Comparison of Morphine and Clonidine as Adjuvants in Paravertebral Block.

BACKGROUND: General anesthesia (GA) has been considered as the gold standard for breast cancer surgery. The problem of postoperative pain as well as the high incidence of nausea and vomiting has led to the search for a better modality for pain management with fewer side effects. In the last few years, paravertebral block (PVB) has gained immense popularity either in combination with GA or by itself for the anesthetic management of patients undergoing breast surgery. CONTEXT: Paravertebral block in breast surgery. AIMS: This study aims to evaluate the efficacy and duration of postoperative analgesia provided by ultrasound (USG)-guided PVB with bupivacaine and morphine versus bupivacaine and clonidine in patients undergoing modified radical mastectomy (MRM). SUBJECT AND METHODS: In the study, 70 patients who were scheduled for MRM were enrolled and randomly divided into Group M (n = 35) and Group C (n = 35). Both groups received USG-guided PVB at T2-T3 after administering GA. Group M received 2 mg/kg 0.5% bupivacaine with 0.05 mg/kg morphine and Group C received 2 mg/kg 0.5% bupivacaine with 1 μg/kg clonidine in the block. Postoperatively, pain intensity was recorded using the visual analog scale (VAS) (0-10 scale) at 1, 2, 6, 18, and 24 h duration when patients were resting and during a standardized movement. Modified Post Anaesthesia Discharge Scoring System was assessed at 1, 2, 6, 18 and 24 h after surgery.
RESULTS: In this study conducted on 70 patients, VAS scores (both at rest and on movement) were found comparable at postoperative 1, 2, 6, 18, and 24 h (P > 0.05). There was no statistical difference in comparing postanesthesia discharging scoring in both the groups. No incidence of postoperative nausea and vomiting was seen in any group.
CONCLUSIONS: Morphine and clonidine in PVB are equally effective, and there is no superiority of one agent over the other. Hence, both drugs may be used with equal efficacy as adjuvants to bupivacaine in PVB for providing postoperative analgesia.

INTRODUCTION

General anesthesia (GA) has been considered as the gold standard for breast cancer surgery. However, it has been associated with troublesome postoperative pain as well as a high incidence of nausea and vomiting.[12] During recent years, addition of paravertebral nerve block (PVB) has been suggested for breast surgery, to provide adequate and prolonged pain relief with reduced incidence of postoperative nausea and vomiting (PONV).[2] The aim of our study was to compare the analgesic efficacy as well as safety profile of morphine and clonidine as adjuvants with bupivacaine in patients undergoing modified radical mastectomy.

In recent years, PVB has gained popularity for managing intraoperative and postoperative analgesia in thoracic, chest wall, breast, and pelvic surgeries. Many studies have been done to compare the thoracic paravertebral block for postoperative analgesia with other modalities of analgesia.[345] Thoracic paravertebral blocks have proven itself as a feasible and effective method. It has been found that the thoracic paravertebral block in addition to GA or alone provides better postoperative pain control with little adverse effects as compared to other analgesic treatment modalities.[678]

Thoracic PVB involves the injection of local anesthetic at the site where the spinal nerves emerge from the intervertebral foramen in the thoracic spine. There are different techniques for administrating the PVB. It can be given unilaterally or bilaterally, as a single injection technique, a multiple injection techniques or even through a catheter.[910] Multiple injections technique involves identification of the spinous process and local anesthetic injection in the paravertebral space at multiple levels. In breast cancer surgeries, the block can be given at multiple levels from C7 to T7[111213] or as a single injection block at T3–T4. The possible complication can be inadvertent vascular puncture, pleural puncture, pneumothorax, hypotension, epidural or intrathecal spread, and failure of the technique. To minimize the complications, many modalities have been introduced, for example, nerve stimulator technique, ultrasound-guided technique, and under fluoroscopic guidance.

