Various additives have been used to prolong regional blockade.1–4 Based on scientific concepts of peripheral opioid activity, the use of opioids alone or in combination with local anesthetics for peripheral nerve blocks has been evaluated.5 One study indicated that the opioids can elicit excitatory as well as inhibitory modulation of the action potentials of sensory neurons. Ultra-low doses of opioid antagonists could selectively block the excitatory effects of opioids.6 Therefore, it is likely that an ultra-low dose of naloxone, added to local anesthetic solution, prolongs nerve sensory and motor blockades with enhanced opioid effect or direct antagonism of these excitatory μ receptors.
The exposure of a nerve sheath to the ultra-low dose of naloxone raises concerns regarding neurotoxicity. However, animal experiments have shown the safety of intrathecal naloxone administration.7,8 In humans, naloxone was uneventfully coadministered with epidural opioids to reduce the adverse effects of opioids such as pruritus and nausea and vomiting.9–14
The present placebo-controlled clinical trial evaluated the effect of an ultra-low dose of naloxone added to lidocaine and lidocaine-fentanyl mixture on the duration of axillary brachial plexus block anesthesia. We hypothesized that naloxone will prolong the duration of sensory block when added to lidocaine during axillary brachial plexus anesthesia. Our primary outcome was duration of sensory block, whereas secondary outcomes included duration of motor block, incidence of pruritus, and incidence of postoperative nausea and vomiting (PONV).
To evaluate the safe administration of naloxone perineurally, first, we searched Medline, ISI, and other databases. Previous animal and human studies involving neuroaxial administration of the usual doses of naloxone reported no neurotoxic effects.7–17 This trial was then registered with and approved by the Research Ethics Committee of Tehran University of Medical Sciences and Iranian Registry of Clinical Trials.
After obtaining informed patient consent, 112 ASA physical status I and II patients aged 20-50 yr scheduled for elective short (<60 min) forearm surgery under axillary brachial plexus block were included in the study. Patients with an addiction to opioids, cocaine, benzodiazepines, and clonidine, as well as patients with a history of diabetes mellitus, hepatic or renal failure, pregnant women, and those receiving opioids within 48 h of surgery were excluded from the study.
Using a computer-generated randomization list, patients were allocated into 4 groups in a controlled, randomized, double-blind study to receive 34 mL lidocaine 1.5% with 3 mL of isotonic saline chloride (control [C] group, n = 28), 34 mL lidocaine 1.5% with 2 mL (100 μg) of fentanyl and 1 mL of isotonic saline chloride (fentanyl [F] group, n = 28), 34 mL lidocaine 1.5% with 2 mL saline chloride and 100 ng (1 mL) naloxone (naloxone [N] group, n = 28), or 34 mL lidocaine 1.5% with 2 mL (100 μg) of fentanyl and 100 ng (1 mL) naloxone (naloxone + fentanyl [NF] group, n = 28). Neither epinephrine nor bicarbonate was added to mixtures. All local anesthetic solutions and adjuvant drugs were prepared by an anesthesiologist who was not involved in the performance of brachial plexus block, patient care, or data collection. The randomization list was concealed from investigators.
On arrival to the operating room, standard monitoring was established (pulse oximetry, electrocardiography, and noninvasive arterial blood pressure monitoring), and oxygen was delivered via a Venturi facemask at a rate of 3 L/min. After insertion of a 20-gauge IV catheter in a peripheral vein in the contralateral arm and administration of 1 mg IV midazolam, axillary block was performed with the patient in the supine position and the upper arm abducted 90° and the elbow flexed at 110°. A nerve stimulator (Polymedic®) with a 24-gauge, 7-cm Sprotte needle was used for precise localization of each nerve. The stimulation frequency was set at 2 Hz, the duration of stimulation at 0.1 ms, and the intensity of the stimulating current was initially set to deliver 3 mA and was then gradually decreased. The position of the needle was considered to be acceptable when an output current <0.7 mA still elicited a slight distal motor response in each of the nerve distributions (thumb opposition for median, thumb abduction for radial, thumb adduction or ulnar deviation of the hand for ulnar, and flexion of forearm on the arm for musculocutaneous nerves). We used a multiple stimulation technique in all of the patients. Increments of anesthetic mixture (8 mL/nerve in total) were injected after identifying the 4 nerves in each patient in the following order: median, radial, ulnar, and musculocutaneous. The remaining 5 mL was injected subcutaneously as the needle was withdrawn to block the intercostobrachial nerve. In case of blockade failure in any of the nerve distributions (i.e., if the patient felt pain in those regions) or in any of the nerve distributions that complete sensory or motor block was not achieved, the patients were excluded from the study, even when the block was adequate for surgery.
