Subarachnoid Sufentanil for Early Postoperative Pain...

Anesthesiology 2001; 94:230–8 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Subarachnoid Sufentanil for Early Postoperative PainManagement in Orthopedic Patients

A Placebo-controlled, Double-blind Study Using Spinal MicrocathetersThomas G. Standl, M.D.,* Ernst-Peter Horn, M.D.,† Michael Luckmann, M.D.,‡Marc-Alexander Burmeister, M.D.,§ Stefan Wilhelm, M.D.,§ Jochen Schulte am Esch, M.D.i

Background: Continuous spinal anesthesia is frequently usedfor intraoperative anesthesia but rarely for postoperative painmanagement. Because even small doses of local anesthetics canbe associated with motor deficits, subarachnoid opioid injec-tion may be an alternative.

Methods: Eighty patients randomly received a subarachnoidinjection of 10 mg sufentanil, 5 mg bupivacaine, 2.5 mg sufen-tanil plus 2.5 mg bupivacaine, or saline through 28-gauge spinalmicrocatheters for early postoperative pain relief after majorlower-limb surgery (n 5 20 in each group). Hemodynamic andrespiratory parameters, pain scores, and motor function weremonitored, and sufentanil concentrations in plasma and cere-brospinal fluid were measured. Ten additional patients receivedup to three repetitive injections of 10 mg sufentanil over 24 h.

Results: All drugs provided excellent pain relief within15 min after injection, lasting 128 6 61 min with sufentanil,146 6 74 min with bupivacaine, and 167 6 78 min with themixture. Patients receiving bupivacaine showed the highestcephalad extension of sensory block (median, T6) and the mostintense motor block, whereas patients given only sufentanilhad no motor deficit. The duration of analgesia was shorterafter subsequent sufentanil injection (100–115 min) than afterthe first injection (198 6 70 min). Six of 50 patients withsufentanil experienced a short episode of respiratory depres-sion within 30 min after the first injection. Cerebrospinal fluidconcentrations of sufentanil peaked at 5 min after injection(183 6 167 ng/ml) but were at the level of detection in theplasma.

Conclusions: Sufentanil injected through microspinal cathe-ters provided profound pain relief without impairing motorfunction when compared with bupivacaine. However, closemonitoring remains mandatory in this setting.

CONTINUOUS spinal anesthesia (CSA) allows small, re-peated amounts of local anesthetic to be administered,resulting in a careful establishment of the desired level ofanesthesia.1–4 This advantage, in combination with theprofound motor block provided by subarachnoid localanesthetic injection, makes CSA an excellent techniquefor many operative procedures.5 Like any catheter tech-nique, CSA also allows supplementation of anesthesiaduring long-lasting operations and can be used for post-

operative pain therapy. However, although several stud-ies report on technical aspects and the usefulness of CSAduring anesthesia,5–8 only few publications deal withCSA for postoperative pain management.9–11 One possi-ble reason for the limited interest about CSA in thepostoperative therapy of pain may be related to thecontroversy about spinal catheters. Although microcath-eters were withdrawn from the market in the UnitedStates and Canada in 1992, after case reports on caudaequina syndromes after CSA with 28-gauge catheters andhyperbaric 5% lidocaine,12 microcatheters are still in usein most European countries.13 Nevertheless, many anes-thesiologists who are not concerned about the use ofspinal microcatheters for intraoperative anesthesia re-move the catheters at the end of the operation withoutusing them for postoperative pain management.

Two major groups of drugs, local anesthetics and opi-oids, can be used in the subarachnoid space for thetreatment of postoperative pain. Local anesthetics pro-vide profound pain relief but also motor weakness oreven paralysis of the lower extremity. Spinal opioidsprovide analgesia without motor block but may be asso-ciated with harmful side effects, such as respiratorydepression.14

The present prospective, randomized, double-blind,placebo-controlled study was designed to examine theefficacy of different subarachnoid applications of sufen-tanil and bupivacaine using microcatheter CSA for earlypostoperative pain relief after major orthopedic surgery.A second part of the study was designed to evaluate theefficacy of repetitive subarachnoid sufentanil injections.