Various adjuvants such as clonidine, morphine, fentanyl, epinephrine, and dexmedetomidine have been used with local anesthetics (e.g., bupivacaine, ropivacaine, and lignocaine) for improving and prolonging the postoperative analgesia with encouraging results.[61114151617181920] There are many studies involving clonidine as adjuvant in PVB,[611] but literature has shown very few studies involving morphine as an adjuvant in PVB.[19] In view of the paucity of literature regarding use of morphine as an adjuvant, we conducted a prospective randomized study to compare the analgesic efficacy of USG-guided single injection PVB with morphine and clonidine as adjuvant with bupivacaine in patients undergoing modified radical mastectomy (MRM).

SUBJECT AND METHODS

The study was conducted, after obtaining the ethical committee approval and written informed consent from all the patients. The study period was 1 year. This prospective randomized controlled study was conducted on 70 patients of breast carcinoma of either gender, scheduled to undergo MRM. The patients were randomly divided into two groups, group M and group C using a list of random numbers, generated by a sealed envelope system. Both groups received thoracic PVB at T2–T3. Group M received 2 mg/kg (not exceeding 20 ml) 0.5% bupivacaine with 0.05 mg/kg morphine and Group C received 2 mg/kg (not exceeding 20 ml) of 0.5% bupivacaine with 1 μg/kg of clonidine in the block.

Inclusion criteria

Age group: 20–60 years

Gender: Male and female

American Society of Anesthesiology Class I–III

Surgery: MRM.

Exclusion criteria

Coagulation disorder

Local infection

Allergy to local anesthetic agents

Anatomic deformity of spine or chest wall

Pregnant or breastfeeding patient

Preexisting neurological deficit

Liver or renal insufficiency

Morbid obesity (body mass index >35 kgm−2)

Psychiatric disease.

Methodology

Preoperative period

All patients underwent a detailed preanesthetic evaluation with all the relevant investigations. All the patients were kept nil per orally as per the recommended guidelines. They were premedicated with tablet alprazolam 0.25 mg, tablet ranitidine 150 mg, and tablet metoclopramide 40 mg at 10 pm at night before surgery and 2 h before the surgery with 1–2 sips of water. The procedure was explained to the patients and consent for the same was taken. Visual analog scale (VAS) was used for determining the intensity of pain, with 0 at one end representing “no pain” and 10 at the other end representing “worst pain imaginable” and explained to the patients. The patients were enrolled in two groups using a list of random numbers, generated by a sealed envelope system.

Intraoperative period

The patients were taken to the operation theater and standard monitors were attached before induction of anesthesia. Basal parameters such as heart rate (HR); blood pressure (BP) – systolic, diastolic, and mean (SBP, DBP, MAP); oxygen saturation (SpO2); and electrocardiography (ECG) were recorded. After securing the intravenous (IV) access with an 18G IV cannula; IV infusion was started using Ringer lactate solutions. All the patients were sedated by injection midazolam 0.01 mg/kg/IV.

General anesthesia

The patients were induced using a standard anesthetic protocol, with injection fentanyl 2 μg/kg, injection propofol 2 mg/kg, and injection vecuronium 0.1 mg/kg.

After intermittent positive-pressure ventilation, Proseal laryngeal mask airway (PLMA) of an appropriate size was inserted to control the airway

Hemodynamic parameters (HR, SBP, DBP, and MAP) along with SpO2 and ETCO2 were monitored

Patients were maintained on O2, nitrous oxide, isoflurane, and vecuronium.

Paravertebral block

After administration of GA, patients were put in the lateral decubitus position with the operative side up. Under all aseptic precautions, using the ultrasound system with a linear probe at 10–12 MHz, the transverse process and pleura were identified and the paravertebral space was entered using an 18G, 10 cm Tuohy's needle at T2–T3. Once the needle was in the paravertebral space as seen with USG, the site was confirmed using hydrodissection technique by injecting 1–2 ml normal saline leading to dipping of pleura. This was followed by injecting drugs (2 mg/kg of 0.5% bupivacaine with 0.05 mg/kg morphine in Group M and 2 mg/kg of 0.5% bupivacaine with 1 μg/kg clonidine in Group C).

