|Year : 2016 | Volume
| Issue : 2 | Page : 90-95
Intrathecal nalbuphine versus intrathecal fentanyl as adjuvant to 0.5% hyperbaric bupivacaine for orthopedic surgery of lower limbs under subarachnoid block: A comparative evaluation
Kumkum Gupta1, Bhawana Rastogi1, Prashant K Gupta2, Ivesh Singh1, Manoranjan Bansal1, Vasundhera Tyagi1
1 Department of Anaesthesiology and Critical Care, Subharti Medical College, Swami Vivekanand University, Meerut, Uttar Pradesh, India
2 Department of Radiodiagnosis and Interventional Imaging, Subharti Medical College, Swami Vivekanand University, Meerut, Uttar Pradesh, India
|Date of Web Publication||18-Jul-2016|
108-109, Chanakyapuri, Shastri Nagar, Meerut - 250 004, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Subarachnoid block (SAB) possesses many benefits with a drawback of short duration of anesthetic action. Intrathecal opioids have been used to enhance the clinical efficiency and duration of action of local anesthetic drugs. The present study was aimed to compare the clinical efficiency of intrathecal fentanyl with nalbuphine as adjuvant to 0.5% hyperbaric bupivacaine for orthopedic surgery of lower limbs. Patients and Methods: Sixty-eight adult patients of American Society of Anesthesiologist physical status I and II of both gender aged 25-65 years were randomized into two groups of 34 each to receive either fentanyl 25 μg (Group I) or nalbuphine 2 mg (Group II) with 3.5 mL 0.5% hyperbaric bupivacaine, making intrathecal drug volume to 4 mL in each group. Sensory and motor block characteristics and time to first rescue analgesic (intravenous tramadol 100 mg) were recorded as the primary end points. Drug-related side effects of pruritus, nausea/vomiting, and respiratory depression were recorded as the secondary outcomes. Results: Both groups were comparable regarding the onset and cephalic extension of block. The time to two dermatome regressions and time for complete motor recovery were significantly prolonged in patients of Group II with statistical significant difference (P < 0.05). Duration of analgesia was also extended in patients of Group II (378.0 ± 35.72 min) as compared to Group I (234.0 ± 24.10 min) with highly significant difference (P < 0.001). No drug-related side effects were observed in either group. Conclusion: Intrathecal nalbuphine 2 mg as adjuvant to 0.5% bupivacaine was clinically more efficient than fentanyl for enhancing the postoperative analgesia.
Keywords: Fentanyl, nalbuphine, postoperative analgesia, subarachnoid block
|How to cite this article:|
Gupta K, Rastogi B, Gupta PK, Singh I, Bansal M, Tyagi V. Intrathecal nalbuphine versus intrathecal fentanyl as adjuvant to 0.5% hyperbaric bupivacaine for orthopedic surgery of lower limbs under subarachnoid block: A comparative evaluation. Indian J Pain 2016;30:90-5
|How to cite this URL:|
Gupta K, Rastogi B, Gupta PK, Singh I, Bansal M, Tyagi V. Intrathecal nalbuphine versus intrathecal fentanyl as adjuvant to 0.5% hyperbaric bupivacaine for orthopedic surgery of lower limbs under subarachnoid block: A comparative evaluation. Indian J Pain [serial online] 2016 [cited 2019 Mar 26];30:90-5. Available from: http://www.indianjpain.org/text.asp?2016/30/2/90/186463
| Introduction|| |
Regional anesthetic techniques of spinal anesthesia offer many advantages over general anesthesia including reduced stress response to surgery with postoperative analgesia. Since spinal anesthesia provided postoperative analgesia for a short time, many intrathecal adjuvants to local anesthetic have been addressed to augment the clinical efficiency and duration of analgesia. Among various adjuvants, intrathecal opioid has provided an effective prolongation of postoperative analgesia after orthopedic surgical procedures. ,
Opioid analgesics activate opioid receptors located on the primary afferent neurons, resulting in the activation of pain modulating systems. Their activation may either directly decrease neurotransmission or inhibit the release of excitatory neurotransmitters. Opioid receptors are classified as mu, delta, and kappa receptors. Opioid agonist acts on mu receptors and are principally responsible for supraspinal and spinal analgesia along with sedation, nausea, vomiting, pruritus, and respiratory depression. Opioid, an agonist-antagonist, act principally on kappa receptors. Site of action in the spinal cord is substantia gelatinosa. Analgesia with neuraxial opioids is dose-related and specific for visceral rather than somatic pain. 
