TITLE: Perineural Nalbuphine in Ambulatory Upper Limb Surgery: A Comparison of Effects of Levobupivacaine with and without Nalbuphine as Adjuvant in Supraclavicular Brachial Plexus Block – A Prospective, Double-blinded, Randomized Controlled Study

  ABSTRACT.BACKGROUND AND AIMS:
Various opioid additives have been trialed to prolong brachial plexus block. We evaluated the effect of adding nalbuphine hydrochloride to levobupivacaine for supraclavicular brachial plexus blockade. The primary end-points were the onset and duration of sensory and motor blocks and duration of analgesia.

ABSTRACT.MATERIALS AND METHODS:
Seventy-eight patients (aged 25–45 years) posted for ambulatory forearm and hand surgery under supraclavicular brachial plexus block were divided into two equal groups (Groups LN and LC) in a randomized, double-blind fashion. In Group LN (n = 39), 30 ml 0.5% levobupivacaine + 10 mg (diluted in 2 ml 0.9% saline) nalbuphine hydrochloride, and in Group LC (n = 39), 30 ml 0.5% levobupivacaine + 2 ml normal saline (0.9%) were administered in supraclavicular block. Sensory and motor block onset times and block durations, time to first analgesic use, total analgesic need, postoperative visual analog scale (VAS), hemodynamics, and side effects were recorded for each patient.

ABSTRACT.RESULTS:
Although with similar demographic profile and block (sensory and motor) onset time, sensory and motor block duration and time to first analgesic use were significantly longer and the total need for rescue analgesics was lower in Group LN (P < 0.05) than Group LC. Postoperative VAS value at 24 h was significantly lower in Group LN (P < 0.05). Intraoperative hemodynamics was comparable between two groups, and no any appreciable side effect was noted throughout the study period.

ABSTRACT.CONCLUSION:
It can be concluded that adding nalbuphine hydrochloride to supraclavicular brachial plexus block increases the sensory and motor block duration and time to first analgesic use, and decreases total analgesic use with no side effects.

BODY.I:
Pain frequently hampers the implementation of ambulatory surgery in spite of so many analgesic drugs and regimens.[1] Postoperative pain has a negative impact on patient's early mobilization and discharge as well as it causes unanticipated hospital admission, particularly in a day care setting.[2]  Upper limb surgeries below mid arm are mostly performed under peripheral blocks such as the brachial plexus block. Peripheral nerve blocks provide intraoperative anesthesia as well as it extends analgesia in the postoperative period without major systemic side effects by minimizing stress response and using minimal analgesic drugs.[3]  Levobupivacaine, the S-enantiomer of bupivacaine, is a comparatively newer local anesthetic agent acting on voltage-dependent Na+ channels, introduced into clinical practice, and it also possesses less cardiac and neural toxicities. Levobupivacaine has been shown to be safe and effective for epidural and spinal anesthesia[4] and blockade of the brachial plexus.[456]  Local anesthetics alone for supraclavicular brachial plexus block provide good operative conditions but have a shorter duration of postoperative analgesia. Hence, various adjuvants such as opioids,[7] clonidine,[8] neostigmine, dexamethasone,[9] midazolam,[10] and magnesium[11] have been added to local anesthetics in brachial plexus block to achieve quick, dense, and prolonged block; however, the results are either inconclusive or associated with side effects.  Nalbuphine, derivative of 14-hydroxymorphine, is an agonist-antagonist opioid acting on μ (mu) receptors as antagonist and κ (kappa) receptors as agonist with an analgesic potency equal to morphine and its antagonistic potency is approximately 1⁄4th of that of naloxone.[12] Unlike morphine, it exhibits a ceiling effect on respiratory depression.[13] Nalbuphine has the potential to maintain or even enhance μ-opioid-based analgesia while simultaneously mitigating the μ-opioid side effects.[14] Nalbuphine has the onset of action between 2 and 3 min, duration of action of 3–6 h with cardiovascular stability, and minimal side effects in the dose of 0.2–0.4 mg/kg.[1315] Because of its safety profile, nalbuphine can be used for pain management in children with burns, neoplastic or hematological diseases.[16] Freedom from controlled drug act regulations and improved analgesia with nalbuphine render it more satisfactory for day care surgery than other commonly used opioids.[1718] Despite its known benefits for pain control, nalbuphine has never been studied extensively for its effects as an adjuvant to anesthetics during brachial plexus blocks.  Our current study was designed to test the hypothesis that nalbuphine when added as an adjuvant to levobupivacaine in supraclavicular brachial plexus block enhanced the onset, duration of sensory and motor blocks, duration of analgesia, and quality of block for the patients undergoing ambulatory forearm and hand surgery.

