|Year : 2020 | Volume
| Issue : 3 | Page : 253-259
Effect of ultra-low-dose naloxone during supraclavicular brachial plexus block on the antinociceptive criteria of postoperative opioid in orthopedic upper limb surgeries
Doaa G Diab, Eiad A Ramzy, Heba Allah M Zaghloul, Mona A Hasheesh
Department of Anesthesia and Surgical ICU, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||01-Jun-2019|
|Date of Acceptance||01-Mar-2020|
|Date of Web Publication||29-Sep-2020|
Msc Heba Allah M Zaghloul
Assistant Lecturer of Anesthesia and ICU, Mansoura Univeristy, 35516
Source of Support: None, Conflict of Interest: None
Background Brachial plexus block is a popular and widely used regional nerve block technique for perioperative anesthesia and analgesia for upper extremity surgeries. Many drugs such as morphine and midazolam have been used as an adjuvant with local anesthetics to achieve quick, dense, and prolonged block. Drugs with minimal side effects are always looked for. Naloxone as opioid antagonists could selectively block excitatory effects of opioids, stimulate release and displace endorphins from receptor sites, and reduce the side effects of opioids. An ultra-low-dose naloxone, added as an adjuvant to local anesthetic, may prolong sensory and motor blockades with enhanced opioid effect or direct antagonism of its excitatory receptors.
Patients and methods After approval by Institutional Research Board, clinical trial registration, and obtaining informed consents, 64 patients scheduled for orthopedic upper limb surgeries under supraclavicular brachial plexus block were enrolled into two equal groups: group B (bupivacaine 0.5%) and group BN (bupivacaine 0.5% plus 100 ng naloxone).
Results There was significant decrease in fentanyl consumption in GBN (216.6±76.10) versus group B (507.5±117.50). Also, the number of fentanyl requests was lesser in group BN (3.0±1.11) than in group B (7.3±1.73). The onset time for sensory and motor blocks showed no significant difference among groups; the duration of sensory and motor blocks was prolonged in GBN (17.2±2.96–7.7±1.93 h) versus GB (7.3±1.22–4.7±.79 h). The time to first rescue fentanyl was prolonged in GBN (18.3±3.21 h) than in GB (8.0±1.41 h). There was significant reduction in visual analog scale score at 8, 12, and 18 h postoperatively in GBN versus GB. There were no significant changes in Ramsay sedation scale or complications within 48 h postoperatively.
Conclusion Ultra-low dose of naloxone (100 ng) added to 20 ml bupivacaine 0.5% for supraclavicular brachial plexus block enhanced the postoperative opioid analgesia by reducing the total postoperative opioid consumption, prolonging the interval between opioid doses and the duration of sensory and motor block.
Keywords: naloxone, opioid, supraclavicular brachial plexus block, upper limb surgeries
|How to cite this article:|
Diab DG, Ramzy EA, Zaghloul HM, Hasheesh MA. Effect of ultra-low-dose naloxone during supraclavicular brachial plexus block on the antinociceptive criteria of postoperative opioid in orthopedic upper limb surgeries. Res Opin Anesth Intensive Care 2020;7:253-9
|How to cite this URL:|
Diab DG, Ramzy EA, Zaghloul HM, Hasheesh MA. Effect of ultra-low-dose naloxone during supraclavicular brachial plexus block on the antinociceptive criteria of postoperative opioid in orthopedic upper limb surgeries. Res Opin Anesth Intensive Care [serial online] 2020 [cited 2020 Oct 23];7:253-9. Available from: http://www.roaic.eg.net/text.asp?2020/7/3/253/296619
| Introduction|| |
Regional block techniques help to avoid the hazards of anesthetic drugs used for general anesthesia besides the hemodynamic stress during laryngoscopy and intubation. These techniques are especially beneficial for patients with various cardiorespiratory comorbidities .