Materials and Methods

After obtaining approval from the local ethics commit-tee (Arztekammer Hamburg) and written informed con-sent, 90 patients (table 1) undergoing elective lower-limb surgery, e.g., hip and knee replacement, revisionhip or knee arthroplasty, or major tumor resection withfemoral or knee reconstruction, were included in thestudy. Exclusion criteria were coagulation disorders,acute neurologic diseases, and a history of acute orchronic consumption of any opioids or a2-adrenergicagonists (e.g., clonidine).

Part 1Patients (n 5 80) were orally premedicated with 7.5

mg midazolam (Hofmann-La Roche, Grenzach-Wyhlen,

* Professor, † Assistant Professor, ‡ Attending Anesthesiologist, § AnesthesiaFellow, i Professor and Chairman.

Received from the Department of Anesthesiology, University Hospital Ham-burg-Eppendorf, Hamburg, Germany. Submitted for publication December 17,1999. Accepted for publication September 1, 2000. Supported in part by Janssen-Cilag, Neuss, Germany. Presented in part at the annual meeting of the AmericanSociety of Anesthesiologists, San Diego, California, October 18–22, 1997, and atthe 22nd Annual Meeting of the American Society of Regional Anesthesia,Atlanta, Georgia, April 10–13, 1997.

Address reprint requests to Dr. Standl: Department of Anesthesiology, Univer-sity Hospital Hamburg-Eppendorf, Martini Strasse 52, 20246 Hamburg, Germany.Address electronic mail to: [email protected]. Individual article re-prints may be purchased through the Journal Web site, www.anesthesiology.org.

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Germany) 1 h before arriving at the anesthesia depart-ment, where they were monitored by electrocardio-gram, noninvasive blood pressure measurement, andpulse oximetry. A large peripheral intravenous cannulawas placed, and an infusion of 500 ml lactated Ringer’ssolution was started. CSA was performed with the pa-tient in the sitting position (performed at L2–L3 in 5%,L3–L4 in 65%, or L4–L5 in 30% of patients). A 22-gaugeSprotte needle (Pajunk, Geisingen, Germany) was in-serted into the subarachnoid space using the midlineapproach. When free flow of cerebrospinal fluid (CSF)had been obtained, a 28-gauge nylon catheter (Cospan;Kendall, Neustadt/Donau, Germany) was inserted 3 cminto the subarachnoid space. After the needle and thecatheter stylet had been withdrawn, a microfilter wasattached to the proximal end. After aspiration of CSFthrough the catheter, all patients received repetitiveinjections of 1 ml plain 0.5% bupivacaine to achieve ananalgesic level (pin prick) of at least T12 before theoperation. When the sensory block had been estab-lished, a central venous and urinary catheter were in-serted, and the patients were transferred to the operat-ing room.

During surgery, the analgesic level was assessed every15 min and maintained constant (target T10, with arange between T8 and T12) by subarachnoid injectionsof 1 ml plain 0.5% bupivacaine every 90 min. Patientsreceived oxygen via face mask to maintain oxygen sat-uration greater than 95% and intravenous titration ofmidazolam at 1-mg bolus doses for sedation. In caseof pain or discomfort during the operation, small dosesof 0.025–0.05 mg fentanyl (Janssen-Cilag, Neuss, Ger-many) were injected intravenously. Blood loss less than1 l was replaced by hydroxyethyl starch infusion and, in

case of hemoglobin concentration less than 8 g/dl, bytransfusion of autologous or allogeneic erythrocytes.

After completion of surgery, patients were transferredto the postanesthesia care unit. The protocol startedwhen patients could move their legs and rated postop-erative pain greater than 50 on a visual analog scale(VAS) ranging from 0 to 100 mm (0 5 no pain; 100 5unbearable pain). According to a computer-generatedrandomization list, patients received a subarachnoid in-jection of 10 mg sufentanil (Janssen-Cilag), 5 mg plainbupivacaine in a dose of 2 ml of 0.25% bupivacaine(Astra, Wedel, Germany), a mixture of 5 mg sufentaniland 2.5 mg plain bupivacaine (mixture), or saline (pla-cebo), respectively. All drugs were prepared as a 2-mlbolus dose in an unlabeled syringe by an anesthesiologistwho was the only person who had access to the ran-domization list but was not otherwise involved in thestudy. The subarachnoid dose was injected through thecatheter within 1 min by a research fellow who wasblinded to the content of the syringes. After the bolusinjection, the catheter was cleared by subsequent injec-tion of 2 ml saline.