BODY.M:
After obtaining permission from the Institutional Ethics Committee, written informed consent was taken. Totally, 78 adult patients were randomly allocated to two equal groups (n = 39 in each group) using computer-generated random number list. The American Society of Anesthesiologists (ASA) physical status I and II aged between 25 and 45 years of both sexes undergoing ambulatory elective orthopedic surgeries of forearm and hand under supraclavicular brachial plexus block were enrolled in the study. Patients in Group LN received 30 ml 0.5% levobupivacaine + 10 mg (diluted in 2 ml 0.9% saline) nalbuphine hydrochloride for supraclavicular block. Group LC received 30 ml 0.5% levobupivacaine + 2 ml normal saline (0.9%) for the same block.

BODY.M.EXCLUSION CRITERIA:
Patient refusal, any known hypersensitivity or contraindication to levobupivacaine, nalbuphine hydrochloride, pregnancy, lactating mothers, hepatic, renal or cardiopulmonary abnormality, alcoholism, diabetes, long-term analgesic therapy, bleeding diathesis, and local skin site infections were excluded from the study. Patients having a history of significant neurological, psychiatric, or neuromuscular disorders were also excluded.  In preoperative assessment, the patients were enquired about any history of drug allergy, previous operations, or prolonged drug treatment. General examination, systemic examinations, and assessment of the airway were done. Preoperative fasting of minimum 6 h was ensured before the operation. All patients received premedication of tablet diazepam 10 mg orally the night before surgery as per preanesthetic check-up direction to allay anxiety, apprehension, and for sound sleep. The patients also received tablet ranitidine 150 mg in the previous night and the morning of operation with sips of water.  All patients were clinically examined in the preoperative period and routine investigations were checked, and at the same time, whole procedure was explained. Ten centimeters visual analog scale (VAS) (0 – no pain and 10 – worst pain imaginable) was also explained during preoperative visit. On entering the patient in the operating room, standard intraoperative monitors such as electrocardiogram, pulse oximeter, and noninvasive blood pressure were attached and baseline parameter was recorded. Philips IntelliVue MP20 monitor was used for this purpose. Intravenous infusion of Ringer's lactate was started and oxygen was given at 2 L/min via nasal prong. All patients received injection midazolam 0.04 mg/kg before the procedure.  After proper explanation of technique, positioning interscalene groove was indentified, where a mark was made approximately 1.5–2.0 cm posterior to the mid-clavicle point. The stimulation frequency was set at 1 Hz, and the intensity of the stimulating current was initially set to deliver 2 mA and was then gradually decreased. The 22-gauge 5 cm, insulated, Stimuplex® A needle was used. The position of the needle was considered to be acceptable when an output current <0.5 mA still elicited a slight distal motor response in forearm and hand. On negative aspiration for blood, a total volume of 32 ml solution was injected slowly as per allotment of the group and drug. The anesthesiologist performing supraclavicular block was unaware of the constituent of the drug and allotment of the group, and similarly, resident doctors keeping records of different parameters were also unaware of group allotment. Thus, blinding was properly maintained.  Sensory and motor blockades were assessed every 2 min after the completion of injection till 30 min and then every 30 min after the end of surgery till first 10 h, thereafter hourly until the block had completely worn off. Sensory blockade of each nerve was assessed by pinprick. Onset time of motor blockade was defined as the time interval between the end of local anesthetic injection and paresis in all the nerve distributions.  The duration of sensory block was defined as the time interval between the onset of sensory block and the first postoperative pain. The duration of motor block was defined as the time interval between the onset of motor block and complete recovery of motor functions. After 30 min, if the block was considered to be adequate, surgery commenced. Injection diclofenac sodium (rescue analgesic) 75 mg was given intramuscularly when VAS ≥3 cm. The number of injection diclofenac sodium given to each patient during first 24 h of the postoperative period was recorded.

