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ANALGESIA

Clonidine and Analgesic Duration After Popliteal Fossa Nerve Blockade: Randomized, Double-Blind, Placebo-Controlled Study

Jacques T. YaDeau, MD, PhD^*, Vincent R. LaSala, MD^*, Leonardo Paroli, MD, PhD^*, Richard L. Kahn, MD^*, Kethy M. Jules-Elysée, MD^*, David S. Levine, MD, Barbara L. Wukovits, RN, BSN, C^*, and Jane Y. Lipnitsky, BA^*

From the *Department of Anesthesiology and Foot and Ankle Service, Department of Orthopedic Surgery at Hospital for Special Surgery, Weill Medical College of Cornell University, New York City, NY.

Address correspondence to Jacques T. Ya Deau, MD, PhD, Hospital for Special Surgery, 535 E 70th St., New York, NY 10011. Address e-mail to yadeauj{at}hss.edu.

Abstract

BACKGROUND: We tested the hypothesis that 100 µg clonidine added to 0.375% bupivacaine would prolong the duration of analgesia from popliteal fossa nerve blockade.

METHODS: Ninety-nine patients scheduled for hospital admission after foot or ankle surgery entered this randomized, double-blind, placebo-controlled trial. Patients received a popliteal fossa block (nerve stimulator technique, via the posterior approach) using 30 mL 0.375% bupivacaine, with epinephrine. Patients were randomized to receive no clonidine, 100 µg clonidine IM, or 100 µg clonidine with bupivacaine for the popliteal block. Patients also received a combined spinal-epidural anesthetic, a saphenous nerve block, and postoperative IV patient-controlled analgesia. The primary outcome was patient-reported duration of analgesia.

RESULTS: Duration of analgesia was statistically longer in the block clonidine group (18 ± 6 h for clonidine with bupivacaine vs 14 ± 7 h for IM clonidine and 15 ± 7 h for control, P = 0.016 for control vs clonidine with bupivacaine). Pain scores, analgesic use, and side effects attributable to pain management were similar among groups.

CONCLUSIONS: Clonidine significantly prolongs the analgesic duration after popliteal fossa nerve blockade with bupivacaine.

Popliteal fossa nerve blockade with bupivacaine can reduce postoperative pain for 14–20 h after major foot and ankle surgery, with minimal side effects.1,2 However, the duration of analgesia after single-injection nerve blocks may not be sufficient for a comfortable transition to oral analgesics. Adjuncts have been added to prolong the period of analgesia after nerve blockade, but with mixed success.3 Clonidine appears to prolong nerve blockade,4,5 but many studies are difficult to interpret because they lack systemic controls.6 Additionally, some studies with positive results used intermediate-acting local anesthetics, e.g., lidocaine,5 or used low concentrations of local anesthetics.7 When added to long-acting local anesthetics, clonidine failed to demonstrate prolongation of axillary,8 or interscalene9 block. Power analysis for the interscalene study was based on prolongation of analgesia of at least 30%. Furthermore, a systemically controlled study indicated that prolongation of analgesia may be mediated centrally in that IV clonidine prolonged the effects of a psoas block, but clonidine included with the local anesthetic had no significant effect.10

This randomized, double-blind, and placebo-controlled study tested the hypothesis that inclusion of clonidine with the local anesthetic prolongs the duration of analgesia after popliteal fossa nerve blockade with bupivacaine.

METHODS

After approval by The Hospital for Special Surgery IRB, written informed consent was obtained from 99 patients scheduled for hospital admission after foot or ankle surgery by a single attending surgeon. Exclusion criteria were planned surgery that would cause pain outside the distribution of the sciatic nerve (e.g., iliac crest bone graft), revision surgery, neuropathy in the surgical extremity or chronic pain (defined as chronic use of opioid analgesics), inability of the patients to describe postoperative pain to the investigators (language barrier, psychiatric disorder, or dementia), and contraindications to any of the following: performance of popliteal fossa nerve block, performance of neuraxial anesthesia, administration of clonidine or hydromorphone. Patients were not excluded based on medial or lateral location of the incision. Operations were classified as either acute traumatic (e.g., open reduction, fixation of fracture, or Achilles tendon repair) or chronic reconstructive (e.g., joint arthrodesis or fusion).

