Analgesic effect of ketorolac as an adjuvant to bupivacaine in ultrasound-guided pectoral nerve block (I + II) for patients undergoing modified radical mastectomy: A randomized controlled clinical trial

Abstract

Background and Aims:

Many drugs have been tried as adjuvant to local anesthetic in different nerve blocks. Ketorolac is one of them, but it has never been used in pectoral nerve block. In this study, we evaluated its adjuvant effect with local anesthetic on postoperative analgesia in ultrasound (US)-guided pectoral nerve (PECS) blocks. The aim was to assess the quality and the duration of analgesia by the addition of ketorolac in the PECS block.

Material and Methods:

46 patients who underwent modified radical mastectomies under general anesthesia were randomized into two groups: control group, where pectoral nerve block was given with bupivacaine 0.25% only; and ketorolac group, where the block was given with bupivacaine 0.25% and ketorolac 30 mg.

Results:

Patients who needed postoperative supplemental analgesia were significantly less in the ketorolac group (9 vs 21 patients, P = 0.00) and that first-time analgesic requirement was significantly later in the ketorolac group (14 hrs) postoperatively compared to the control group (9 hrs) postoperatively.

Conclusion:

Adding ketorolac to bupivacaine in pectoral nerve block safely increases postoperative duration of analgesia.

Introduction

Multiple regional analgesic blocks have been used for reducing pain in breast surgeries. These include local infiltration of the wound, thoracic epidural block,^[1,2] thoracic paravertebral block,^[3,4] intercostal nerve block,^[5] thoracic spinal anesthesia,^[6] and the newly described ultrasound (US)-guided pectoral nerve (PECS) blocks I and II, and the serratus plane block (SPB). Blanco defined pectoral nerve block (PECSB) for pain relief in breast surgeries.^[7] It is done by injecting local anesthetic in the interfascial plane between pectoralis major and minor muscles (PECS-I block) and above the serratus anterior muscle at the third rib (PECS-II block). It is a safe and effective technique.^[8] Regional anesthesia could have beneficial outcomes on long-term oncological changes, including decreasing tumor progression by blocking the surgical stress response, providing good analgesia, and requiring less opioid, and the direct protective effect of local anesthetics on migration of tumor cells.^[9]

Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) that abolishes synthesis of prostaglandins which play a role in sensitization of nociceptor at surgical site.^[10] It has been used as an additive to local anesthetics in some regional analgesic techniques.^[11] No one has tried ketorolac as an adjuvant in PECS blocks, so in this study we assessed whether it improves the quality and/or the duration of postoperative analgesia when added to bupivacaine in PECS block in breast surgery in comparison to bupivacaine alone.

Material and Methods

The trial was registered at Pan African Clinical Trials with trial no: PACTR201907766143535, after obtaining approval by the Research Ethics Committee, (10/3/2019, Research N 3322#).

A written informed patient consent was obtained with an explanation regarding the purpose, methods, effects, and complications from 46 ASA physical status I or II female patients aged 21–60 years old with BMI less than 35 undergoing unilateral modified radical mastectomy (MRM) under general anesthesia were included. Exclusion criteria was patients with previous surgery in ipsilateral infraclavicular region; known allergy to any of the study drugs, psychiatric illnesses, opioid dependence; or drug abuse that would affect perception and pain evaluation.

The sample size was calculated by the equation N = 2 δ² (Zα + Zb)²/D^2[12] where N is the number of the subjects of each group, Zα is the value of standard normal distribution; P value 5% for two-sided test is 1.96. Zb is the value of a standard normal for the desired statistical power 90% and it equals 1.28; D is the detectable difference between the means of total postoperative analgesic consumption between both groups.^[13] It equals 6.36 mg and δ is the highest within group standard deviation 6.28^. So when N was 20.47, an expected dropout of 10% was added. So, we recruited 23 patients for each group.

The study was randomized, controlled, and triple-blinded. The study patients were randomly allocated to two equal groups (23 patients in each group) using computer generated random numbers which were concealed in closed envelopes that were sequentially numbered. An anesthesiologist, who did not participate in the study, selected an envelope and prepared the drugs. A CONSORT flow diagram shows patients’ enrollment in the study [Figure 1].^[9]

Figure 1.

CONSORT flow diagram

Preoperatively, patients were taught how to evaluate their own pain intensity using the Visual Analogue Scale (VAS) scored from “no pain” to “worst pain imaginable”. The patients’ age, height, weight, and ASA status were recorded. In the operating room, after pre-oxygenation, induction of anesthesia for all participating patients was done with two mcg/kg fentanyl and (1.5 – 2) mg/kg propofol. Endotracheal intubation was facilitated by cis-atracurium at 0.15 mg/kg dose The patients were randomized to two groups: first group received 30 ml anesthetic solution (a mixture of 15 ml bupivacaine 0.5% plus 15 ml of normal saline), a second group received 30 ml solution (a mixture of 15 ml bupivacaine 0.5% and 2 ml of ketorolac 30 mg with 13 ml of normal saline).