Effective postoperative pain control can reduce patient morbidity and affect the patient outcome . So, postoperative analgesia is a prerequisite in order to boost recovery and decrease morbidity 
Brachial plexus block is one of the most popular and widely used regional nerve block techniques for perioperative anesthesia and analgesia for surgery of the upper extremity. Different drugs have been used as adjuvants with local anesthetics in brachial plexus block to achieve quick, dense, and prolonged block . Drugs such as morphine, pethidine, clonidine, dexmedetomidine, butorphanol, and midazolam are commonly used along with local anesthetics for this purpose. Owing of their side effects like heavy sedation, respiratory depression, and psychotomimetic effects, drugs with minimal side effects are always looked for .
Naloxone is an opioid antagonist which could selectively block the excitatory effects of opioids. It releases endorphins and also displaces it from its receptor site. It also reduces the opioid-induced side effects, such as vomiting, nausea, pruritus, and respiratory depression. Various studies have suggested that an ultra-low dose of naloxone, added as an adjuvant to local anesthetic solution may prolong nerve sensory and motor blockades with enhanced opioid effect or direct antagonism of these excitatory receptors ,.
Opioids are usually used to achieve sufficient relief of postoperative pain , but its side effects are dose dependent; so, multimodal analgesia can be used for decreasing the consumption of opioid and its related side effects and improve analgesia . Information obtained from animals and human studies have illustrated that a combination of low doses of opioid antagonists with opioids intravenously might increase analgesia. Also, naloxone in low doses leads to a decrease in opioid-related side effects, such as vomiting, nausea and respiratory depression .
To our knowledge till now, there is a paucity of studies on the effect of naloxone as an adjuvant to local anesthetic in supraclavicular block on postoperative opioid consumption.
From the previous section, a question is raised: Could the ultra-low doses of naloxone in supraclavicular block in upper limb surgeries enhance the antinociceptive effect of postoperative opioid and decrease its related side effects?
| Aim|| |
We aimed to evaluate the effect of adding ultra-low-dose naloxone to bupivacaine in supraclavicular brachial plexus block in upper limb orthopedic surgeries by its effect on total dose of opioid required in 48 h postoperatively, which is the primary outcome; and its effect on the antinociceptive criteria of postoperative opioid by its effect on (onset and duration of sensory and motor block, severity of postoperative pain, sedation, first time of analgesic request, number and intervals between each analgesic doses), which is the secondary outcome.
| Patients and methods|| |
After approval by the Institutional Research Board − Mansoura University (IRB code number MD/17.07.95) and clinical trial registration (Clinical Trial.gov ID NCT03372486), informed consent was obtained from all patients before enrollment into this study. This prospective, randomized, and double-blinded study was conducted on 64 patients scheduled for orthopedic upper limb surgeries under supraclavicular brachial plexus block.
The total of 64 patients included were in the age group of 21–50 years of American Society of Anesthesiologists physical state classes Ι and Π of either sex, BMI more than or equal to 30, submitted for elective upper limb orthopedic surgeries.
Patients with a history of allergy to the drug of the study, coagulation disorders, infection at the puncture site, pregnancy, and addiction are excluded.
Randomization and grouping
Sixty-four patients were computer randomized into two equal groups: group B (the bupivacaine group):
Patients received 20 ml bupivacaine 0.5% plus 3 ml of saline (to achieve blindness).
Group BN (bupivacaine plus naloxone group):
Patients received 20 ml bupivacaine 0.5% plus 100 ng naloxone (1 ml) in 2 ml saline (naloxone ampoule 0.4 mg diluted in 400 ml of saline, then 1 ml of it diluted in 10 ml saline, so each ml had 100 ng naloxone).
Following preoperative assessment by careful history taking, general and local examination, basal laboratory investigation: complete blood count, liver function tests, renal function tests, coagulation profiles was done.
Preparation of local anesthetics and adjuvant drugs were done by an anesthetist, who was not participating in the data collection or in the study. At the theater, all the standard monitors were applied (the pulse oximeter, noninvasive arterial blood pressure, and electrocardiography). The oxygen was supplemented by a face mask (3–5 l/min). Two 18-G intravenous cannulas were inserted in the noninjured hand. The patients received intravenous midazolam (1 mg). Then the supraclavicular block under US (Acuson ×300; Siemens, USA) guidance was done.
