Effect of Verapamil as an Adjuvant to Levobupivacaine in Supraclavicular Brachial Plexus Block.

BACKGROUND: Many adjuvants have been used with local anesthetics to reduce the time of onset and prolong the duration of analgesia in brachial plexus blocks. However, few studies are there using verapamil as an adjuvant with levobupivacaine. AIMS: This study aims to study the effects of verapamil as adjuvant to levobupivacaine in supraclavicular block for upper extremity surgery.
METHODS: In this double-blinded clinical trial, 60 American Society of Anesthesiologist Class I and II patients posted to undergo upper extremity surgery were divided into 2 different groups randomly. In Group A, the patients received 30 ml levobupivacaine 0.5% plus 2 ml normal saline and Group B patients received 30 ml levobupivacaine 0.5% plus 5 mg verapamil diluted to 2 ml normal saline for supraclavicular block. Time of request for rescue analgesia, onset and duration of sensory motor blocks and changes in hemodynamic parameters were studied and analyzed. P < 0.001 was considered statistically significant.
RESULTS: Time for a request for rescue analgesia was 425.80 ± 90.46 min in Group B and 366.13 ± 70.42 min in Group A which was clinically significant. The mean of sensory and motor block onset time in Group B was less than in Group A, the difference between the two groups being statistically significant (P < 0.001). In Group A, mean duration of sensory block was 316.13 ± 91.08 min and in Group B was 375.83 ± 114.48 min, which was statistically significant (P < 0.001).
CONCLUSION: The addition of verapamil as an adjuvant to levobupivacaine in brachial plexus blockade delayed the requirement of rescue analgesia with decreased onset time and prolonged duration of sensory and motor block characteristics.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Various adjuvant drugs have been used with commonly used local anesthetics like bupivacaine in the regional block to reduce the time of onset and prolong the duration of analgesia but none has been found to be ideal. Due to cardiac side effects of bupivacaine, levobupivacaine is now more commonly used in regional blocks.[1] There are many studies using adjuvants like opioids with levobupivacaine. But due to opioid-related side effects, nonopiod adjuvants are commonly used instead of opioids. Dexmedetomidine and clonidine are commonly used nonopioids used as an adjuvant but they have side effects such as bradycardia, hypotension and sedation.[2] Hence, we have used calcium channel blocker as adjuvant to levobupivacaine in supraclavicular block. Calcium plays an important role in analgesia produced by local anesthetics. The activation of N-methyl-D-aspartate receptors may lead to calcium entry into cells and potentiation of spinal cord and plays a role in pain formation. Hence, calcium channel blockers may prevent central sensitization and provide better sensory motor block characteristics.[3] Verapamil, a calcium channel blocker can potentiate analgesic action of local anesthetics and reduce postoperative pain and analgesic consumption.[4] Due to paucity of studies in literature, we have used verapamil as adjuvant to Levobupivacaine in supraclavicular block. Few studies were there using 2.5 mg of verapamil, showing no impact on onset and duration of sensory motor block. Hence, we have used 5 mg of verapamil as adjuvant to levobupivacaine. The primary aim of the present study was to know whether verapamil (5 mg) as adjuvant to levobupivacaine in supraclavicular brachial plexus block would delay the need of rescue analgesia and to find any impact on number of rescue analgesia required in first 24 h of operation. Effect on sensory or motor block characteristics like onset and duration were the secondary aims of the study.

METHODS

This was a prospective randomized placebo-controlled, doubled-blinded study, conducted in a tertiary care hospital from June 2016 to December 2016 after approval of the Institutional Ethics Committee. It included sixty patients, aged 18–60 years of the American Society of Anesthesiologist Grade I and II of either sex who were scheduled to undergo elbow, forearm, and hand surgery under supraclavicular brachial plexus block. A written informed consent was obtained from each patient after explaining the technique before inclusion in this study. Patient refusal, uncontrolled diabetes mellitus, renal or liver disease, circulatory instability, pregnant women, allergy to local anesthetic, coagulation disorder, and neurological deficit were excluded from study. The subjects were allocated by computer generated randomized number into two equal groups of 30 each. In Group A, patients received 30 ml of levobupivacaine 0.5% with 2 ml of normal saline while in Group B patients received injection verapamil (5 mg) diluted to 2 ml in addition to 30 ml of levobupivacaine 0.5%. Drugs were prepared by the anesthetist not involved in the procedure.