Both fentanyl and nalbuphine are opioid analgesics. Fentanyl is an opioid agonist and acts on μ-opioid receptors.  Nalbuphine is a synthetic opioid analgesic with agonist-antagonist activity and acts as antagonist at μ-receptors and agonist at k-receptors to provide reasonably potent analgesia. Nalbuphine, when used as adjuvant to hyperbaric bupivacaine, has improved the quality of perioperative analgesia with fewer side effects.  Nalbuphine has been used intrathecally by various investigators to enhance the postoperative analgesia and they did not document any reports of neurotoxicity. ,
Morphine, fentanyl, and other μ-opioids come under Narcotics Act, thus their availability is a major concern in many hospitals in India, while nalbuphine is easily available and devoid of side effects such as nausea, vomiting, pruritus, and respiratory depression.
This randomized double-blind study was aimed to compare the clinical efficiency of intrathecal fentanyl (25 μg) with nalbuphine (2 mg) as adjuvant to 0.5% hyperbaric bupivacaine during orthopedic surgery of lower limbs under subarachnoid block (SAB).
| Patients and Methods|| |
After getting approval of the Institutional Ethical Committee and written informed consent, this prospective randomized double-blind study was conducted from April 2015 to February 2016 at the Department of Anaesthesiology and Critical Care, CSS Hospital Associated to NSCB Subharti Medical College, Meerut, India, on 68 adult patients of American Society of Anesthesiologist (ASA) physical status I and II of both genders aged 25-65 years, weighing 50-90 kg, and height ≥150 cm, scheduled for elective orthopedic surgery of lower limbs under SAB.
After complete preanesthetic check-up and investigation, patients with a history of clinically significant cardiovascular, pulmonary, hepatic, renal, neurologic, psychiatric, or metabolic disease were excluded from the study. Patients who were obese (BMI >25 kg/m 2 ), having coagulation or bleeding abnormalities, severe spinal deformity, allergy to local anesthetic, or any contraindication to spinal anesthesia were also excluded from the study.
The selected patients were randomized into two comparable groups of 34 patients each by computer-generated random number table. Patients of Group I were given 17.5 mg (3.5 mL) of 0.5% hyperbaric bupivacaine with intrathecal fentanyl 25 μg and patients of Group II were given 17.5 mg (3.5 mL) of 0.5% hyperbaric bupivacaine with preservative-free intrathecal nalbuphine 2 mg (Nacphin, Neon Laboratories Limited), making intrathecal drug volume to 4 mL for each patient.
To ensure double blindness of the study, the study drug solutions were prepared by the resident anesthesiologist while SAB was instituted by another anesthesiologist. None of them were further involved for data collection of the study. Postoperative data were recorded by postoperative resident, who was unaware of the group allocation.
All enrolled patients remained fasting overnight prior to surgery and were premedicated with tablet alprazolam 0.5 mg and tablet ranitidine 150 mg on the night prior to surgery. Before commencement of anesthesia, patients were explained about the methods of sensory and motor blockade assessments. All patients were explained regarding the visual analog scale (VAS) scoring system. The VAS consisted of a 10 cm horizontal paper strip with two end points: 0 = no pain and 10 = worst possible pain.
After arrival to operation theater, standard monitoring for heart rate (HR), noninvasive blood pressure, electrocardiogram, and pulse oximetry (SpO 2 ) was commenced and recorded at 5 min intervals throughout the surgery. A peripheral intravenous (IV) access with 18G IV cannula was secured and lactated Ringer's infusion was stared to replenish the overnight fasting at a rate of 10 mL/kg.
Under all aseptic precautions, all patients received SAB via midline approach in the sitting position at L3-L4 intervertebral space, using 25-gauge Quincke spinal needle. The study drug solution was administered intrathecally as per group allocation and the patient was placed in the supine position with 10° Trendelenburg position immediately after SAB to achieve the desirable level of block. They were supplemented with oxygen at a rate of 4 L/min via face mask. IV fluid and blood volume were administered according to the hemodynamic parameters and blood loss.