The vital parameters were monitored during the procedure and throughout the intraoperative period. If there was any increase in HR/BP more than 20% of the baseline then injection fentanyl bolus was given in a dose of 0.5 μg/kg IV. After the completion of surgery, injection ondansetron 4 mg was given and the neuromuscular blockade was reversed using 100% O2, injection neostigmine 50 μg/kg, and injection glycopyrrolate 10 μg/kg. On adequate neuromuscular reversal, PLMA was removed and the patients were shifted to the recovery room.

Postoperative period

The patients were monitored for 2 h in the recovery room before being shifted to the ward. The parameters monitored in the recovery room were HR, SpO2, SBP, DBP, MAP, and ECG.

Postoperatively, pain intensity using VAS (0–10) was recorded as soon as patients were awake, at 1, 2, 6, 18, and 24 h duration at rest and during a standardized movement (folding hands and moving both arms to an angle of 90° to the body.

Rescue analgesia

Patients were given injection paracetamol 1 g IV when VAS score at rest was more than 4 and injection tramadol 50 mg IV if the pain still persisted.

Postanesthesia discharge score using modified postanesthesia discharging scoring (PADS) system was assessed at 1, 2, 6, 18, and 24 h after the surgery.

Any complication was noted and treated accordingly.

Statistical analysis

This prospective randomized comparative study was analyzed using Cohen's effect size to calculate sample size of two samples with a continuous outcome variable. Quantitative variables were compared using Independent t-test/Mann–Whitney test (when the data sets were not normally distributed) between the two groups. Qualitative variables were compared using Chi-square test/Fisher's exact test. A P < 0.05 will be considered statistically significant. The data were entered in MS Excel spreadsheet and analysis was done using Statistical Package for the Social Sciences (SPSS, IBM) version (latest one).

RESULTS

A total of 70 patients were enrolled and were equally divided into Group C (n = 35) and Group M (n = 35). Demographic profile was similar in both groups, with no significant statistical difference, as shown in Tables 1 and 2. Duration of surgery was 2.81 ± 0.48 h in Group C, while it was found to be 2.72 ± 0.59 h in Group M. The distribution of ASA class among the two groups has been shown in Table 3. The VAS score was found comparable at postoperative 0, 1, 2, 6, 18, and 24 h with no statistical significance, as shown in Tables 4 and 5. In Group C, 34 out of 35 (97%) patients required rescue analgesia at 18-h postoperative duration, while in Group M, 28 out of 35 (80%) patients required rescue analgesia though the results were not significant statistically, as shown in Table 6. The intraoperative fentanyl requirement was found to be comparable in both groups without any significant statistical difference [Table 7]. No statistical difference was observed in PADS, denying any indication of the advantage of clonidine or morphine over each other [Table 8]. PADS score of >9 was achieved in 82.9% patients under 24 h in Group C as compared to 85.7% patients in Group M, as shown in Table 9.

Table 1

Age distribution

Table 2

Body mass index in both the groups

Table 3

American Society of Anesthesiologists classfication

Table 4

Visual analog scale at rest

Table 5

Visual analog scale at movement

Table 6

Rescue analgesia

Table 7

Intra-operative fentanyl requirement

Table 8

Postanesthesia discharging scoring score in both the groups

Table 9

Time to achieve postanesthesia discharging scoring

DISCUSSION

Paravertebral block has established itself as a modality for superior perioperative pain relief with decreased nausea and vomiting in comparison to GA alone in patients undergoing breast surgeries.[168112122232425] However, there is a paucity of literature regarding evidence of superiority of one adjuvant over another to improve the effectiveness of the block. The use of the PVB as a modality of postoperative pain relief has also been studied, and it is found to have an improved postoperative pain control as well as a significant reduction in PONV.[2451724] In our study, we compared the analgesic efficacy of PVB with clonidine and morphine with bupivacaine in patients undergoing MRM.