Pulse rate (PR), systolic and diastolic blood pressures (SBP/DBP) and oxygen saturation were recorded just before and after the block. An intravenous line was accessed. Eighteen gauge intravenous (iv) cannula was inserted and ringers lactate was started.

The brachial plexus block was carried out with the patient lying in the supine position without a pillow. Arms kept at sides and head turned to side opposite to the side being blocked. The upper limb to be anesthetized was adducted and extended along the side toward the ipsilateral knee. About 2 cm above the midclavicular point, just lateral to subclavian artery pulsation, a 24-gauge 1.5 inch needle was introduced and directed caudally and medially to reach the first rib. Paraesthesia was elicited in hand by “walking over the first rib, after which 32 ml of drug solution was injected.

After injection, patients were pinpricked at every minute to assess for sensory blockade. The palmar surfaces of the index and little finger were used to test the median and ulnar nerve in the hand, respectively. To test the radial nerve, the dorsal surface of the thumb was used. Sensory characteristics of the block were assessed using response to pinprick to 23-gauge hypodermic needle using the Hollmen scale. 1-Normal sensation to pinprick. 2-Pinprick felt as sharp pointed but weaker with the same area in other limb. 3-Pinprick recognized as touch with blunt object. 4-no response to pinprick.[5]

A modified Lovett rating scale was used for assessing motor block, ranging from 6 (usual muscular force) to 0 (complete paralysis). Thumb abduction was evaluated for the radial nerve, thumb adduction for the ulnar nerve, thumb opposition for the median nerve and flexion of elbow for the musculocutaneous nerve. Lovett Rating Scale: 6-Normal muscular force. 5- Slightly reduced muscular force. 4-Pronounced reduction of muscular force 3-Slightly impaired mobility. 2-Pronounced mobility impairment. 1-Almost complete paralysis. 0-Complete paralysis.[5]

Surgery started at sensory block scale-3. The time of onset of sensory block was defined as the interval between the injection of drug to Hollmen sensory scale 2. The duration of the sensory block was defined as the time interval between the complete sensory block and the return of normal sensation (Scale-1).

The onset time of motor block was defined as the time between the completion of the local anesthetic injection and complete paralysis.

The duration of motor block was defined as the time interval between the complete paralysis and complete recovery of motor function.

The time to first analgesic use and total dose of analgesics needed were recorded during the first postoperative 24 h.

Pain was evaluated using the visual analog scale (VAS) where zero represented no pain and 1–3 mild pain, 4–7 moderate pain, and 8–10-severe pain.[6] VAS monitored at 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h after surgery.

If VAS values were >4, it was considered that analgesic action of the drugs was terminated and rescue analgesic (iv paracetamol 1 g) given. Time to the first dose of rescue analgesia was noted.

PR, SBP, and DBP were monitored at every 15 min interval up to 2 h and then at 4 h, 8 h, 12 h, and at 24 h. The level of sedation was assessed by Ramsay sedation scale.

The possible side-effects such as drowsiness, pruritus, nausea/vomiting, horner's syndrome, phrenic nerve palsy, pneumothorax, respiratory depression, bradycardia, hypotension, and hypoxemia were noted.

The above assessments were carried out by the principal investigator who was blinded to the drugs administered in the brachial plexus block. Neither the patient nor the principal investigator knew about the drug preparation and treatment group of the patient.

In the circumstance of inadequate or patchy block, the block was supplemented with general anesthesia.

Statistical analysis

Based on the primary end point of the study, “time needed for first rescue analgesia” with α error 0.05 and power of the study (1−β) =80%, sample size was calculated to be 28. The patient data and block characteristics like the time of onset and duration of block were categorized and analyzed appropriately using student's unpaired t-test and Chi-square test. A P < 0.05 was considered as statistically significant and P < 0.001 as statistically highly significant.

RESULTS

Block was successful in all the patients, and all the enrolled patients completed the study [Figure 1]. Demographic parameters such as age, sex, weight, and duration of surgery between two groups were statistically not significant (P > 0.05) [Table 1]. The request for first rescue analgesia was earlier in Group B than Group A which was statistically significant [Table 2]. It [Figure 2] showed that in Group B, 14 patients were given only 1 rescue analgesic dose and nine patients were given 2 whereas only seven patients were given 3 rescue analgesic doses in postoperative 24 h. In Group A, 23 patients required three and five patients were given two rescue analgesic and two patients were given 1 dose in postoperative 24 h. This difference in both groups was statically highly significant (P < 0.001)

Figure 1

The patients enrolled in the study and analysis

Table 1

Demographic parameters

Table 2

Sensory-motor block characteristics

Figure 2

Distribution of number of rescue analgesia

In this study, onset of motor and sensory block in Group B was earlier in comparison to Group A. This difference in both Group A and Group B was highly significant (P < 0.001) [Table 2]. The duration of motor and sensory block in Group B was prolonged compared to Group A, the difference between both groups being highly significant (P < 0.001). HR, SBP, and DBP were comparable in both groups which was not statistically significant [Figures 3–5].