At the end of injection, motor and sensory block was tested at 5, 15, and 30 min and every 30 min till the end of surgery. Assessment of the sensory block was done by a pinprick test using the verbal rating scale ranging from 100% (normal sensation) to 0% (no sensation) . The evaluation of the motor block was done by applying the thumb abduction (radial nerve), thumb adduction (ulnar nerve), thumb opposition (median nerve), and elbow flexion in supine and prone positions (musculocutaneous nerve). The motor block was evaluated by the modified Lovett rating scale from 6 (normal muscular power) to 0 (complete muscle paralysis). The onset time of the sensory and the motor block is the duration between the end of the last injection and complete absence of response of the pinprick test and complete muscle paralysis (Lovett rating scale=0) in all nerve distributions . The duration of the sensory block is the time between the complete sensory block (complete absence of pinprick response) and first postoperative pain. The duration of the motor block is the time between complete paralysis (Lovett rating scale=0) and complete recovery (Lovett rating scale=6).
Heart rate (HR), mean arterial blood pressure (MAP), SpO2, and sedation score were measured every 5 min during the first 15 min and thereafter half hourly till the end of procedure. Degree of sedation was assessed by Ramsay sedation scale (RSS) from 1 to 6 points : 1=awake and anxious and up to 6=asleep with no response.
In postanesthesia care unit (PACU), HR, MAP, and SpO2 were recorded every 15 min for 1 h. The RSS was assessed when discharged to the PACU, and after that at 2, 4, 6, 8, 12, 18, 24, 36, and 48 h following the patient discharged to the ward.
The severity of the pain postoperatively will be assessed by the visual analog scale (VAS), where 0 (no pain) and 10 (worst pain). It was assessed first time when the patients were discharged to the PACU, and after that at 2, 4, 6, 8, 12, 18, 24, 36, and at 48 h when the patients were discharged to the ward.
Fentanyl 1 μg/kg was administered as an analgesia at VAS was more than or equal to 4 or upon patient request. The interval between each fentanyl dose (analgesic request) was calculated for each patient. The total analgesic consumption and the total number of analgesic requirements during the first 48 h were recorded.
Postoperative nausea and vomiting, paresthesia, pruritus, sedation, and any other side effects of opioids were recorded for 48 h. All data were collected by an anesthetist who was not involved in the study.
Sample size calculation
A prior G-power analysis was done to estimate the study sample size. Power of 80% was estimated with an effective size sample of 0.3 and type α error of 0.05 between the two groups of study to yield a total sample size of 64 cases (32 cases per group).
| Results|| |
Patient characteristics such as sex, age, American Society of Anesthesiologists classification, weight, height, and surgery duration were comparable in both groups ([Table 1]). Also, there were not any differences of significant value between the two groups in hemodynamic parameters (HR, MAP) ([Figure 1] and [Figure 2]).
|Table 1 Patient characteristics: age, sex, weight, height, American Society of Anesthesiologists, and duration of surgeries|
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|Figure 2 Perioperative. MAP, mean arterial blood pressure in the studied groups.|
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There was significant difference between the group BN in opioid (fentanyl) consumption (216.6±76.10) versus group B (507.5±117.50) and also the number of fentanyl request was lesser in group BN (3.0±1.11) than group B (7.3±1.73) Also, there was significant difference in the time to first rescue fentanyl request between the two groups; it was prolonged in GBN (18.3±3.21 h) than the GB (8.0±1.41 h). Also, the interval between analgesic doses (min) was significantly different in GBN (211.94±72.24) versus GB (184.07±71.68) as shown in [Table 2].
|Table 2 Analgesic profile (total dose of rescue fentanyl, number of rescue analgesic boluses, interval between analgesic doses, time to first rescue fentanyl request)|
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[Table 3] shows that the sensory and the motor block onset time showed no significant difference between two groups, respectively, while the duration of sensory and motor block was prolonged in GBN (17.2±2.96–7.7±1.93 h) more than the other group (GB) (7.3±1.22–4.7±.79 h).
|Table 3 Anesthetic criteria (onset of sensory and motor block, duration of sensory, and motor block)|
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In [Table 4] there was significant reduction in VAS score at 8, 12, 18 h postoperatively in GBN compared with GB.