Sensory and motor block characteristics were assessed in the normal lower limb at every 2 min interval until no pinprick sensation was achieved. All time intervals were calculated from the time of end of intrathecal injection. Onset of sensory block, defined as time to reach sensory block at T10, maximum cephalic level, time taken to achieve maximum sensory block, and time taken to two dermatome regressions of sensory analgesia were recorded.
Grading for motor block was done according to Bromage scale: 1 - free movements of legs and feet (no motor block - 0%); 2 - able to move knee with free movement of feet (partial motor block - 33%); 3 - unable to flex knee with free movement of feet (near complete motor block - 66%); and 4 - unable to move any part of lower limb (complete motor block-100%).  Onset of motor block was defined as the time taken to achieve Bromage scale 3. Time taken to achieve complete motor blockade was also noted.
The surgical anesthesia was considered to be achieved when the levels of sensory block were reached to T10 thoracic dermatome level or above with attainment of complete motor block (Bromage-3).
For recovery of block, time to two dermatome regressions and time to complete motor recoveries were recorded. The duration of effective analgesia was taken as the time from the completion of spinal injection to the time of administration of the first rescue analgesic reflected on VAS 10: 0 where 0 = no pain to 10 = worst possible pain. Patients with VAS score ≥3 received diclofenac 75 mg intramuscularly for rescue analgesia. The VAS score of >3 constituted the end point of the study. Postoperatively, the sensory and motor block levels were assessed at 15 min intervals until normal sensations returned.
Hemodynamic parameters of HR, systolic blood pressure (SBP), and peripheral oxygen saturation (SpO 2 ) were recorded just after spinal injection, then at every 5 min till the end of surgery. For the study, hypotension was defined as the fall in SBP of more than 20% from baseline or <100 mmHg and treated with increasing the infusion rate of crystalloid solution and if further required by incremental doses of IV mephentermine 6 mg. Bradycardia was treated with 0.6 mg atropine intravenously.
Intraoperative nausea was treated with ondansetron (4 mg) and any incidence of pruritus was treated with injection pheniramine maleate 2 mL (45 mg) intravenously. Any need for additional medication was also recorded.
Sedation was assessed by a categorical scale as used by Mostafa et al. and graded as: 1 - awake and alert, 2 - awake but drowsy, responding to verbal stimulus, 3 - drowsy but arousable, responding to physical stimulus, and 4 - unarousable, not responding to physical stimulus. 
Respiratory depression was defined as respiratory rate <8 breaths/min or SpO 2 <94% on room air and treated with oxygen supplementation or ventilatory support, if required.
Postoperatively, the patients were transferred to the recovery room for further monitoring. The VAS score was serially assessed at every 30 min for 6 h, and then at every 2 h till the patients complain of pain (VAS score >3).
The sample size was calculated with standard programs which computed that approximately 30-32 patients should be included in each group to detect clinically significant difference of 30 min in the mean duration of sensory and motor blockade between the groups for type 1 error of 0.05 and power of 80%. Sixty-eight patients were enrolled, accounting for dropout of 5% for better validation of results.
At the end of the study, all data were compiled in a tabulated manner and the results were expressed as mean ± standard deviation (SD), considering the latter as the best predictor for the statistical analysis using Stat Graphics Centurion (version 16.2). The demographic data for categorical variables were compared using Chi-square test and statistical significance in the mean difference was found using analysis of variance. P < 0.05 was considered statistically significant and P < 0.001 was considered statistically highly significant.
| Results|| |
The present study compared the clinical efficiency of intrathecal fentanyl and nalbuphine as adjuvant to intrathecal 0.5% hyperbaric bupivacaine in 68 adult consented patients, scheduled for elective lower limb orthopedic surgery under SAB. There was no protocol deviation and all patients successfully completed the study protocol and were cooperative with subsequent assessment. Hence, all patients were included for data analysis. Surgical procedures were performed uneventfully and there were no surgical or anesthetic complications.
