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Intradermal sufentanil does not improve lidocaine-induced local anesthesia [L’administration intradermique de sufentanil n’améliore pas l’anesthésie locale induite par la lidocaïne] Maximilian W.B. Hartmannsgruber MD,* Peter G. Atanassoff Zeev N. Kain MD,* David G. Silverman MD*
Purpose: Peripheral opioid receptors may result in antinociceptive effects when occupied by opioids. This study examined intradermally injected sufentanil (S), a highly lipid soluble opioid, administered with and without lidocaine (L), in a thermal pain model. Methods: Nine volunteers were instructed on the method of magnitude estimation of pain before undergoing baseline testing with seven seconds thermal stimuli between 44 and 52°C, delivered by a contact thermal stimulator at five cutaneous forearm sites. Then, four sites randomly received injections of equal volumes (0.1 mL) of either normal saline (NS), lidocaine 0.5% (L), sufentanil 0.75 µg (S), lidocaine 0.5% plus sufentanil 0.75 µg (L+S), and one site was not injected and served as reference (REF). Testing was repeated at six, 30, 60, 90, 120, and 150 min following injection. The pain elicited by each stimulus was normalized to the subject’s response to the 50°C stimulus at the REF site. Results: Baseline testing showed small (P = ns) differences in pain scores. At six minutes, the lidocaine sites (L, L+S) had pain scores that were mean 83% (range 78–88%) lower than the other sites (P < 0.05), but there was no difference between the L and L+S sites or between the S and NS or REF sites. At 30 and 60 min these pain scores were mean 38% (29–44%) and 20% (8–30%) less than at the REF, NS, and S sites (P = ns). At 90 min and later times, the pain scores had returned to baseline. Conclusions: These results suggest that intradermal sufentanil alone has no analgesic effect. Further, in combination with lidocaine, sufentanil does neither potentiate nor prolong the analgesic effect of lidocaine.
MD,*
Arne Budde
MD,*
Sorin J. Brull
MD,†
Objectif : Les récepteurs d’opioïdes périphériques peuvent produire des effets nociceptifs quand ils sont occupés par les opioïdes. Notre étude utilise un modèle de douleur thermique et examine le sufentanil (S) en injection intradermique, un opioïde hautement liposoluble, administré avec ou sans lidocaïne (L). Méthode : La méthode d’estimation du degré de douleur a été expliquée à neuf volontaires avant les tests de base réalisés avec sept stimuli thermiques de sept secondes appliqués entre 44 et 52 °C par un stimulateur thermique à contact sur cinq sites cutanés de l’avantbras. Puis, sur quatre sites choisis au hasard, nous avons procédé à l’injection d’un volume égal (0,1 mL) de solution salée (SS), de lidocaïne à 0,5 % (L), de 0,75 µg de sufentanil (S) ou de lidocaïne à 0,5 % plus 0,75 µg de sufentanil (L+S). Un site est demeuré libre comme référence (REF). L’épreuve a été reprise à 6, 30, 60, 90, 120 et 150 min après l’injection. La douleur provoquée par chaque stimulation a été normalisée selon la réponse du sujet au stimulus fait au site REF à 50 °C. Résultats : L’épreuve de base a montré de faibles différences (P = ns) entre les scores de douleurs. À six minutes, les sites de lidocaïne (L, L+S) ont affiché des scores de douleurs d’une moyenne de 83 % (limites de 78–88 %) plus faibles que ceux des autres sites (P < 0,05), mais il n’y avait pas de différence entre les sites L et L+S ou entre les sites S et SS ou REF. À 30 et 60 min, les scores de douleurs présentaient une moyenne de 38 % (29–44 %) et 20 % (8–30 %) de moins qu’aux sites REF, SS et S ( P = ns). À 90 min et aux temps de mesure ultérieurs, les scores de douleurs étaient revenus aux mesures de base. Conclusion : Ces résultats laissent penser que l’administration intradermique de sufentanil seule n’a pas d’effet analgésique. De plus, en combinaison avec la lidocaïne, le sufentanil ne potentialise pas, ou ne prolonge pas, l’effet analgésique de la lidocaïne.
