Anesth Analg 2007;104:982-983
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000257949.46444.a8
ANALGESIA
Co-injection of Clonidine Prolongs the Anesthetic Effect of Lidocaine Skin Infiltration by a Peripheral Action
Jayant Nick Pratap, MA, MRCPCH, FRCA*,
Rajesh K. Shankar, FRCA , and
Teodor Goroszeniuk, FCA RCSI*
From the *Department of Anaesthesia, Guy's & St. Thomas' NHS Foundation Trust, London, UK; and Department of Anaesthesia, St Richard's Hospital, Royal West Sussex NHS Trust, Chichester, UK.
Address correspondence and reprint requests to Teodor Goroszeniuk, FCA RCSI, Department of Anaesthesia, Guy's Hospital, Guy's & St. Thomas' NHS Foundation Trust, St. Thomas St., London SE1 9RT, UK. Address e-mail to teogoroszeniuk{at}doctors.org.uk.
Abstract
BACKGROUND: The addition of clonidine to local anesthesia prolongs the local anesthetic action, but in humans, the contribution of a peripheral mechanism remains unclear.
METHODS: We investigated clonidine's peripheral effect in 20 healthy volunteers undergoing double-blind, subcutaneous infiltration of 0.5% lidocaine with normal saline to one forearm and then, immediately, of lidocaine with 10 µg clonidine to the contralateral arm. Pinprick sensation was tested every 15 min for 6 h.
RESULTS: Median time to return of normal sensation was 3.5 h for lidocaine alone, but at least 6 h if combined with clonidine (P < 0.001).
CONCLUSIONS: Clonidine has a significant peripheral action in enhancing duration of local anesthesia on superficial co-infiltration with lidocaine.
Addition of the  2-adrenoceptor-specific agonist clonidine to local anesthetic increases the duration of anesthesia in intrathecal, extradural, and peripheral nerve blockade (1). Moreover, clonidine alone provides analgesia for extradural (2), intrathecal (3), or intraarticular (4), but not axillary (5), blocks. Spinal, supraspinal, and peripheral sites of antinociceptive action have been proposed for clonidine. Both pharmacokinetic and pharmacodynamic interactions may explain the anesthesia-prolonging effect. The relative contributions of each of these mechanisms of action remain unclear (1).
To demonstrate that the mechanism of action of clonidine includes a peripheral contribution, we tested whether the addition of a small dose of this drug would prolong the duration of action of a short-acting local anesthetic after skin infiltration in volunteers.
METHODS
The study design consisted of subcutaneous infiltration of lidocaine, with or without clonidine, to each forearm of volunteer subjects so as to permit simultaneous comparison of drug duration of action with each individual acting as his or her own control. The intended primary outcome variable was duration of anesthesia to pinprick. Sample size was calculated, assuming that duration of anesthesia from lidocaine alone would be normally distributed with mean and standard deviation of 75 and 30 min, respectively. Approximately 20 subjects were needed to provide 80% power to demonstrate a clinically relevant 30% prolongation of action with the addition of clonidine, with a risk of type I error of 5%.
Institutional ethical committee approval and written informed consent from all subjects were obtained. In a double-blind protocol, 20 volunteers received subcutaneous infiltration of 0.5 mL lidocaine 0.5% with 0.1 mL saline 0.9% to the skin on the medial aspect of one forearm, followed immediately by another injection of 0.5 mL lidocaine 0.5% with 0.1 mL clonidine (10 µg) on the other. All injections were performed with a 25-gauge sharp-beveled needle. The clonidine dose was chosen from previous studies to be effective yet free of systemic effects (6,7). Care was taken to avoid subcutaneous veins to prevent intravascular injection.
Cutaneous sensation was assessed at 15-min intervals on a simple four-point scale using Neurotip neurological testing pins (Owen Mumford, Woodstock, Oxon, UK), which were applied firmly to the skin but without breaking its integrity. Patients were permitted to observe the testing procedure, but asked to compare sensation in infiltrated skin with adjacent areas that had not received local anesthetic injection. Scoring was 0 for no sensation, 1 for sensation of pressure only, 2 for abnormal sensation of pressure and sharpness, and 3 for normal sensation of sharpness. Testing was continued for 6 h postinjection, a period of time chosen to avoid undue inconvenience to unpaid volunteer subjects. The injection sites were observed for adverse effects.
RESULTS
At the infiltration site of local anesthetic without clonidine, 19 of 20 volunteers regained normal sensation (score 3) by 6 h (median time to return of normal sensation 3.5 h, range 1.25–6 h). No volunteer reported normal sensation by 6 h at the site of lidocaine and clonidine co-infiltration (P < 0.001 by Wilcoxon–Sigard rank test).
All but one of the volunteers showed blanching of the skin at the site of injection of lidocaine plus clonidine, but none in the control area. There were no other adverse events.
DISCUSSION
This study is useful in dissecting the contributions of peripheral and central clonidine-mediated effects in local anesthesia prolongation. Most importantly, control and experimental sites were injected and assessed simultaneously in each individual, and therefore, any difference between the sites would be attributable to the local action of clonidine. Furthermore, the clonidine dose was chosen from published evidence to be clinically active in prolonging the local anesthetic effect yet free of measurable systemic effects (6,7). Primary neuraxial or systemic mechanisms are therefore effectively excluded, and the existence of a peripheral site of action of clonidine in prolonging local anesthetic action in humans is supported by this study.
Some previous studies, both scientific and clinical, have also provided evidence for the mechanism of action of clonidine as a local anesthetic additive, as well as suggesting local anesthetic-like properties of clonidine itself (8,9).
A local effect of clonidine in antinociception has been demonstrated in mice by topical administration of clonidine (10). A partial pharmacokinetic contribution mediated by vasoconstriction is also suggested by a human microdialysis study (11). In the current study, the significance of vasoconstriction to the lengthening of local anesthetic action by clonidine cannot be assessed, as no control of co-infiltration with a known vasoconstrictor was used and tissue blood flow was not studied.
Some clinical studies also have addressed the issue of the site of action of clonidine. They offer conflicting evidence regarding the relative contributions of peripheral versus central actions of clonidine in different regional anesthesia techniques. In the context of field blockade for hernia surgery, clonidine prolongs anesthesia whether co-administered with local anesthetic or given parenterally (12). By contrast, clonidine prolongs psoas compartment block only when given parenterally and not when co-administered (13), whereas the reverse is true for postarthroscopy analgesia (14).
The present study shows that, on subcutaneous co-infiltration with lidocaine, clonidine has significant peripheral action in enhancing local anesthesia duration. As volunteer subjects were used, it was not possible to confirm the clinical benefits of adding clonidine to local anesthetic for peripheral infiltration. The results however suggest that use of this additive may be beneficial for postoperative analgesia in the context of plastic or other superficial surgical procedures, in addition to reducing local blood flow (15), which may aid surgery. Additional, more clinically focused trials may clarify the benefits of adding clonidine to local anesthetic for infiltration, particularly in relation to other local anesthetic additives such as epinephrine and bicarbonate. Further studies are required to elucidate the mechanism underlying the peripheral effect of clonidine.
Footnotes
Accepted for publication December 22, 2006.
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