Data recorded immediately before the first postopera-tive subarachnoid injection were defined as baseline(time 0). The quality (VAS 0–100) and dermatomal levelof analgesia (pin prick and cold swabs), the degree ofmotor block (Bromage scale: 0 5 none, full flexion ofboth legs against gravity; 1 5 partial, patient is able tomove feet and knees but is not able to elevate his legsagainst gravity; 2 5 almost complete, patient is able tomove feet but not knees; 3 5 complete, patient is unableto move feet or knees), hemodynamics (heart rate, meanarterial pressure), and respiratory parameters (respira-tion rate, oxygen saturation by pulse oximetry) were

Table 1. Demographic Characteristics and Intraoperative Data

Part 1 Part 2

Sufentanil Bupivacaine Mixture Placebo PSufentanilRepetition

n 20 20 20 20 10Age (yr) 64 6 16 57 6 17 59 6 18 61 6 17 0.55 67 6 14Sex (F/M) 13/7 8/12 12/8 9/11 0.34 5/5Height (cm) 167 6 9 171 6 8 167 6 9 171 6 9 0.29 167 6 14Weight (kg) 73 6 9 73 6 11 71 6 14 77 6 15 0.44 74 6 14ASA class I/II/III 4/15/1 10/8/2 5/12/3 6/11/3 0.32 0/5/5Duration of surgery (min) 130 6 50 119 6 44 163 6 84 131 6 49 0.10 187 6 45Hip replacement (n) 9 10 12 9 6Knee replacement (n) 8 8 7 9 4Femoral tumor resection (n) 3 2 1 2 0.933 0Intraoperative doses

Median (75–90)PercentilesSubarachnoid bupivacaine

(mg)12.5 (18.8–20.0) 12.5 (17.5–23.5) 12.5 (15.0–20.0) 12.0 (16.3–21.3) 0.51 18.8 (20.0–25.1)

Intravenous midazolam (mg) 1.0 (4.5–6.5) 0 (5.0–5.5) 1.0 (4.0–6.6) 2.0 (4.5–7.5) 0.88 1.8 (3.2–3.9)Intravenous fentanyl (mg) 0.0 (0.0–0.1) 0.0 (0.0–0.05) 0.0 (0.05–0.1) 0.0 (0.08–0.13) 0.42 0.0 (0.08–0.10)

Data are mean 6 SD (if not otherwise indicated). Analysis of variance with Scheffe F test. Chi-square test.

ASA 5 American Society of Anesthesiologists.

231SUBARACHNOID SUFENTANIL FOR POSTOPERATIVE ANALGESIA

Anesthesiology, V 94, No 2, Feb 2001


determined at 5, 15, 30, and 45 min after injection by ananesthesiologist who was also blinded to the appliedstudy drugs.

At each measurement interval and again 120 min afterthe injection, 5 ml of central venous blood and 1 ml ofCSF were taken for measurements of the sufentanil con-centration in the sufentanil and mixture groups. Thevenous blood was centrifuged over 10 min at 4,000revolutions per minute, and the supernatant serum wasremoved. All samples were immediately frozen at 220°Cuntil the analyses were performed. The sufentanil con-centration in plasma and CSF was measured by a specialradioimmunoassay (Janssen-Cilag, Beerse, Belgium). Themethod of the radioimmunoassay has been described byMichiels et al.15 The lowest detectable sufentanil con-centration was 0.02 ng/ml.

In case of recurrent pain (VAS . 25), patients receiveda subarachnoid injection of 1 ml 0.25% plain bupivacaineon the condition that at least 45 min after the firstsubarachnoid drug injection had elapsed. Duration ofanalgesia was defined as the interval between the first(study drug) and the second (0.25% bupivacaine) sub-arachnoid drug injection.