BODY.M.STATISTICAL ANALYSIS:
After a crossover pilot study of ten patients, we estimated the first rescue analgesic requirement time in each group was 510 min. The sample size was estimated using first rescue analgesic requirement between two groups as the main primary variable. The average duration in each group was 510 min and to detect a difference of 10% (i.e., 51 min), at the P < 0.05 level, with a probability of detecting a difference of 80% (1−beta = 0.80). On the basis of previous study assuming within group standard deviation of 90 min, we need to study at least 36 patients per group to be able to reject the null hypothesis that the population means of the groups are equal with probability (power) 0.80. We had taken 39 patients in each group for this prospective study. Raw data were entered into Microsoft Excel spreadsheet and analyzed using standard statistical software SPSS® Statistical Package for the Social Sciences version 18.0 (SPSS Inc., Chicago, IL, USA). Categorical variables were analyzed using the Pearson's Chi-square test. Normally distributed continuous variables were analyzed using the independent sample t-test and P < 0.05 was considered statistically significant.

BODY.R:
We recruited 78 subjects per group, more than the calculated sample size. There were no dropouts. Thirty-nine patients in the nalbuphine group (LN) and 39 in the normal saline control group (LC) were eligible for effectiveness analysis.  The age, body weight, sex distribution, ASA status, and duration of surgery and tourniquet time in the two groups were found to be comparable [Table 1]. Indications for different upper limb orthopedic surgeries were also similar and had no clinical significance (P > 0.05) [Table 2]. The onset of both sensory and motor blocks was statistically comparable between two groups [Table 3] and was clinically insignificant (P > 0.05). Whereas Table 4 and Figure 1 show that sensory and motor block durations were both clinically and statistically greater in the group receiving nalbuphine (LN) (P < 0.05) than Group LC.   Table 1 Comparison of demographic data between the two study groups   Table 2 Indications of upper limb surgeries for two groups   Table 3 Onset time for sensory and motor blocks   Table 4 Duration of sensory and motor blocks   Figure 1Duration of sensory and motor blocks.  The mean time from block placement to the first request for pain medication, i.e., the duration of analgesia was 531.45 min in the nalbuphine group but 501.02 min in the control normal saline group. This difference (about 30.43 min) was statistically as well as clinically significant (P < 0.05) [Table 5 and Figure 2].  Table 5 Rescue analgesic requirement in postoperative period (time and no of intramuscular diclofenac sodium injections)   Figure 2Time of first intramuscular diclofenac injection as rescue analgesic.  Table 5 shows that Group LN required less amount of diclofenac sodium injection as rescue analgesics than patients in Group LC (control saline group) in first 24 h of postoperative period, and the difference is statistically highly significant (P < 0.05).  Table 6 shows the side effects encountered throughout our study which indicates that Group LN suffered from slightly more nausea and sedation, but it was statistically insignificant (P > 0.05) when compared with Group LC.  Table 6 Comparison of side effects   Figure 3 shows that VAS score was of much higher value in Group LN than LC Group. Consort flow diagram shows the patient enrollment, allocation, follow-up, and analysis of all the patients in the study [Flow Chart 1].  Figure 3Comparison of visual analog scale score between Group LN and Group LC.  Flowchart 1CONSORT 2010 flow diagram.