We used the two-needle approach of PECS block, with the patient in supine position and abducted ipsilateral upper limb at 90°. We used 90 mm 22 G spinal needle and linear array ultrasound probe of high frequency (SonoSite M -TURBO, Inc. U.S.A) scanning from the lateral third of the clavicle going towards the mid axillary line. The first needle was introduced in plane using ultrasound probe, to the fascial plane between two pectoralis muscles, and 10 ml of anesthetic solution was injected between them [Figures 2–4]. We moved the probe towards axilla till the serratus anterior muscle (seen above the second, third, and fourth ribs); then a second needle was inserted into the fascial plane between pectoralis minor and serratus anterior muscles, and 20 ml of anesthetic solution was injected after negative aspiration. This brakes through the axillary door and reaches the long thoracic nerve and at least two intercostal nerves. After 20 minutes, skin incision was allowed. Maintenance of anesthesia was done by Isoflurane 1.5% and 0.1 mg/kg cis-atracurium was given when more than two twitches were seen in train of four by using nerve stimulator. Fentanyl boluses of 50mcg were given intravenously if heart rate (HR) and mean arterial blood pressure (MAP) increased more than 20% from the preoperative baseline.

Figure 2.

US view showing pectoralis major muscle (PMm) and pectoralis minor muscle (Pmm)

Figure 4.

Injection of local anesthetics (LA)

Figure 3.

The needle introduced with ultrasound probe to the fascial plane between the two pectoralis muscles

We recorded vital signs (patient’s heart rate, non-invasive blood pressure, oxygen saturation) every minute for the first five minutes, then every five minutes in the next 30 minutes, then every 15 minutes till the end of surgery. Neuromuscular monitoring was continued until the end of anesthesia and at least until recover of the TOF T4/T1 ratio to 0.9.

Reversal of muscle relaxant was carried out with 0.07 mg/kg of neostigmine and 0.01 mg/kg of atropine, and tracheal extubation was performed on return of consciousness. Postoperative analgesia was given by intravenous patient-controlled analgesia (IVPCA). Once pain was experienced by the patient, patient pressed a button on the IV-PCA pump (Graseby 3300 Pump; Smith Medical International, Ashford, Kent, UK) which was programmed to deliver a bolus of 1 ml, with 15 minutes lockout interval and no basal infusion. Each 1 ml of IVPCA solution contained ten mg meperidine, and maximum dose of meperidine in four hours was 160 mg. Postoperatively, they were monitored for vital signs and the VAS score for 24 hours. Also, the time for the first request of analgesia, and total meperidine consumption were monitored in those 24 hours.

Statistical analysis

We used SPSS® version 22 (SPSS Inc., Chicago, IL, USA) for Windows. Descriptive data was expressed as mean and SD for continuous variables, and count and/or percentages (%) for discrete variables. To analyze continuous variables between groups, independent sample student t test was used. One-way ANOVA was used to analyze the parametric follow-up data within the same group. Categorical variables were analyzed using the Chi-squared test. P < 0.05 was considered statistically significant. Presentation of the statistical outcomes had been performed in a form of tables and graphs using the “Microsoft Office Excel® 2010” program.

Results

Both groups were comparable regarding patients’ characteristics, as shown in Table 1.

Table 1.

Demographic data among both groups variable ketorolac group

Variable	Control group (M±SD)	Ketorolac group (M±SD)	P
Age (years)	45.87±10.7	49.57±6.8	0.170 (NS)
Height (cm)	162.00±4.5	161.83±3.4	0.883 (NS)
Weight (kg)	77.52±5.9	75.13±6.1	0.184 (NS)
BMI (kg/m2)	29.60±2.8	28.73±2.7	0.302 (NS)
ASA physical
status I	12 (52.2%)	15 (65.2%)	0.369 (NS)
N (%) II	11 (47.8%)	8 (34.8%)
Total number/group	23	23

Data are presented as mean (M) ± standard deviation (SD), Number (N) and percentage (%). NS: no significant difference (P>0.05)

Both tables [Tables 2 and 3] show that the proportion of patients who needed postoperative analgesia were significantly less in the ketorolac group (9 patients) as (7 patients needed 10 mg and another 2 needed 20 mg) compared to 21 patients in the control group (4 patients needed 10 mg, 15 needed 20 mg and another 2 needed 30 mg). Moreover, the duration of the first analgesic request was significantly longer in the ketorolac group (14 hrs) postoperatively compared to the control group (9 hrs) postoperatively. Also, total 24-hr meperidine consumption (mg) was significantly less in the ketorolac group (12 mg) compared to the control group (19 mg). There were no hemodynamic changes in both groups during intra and postoperative periods.

Table 2.