The incidence of side effects such as nausea, vomiting,pruritus, and dizziness was registered by the same anes-thesiologist who assessed the level and quality of anal-gesia, using a standardized questionnaire. This investiga-

tor also registered respiratory depression if therespiratory rate of the patient decreased below 8breaths/min before the interview, and shivering if thepatient showed any sign of muscular trembling. If theoxygen saturation measured by pulse oximetry de-creased below 95%, patients were treated with oxygeninsufflation (4 l/min) via a face mask.

Part 2After the 80 patients completed the study, a second

part of the study was added to evaluate the efficacy ofrepeated subarachnoid sufentanil injections for postop-erative pain relief. Ten patients (table 1) undergoingmajor lower-limb surgery (hip or knee replacement) un-derwent the same protocol with microcatheter CSA aspreviously described. After admission to the intensivecare unit, these patients received the first subarachnoiddose of 10 mg sufentanil when postoperative pain wasassessed as greater than 50 on the VAS (0–100 mm). Thequality of pain relief and motor function of the lowerextremity were assessed by VAS and by the Bromagescale (see above) immediately before injection (0 min)and 5, 15, 30, 45, and 60 min after the injection ofsufentanil into the microcatheter.

In case of recurrent postoperative pain greater than 25on the VAS, patients received a maximum of three addi-tional doses of 10 mg sufentanil each. When the maximal

Table 2. Hemodynamic and Respiratory Parameters

HR(beats/min)

MAP(mmHg)

PO(%)

RR(l/min)

BaselineSufentanil 83 6 14 98 6 17 97 6 2 17 6 4Bupivacaine 76 6 16 97 6 16 97 6 3 16 6 2Mixture 77 6 15 94 6 15 98 6 2 16 6 3Placebo 79 6 16 97 6 18 97 6 3 17 6 3

5 minSufentanil 81 6 14 95 6 16 97 6 2 15 6 3Bupivacaine 74 6 17 90 6 15* 98 6 1 15 6 2Mixture 78 6 17 90 6 18 98 6 2 14 6 3*Placebo 79 6 16 91 6 12 97 6 4 17 6 4†

15 minSufentanil 79 6 13 92 6 17 96 6 1 15 6 2Bupivacaine 73 6 17 87 6 14* 98 6 2 14 6 2*Mixture 78 6 17 89 6 16 98 6 2 14 6 3*Placebo 78 6 16 92 6 15 96 6 3 18 6 5†‡

30 minSufentanil 77 6 15 91 6 16 96 6 2 15 6 3Bupivacaine 74 6 14 88 6 14* 98 6 2 14 6 2*Mixture 77 6 18 86 6 12* 98 6 2 14 6 2*Placebo 76 6 15 85 6 12* 97 6 4 16 6 3

45 minSufentanil 80 6 15 92 6 14 98 6 1 15 6 2Bupivacaine 75 6 16 86 6 13* 98 6 1 14 6 2*Mixture 80 6 18 85 6 14* 98 6 1 15 6 3Placebo 79 6 16 84 6 13* 97 6 3 16 6 2

Data are mean 6 SD.

* P , 0.05 versus baseline. Analysis of variance for repeated measurements with paired t test. † P , 0.05 versus mixture. ‡ P , 0.05 versus bupivacaine.Analysis of variance with Scheffe F test.

HR 5 heart rate; MAP 5 mean arterial pressure; PO 5 oxygen saturation measured by pulse oximetry; RR 5 respiration rate.

232 STANDL ET AL.



dose of sufentanil (total dose, 40 mg) was reached, pa-tients with pain were treated by injection of 1 ml 0.25%plain bupivacaine. The incidence of side effects such asnausea, vomiting, pruritus, dizziness, respiratory depres-sion (respiratory rate , 8 breaths/min), and shiveringwas registered at the respective times of measurement

by an anesthesiologist (in accordance with part 1). Themicrocatheters were withdrawn on postoperative day 1.

All 90 patients were visited by an anesthesiologist onthe morning of postoperative day 2 and before they leftthe hospital and were asked about postdural punctureheadache or any neurologic sequelae.