Tables 5 and 6 showed no significant changes in RSS within 48 h or complications postoperatively.
|Table 6 Numbers of patients suffered from postoperative complications in the studied groups|
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The collected data were coded, processed, and analyzed by the Statistical Package for the Social Sciences, version 15 for Windows (SPSS Inc., Chicago, Illinois, USA). Qualitative data were presented as number and percent. Comparison between groups was done by c
2 test. Quantitative data were tested for normality by Kolmogorov–Smirnov test. Normally distributed data were presented as mean±SD. Student’s t test was used to compare between two groups. Nonparametric data was presented as minimum–maximum and median. Mann–Whitney test was used for comparison between groups. P value less than 0.05 was considered to be statistically significant.
| Discussion|| |
The result of this study showed that a combination of naloxone in ultra-dose (100 ng) to 20 ml of bupivacaine 0.5% for supraclavicular brachial plexus block enhances the postoperative opioid analgesic effect by a decrease in the total postoperative opioid consumption and prolongs the time interval between each opioid dose. Also, the time of sensory and motor block was prolonged; however, the time for the onset of the sensory and the motor block showed no significant differences.
Previous studies were consistent with the recent study.
Movafegh et al.  studied the posthysterectomy analgesia and illustrated that the infusion of naloxone 0.25 mg/kg/h intravenously following a loading dose 0.1 ng/kg decreases postoperative morphine consumption. Another experimental research has demonstrated that intrathecal ultra-dose naloxone 15 μg enhanced the antinociceptive criteria of opioid (morphine) by increasing the uptake of excitatory amino acids from the synaptic cleft in the spinal cord of partial sciatic nerve-transected rats .
Although the opioids activate μ-receptors which have inhibitory effect on neuronal activity, it can produce excitatory effects on sensory neurons . Studies have shown that naloxone has a dose-dependent pain response in humans and animals. Naloxone in low doses can produce analgesia, whereas large doses resulted in hyperalgesia in a rat model ,.
Naloxone in small doses may enhance the antinociceptive effect of opioid (morphine) by increasing the reuptake of excitatory amino acids at the synaptic cleft . In a recent study, low doses of naloxone can augment the effect of bupivacaine even without addition of the opioid.
In contrast with the present study, there was a study which illustrated that addition of a low dose of naloxone (100 ng) in supraclavicular brachial plexus block does not affect the postoperative consumption of opioids. It can be explained that the sample size used in this study was small (17 patients) .
A previous study has proved that the addition of ultra-low doses of naloxone to lidocaine 1.5% in brachial plexus block has prolonged the time of motor block and the first analgesic request . Also, it has been shown in another study that low doses of naloxone added to 0.5% bupivacaine, in supraclavicular brachial plexus block, increases the time of sensory and motor block . This finding agrees with the present study where there was prolongation in the time of sensory and motor block.Endorphins were suggested to be released or displaced at its receptor sites by a low dose of naloxone . This phenomenon may clarify the prolongation of sensory and motor block of patients in the naloxone group in the present study. But, at the same time, it has no effect on the onset time of sensory or motor block; this was evidenced also by Amal et al.  which concluded the same fact.
In the present study, addition of 100 ng naloxone to 0.5% bupivacaine in supraclavicular brachial plexus block did not affect the incidence of postoperative nausea and vomiting, pruritic, paresthesia, or sedation which is consistent with the findings of Marashi et al. .
| Conclusion|| |
In conclusion, naloxone in ultra-low dose (100 ng) added to 20 ml bupivacaine 0.5% for supraclavicular brachial plexus block for orthopedic upper limb surgeries resulted in enhancement of postoperative opioid analgesia by reducing the total postoperative opioid consumption and prolonging the interval between each opioid dose. Also, there were prolonged sensory and motor block duration. However, there were no significant differences in the onset of sensory and motor blocks, sedation, or postoperative complications.
Protocol/thesis: submitted in partial fulfillment of the requirement of the MD degree of Anesthesia and Surgical Intensive Care.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]