From the Departments of Anesthesiology, Yale University School of Medicine,* New Haven, Connecticut, and the University of Arkansas for Medical Sciences,† Little Rock, Arkansas, USA. Address correspondence to: Dr. Peter G. Atanassoff, Department of Anesthesiology, Yale University School of Medicine, P.O. Box 208051, New Haven, Connecticut 06520-8051, USA. Phone: 203-785-2802; Fax: 203-785-6664; E-mail:
[email protected] Accepted for publication August 20, 2002. Revision accepted November 4, 2002. CAN J ANESTH 2003 / 50: 2 / pp 153–158
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ARCOTICS were long believed to exert their analgesic action exclusively by blocking pain signals in the brain and modifying the affective component of pain, but now are known to block pain pathways at the level of the spinal cord as well.1–4 Furthermore, in an isolated sheathed and desheathed rabbit vagus nerve preparation, high concentrations of opioids have been shown to exert a weak local anesthetic-type action,5 and recent investigations suggest the existence of opioid receptors mediating analgesia on the peripheral terminals of afferent nerves.6–10 The analgesic effects of peripherally applied opioids, which may be reversed with an opioid antagonist such as naloxone7 are especially prominent in inflamed tissue. In normal, uninflamed tissues, the opiate receptors appear to be shielded by a perineural barrier. Inflammation may cause up-regulation of peripheral receptors,10 as well as increased access to such receptors as a consequence of a disruption of the perineural tissue.7 Investigations into analgesia produced by peripheral opioid administration are important clinically since the dose requirements for local application are relatively small, and therefore can avoid many of the undesirable side effects associated with systemic narcotic administration.11 In a previous investigation,12 it was hypothesized that inflammation induced by a thermal stimulus (first degree burn) would open perineural barriers and expose peripheral nerve endings, and that the exposure would be facilitated by concomitant administration of an amide local anesthetic (lidocaine). However, morphine added to a lidocaine solution did not improve the analgesic effect of either drug; instead the development of hyperalgesia and itching was observed, presumably due to local histamine release. The goal of the present investigation was to determine whether a more lipid soluble opioid, devoid of histamine releasing properties can gain access to opioid receptors with and/or without lidocaine, following thermal stimulation. We put forth the primary hypothesis that, when mixed with lidocaine, intradermally administered sufentanil would provide analgesia superior to that of lidocaine alone. Methods The experimental protocol was approved by the Human Investigational Committee at Yale University. With written informed consent, nine healthy volunteers between 25–45 yr of age and without use of analgesic or sedative drugs for at least seven days were recruited for this one-session investigation. Prior to the study day, each volunteer was familiarized with the experimental thermal stimuli (described below) and instructed on the method of magnitude estimation of pain.13,14 The vol-
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unteer was told to assign 0 to non-painful sensations and positive numeric values to painful thermal stimuli, such that the values assigned to different stimuli would be proportional to the volunteer’s estimate of the relative pain intensities. As originally suggested by Stevens,13 each volunteer was instructed to call the first painful stimulus any number that seemed appropriate, followed by numbers to subsequent stimuli reflecting the relative degree of perceived pain. The subjects underwent baseline pre-injection thermal testing at five 1 × 1 cm cutaneous sites, three on one, two on the contralateral volar forearm. Test sites were chosen approximately 5 cm apart and marked on the skin. Computerized thermal testing was performed such that a base temperature of 36°C was maintained for one minute before the first stimulus and for the 23sec duration between stimuli. The temperature of each test stimulus was reached at the end of one second with a linear ramp increase from 36°C to the desired value, maintained for five seconds and then decreased within one second to the base temperature.14 The volunteers were tested with five thermal stimuli (44°C, 46°C, 48°C, 50°C, and 52°C) delivered in random sequence. The pain elicited by each stimulus was recorded and normalized to the subject’s response to the 50°C stimulus at the reference site at baseline.14 Following baseline testing, four of the sites were randomly assigned to receive an intradermal injection of equal volumes (0.1 mL) of normal saline (NS), lidocaine 0.5% (L), sufentanil 0.75 µg (S), or a combination of lidocaine (0.5%) plus sufentanil 0.75 µg (L+S) via a 27-gauge tuberculin needle. The vehicle for all injectates was NS. The remaining site served as a reference (REF). At six, 30, 60, 90, 120, and 150 min following injection, thermal testing was repeated. The hypothesis of the present investigation was that intradermal injection of sufentanil would prolong or potentiate a lidocaine-induced reduction in thermal pain. The primary endpoint for the study was the amount of pain experienced during the various stimuli. Two-way ANOVA with repeated measures was used to analyze the changes in pain level experienced over seven time points, baseline (T1), six (T2), 30 (T3), 60 (T4), 90 (T5), 120 (T6), and 150 (T7) min. The between group variable was the intervention group, and the within group variable was the change within each intervention group. Results are presented as mean ± standard error (SEM); P < 0.05 was considered statistically significant. Results All volunteers completed the study. Thermal testing led to an erythematous reaction at all testing sites.