Sensory and motor blockades of radial, median, musculocutaneous, and ulnar nerves were recorded after 5, 15, and 30 min and every 10 min after the end of the surgery. Sensory blockade of each nerve was assessed by pinprick and compared with the same stimulation on the contralateral hand. Sensory blockade of each nerve was rated by the patient on a verbal analog scale from 100% (normal sensations) to 0% (no sensation). Motor block was evaluated by thumb abduction (radial nerve), thumb adduction (ulnar nerve), flexion of the elbow in supination and pronation of the forearm (musculocutaneous), and thumb opposition (median nerve). Measurements were performed using a modification of the Levvott rating scale from 6 (normal muscular force) to 0 (complete paralysis).1 The onset time of the sensory and motor blockades was defined as the time between the end of the last injection and the total abolition of the pinprick response and complete paralysis in all of the nerve distributions. The duration of sensory block was considered as the time interval between the complete sensory block and the first postoperative pain, and the duration of motor block was defined as the time interval between the complete paralysis and complete recovery of motor function. The patients and the anesthesiologist who evaluated the sensory and motor blockades were blinded as to the mixture used.
Based on a pilot study of 20 patients (5 in each group), we determined that a sample size of 28 in each group would be sufficient to detect a 30-min difference in time to first postoperative pain, estimating an sd of 30 min, a power of 95%, and a significance level of 5%. Statistical analysis was performed using SPSS package (version 13.5, SPSS, Chicago, IL).
The distribution of age, height, weight, surgery time, onset time, and duration of sensory and motor block was evaluated by the Kolmogorov-Smirnov test. They followed a normal distribution. Age, height, weight, surgery time, onset time, and duration of sensory and motor block were compared among the 4 groups by 1-way analysis of variance (ANOVA) and Tukey post hoc tests. The sex and ASA physical status were compared with χ2 test and Fisher’s exact test. Two-tailed P < 0.05 was considered significant.
Nine patients (2 from Group C, 3 from Group N, 2 from Group F, and 4 from Group NF) were excluded from the study because of unsuccessful blockade (Appendix). The patients’ mean age, weight, and height; type and duration of surgery; distribution of sex; and ASA physical status were similar in the 4 groups (Table 1). Both sensory and motor onset times were longer in Groups N and NF than in Group C or F (P < 0.001, 1-way ANOVA, Tukey post hoc test) (Table 2). The duration of time to first postoperative pain and motor blockade was significantly longer in Groups N and NF than in Groups C and F (P < 0.001). There were no significant differences in the time to first postoperative pain or motor blockade time between Groups N and NF (P < 0.001, 1-way ANOVA, Tukey post hoc test) (Table 2). In all groups, there were no significant differences in the incidence of PONV and pruritus (Table 2).
This study indicates that the addition of 100 ng naloxone to 34 mL lidocaine 1.5% or 34 mL lidocaine 1.5% and 100 μg fentanyl for axillary brachial plexus block results in a significant increase in duration of time to first postoperative pain and motor blockade time. The onset time of sensory and motor blockades is also significantly prolonged.