Naja et al., in 2013, carried out a prospective randomized study to compare the use of nerve stimulator-guided paravertebral block with and without clonidine for women undergoing breast surgery.[11] In MRM, they gave the block at T1–T5 level as separate injections. At each level, they injected 0.06 ml/kg of local anesthestic mixture. Each 20 ml mixture contained 6.5 ml lidocaine 2%, 6 ml lidocaine 2% with epinephrine 5 μ/ml, 7 ml bupivacaine 0.5%, and either 0.5 ml clonidine (150 μ/ml) or 0.5 ml normal saline depending on the group. The surgery was conducted under paravertebral block only. There were no significant differences in hemodynamics, intraoperative fentanyl requirement, duration of surgery, readiness to discharge, and incidence of PONV. The pain score was also found to be significantly less (at rest and on movement) in clonidine group as compared to the control group. The average time to resume normal daily activity was found to be shorter in clonidine group. Hence, it was concluded that the addition of clonidine as an adjuvant to local anesthestic increased the effectiveness of the block, decreasing the postoperative analgesic consumption with lower pain score from day 1 up to 3 days of surgery with no adverse effects or complication. In our study, the rescue analgesia was required at 18 h was 80% and 97.1% in Group M and Group C, respectively. At 24 h, the rescue analgesia requirement was found to be 100% in both the groups. Mean time to achieve PADS > 9 in our study was 24 h in 82.9% and 85.7% of patients in Group C and M, respectively. In his study, consolidated 75 μg clonidine was given in the block and 13% patients required rescue analgesia in first 24 h as compared to 100% in our study. One reason for this may be that we used clonidine in a dose of 1 μg/kg. Whether consolidated use offers an advantage raises a further study question.

In 2013, Björnsson et al. conducted a study in which they compared the effects of adding morphine in the paravertebral block in breast cancer surgery.[18] The block was given as single injection bolus at level T3. Group BA received paravertebral block using 20 ml mixture of 0.5% bupivacaine, epinephrine 5 μg/ml, and 0.4 ml isotonic saline. They also received 0.4 ml morphine (10 mg/ml) subcutaneously. The other group BAM received the 20 ml mixture of 0.5% bupivacaine, epinephrine 5 μg/ml and 0.4 ml morphine (10 mg/ml), and subcutaneous injection of 0.4 ml isotonic saline. Following the block, all patients received GA. There was no significant difference found in VAS pain scores, postoperative analgesic consumption, and nausea score. In the study, it was concluded that paravertebral block is a safe and efficient way to provide postoperative analgesia without any added side effects. Although addition of morphine, however did not improve the efficacy or alter the safety profile.

In our study, we have compared the efficacy of clonidine with morphine as an adjuvant with bupivacaine. We have found no difference in efficacy, postoperative pain relief, and PADS scoring in between the two. In the meta-analysis conducted by Schnabel in 2010, they concluded that PVB in addition to GA or alone provides better postoperative analgesia with less adverse effects.[19] None of the studies have compared the efficacy of clonidine versus morphine as adjuvants in the past. This is the first study to prospectively compare both the drugs. Although Zohar et al. found out in the trial that clonidine enhances efficacy of paravertebral block in comparison to GA, while Björnsson et al. came to conclusion that morphine is ineffective in enhancing paravertebral block when compared to subcutaneously used morphine, We in our study have not found significant difference between adjuvant role of both the drugs.[61118] During the study, we observed that the patients receiving morphine in the PVB were more comfortable and had a longer duration of analgesia. However, this difference was not enough to be statistically significant.

CONCLUSIONS

Paravertebral block is safe and effective technique to provide postoperative analgesia and less side effects. Both the drugs which are used as adjuvants (morphine and clonidine) are safe to administer with minimal side effects. No superiority of one drug over another in any criteria could be found. There is no ambiguity in literature that PVB is the modern anesthesia technique of choice for breast surgeries, superseding GA in almost all aspects of intraoperative analgesia use, PONV, postoperative pain relief, and overall safety benefit for the patient. There is a need to further research and enhance efficacy of paravertebral block by comparing and studying different drugs, our study is a step to compare agents in paravertebral block as a prospective randomized trial in a tertiary care center, though the present study fails to conclude superiority of one drug over another, still there is a need to conduct further research in the light of newly developing anesthetic agents and techniques.

Financial support and sponsorship

This study was financially supported by the Department of Anesthesiology and Critical Care, Safdarjung Hospital, New Delhi, India. CTRI No. CTRI/2018/01/011161.

Conflicts of interest

There are no conflicts of interest.