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FIGURE 1 Magnitude estimate scores at the lidocaine and lidocaine + sufentanil sites at each time-point. Values represent mean ± SE of average score of all temperatures at a given time normalized to the score in response to the 50°C stimulus at the reference site at baseline. P < 0.05 for difference vs baseline.
FIGURE 2 Magnitude estimate scores at the sufentanil, lidocaine, and lidocaine + sufentanil sites at baseline. Values represent mean ± SE of score at each temperature normalized to the score in response to the 50°C stimulus at the reference site at baseline.
Blister formation was not observed in any study subject at any test site. In response to testing after injection, the REF site showed no evidence of hyperalgesia as a result of prior testing. The normalized magnitude estimates over all temperatures at the REF site averaged 0.58 ± 0.08, 0.57 ± 0.09, 0.55 ± 0.09, 0.57 ± 0.08, 0.54 ± 0.08, 0.55 ± 0.08, 0.50 ± 0.08 at baseline and the six later phases, respectively.
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FIGURE 3 Magnitude estimate scores at the sufentanil, lidocaine, and lidocaine + sufentanil sites at six minutes following intradermal injection. Values represent mean ± SE of score at each temperature normalized to the score in response to the 50°C stimulus at the reference site at baseline.
Saline had no effect on pain: normalized pain scores at the NS sites were -17%, +23%, -7%, +35%, +48%, +20%, 0% of REF at baseline, six minutes, 30 min, 60 min, 90 min, 120 min, and 150 min, respectively. Lidocaine alone provided normalized pain scores of +3%, -77%, -32%, -3%, +22%, +7%, -23% of REF at the respective time points. In contrast to lidocaine, sufentanil alone had no effect on pain: normalized pain scores at the S sites were +3%, 0%, +3%, +25%, +33%, -14%, +3% of REF at baseline, six minutes, 30 min, 60 min, 90 min, 120 min, and 150 min, respectively. The addition of sufentanil to lidocaine provided normalized pain scores that were similar to those of lidocaine alone: -11%, -86%, -37%, 0%, +28%, -3%, -10% of REF at baseline, six minutes, 30 min, 60 min, 90 min, 120 min, and 150 min, respectively (Figure 1). The average normalized pain scores (with all temperatures included) at the L and L+S sites at each time point are summarized in Figure 1. There was no difference between the L and L+S sites at baseline or during any temperature at any time point (P = ns). After injection, both sites had significantly lower pain scores as compared to the REF, NS, and S sites (P < 0.05). Figures 2 to 5 summarize the lack of a sufentanil effect at the S, L, and L + S sites. Figure 3 shows the similar decline in magnitude estimates at the L and L+S sites at six minutes: over all temperatures, the S, L, and
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FIGURE 4 Magnitude estimate scores at the sufentanil, lidocaine, and lidocaine + sufentanil sites at 30 min following intradermal injection. Values represent mean ± SE of score at each temperature normalized to the score in response to the 50°C stimulus at the reference site at baseline.