Postoperative analgesic requirements between both groups

	Control group (N=23) N (%)	Ketorolac group (N=23) N (%)	P
Patients who needed meperidine (PCA) analgesia N (%)
10 mg	4 (17.4%)	7 (30.4%)	0.300 (NS)
20 mg	15 (65.2%)	2 (8.7%)	0.000*
30 mg	2 (8.7%)	0 (0%)	0.148 (NS)
Total	21 (91.3%)	9 (39.1%)	0.000*
Those who didn’t need analgesia	2 (8.7%)	14 (60.9%)	0.000*

Data are presented as number of patients (N) and percentage (%). *statistically significant difference (P<0.05), NS: non-significant difference (P>0.05)

Table 3.

Postoperative meperidine consumption and first request of analgesia in patients who consumed analgesia

	Control group (N=21) M±SD	Ketorolac group (N=9) M±SD	P
1st request of analgesia (hours)	9.05±3.4	14.22±1.9	0.000*
Total 24-hour meperidine consumption (mg)	19.05±5.4	12.22±4.4	0.002*

Data are presented as mean±standard deviation, *statistically significant difference (P<0.05)

Discussion

Post-mastectomy pain syndrome (PMPS) is a chronic pain condition, typically neuropathic in nature, which can complicate breast surgery.^[9] Treating acute postoperative pain properly is important to prevent post-mastectomy pain syndrome (PMPS). Peripheral nerve block (PNB) plays a significant role in decreasing this pain. Adjuvants may eliminate the need for continuous catheter to extend the duration of the PNB, and thereby reduce the risk of catheter-mediated infection.^[14] Adding NSAIDs such as ketorolac for wound instillation may affect peripheral inflammatory reaction and cytokine release.^[15]

Ketorolac has been used as an adjuvant to local anesthetics in Bier block,^[10] brachial plexus block in different surgeries, and popliteal nerve block.^[11,16-18] However, no one has thus far used it with PECS block. The aim of this study was to evaluate the efficacy of its use with local anesthetics in PECS block for surgical treatment of breast cancer. In this research, 46 women undergoing unilateral MRM were recruited and assigned into one of two equal groups: the control group, which received PECSB with bupivacaine alone, and the ketorolac group, which received bupivacaine with 30 mg ketorolac. Regarding our primary outcome, we found that only 39.1% of the patients in ketorolac group needed postoperative analgesics compared to 91.3% of the control group. The time of the first analgesic request and total dose required were after 14 hours postoperatively and 12 mg in the ketorolac group compared to 9 hours and 19 mg in the control group. Postoperative pain intensity, assessed by VAS score, was not-significantly different between both groups over the time intervals.

Some studies used ketorolac locally in the breast and showed similar results. Mahabir assessed the effect of injecting local anesthetics, NSAIDs, or both into the pocket of the breast implant in surgeries for breast augmentation. He observed that the ketorolac and bupivacaine group spent lesser time in the recovery room and used less analgesia postoperatively than the other group.^[19] Mahabir also studied the effect of intraoperative local application of ketorolac and bupivacaine over the first ten days and documented that it had significant effect in relieving pain for five days postoperatively.^[20] McCarthy assessed the role of pocket irrigation with bupivacaine-ketorolac solution in relieving pain in subpectoral breast augmentation surgery. Patients who had pocket irrigation experienced lower VAS in the early postsurgical period (1 and 6 hours) than those who hadn’t; however, there was no difference in narcotic dose in the same period between both groups. However, they consumed more analgesics on day 1 to day 3 postoperatively. This can be explained by the effect of intraoperative analgesics that were applied into the implant pocket which improved the early postsurgical recovery and pain; but later, the patients required analgesia as the effect of the local anesthetic started to fade after the first few days.^[21]

Clerc documented that combination of S (+) ketamine or ketorolac-to-bupivacaine has slightly better analgesic effect than bupivacaine alone. This could be due to the tension-free technique in hernia repair that already produced less postoperative pain.^[22] A systematic review of the effect of local NSAIDs on postoperative pain in non-ophthalmologic surgeries concluded that it decreased the pain score, delayed the need for analgesia, and reduced the total dose of required analgesics.^[23] Andersen et al.,^[18] applied wound infiltration at the end of total hip replacement surgery and placed an intra-articular catheter 24 hours postoperatively. One group received solutions of ropivacaine, ketorolac, and adrenaline, and the control group were injected with saline; both were observed for six weeks. Patients who received the analgesic solution had less pain up to two weeks postoperatively. Postoperatively, they had lower use of analgesia up to day 4, and were more satisfied as there was less joint stiffness and better function for a week.

Conclusion

Adding 30 mg ketorolac to bupivacaine in PECS block prolongs the duration of postoperative analgesia without affecting the hemodynamics.

Financial support and sponsorship

Sponsors and funding sources: Suez Canal University Hospital provided direct financial support to the research work contained in the manuscript.

We purchased the ketorolac ampules only.

Conflicts of interest

There are no conflicts of interest.