Statistical AnalysisNormally distributed data were described as mean 6

SD. Median (range) was used if nonnormality can beassumed or if data are censored. Categoric data (table 1:sex, American Society of Anesthesiologists class) aredescribed as frequency distribution. Differences withingroups were tested by analysis of variance for repeatedmeasurements and post hoc paired Student t test. Differ-ences between groups were tested by analysis of vari-ance and the Scheffé F test in case of parametric andnormally distributed data. If data were not normallydistributed, the Kruskal-Wallis test was applied. Non-parametric data were tested by the chi-square test.

Data of part two of the study were tested by analysis ofvariance for repeated measurements and post hoc com-parison by paired Student t test (after each sufentanilinjection) and by the Kruskal-Wallis test comparing thefour repetitive injections. Nonparametric data weretested by the chi-square test with Fisher exact test forsmall samples. All differences were considered signifi-cant at P less than 0.05.

Results

Morphometric data, time of surgery, and intraoperativedrug administrations were comparable among groups(table 1).

Fig. 1. Pain scores assessed by patients (visual analog scale [VAS]1–100 mm) before (time 5 0) and 5, 15, 30, and 45 min aftersubarachnoid injection of 10 mg sufentanil, 5 mg plain bupiva-caine, 5 mg sufentanil and 2.5 mg plain bupivacaine (mixture),or saline. Data are mean 6 SD. **P less than 0.01 versus base-line; #P less than 0.05 versus other groups; ##P less than 0.01versus groups; †P less than 0.01 versus placebo (analysis ofvariance with Scheffé F test).

Fig. 2. Changes of sensory levels (pin prick) before (time 5 0)and 5, 15, 30, and 45 min after subarachnoid injection of 10 mgsufentanil, 5 mg plain bupivacaine, 5 mg sufentanil and 2.5 mgplain bupivacaine (mixture), or saline. Data are median. Thecircled numbers over the columns indicate the respective num-ber of patients who experienced the highest assessed sensorylevel at the respective time. *P less than 0.05 versus baseline; #Pless than 0.05 versus sufentanil and placebo (chi-square test).

Fig. 3. Changes of degree of motor block (Bromage scale) before(time 5 0) and 5, 15, 30, and 45 min after subarachnoid injec-tion of 10 mg sufentanil, 5 mg plain bupivacaine, 5 mg sufentaniland 2.5 mg plain bupivacaine (mixture), or saline. Bromage 0 5none, 1 5 partial, 2 5 almost complete, 3 5 complete. Data aremedian. *P less than 0.05 versus baseline; #P less than 0.05versus other groups (chi-square test).




Part 1Although heart rate and oxygen saturation measured

by pulse oximetry did not change in any group, themean arterial pressure decreased below baseline in allgroups with exception of the sufentanil group (table 2).In the bupivacaine and mixture groups, the respirationrate was lower after drug injection when compared withbaseline, whereas the highest respiration rates weremeasured in the placebo group until the rescue medica-tion was given.

Figure 1 shows the VAS mean values that were signifi-cantly decreased in comparison with baseline (P , 0.01)after the first 5 min after drug injection in all groupsexcept the placebo group. In groups 1–3, the VAS valuesdecreased further until they reached their nadir 45 minafter injection (P , 0.01 vs. baseline). In the placebogroup, the VAS mean values did not decrease belowbaseline before 45 min after saline injection. Five pa-tients in the placebo group, whose data are not included

in figures 1–3, received 1 ml 0.25% bupivacaine within45 min after saline injection because of unbearable pain.

The mean duration of analgesia (pain on VAS . 25)was 128 6 61 min in the sufentanil group, 146 6 74 minin the bupivacaine group, 167 6 78 min in the mixturegroup, and 47 6 62 min in the placebo group (P , 0.01placebo vs. other groups). No patient required paren-teral analgesics within the first 4 h postoperatively.