BODY.D:
Day care surgery has proven over the years as the best method to reduce the burden on the health-care resources as well as achievement of extreme patient satisfaction.[19] In developing countries, most of the patients avoid bearing expenses of prolonged hospital stay. In the present day scenario, pain is the most common medical cause of delayed recovery and discharge after ambulatory surgery and a frequent cause of unplanned admission and subsequently delayed return to work.[2021]  In supraclavicular blocks, typical features include rapid onset, predictable, and dense anesthesia along with its high success rate.[22] Various adjuvants have been tried along with local anesthetics in brachial plexus block to achieve quick, dense, and prolonged block;[23] however, the results are either inconclusive or associated with side effects.  Nalbuphine has been used as ambulatory sedative along with propofol for pediatric MRI.[24] Again, the drug has been proven to prevent hemodynamic surges associated with endotracheal intubation.[25] Nalbuphine, like fentanyl, is also popular in producing analgesia during conscious sedation for outpatient oral surgery.[26] The drug is also very effective in subarachnoid as well as epidural route for prolonging sensory block duration and delays analgesic requirement.[2728] Success and nontoxicity of the drug in subarachnoid and epidural route ensure the drug can safely be used perineurally in any peripheral nerve block.  In this prospective, randomized, double-blinded trial, we had compared the effect of nalbuphine hydrochloride (10 mg) diluted in 2 ml normal saline solution and the same volume of normal saline (as control) as an adjuvant to 30 ml 0.50% levobupivacaine in supraclavicular brachial plexus block, on the onset and duration of sensory and motor blocks as well as on the postoperative rescue analgesic (injection diclofenac sodium) requirement for the patients undergoing ambulatory forearm and hand surgery.  The demographic profile, between two groups, which was statistically insignificant (P > 0.05), of our patients was quite similar with other research investigations and provided us the uniform platform to evenly compare the results obtained. A study on the role of nalbuphine for prolongation and quality of postoperative analgesia was conducted by Chatrath et al. in a total of eighty patients yielded similar results.[28] The mean duration of surgery and tourniquet time was almost comparable in both groups with no statistically significant difference [Table 1]. From Table 2, it is quite evident that indications of surgical procedures were almost similar in both groups and had no statistical significance.  The onset time of sensory block, 15.46 ± 3.44 min, in LN Group versus 16.10 ± 4.08 min in LC Group was quite comparable between the two groups (P = 0.46) [Table 3]. Similarly, onset of motor block (20.34 ± 4.76 min in LN Group vs. 21.86 ± 5.34 min in Group LC) was also comparable between the two groups (P = 0.19). Tiwari et al.[27] found that the use of intrathecal nalbuphine and its increased concentration caused a proportional earlier onset of sensory and motor blocks, but it was statistically insignificant. Similar results were also observed by Mukherjee et al.,[29] who also found that with increasing dose of nalbuphine, earlier onset of sensory and motor blocks occurs, but these values have no statistical significance (P > 0.05).  In our study, the duration of sensory block (519.11 ± 38.56 min in Group LN vs. 484.54 ± 41.34 min in Group LC) was significantly longer in the nalbuphine group than in the control group (P = 0.0003). The duration of motor block (484.54 ± 40.44 min in LN Group vs. 455.89 ± 39.43 min in LC Group) was also significantly longer in the nalbuphine group than in the control group (P < 0.0022). These findings were quite similar with Ahluwalia et al.[30] who also found that, in subarachnoid route, sensory and motor blocks were significantly prolonged in nalbuphine-treated group while compared with control. However, on the contrary, Mukherjee et al.[29] found that though sensory block was significantly prolonged along with increasing concentration of nalbuphine, motor was quite comparable between two groups.  In our study, duration of analgesia was 531.45 min and 501.02 min in nalbuphine and control groups, respectively. Thus, the duration of analgesia was significantly (P < 0.05) prolonged in nalbuphine-treated group. However, Chatrath et al.[28] found that epidurally administered nalbuphine does not prolong the duration of analgesia in a statistically significant manner while compared with the equipotent dose of tramadol in the same route. Again, Mukherjee et al.[29] found that duration of analgesia in subarachnoid block increases proportionally with the increase in the dose of nalbuphine applied intrathecally and the difference was statistically significant.  In our study, patients of LN Group required significantly less number of diclofenac sodium injection in first 24 h of the postoperative period than the patients of LC Group (P < 0.05). Mukherjee et al.