After arrival to the operating room, popliteal fossa nerve block was performed with 30 mL of 0.375% bupivacaine with 5 µg/mL epinephrine + 1 mL study solution. Patients were randomized via computer-generated random assignment; only the pharmacy department had access to the randomization table. No investigator had any knowledge of group assignment. Two syringes, labeled "block" and "IM" and containing 1 mL of either normal saline or clonidine, 100 µg, were supplied by the pharmacy department. Thirty-three patients (controls) received normal saline added to the local anesthetic and saline IM (deltoid muscle). Thirty-three patients received normal saline added to the local anesthetic and clonidine IM. Thirty-three patients (block clonidine) received clonidine added to the local anesthetic and normal saline IM. Popliteal fossa nerve block (posterior approach)11 was performed using a Braun (Bethlehem, PA) 2 inches Stimuplex needle and a Braun Stimuplex Dig RC nerve stimulator, starting at 1.5 mA and decreasing to 0.5 mA (2 Hz). Details of the block performance were recorded (minimum current obtained and type of muscle twitch observed). Side effects that occurred during popliteal fossa nerve block were recorded (paresthesia, aspiration of blood, seizures, tachycardia, or other cardiac effects). Popliteal fossa nerve block was performed in the operating room, before the neuraxial block. IV sedation was determined by the attending anesthesiologist.

Immediately after performance of the nerve block, patients received a combined spinal-epidural anesthetic, which allowed the use of a thigh tourniquet during surgery. Saphenous nerve blockade was performed at the level of the proximal tibia with 7 mL 0.5% bupivacaine. In the recovery room, patients were connected to demand-only IV hydromorphone patient-controlled analgesia pumps, with no basal rate. Patients were offered oral analgesics (acetaminophen with oxycodone) concurrent with the IV patient-controlled analgesia. Oral analgesics were given only by patient request. The primary end-point of the study was time from performance of popliteal fossa nerve block to onset of pain in the distribution of the sciatic nerve, determined by patient interview. Secondary end-points of the study included total analgesic use, numerical rating scale scores of pain intensity, from 0 to 10, and incidence of side effects attributed to pain control (nausea, emesis, and sedation).

Block duration was defined as time from administration of the nerve block to return of pain, as reported by the patient. Dysesthesia was defined as any abnormal sensation in the distribution of the sciatic nerve, most commonly described as tingling or "pins and needles" sensation. Neuropraxia was defined as an objective abnormality of the neurologic examination in the distribution of the sciatic nerve on the operative side.

Sedation was defined in two ways: as a patient receiving 3, 4, or 5 (on the 1–5 sedation scale: 1 = wide awake, 2 = drowsy, 3 = dozing intermittently, 4 = mostly sleeping, 5 = awakens only when aroused) during the morning hours as recorded by the nurses, or as assessed by an investigator during the one-on-one interview with the patient.

Previous work indicated that analgesia after popliteal fossa nerve block with 0.375% bupivacaine lasted 14 ± 8 h (mean ± sd).12 Before initiation of the study, an ANOVA power analysis, performed using "Sigma-Stat" program (Jandel Scientific, Version 2.0, San Rafael, CA), indicated that 33 patients would be needed in each of three groups to give an 80% power of detecting prolongation of the block from a mean of 14 ± 8 h to 20 ± 8 h.

Statistical analysis was performed with Statview for Windows (SAS Institute Inc., Version 5.0, Cary, NC). Descriptive analyses consisted of frequencies and percentages for discrete data, means, and standard deviations for normally distributed continuous data and medians with 25th and 75th percentiles for non-normally distributed continuous data. Initial quality control Kolgomorov-Smirnov normality tests were conducted on continuous data to test distribution normality. For continuous variables found to be normally distributed (Kolgomorov-Smirnov >0.05), a one-way ANOVA model was performed. If the overall ANOVA model was statistically significant, a post hoc analysis was undertaken using the Fisher’s protected least squares difference test to further examine the directional quality of significance. The post hoc test of choice was the Fisher’s PLSD (protected least squares difference) since it is considered to be most sensitive to Type 1 error.13 For continuous variables found not to be normally distributed as well as discrete variables, the nonparametric Kruskall–Wallis test was used to compare differences in the medians among the three groups. Inferential analyses were performed using contingency tables for raw data for categorical variables; the ² P value was reported.

RESULTS

Of the patients assessed for eligibility (n = 167), 68 were excluded (37 did not meet inclusion criteria, 15 refused, and 16 for other reasons). One patient (in the saline control group) was enrolled in error; he had profound peripheral neuropathy (a pre-established exclusion criterion) and was excluded from analysis. All other patients were analyzed. The recruitment period was from December 21, 2004, to February 12, 2007. A suitable muscular response at nerve stimulator current 0.5 mA was obtained in all patients. After resolution of the neuraxial block, all patients reported decreased sensation in the operative foot, indicating successful popliteal fossa nerve block. Patient demographics were similar in all groups (Table 1).

Clonidine resulted in a statistically significant prolongation of analgesia when included with the local anesthetic for popliteal fossa nerve block (Table 2). Analgesia in the group that received clonidine mixed with bupivacaine lasted for a mean of 18.3 h (95% confidence intervals of 17.3 through 19.3 h). Analgesia in the control group lasted for a mean of 14.8 h (95% confidence intervals of 13.5 through 16.0 h). IM clonidine did not prolong analgesia from popliteal fossa nerve block; analgesia in the IM clonidine group lasted for a mean of 13.8 h (95% confidence intervals of 12.6 through 14.9 h).