Figures 2 and 3 show the level of analgesia and thedegree of motor block during 45 min after the firstsubarachnoid injection. Patients with bupivacaine expe-rienced the most cephalad dermatomal levels (median,T6; one patient with T1 at 45 min). In all treatmentgroups, the median analgesic level had its highest exten-sion 30 min after injection. While patients in the sufen-tanil group did not show any detectable signs of motorblock and patients with the mixture only had a short-term restriction of their motor function after 15 min(Bromage 1), patients in the bupivacaine group experi-

Fig. 4. Changes of plasma and cerebrospinal fluid (CSF) concentrations of sufentanil after subarachnoid injection of 10 mg sufentanil(A) or 5 mg sufentanil (mixture; B) at time 0 (baseline) and 5, 15, 30, 45, 60, and 120 min after injection. Data are depicted as boxplots with extreme concentrations represented by filled circles. *P less than 0.05 versus baseline within groups; #P less than 0.05versus sufentanil 10 mg (paired t test and Kruskal-Wallis test).

234 STANDL ET AL.



enced more profound motor block (Bromage 2) 15–45min after the injection (P , 0.05 vs. other groups).

Figure 4 shows the changes of the sufentanil concen-trations in plasma and CSF in groups 1 and 3. Whileplasma concentrations of sufentanil were below orslightly above the level of detection after subarachnoidinjection of 10 mg sufentanil (the maximal mean valueafter 15 min was 0.027 ng/ml), the mean levels werebelow the threshold of 0.02 ng/ml after injection of 5 mgsufentanil. The CSF concentrations of sufentanil peaked 5min after injection of either 10 mg (mean, 183 6 167 ng/ml;maximum, 623 ng/ml) or 5 mg (mean, 120 6 102 ng/ml;maximum, 328 ng/ml) sufentanil and declined continu-ously over the following 60 min.

Patients in the placebo group showed a higher inci-dence of early postoperative nausea compared with pa-tients in other groups (table 3). Patients in the sufentanilgroup had the highest incidence of pruritus, which wasonly moderate and did not require any treatment. Respi-ratory depression (respiration rate , 8 breaths/min)occurred in one patient in the sufentanil group 15 minafter injection and lasted for 30 min, and occurred in twopatients in the mixture group also 15 min after injectionand lasted 10 min. All patients had oxygen insufflationand did not experience oxygen desaturation less than95%. The respiratory depression was easily treated byasking the patients to breathe deeply.

Part 2The demographics of the 10 patients in part 2 were

comparable to the preceding patients (table 1). Each

sufentanil injection provided immediate and profoundpain relief, as shown in figure 5. While the quality ofanalgesia was not different among the four differentinjections at any time (P . 0.2), the duration of analgesiawas significantly longer after the first injection of sufen-tanil (198 6 70 min) when compared with the followinginjections (second, 115 6 72 min; third, 114 6 55 min;fourth, 102 6 52 min; P , 0.001, first vs. followinginjections). Although all patients required the secondand third sufentanil injection, only 6 of 10 patients re-quired the fourth sufentanil injection. In four patients,the observation time expired without the need of thelast subarachnoid injection of sufentanil or any otherparenteral analgesia. Four of the six patients with all thefour sufentanil injections did not need further subarach-noid analgesic drugs, whereas two of these patientsrequired 0.25% bupivacaine 60 min after the last sufen-tanil dose. No patient received additional parenteral an-algesics in the intensive care unit.

The mean arterial pressure did not change over time,and no patient showed any signs of motor block (Bro-mage scale 0) at any time. Table 4 gives an overview onthe incidence of side effects after the respective sufen-tanil injections. Moderate pruritus was the most frequentside effect (90% of patients), and nausea and vomitingwere observed in 20% of the patients. Respiratory de-pression (, 8 breaths/min) occurred in three patientswithin 30 min after the first sufentanil injection. Norespiratory depression was registered after the subse-quent sufentanil injections. No patient experienced ox-ygen desaturation less than 95% or apnea after sufentanilinjection, although four patients received oxygen viaface mask throughout the time. Medical treatment wasnot required for any of the registered side effects.

None of the 90 patients suffered from postdural punc-ture headache or any transient neurologic symptoms,numbness or motor weakness of the lower extremities,or cauda equina syndrome on postoperative day 2 or onthe day of discharge.