Patients of both groups were statistically comparable regarding mean age, weight, height, gender, ASA physical status, and surgical characteristics [Table 1].
The onset of sensory block at T10 level was 4.30 ± 0.79 min in patients of Group I and 3.91 ± 2.25 min in patients of Group II with no statistical significance (P = 0.083). Time to reach maximal cephalic sensory level was also statistically comparable with median cephalic level of T6 in all patients. Time to sensory regression of two dermatomes was significantly extended in patients of Group II (127.86 ± 18.23 min) as compared to patients of Group I (116.75 ± 12.82 min) with statistically highly significant difference (P < 0.001) [Table 2].
Onset of motor block was 8.63 ± 2.43 min in patients of Group I and 7.97 ± 3.29 min in patients of Group II and was comparable with no statistically significant difference (P = 0.37). Duration of motor block was significantly extended in patients of Group II (183.26 ± 29.63 min) as compared to patients of group II (141.63 ± 18.05 min) with statistically significant difference (P = 0.003) [Table 2].
The total duration of analgesia was 278.74 ± 29.67 min in patients of Group I and 318.64 ± 21.92 min in patients of Group II with statistically highly significant difference (P < 0.001) [Table 2].
The hemodynamic characteristics of mean HR and SBP at baseline with intraoperative changes were comparable and there was no statistically significant difference in HR, SBP, and SpO 2 during intra- and post-operative periods between both the groups (P > 0.05) [Table 3] and [Table 4]. Incidence of hypotension and bradycardia during intraoperative period was minimal and did not require any medical intervention.
Mean sedation score was 1.033 ± 0.5 in patients of Group I and 1.133 ± 0.50 in patients of Group II, which was comparable (P = 0.606), which signifies negligible sedation by fentanyl and nalbuphine.
Mild pruritus was observed in 5 (14.7%) patients of fentanyl group which was successfully treated with IV injection pheniramine. The incidence of respiratory depression in the study was minimal and comparable (P > 0.05). Postoperatively, the SpO 2 was well maintained above 97% on air in all patients. No patient suffered from postspinal shivering, nausea, vomiting, or respiratory depression. None of the patient needed supplemented analgesia during surgery.
| Discussion|| |
We compared the clinical efficiency of intrathecal fentanyl with nalbuphine as intrathecal adjuvant to 0.5% hyperbaric bupivacaine by assessing the sensory and motor blockade characteristics and duration of postoperative analgesia as the primary end points and intraoperative hemodynamic changes, sedation, pruritus, and respiratory depression as the secondary end points.
Local anesthetics work by inhibiting voltage-gated sodium channels in the spinal cord by interfering with afferent and efferent sensory and motor impulses while intrathecal opioids activate opioid receptors in the dorsal gray matter of the spinal cord (substantia gelatinosa) to modulate the function of afferent pain fibers. The combination of adjuvants to local anesthetic is synergetic for producing the analgesia of prolonged duration without measurably increasing sympathetic or motor blockade, thus allows early ambulation of patients and reduction in dosages of local anesthetics, hence the decline of their systemic side effects.
Opioids selectively decrease nociceptive input from A delta and C fibers without affecting dorsal root axons or somatosensory-evoked potentials. Various μ-agonists opioids such as morphine, tramadol, and fentanyl are used as adjuvant to hyperbaric bupivacaine to prolong its clinical efficacy and minimize the requirement of postoperative analgesics, but they are associated with side effects of pruritus, nausea, vomiting, respiratory depression, constipation, and urinary retention. ,
Nalbuphine, agonist-antagonist, is a synthetic highly lipid-soluble opioid analgesic and possess an agonist action at the k-opioid receptor and antagonist action at the μ-opioid receptor to provide reasonably potent analgesia of visceral nociception. It has the potential to maintain or even enhance μ-opioid-based analgesia while simultaneously mitigating the μ-opioid side effects.
Intrathecal opioids as an adjuvant to spinal anesthesia in the present study have improved the quality of intra- and post-operative analgesia with minimal side effects and minimal sedation, which helps to take care of psychological impact of operation theater environment.