After the end of the analgesic period from the popliteal block, patients in each group had the same levels of pain (mean numerical rating scale 2.8 for control; 3.0 for IM clonidine; 2.8 for clonidine mixed with bupivacaine; P = 0.9 by ANOVA). Analgesic use (Table 2) and side effects potentially attributable to the pain management (Table 3) were similar in all groups. Rates of nausea, emesis, and sedation refer to any occurrence of symptoms while receiving patient-controlled analgesia.

Dysesthesias were noted in 19 patients. The symptoms were typically described as intermittent tingling in the ankle, foot, or toes. Nine patients had dysesthesias of known duration (51 ± 28 days; range 8–89), 3 additional patients had transient dysesthesias of unknown duration (these patients were unable to give the duration of symptoms), and follow-up was not available for 7 patients. Rates of dysesthesias were similar in the three groups: saline: 4 of 32 (13%); IM clonidine: 9 of 33 (27%); clonidine mixed with bupivacaine; 6 of 33 (18%) (P = 0.14 by ²).

DISCUSSION

This study demonstrated that clonidine significantly prolonged the analgesia obtained from popliteal fossa nerve blockade with bupivacaine compared with a placebo or IM clonidine control. Thus, addition of clonidine to the local anesthetic solution can be recommended when performing popliteal fossa nerve block with bupivacaine. No major side effects were noted from the use of clonidine. Although clonidine may cause sedation and decreased arterial blood pressure, our patients received IV sedation and spinal-epidural anesthetics, which would likely tend to obscure such side effects intraoperatively.

We used both a placebo control (saline) and a systemic control (IM clonidine). The dose of clonidine (100 µg) was likely to be a supramaximal dose yet not likely to have serious systemic side effects.14 A comparison of placebo, 30, 90, and 300 µg clonidine (as an additive to lidocaine for axillary nerve block) concluded that the best dose to use clinically is between 30 and 90 µg.15

Duration of pain relief was the primary outcome and was determined by patient interview, and this methodology may have contributed to the large standard deviation noted for duration of analgesic effect in this study. Wide ranges of analgesic duration after peripheral nerve blockade have been reported: 16 h, range 8–241; 19 ± 3.4 h2; 16 h, range 7–31.16 Analgesia from peripheral nerve blockade with bupivacaine can outlast motor blockade.17 For this reason, the onset of pain depends on patient characteristics and the nature of the surgery, both of which were heterogeneous in this study. Other measures of block offset, such as sensitivity to pinprick, might be more reproducible across patients. This was not judged practical, as it was undesirable to awaken patients during the night to assess their nerve block. Inclusion of patients undergoing a variety of procedures strengthens the generalizability of the trial findings.

Methodologic issues include the use of patient report of onset of pain as the primary outcome. We wished to determine whether clonidine prolonged the patients’ perception of analgesia, and so we asked participants to report on the onset of pain. Motor and sensory blockade were not formally assessed, and block durations would likely have been different had different end-points been used. Confounding issues include relatively prolonged tourniquet periods, postoperative splinting, heterogeneity of operative procedures, and the wide range of patient age.

No patients developed neuropraxias, but temporary dysesthesias ("pins and needles" or tingling) occurred in 19% of the patients. Dysesthesias occur frequently after orthopedic surgery performed under combined spinal-epidural anesthesia; at 1 wk after surgery, 17.2% of patients reported decreased sensation and 13.2% reported a pricking sensation.18 Tourniquet use (mean duration was >2 h), intraoperative and postoperative positioning, use of splints, immobilization, postoperative swelling, and surgery near nerves can all contribute to occurrence of postoperative dysesthesias.

This study demonstrated that clonidine prolonged analgesia after popliteal fossa nerve blockade with bupivacaine by 3–4 h. Other methods that may prolong or improve analgesia after peripheral nerve blockade include other additives, coadministration of oral analgesic adjuvents (such as gabapentin, pregabalin, or nonsteroidal antiinflammatory drugs), and infusion of local anesthetic via a perineural catheter.19 Future studies are needed to assess the roles of additives, adjuncts, and perineural infusions in improving analgesia and patient outcome after foot and ankle surgery.

ACKNOWLEDGMENTS

We thank Stephen Lyman, PhD, and John Rutledge, MAS, for statistical consultation. We are also indebted to Mark Branden Arrington, BS, RPh, and other members of the pharmacy division for their assistance.

Footnotes

Accepted for publication February 15, 2008.

Supported by the Hospital for Special Surgery Department of Anesthesiology Research and Education Fund.

Presented in the abstract form at the 2007 ASA meeting (San Francisco).

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