Discussion

The present study shows that 10 mg sufentanil, 5 mgbupivacaine, or a combination of 5 mg sufentanil and2.5 mg bupivacaine injected through spinal microcath-eters provide immediate and adequate postoperativepain relief for 2–3 h in patients after major orthopediclower-limb surgery.

No significant difference between the treatmentgroups was observed with regard to the quality of painrelief assessed by VAS, the time of onset, and the dura-tion of pain relief. One interesting finding is that insuf-ficient analgesia was associated with a higher incidenceof nausea in the placebo group and not with opioidapplication, as one might have expected. The rapid on-

Fig. 5. Pain scores assessed by patients (visual analog scale [VAS]1–100 mm) before (time 5 0) and 5, 15, 30, 45, and 60 min aftersubarachnoid injection of 10 mg sufentanil (maximum dose, 4 310 mg 5 40 mg sufentanil). Data are mean 6 SD. *P less than 0.01versus baseline (except the fourth application on time 5 min;analysis of variance for repeated measurements with pairedStudent t test.




set of pain relief in all treatment groups can be explainedby the subarachnoid injection of highly lipid solubledrugs such as sufentanil and bupivacaine, which have ahigh affinity to neural tissues, e.g., spinal nerves andcord. The fast onset of pain relief by only small doses oflocal anesthetics or opioids is one of the advantages ofsubarachnoid over epidural or systemic application. Thishas already been demonstrated for obstetric analgesia,where subarachnoid techniques—combined spinal–epi-dural anesthesia more than CSA—have been establishedfor years for this reason.16–18

Camann et al.19 demonstrated that the duration ofanalgesia was significantly longer after subarachnoid ap-plication of 10 mg sufentanil when compared with anepidural or intravenous injection of the same dose inparturients. These results in combination with our datademonstrate that sufentanil acts directly on spinal opioidreceptors. Campbell et al.20 showed that the combina-tion of 2.5 mg bupivacaine and 10 mg sufentanil pro-vided more extended pain relief than did the subarach-noid injection of 10 mg sufentanil or 2.5 mg bupivacainealone. Although different doses to our study have beenapplied and labor pain is not really comparable withpostoperative pain after lower-extremity surgery, theobtained quality and duration of pain relief were similarin our study and that of Campbell et al.

It is known from animal experiments and clinical stud-ies with spinal and epidural analgesia that the combina-tion of local anesthetics with spinal opioids can enhance

or prolong analgesic effects because of a reduction of the“wind-up” phenomenon, which represents a potentia-tion of afferent C-fiber–transmitted nociception causedby repetitive pain stimuli.21–23 Although sufentanil didnot show significant advantages over bupivacaine interms of analgesic effectiveness in the present study,sufentanil analgesia was not associated with significantmotor block or decreases of mean arterial pressure. Car-diovascular stability was also confirmed after subarach-noid sufentanil by Houweling et al.,24 who compareddifferent modes of sufentanil application—intravenous,epidural, and intrathecal—in patients with aortic aneu-rysm repair. However, although significant, the de-creases in mean arterial pressure in the other groupswere not clinically relevant in this study, and they shouldbe avoided in elderly or cardiac patients.

Although the increased incidence of pruritus after sub-arachnoid sufentanil is tiresome but not harmful,25 andwas self-limiting in our patients, respiratory depressionafter subarachnoid opioid application remains poten-tially dangerous. There have been reports on high sen-sory spread and respiratory depression after subarach-noid application of 10 mg sufentanil,14,26,27 althoughsufentanil, as a highly lipid-soluble opioid, may be asso-ciated with a lower risk than morphine; in contrast tomorphine,28 there is no report on late apnea after sufen-tanil. The risk of respiratory arrest after intrathecal sufen-tanil was calculated with 0.02% by Ferouz et al. forobstetric patients.29 However, 6 of the 50 patients who

Table 3. Incidence of Postoperative Side Effects and Oxygen Administration

Nausea Vomiting Pruritus Dizziness RD O2 Shivering

BaselineSufentanil 0 0 0 0 0 10 2Bupivacaine 2 0 0 0 0 8 0Mixture 2 1 0 1 0 10 1Placebo 2 2 0 1 0 9 0