FIGURE 5 Magnitude estimate scores at the sufentanil, lidocaine, and lidocaine + sufentanil sites at 60 min following intradermal injection. Values represent mean ± SE of score at each temperature normalized to the score in response to the 50°C stimulus at the reference site at baseline.
L+S sites differed by 3%, -77%, and -86% from the REF site and there was no evidence of an effect of sufentanil (P < 0.05 for S vs L, S vs L+S sites; P = ns for L vs L+S). Figures 4 and 5 show the similarity of all sites upon resolution of the analgesic effect at the L and L+S sites: by 30 min, over all temperatures, the L and L+S sites differed by -32% and -37% from baseline; this difference decreased progressively at later time points.
tion was induced with oleyl alcohol and sterile peanut oil injection.20 In a clinical investigation of low dose (1 mg) intra-articular morphine administered following arthroscopic knee surgery, significant analgesia was achieved for four hours when compared to the administration of the same dose intravenously.15 The analgesic effects of intraarticular morphine were reversed when intra-articular naloxone was co-administered. Experimentally, various agents such as prostaglandins, carrageenan, killed mycobacteria, acetic acid, formalin, or bradykinin can induce inflammatory states. The effectiveness of opioids is increased in such contexts presumably because the inflammatory agents disrupt the perineural sheath. Neither the erythematous reaction caused by thermal testing in this study nor the addition of lidocaine induced enough of a change to enable an analgesic effect of sufentanil; neither induced an inflammatory condition as postulated necessary to cause the breakdown of the perineurum by inflammatory processes.21 Accompanying non-inflammatory agents also may facilitate the accessibility of opioids to peripheral opioid receptors. For example, the hyperosmolar compound mannitol causes disruption of the perineural barriers thereby facilitating access of opioids to peripheral receptors.10 A comparable effect was not achieved with lidocaine in the present study. Although the combination
Discussion The present findings are of interest because they indicate that the addition of a lipid-soluble opioid would not provide analgesia in a setting where clinicians might consider utilizing such a drug. In the context of acute thermally induced pain, no analgesic benefit was obtained from intradermal sufentanil alone or when sufentanil was added to lidocaine. These results suggest that lidocaine does not expose peripheral opiate receptors to intradermally injected sufentanil. Studies comparing peripheral opioids in inflamed vs non-inflamed tissue have reported greater antinociceptive effects with inflammation.10,15–17 Inflammation not only disturbs the neural barrier but also may cause increased de novo synthesis and peripherally directed axonal transport of opiate receptors,18 as well as conformational changes.19 In experimental canine arthritis, the density of specific opioid radioligand binding was markedly enhanced in homogenates prepared from the joint in which inflamma-
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of local anesthetic and opioid is synergistic at the spinal cord, it was not synergistic in our peripheral pain model. As 0.75 µg of sufentanil was injected and tested in a very small area (1 cm2), and this dose of sufentanil has an estimated relative potency of 0.375–0.75 mg of morphine,22 it is unlikely that this absence of a modifying effect of sufentanil stems from an insufficient amount of the drug. In investigations which detected a prolonged effect of opioids when injected into the brachial plexus sheath of rats23 and humans24 in the absence of inflammation, fentanyl 0.5–1.5 µg·kg–1 (rats) or morphine 50 µg·kg–1 (humans) was administered, doses which may have produced systemic effects. As expected, none of the volunteers in the present study showed any signs of systemic narcotic effect nor side effects from the administration of a total of 1.5 µg sufentanil. Of note, the combination of lidocaine and sufentanil did not cause the hyperalgesia reported with lidocaine plus morphine,12 presumably because sufentanil does not induce the release of histamine. We conclude that a peripheral antinociceptive effect is not achieved by sufentanil when administered alone or in combination with lidocaine. The findings of this investigation suggest that the intradermal injection of a combination of lidocaine plus sufentanil, in an effort to provide superior analgesia compared to the local anesthetic injection alone, provides no clinical benefit. References 1 Calvillo H, Henry JL, Neuman RS. Effects of morphine and naloxone on dorsal horn neurons in the cat. Can J Physiol Pharmacol 1974; 52: 1207–11. 