There has been increasing interest in the combination of local anesthetics and opioids to improve the quality and duration of nerve blocks. Some receptors mediate nociception on peripheral sensory axons, and the peripheral administration of opioids has analgesic effects. The mechanisms of the analgesic effects of these drugs are unclear.3,18 In a systematic review, it was concluded that the benefit from the addition of opioid to single-injection peripheral nerve blocks was unsubstantiated.19 In our study, 100 μg fentanyl added to lidocaine did not affect the duration of sensory or motor blockade. Activation of opioid receptors has generally been considered to produce inhibitory effects on neuronal activity. However, evidence indicates that opioids can elicit excitatory as well as inhibitory modulation of the action potentials of sensory neurons.6 There is evidence to suggest that naloxone produces a dose-dependent pain response in both animals and humans. In a rat model, small doses of naloxone produced paradoxical analgesia, whereas larger doses resulted in hyperalgesia.20–23 Clinically, an ultra-low dose of naloxone enhanced morphine analgesia in an acute intraoperative setting.24
In our study, the duration of blockade was similar in Groups NF and N; we therefore conclude that adding naloxone to lidocaine solution prolongs sensory and motor blockades. Naloxone in low doses has been shown to release endorphins, or perhaps displaces endorphins from receptor sites.24 This phenomenon may explain the naloxone-induced blockade prolongation in our patients.
Previous studies demonstrated that a small dose of IV naloxone could reduce opioid side effects,25,26 but the incidence of PONV and pruritus in our study was similar in all groups. Perhaps our sample size was simply too small to observe any difference in the development of PONV and pruritus.
The patients in Groups N and NF had a prolongation in the onset time of sensory and motor blocks (approximately 7 min). Although this duration is statistically significant, it is probably not a clinically significant finding.
The use of naloxone as an adjuvant to local anesthetics for peripheral nerve block has not been described. The concentration of naloxone used in patients receiving epidural morphine ranged from 0.167 to 0.412 μg · kg−1 · h−1.16 In one study, IV concentrations of 0.1, 0.01, and 0.001 ng/kg were used.27 We evaluated only 1 concentration of naloxone in this study. Other concentrations of naloxone could have been evaluated to find the optimal concentration of naloxone for axillary brachial plexus blockade.
The perineural safety of naloxone may raise some concerns. In animal experiments, intrathecal injections of naloxone did not induce spinal neurotoxicity and was used for improvement of neurological outcome after spinal cord injury.7,15 Furthermore, some opioids have neurotoxicity effects, but naloxone may protect against opioid-induced nerve damage.3 In human studies, naloxone in the usual or low doses has been used epidurally or intrathecally for reducing opioids side effects or enhancing analgesia.9–14,16 This study could be repeated using longer-acting drugs such as bupivacaine or ropivacaine to assess the effect of ultra-low-dose naloxone on duration of sensory and motor blockades with these local anesthetics. In addition, epinephrine was not used to prolong block duration in our study; therefore, further studies must be done to compare the prolonging effect of an ultra-low dose of naloxone with epinephrine or other additives such as clonidine. Also, we used a multiple stimulation technique for brachial plexus blocking; our results may not be applicable to other methods.
In conclusion, the addition of an ultra-low dose of naloxone to lidocaine 1.5% solution with or without fentanyl solution in axillary brachial plexus block prolongs the duration of the time to first postoperative pain and motor blockade. Further studies are needed to evaluate the optimal dose of naloxone to be used for prolonged brachial plexus block as well as the mechanism of this effect.
