower, although not clinically significant, in the experimental group compared to the control groups 12 hours after surgery (0.50 [0–2] vs 2 [0–3], P = 0.025 at 12 hours) [Table 2]. The pain score remained lower 24 hours postoperatively in the experimental group; however, the difference was not statistically significant (0.00 [0–1] vs 1.00 [0–2], P = 0.062 at 24 hours) with both scores remaining below 2. The median survival time to opioid administration in the PACU was not significantly different between the two groups (P = 0.09). Survival analysis is presented in Table 3, and the survival plot is shown in Figure 2.

Table 2.

Post-anesthesia care unit morphine consumption and pain levels

	Control group n=22	Experimental group n=22	P
Post-Anesthesia Care Unit
Total Opioid Consumption (mg)	5.86±4.52	3.14±2.85	0.021
Duration of Stay (min)	81.59±26.96	72.18±14.54	0.576
VAS upon Discharge	0.00 [0 – 0]	0.00 [0 – 0]	0.607
Pain after surgery
6 hours	2.50 [0 – 3]	0.00 [0 – 2]	0.022
12 hours	2.00 [0 – 3]	0.50 [0 – 2]	0.025
24 hours	1.00 [0 – 2]	0.00 [0 – 1]	0.062

Table 3.

Survival analysis

	Median	95% CI	Log-Rank (Mantel-Cox) P
Control	10.00	0.13 – 0.52	0.09
Experimental	25.00	0.23 – 0.72

Figure 2.

Kaplan–Meier survival analysis plot of the time to opioid administration during the post-anesthesia care unit stay shows no statistically significant difference between the control and experimental groups

Discussion

In this study, the addition of dexmedetomidine to ropivacaine in patients undergoing mastectomy with axillary lymph node dissection under general anesthesia significantly reduced PACU opioid consumption compared to ropivacaine alone. Similarly, the effectiveness of adding dexmedetomidine to regional anesthetic techniques for reducing PACU opioid consumption after breast surgery has shown results comparable to ours.[2,15,16,17] Pain scores remained statistically significantly lower in the experimental group compared to the control group up to 12 hours after surgery, although the scores were reflective of mild pain throughout the study monitoring period, VAS <3. This is similar to the results obtained by Kaur et al.,[17] who examined the effect of adding dexmedetomidine to ropivacaine in pecs block in patients undergoing breast oncological surgeries. In the same vein, Wu et al.[15] examined the effect of dexmedetomidine as an adjuvant to ropivacaine in ultrasound-guided deep serratus anterior plane block on the quality of recovery scores in patients undergoing mastectomy. Similar to our findings, they reported significantly lower postoperative opioid consumption and pain VAS scores at 12 hours in patients receiving dexmedetomidine.

Dexmedetomidine’s adjuvant effect improves block success and duration, addressing some variability in fascial plane blocks including ESP and enhancing their opioid-sparing potential in mastectomy patients.[18] Specifically, dexmedetomidine at a dose of 0.5–2 µg/kg has been shown to improve and prolong analgesia in a dose-dependent manner for up to 48 hours.[18] Our dose of 0.5 µg/kg falls within this range. However, the opioid-sparing effect and lower pain scores in the experimental group were not sustained up to 24 hours after surgery in this study. This could be in part explained by a larger sample size needed to power the detection of a significant reduction beyond 12 hours after surgery. Other reasons could also play a role. For instance, Wu et al.[15] showed a significant reduction in pain 24 hours postsurgery in the experimental group. This difference might partially be attributed to the higher dose of dexmedetomidine used in their study (1 µg/kg) and the extended sensory block due to systemic dexmedetomidine administration (1 µg/kg intravenously for 10 minutes before the ESP).[15,19] Several studies have indicated that intravenous dexmedetomidine can effectively reduce the need for opioids during surgery, but it is also associated with a biphasic blood pressure response, initially causing a transient hypertensive phase.[20,21,22] To mitigate this potential side effect, we avoided intravenous administration and used dexmedetomidine exclusively in the ESP block during the mastectomy. This approach offers an intriguing opportunity to reduce postoperative pain and opioid use without the cardiovascular risks associated with intravenous administration.[20,21] Additionally, while the erector spinae plane block has been shown to be superior to the serratus anterior plane block in terms of recovery and pain scores, differences in dexmedetomidine dosage and bupivacaine formulations may influence pain management outcomes.[15,23] Furthermore, Wang et al.[2] recently published a comparable study to ours, but with higher doses of dexmedetomidine. Their results showed significantly lower pain scores in the experimental group compared to patients who received ropivacaine alone 24 hours postsurgery. This discrepancy with their 24-hour pain score result compared to ours might also be explained by the higher doses used in their study: 30 ml of 0.33% ropivacaine with 1 µg/kg dexmedetomidine, compared to 20 ml of 0.375% ropivacaine with 0.5 µg/kg dexmedetomidine in our study.

Dexmedetomidine is associated with bradycardia and hypotension at increased doses; however, in our study, the doses used were safe and coupled with proper monitoring and use of vagolytics, vasopressors, and volume infusions. No major side effects were reported, and hemodynamic management was not significantly different between the control and the experimental group patients, which aligns with other studies.[2,12,15,17] The incidence of postoperative nausea and vomiting was minimal and not significantly different between the two groups studied. This result aligns with other studies where dexmedetomidine administration mitigated postoperative pain and decreased adverse effects such as postoperative nausea and vomiting.[14,24,25,26,27,28]

As with other randomized clinical trials, our study has its set of limitations. First, the study was conducted at a single tertiary hospital in a lower-middle-income country, which may not be representative of other regional hospitals with different care practices. However, conducting a multicenter randomized controlled trial is only practical with adequate funding and the establishment of standardized perioperative care protocols. Second, the study was not powered to detect smaller clinically significant differences in the primary outcome. Future studies are encouraged to consider smaller effect sizes. Third, although assessment by the nursing team in the PACU was followed as per the institutional policy, the research team did not perform the reporting of pain scores in the PACU before opioid administration. This prevented us from comparing PACU pain levels between the two groups. Fourth, a smaller effect size for the sample size calculation might have been more appropriate to detect both clinical and statistical differences in total opioid consumption 24 hours after surgery. However, to our knowledge, the literature on ESP in mastectomy was limited at the time this study was conducted. Last, although beyond the primary objective of this study, chronic pain assessment is a crucial component of post-mastectomy pain management, typically occurring 3 months after surgery. Due to limited resources, prolonged patient follow-up was not feasible.

Conclusions

In conclusion, the incorporation of dexmedetomidine within safe dosing limits into ropivacaine for erector spinae block demonstrates a significant opioid-sparing effect by reducing both opioid consumption in the postoperative care unit and immediate postoperative pain in mastectomy patients. However, this did not extend to delaying the time to the first analgesic request. Future studies should focus on comparing various dexmedetomidine doses to evaluate their efficacy and potential side effects in similar clinical scenarios and should aim to assess chronic pain profiles across the different groups.

Ethics approval statement

This study was reviewed and approved by the LAU Institutional Review Board (LAUMCRH.YJ1.16/Jul/2019).

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Departmental support – The Lebanese American University Medical Center Department of Anesthesiology.