[29] also found in their study that rescue analgesic requirement in the form of IM diclofenac sodium is gradually lesser with increasing dose of nalbuphine applied intrathecally.  In our study, we have found nausea, vomiting, sedation, and pruritus between both study groups, but the incidence was quite comparable between two groups (P > 0.05). For nausea, our patients needed no active management except increasing the fluid transfusion rate. Two patients in LN Group and one patient in LC Group suffered from vomiting. All the three patients managed with slow intravenous metoclopramide 10 mg. Sedation though was higher in nalbuphine group, it was quite arousable and did not cause any respiratory depression. Similarly, pruritus was higher in nalbuphine group, but it was self-limiting. Jyothi et al.,[31] in their study, with three different doses of nalbuphine (0.8, 1.6, and 2.5 mg intrathecally) found complications such as nausea, vomiting, urinary retention, shivering, pruritus, hypotension, and respiratory depression. Shivering, urinary retention, and hypotension were probably due to spinal anesthesia-related complications. Again, Ahluwalia et al.[30] found that only nausea and vomiting (5 vs. 2) was associated with intrathecal nalbuphine group while compared with tramadol in the same route. Mukherjee et al.[29] administered nalbuphine intrathecally (placebo, 0.2, 0.4, and 0.8 mg) for orthopedic surgery and found that few side effects such as pruritus, nausea vomiting, respiratory depression, and bradycardia were exclusively associated with the highest dose of nalbuphine and hypotension was evident in all the groups which was probably due to spinal anesthesia.  Levobupivacaine dose was chosen as per recommendation in the textbook.[32] We had also followed the drug dose used by our previous researchers.[33] Even we had taken slightly lesser amount of drug to be on a safer side. Ambi et al.[33] had taken 36 ml of 0.5% levobupivacaine for perivascular and perineural ultrasound-guided axillary brachial plexus block and here we have taken 30 ml of 0.5% levobupivacaine. Chatrath et al.,[28] in their studies, used 10 mg nalbuphine in the lumbar epidural route safely without any appreciable complication. Again, the blood concentration of anesthetic drugs after various routes of administration reveals that drug concentration is the highest after intercostal nerve blockade, followed in order of decreasing concentration by injection into caudal epidural space, lumbar epidural space, brachial plexus, and subcutaneous tissue.[32] Thus, any drug used in brachial plexus blockade is associated with a lower risk of absorption and side effects than administered epidurally. Hence, we had chosen 10 mg nalbuphine for the use in brachial plexus block. While writing this discussion, we have found the reference of much higher dose (20 mg) of nalbuphine used for brachial plexus block for the patients undergoing elective forearm and hand surgery.  Several hypothesized mechanisms of action have been suggested to explain the analgesic effect of nalbuphine. Nalbuphine is a synthetic mixed κ-agonist-μ-antagonist opioid with a moderate analgesic effect when compared to morphine. Apart from μ-opioid-based spinal and supraspinal analgesia, inhibition of neuronal serotonin uptake leads to augmentation of the spinal inhibitory pathways for pain.[34] Stimulation of opiate receptors on neurons of the central nervous system leads to an inhibition of intracellular adenylyl cyclase, an opening of potassium channels, and closing the calcium channels. This leads to hyperpolarization of the cell membrane potential and inhibition of action potential transmission of ascending pain pathways.[35]  However, the great drawback of our study was that we had not taken any standardized dose of nalbuphine due to nonavailability of proper pharmaceutical reference relating to dose equivalence with other well-known opioids. A control group was included in our study, but it was little unethical to withhold any adjuvant in these patients for prolongation of postoperative analgesia, particularly when being posted for ambulatory surgery.  Finally, we do conclude that, during day care forearm and hand surgery, addition of 10 mg nalbuphine hydrochloride to levobupivacaine 0.50% solution in supraclavicular brachial plexus block prolongs the duration of sensory and motor blockades, reduces the requirement of rescue analgesic in postoperative period but does not hasten the onset time of sensory and motor blockades without any appreciable side effect.

BODY.D.FINANCIAL SUPPORT AND SPONSORSHIP:
Nil.

BODY.D.CONFLICTS OF INTEREST:
There are no conflicts of interest.

Question: Compared to levobupivacaine + saline what was the result of nalbuphine + levobupivacaine on block duration?
Evidence: time to first analgesic use were significantly longer and the total need for rescue analgesics was lower in Group LN (P < 0.05) than Group LC
Answer: significantly increased