APPENDIX: PATIENT FLOWCHART
1. Movafegh A, Razazian M, Hajimohamadi F, Meysamie A. Dexamethasone added to lidocaine prolongs axillary brachial plexus blockade. Anesth Analg 2006;102:263–7
2. Narang S, Dali JS, Agarwal M, Garg R. Evaluation of the efficacy of magnesium sulphate as an adjuvant to lignocaine for intravenous regional anaesthesia for upper limb surgery. Anaesth Intensive Care 2008;36:840–4
3. Alayurt S, Memis D, Pamukcu Z. The addition of sufentanil, tramadol or clonidine to lignocaine for intravenous regional anaesthesia. Anaesth Intensive Care 2004;32:22–7
4. Sen S, Ugur B, Aydin ON, Ogurlu M, Gursoy F, Savk O. The analgesic effect of nitroglycerin added to lidocaine on intravenous regional anesthesia. Anesth Analg 2006;102:916–20
5. Picard PR, Tramer MR, McQuary MG, Moore RA. Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain 1997;72:309–18
6. Crain SM, Shen KF. Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Pain 2000;84:121–31
7. Cole DJ, Drummond JC, Shapiro HM, Hertzog RE, Brauer FS. The effect of fentanyl anesthesia and intrathecal naloxone on neurologic outcome following spinal cord injury in the rat. Anesthesiology 1989;71:426–30
8. Sinz EH, Kofke WA, Garman RH. Phenytoin, midazolam, and naloxone protect against fentanyl-induced brain damage in rats. Anesth Analg 2000;91:1443–9
9. Lee J, Shim JY, Choi JH, Kim ES, Kwon OK, Moon DE, Choi JH, Bishop MJ. Epidural naloxone reduces intestinal hypomotility but not analgesia of epidural morphine. Can J Anaesth 2001;48:54–8
10. Choi JH, Lee J, Choi JH, Bishop MJ. Epidural naloxone reduces pruritus and nausea without affecting analgesia by epidural morphine in bupivacaine. Can J Anaesth 2000;47:33–7
11. Kim MK, Nam SB, Cho MJ, Shin YS. Epidural naloxone reduces postoperative nausea and vomiting in patients receiving epidural sufentanil for postoperative analgesia. Br J Anaesth 2007;99:270–5
12. Jeon Y, Hwang J, Kang J, Han S, Rhee K, Oh Y. Effects of epidural naloxone on pruritus induced by epidural morphine: a randomized controlled trial. Int J Obstet Anesth 2005;14:22–5
13. Kim ES, Lee J, Choi JH. Optimal dose range of epidural naloxone to reduce nausea in patients receiving epidural morphine. Can J Anaesth 2004;51:1048–9
14. Okutomi T, Saito M, Mochizuki J, Amano K. Prophylactic epidural naloxone reduces the incidence and severity of neuraxial fentanyl-induced pruritus during labour analgesia in primiparous parturients. Can J Anaesth 2003;50:961–2
15. Kakinohana M, Marsala M, Carter C, Davison JK, Yaksh TL. Neuraxial morphine may trigger transient motor dysfunction after a noninjurious interval of spinal cord ischemia: a clinical and experimental study. Anesthesiology 2003;98:862–70
16. Blaise G. Should we use naloxone epidurally? Can J Anaesth 2003;50:875–8
17. Hamann S, Sloan PA, Witt W. Low-dose intrathecal naloxone to enhance intrathecal morphine analgesia: a case report. J Opioid Manag 2008;4:251–4
18. Spencer SL, Francis VS. Continuous plexus and peripheral nerve blocks for postoperative analgesia. Anesth Analg 2003;96:263–72
19. Murphy DB, McCartney CJ, Chan VW. Novel analgesic adjuncts for brachial plexus block: a systematic review. Anesth Analg 2000;90:1122–8
20. Levine JD, Gordon NC. Method of administration determines the effect of naloxone on pain. Brain Res 1986;365:377–8
21. Woolf CJ. Analgesia and hyperalgesia produced in the rat by intrathecal naloxone. Brain Res 1980;189:593–7
22. Wang HY, Friedman E, Olmstead MC, Burns LH. Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor-G protein coupling and Gbetagamma signaling. Neuroscience 2005;135:247–61
23. Levine JD, Gordon NC, Fields HL. Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain. Nature 1979;278:740–1
24. Gan TJ, Ginsberg B, Glass PS, Fortney J, Jhaveri R, Perno R. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology 1997;87:1075–81
25. Sadeghi A, Movafegh A, Nooralishahi B. The effect of an intravenous bolus of ultra-low-dose naloxone on intraoperative sedation, post operative pain intensity and morphine consumption in cesarean section patients under spinal anesthesia. RJBS 2008;10:1223–6
26. Kim MK, Nam SB, Cho MJ, Shin YS. Epidural naloxone reduces postoperative nausea and vomiting in patients receiving epidural sufentanil for postoperative analgesia. Br J Anaesth 2007;99:270–5
27. Bijur PE, Schechter C, Esses D, Chang AK, Gallagher EJ. Intravenous bolus of ultra-low-dose naloxone added to morphine does not enhance analgesia in emergency department patients. J Pain 2006;7:75–81