The present study revealed no statistically significant difference in the onset and cephalic extension of sensory blockade of hyperbaric bupivacaine when intrathecal fentanyl or nalbuphine was used as adjuvant. The duration of sensory block and motor block was significantly enhanced by the addition of intrathecal nalbuphine as compared to intrathecal fentanyl in the present study. The results of the present study correlates well with other studies where it was observed that addition of nalbuphine or tramadol allowed a significant reduction in pain score. ,
There are only few studies available of central neuraxial administration of nalbuphine as intrathecal adjuvant, which concluded that nalbuphine significantly enhanced the sensory analgesia with minimal pruritus and respiratory depression. Culebras et al. studied the advantages of nalbuphine at doses of 0.2, 0.8, and 1.6 mg over intrathecal morphine in ninety obstetric patients undergoing cesarean section and concluded that intrathecal nalbuphine was more effective over morphine to provide better postoperative analgesia without any side effects.  We have also observed that nalbuphine provided enhanced sensory analgesia as compared to fentanyl.
Mukherjee et al. studied the duration of analgesia with different dosages of intrathecal nalbuphine (0.2, 0.4, and 0.8 mg) to find out the optimum dose of intrathecal nalbuphine which could prolong the postoperative analgesia without increasing the side effects. Their study concluded that effective analgesia was increased with increase in the doses of nalbuphine as adjuvant to 0.5% hyperbaric bupivacaine without any side effects. 
Yoon et al. studied sixty obstetric patients scheduled for cesarean section under spinal anesthesia. Patients received morphine 0.1 mg or nalbuphine 1 mg or morphine 0.1 mg with nalbuphine 1 mg in addition to 0.5% bupivacaine (10 mg) and concluded that effective analgesia was prolonged in the morphine group and morphine with nalbuphine group, but the incidence of pruritus was significantly lower in the nalbuphine group.  Their study is in accordance with the finding of our study.
Mostafa et al. compared the analgesic efficacy and duration of analgesia with side effects of intrathecal tramadol 50 mg with nalbuphine 2 mg for postoperative analgesia after transurethral resection of the bladder tumor. They found no clinically significant difference for intensity and duration of motor block and sensory analgesia. The incidence of hypotension, bradycardia, itching, respiratory depression, nausea, and other side effects was minimal and was well tolerated by the patients. The sedation score was also equal for both the groups, but the number of rescue analgesia was less in the nalbuphine group.  We found statistically significant difference in the duration of motor and sensory block in the present study between fentanyl and nalbuphine groups. All patients were calm and comfortable during surgery, and no drug-related side effects were occurred.
Sapate et al. observed the effects of intrathecal nalbuphine (0.5 mg) with 0.5% spinal bupivacaine (3 mL) for lower abdominal surgeries in elderly patients in a randomized control study. They concluded that nalbuphine provided better quality of SAB as compared to bupivacaine alone and also enhanced the postoperative analgesia. No patients in their study developed any side effects. 
Verma et al. compared the postoperative analgesic efficacy of intrathecal tramadol (50 mg) with nalbuphine (2 mg) as adjuvant to hyperbaric bupivacaine (12.5 mg) in spinal anesthesia for lower limb orthopedic surgery. They concluded that addition of nalbuphine to hyperbaric bupivacaine was effective in prolonging the duration of sensorimotor block and enhancing the postoperative analgesia following lower limb orthopedic surgery. Intrathecal tramadol could not make a significant difference in postoperative analgesia as compared to when bupivacaine was used alone.  The results of their study go well with the results of the present study.
Ahmed et al. evaluated the potentiating effect of intrathecal nalbuphine with bupivacaine for postoperative analgesia in three different doses (0.8, 1.6, and 2.4 mg) in a randomized control study. They concluded that the combination of intrathecal bupivacaine with nalbuphine significantly prolonged postoperative analgesia as compared to control group and a 1.6 mg dose showed the best results. 
| Conclusion|| |
Nalbuphine (2 mg) as intrathecal adjuvant to 0.5% hyperbaric bupivacaine (17.5 mg) for subarachnoid blockade was clinically more efficient than fentanyl for extending the duration of sensory motor block and enhancing the postoperative analgesia following orthopedic surgery of lower limb, with negligible adverse effects.
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[Table 1], [Table 2], [Table 3], [Table 4]