2 Kitahata LM, Kosaka Y, Taub A, Bonikos K, Hoffert M. Lamina-specific suppression of dorsal-horn unit activity by morphine sulphate. Anesthesiology 1974; 41: 39–48. 3 Le Bars D, Menetrey D, Conseiller C, Besson JM. Depressive effects of morphine upon lamina V cells activities in the dorsal horn of the spinal cat. Brain Res 1975; 98: 261–77. 4 Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology 1979; 50: 149–51. 5 Gissen AJ, Gugino LD, Datta S, Miller J, Covino BG. Effects of fentanyl and sufentanil on peripheral mammalian nerves. Anesth Analg 1987; 66: 1272–6. 6 Joris JL, Dubner R, Hargreaves KM. Opioid analgesia at peripheral sites: a target for opioids released during stress and inflammation? Anesth Analg 1987; 66: 1277–81. 7 Stein C, Millan MJ, Shippenberg TS, Herz A. Peripheral effect of fentanyl upon nociception in inflamed tissue
157 of the rat. Neurosci Lett 1988; 84: 225–8. 8 Stein C, Millan MJ, Shippenberg TS, Peter K, Herz A. Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther 1989; 248: 1269–75. 9 Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med 1995; 332: 1685–90. 10 Antonijevic I, Mousa SA, Schafer M, Stein C. Perineurial defect and peripheral opioid analgesia in inflammation. J Neurosci 1995; 15: 165–72. 11 Stein C, Schafer M. Hassan AH. Peripheral opioid receptors. Ann Med 1995; 27: 219–21. 12 Atanassoff PG, Brull SJ, Printsev Y, Silverman DG. The effect of intradermal administration of lidocaine and morphine on the response to thermal stimulation. Anesth Analg 1997; 84: 1340–3. 13 Stevens SS, Gallanter EH. Ratio scales and category scales for a dozen perceptual continua. J Exp Psychol 1957; 54: 377–417. 14 Lundell JC, Silverman DG, Brull SJ, et al. Reduction of postburn hyperalgesia after local injection of ketorolac in healthy volunteers. Anesthesiology 1996; 84: 502–9. 15 Stein C, Comisel K, Haimerl E, et al. Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N Engl J Med 1991; 325: 1123–6. 16 Jaureguito JW, Wilcox JF, Cohn SJ, Thisted RA, Reider B. A comparison of intraarticular morphine and bupivacaine for pain control after outpatient knee arthroscopy. A perspective, randomized, double-blinded study. Am J Sports Med 1995; 23: 350–3. 17 Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg 1993; 76: 182–91. 18 Hardy GW, Lowe LA, Sang PY, et al. Peripherally acting enkephalin analogues. 1. Polar pentapeptide. J Med Chem 1988; 31: 960–6. 19 Stein C, Lehrberger K, Yassouridis A, Khoury G. Opioids as novel intra-articular agents in arthritis. In: Fields HL, Liebeskind JC (Eds). Progress in Pain Research and Management (Vol. 1). Seattle: IASP Press; 1994: 289–97. 20 Keates HL, Cramond T, Smith MT. Intraarticular and periarticular opioid binding in inflamed tissue in experimental canine arthritis. Anesth Analg 1999; 89: 409–15. 21 Hassan AH, Ableitner A, Stein C, Herz A. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 1993; 55: 185–95. 22 Murphy MR. Opioids. In: Barash PG, Cullen BF, Stoelting RK (Eds). Clinical Anesthesia. Philidelphia: J.B. Lippincott Company; 1992.
158 23 Kayser V, Gobeaux D, Lombard MC, Guilbaud G, Besson JM. Potent and long lasting antinociceptive effects after injection of low doses of a mu-opioid receptor agonist, fentanyl, into the brachial plexus sheath of the rat. Pain 1990; 42: 215–25. 24 Viel EJ, Eledjam JJ, De La Coussaye JE, D’Athis F. Brachial plexus block with opioids for postoperative pain relief: comparison between buprenorphine and morphine. Reg Anesth 1989; 14: 274–8.
Early Snow in Tremblant - Quebec
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