Figure 3

Trend of pulse rate at different time interval in both groups

Figure 5

Trend of diastolic blood pressure at different time interval in both groups

Trend of systolic blood pressure at different time interval in both groups

There was no case of failed block or patchy block noted. Qualities of the operative condition in both groups were excellent, and there was no statistically significant difference between two groups. There was no untoward events happened during intra- and post-operative period.

DISCUSSION

Verapamil, a synthetic papaverine derivative, is an L type calcium channel blocker. Verapamil has been shown to have potent local anesthetic activity, reflecting inhibition of fast sodium channels. It induces fast channel blocking effects similar to local anesthetics.[7] We have used verapamil with levobupivacaine in brachial plexus block and concluded that verapamil not only reduced the onset of sensory and motor block but also increased the duration of sensory and motor block. No of rescue analgesia required was low in B Group compared to A Group. Nowycky et al. in 1985 reported the evidence of three distinct types of voltage-gated calcium channels in sensory neurons namely L, T, and N type. Of these L and N type of voltage-gated channels have a significant role in regulating neurotransmitter release from neurons.[8] The N type channel blockers has much more potent antinociceptive effects than L type but are not clinically suitable for their neurotoxicity. Pirec et al. have shown that application of morphine and N type calcium channel blockers attenuate pain mediated by A delta and C fiber mediated nociception.[9] In a series of in vitro experiments on rats, Hara et al. showed that L type channel blockers like verapamil and diltiazem produced both somatic and visceral pain relief in a dose-dependent manner suggesting the relevance of L type channel blockers in pain management.[10]

Lalla et al. in his study concluded that addition of verapamil to lignocaine and bupivacaine combine increases the duration of sensory blockade which was statistically significant but onset of sensory and motor block and duration of motor block was not statistically significant.[11]

Tabaeizavareh et al. in his study concluded that verapamil as adjuvant to epidural bupivacaine could not improve the level of sensory and motor block characteristics.[12]

Mosaffa et al. evaluated analgesic effect of 2 doses of verapamil with bupivacaine in supraclavicular brachial plexus block. They concluded that verapamil (both 2.5 mg and 5 mg) decreased the onset of sensory and motor block and increased the duration of analgesia which was statistically significant.[13]

Kim et al. opined that verapamil, when added to epidural bupivacaine, decreased the postoperative pain through central desensitization.[14]

Messeha and Eldeen studied role of nimodipine, a calcium channel blocker when added to lignocaine in brachial plexus block and found prolongation of sensory blockade.[15]

Choe et al. demonstrated that addition of verapamil (5 mg) to bupivacaine administered epidurally resulted in less postoperative pain and less analgesic requirement.[16]

But Reuben and Reuben in his study concluded that the addition of verapamil to brachial plexus block had no effect on analgesic duration or 24 h analgesic requirement.[17] Multiple other investigations by Hasegawa and Zacny[18] Miranda et al.[19] and Carta et al.[20] suggested that calcium channel blockers combined with local anesthetics could increase analgesic effects.

Omote et al. showed that intrathecal verapamil alone demonstrated neither sensory nor motor block but the combination of lidocaine-tetracaine solution and verapamil produced potent and prolonged pain relief when compared with the local anesthetic solution alone.[21]

Laurito et al. demonstrated that verapamil failed to prolong the duration of lignocaine anesthesia when given subcutaneously.[22] Del Pozo et al. found that subcutaneous verapamil failed to exhibit antinociceptive effects, but analgesic effect was seen when administered by intracerebroventricular route in rats.[23]

Some researchers have suggested that the analgesic effect of verapamil is centrally and not peripherally mediated. There were no side effects in both groups. The limitation of our study was that we have not measured the blood verapamil level. Hence, more number of studies must be done to support our study.

CONCLUSION

We conclude that no of rescue analgesia required was low in verapamil group. Verapamil, when added to Levobupivacaine in supraclavicular brachial plexus, block reduced the onset time of sensory and motor block and increased the duration of sensory and motor block.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.