5 minSufentanil 0 0 1 0 0 10 2Bupivacaine 0 0 1 0 0 8 0Mixture 0 0 2 1 0 10 1Placebo 2 1 1 1 0 9 1

15 minSufentanil 0 0 6*† 0 1 10 1Bupivacaine 0 0 1 0 0 8 0Mixture 1 0 1 1 2 10 0Placebo 3 2 1 1 0 9 0

30 minSufentanil 0 0 6*‡ 0 1 10 1Bupivacaine 0 0 1 0 0 8 0Mixture 0 0 4* 0 0 11 1Placebo 4§ 1 1 0 0 9 1

45 minSufentanil 0 0 5* 0 1 10 0Bupivacaine 0 0 1 0 0 8 1Mixture 1 0 4* 0 0 10 1Placebo 1 0 1 0 0 9 2

Data are number of patients.

* P , 0.05 versus baseline. † P , 0.05 versus groups 2–4. ‡ P , 0.05 versus bupivacaine and placebo. § P , 0.05 versus groups 1–3. Chi-square test.

RD 5 respiratory depression , 8 min21; O2 5 patients with oxygen insufflation.

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received subarachnoid sufentanil in our study showedsymptoms of mild respiratory depression. Therefore, sur-veillance and monitoring of the patients after subarach-noid sufentanil application for at least 30 min is manda-tory in this setting. In a pharmacokinetic study byHansdottir et al.,30 the concentration peak in CSF wasreached 39 6 10 min after subarachnoid injection of15 mg sufentanil, with a mean residence time of 55 minin the CSF and 6.8 h in the plasma. As a consequence,repetitive intrathecal sufentanil injections may enhancethe risk of plasma accumulation because of the rapid CSFclearance and prolonged intravascular half-life of sufen-tanil. Thus, the plasma rather than the CSF concentra-tions of sufentanil may cause side effects after repetitiveintrathecal injection.31 However, in this study, threeadditional injections of 10 mg sufentanil were not asso-ciated with an increased risk of respiratory depression,because all episodes of respiratory depression occurredafter the first rather the following injections. In contrastto the higher sufentanil plasma concentrations after epi-dural application,32 the plasma levels in this study weresignificantly lower and may not have contributed tosystemic side effects.

The question arises, if a lower dose of sufentanil, e.g.,5 mg alone, would have been able to provide comparablepain relief while reducing the incidence of respiratorydepression. However, two patients in our study also expe-rienced respiratory depression after injection of 5 mgsufentanil plus bupivacaine.

The main advantage of subarachnoid sufentanil wasthe lack of motor block in this study. Earlier studiescould also demonstrate that postoperative pain relief canbe performed using bupivacaine infusions33 or smalldoses of low concentrated plain bupivacaine as repeti-tive bolus injections11 or via patient-controlled analge-sia34 over a period of 17–24 h. However, significantmotor dysfunction or inadvertent extension of the blockassociated with hypotension occurred in these studiesusing higher doses, whereas smaller bupivacaine dosesrequired higher parenteral rescue medication. Motorblock is unwanted because patients should be able tomobilize or undergo active physiotherapy postopera-tively. A higher incidence of thromboembolic eventsmay also result if orthopedic patients are unable to movetheir lower extremities. The inability to monitor motor

function in CSA may be one of the reasons why thistechnique is not frequently used for postoperative painrelief thus far. Another reason is the fear of CSF infec-tion, although studies show that there is no increasedrisk for infection during the first postoperative dayswhen spinal catheters are used for pain manage-ment.11,35 In our opinion, the minimal risk associatedwith the use of 28-gauge spinal catheters and isobariclocal anesthetics or opioids is much more than compen-sated by advantages over large-bore catheters, e.g., thelower incidence of postdural puncture headache.11,34

In addition to case reports with meperidine and fent-anyl for pain relief using CSA,36,37 three studies dealtwith subarachnoid morphine and fentanyl applicationfor postoperative pain management after lower-extremityprocedures.9,10,38 Although Niemi et al.10 did not recom-mend continuous morphine infusions via 28-gauge spi-nal catheters because of a high incidence of technicalproblems and side effects, they stated in a later study thatintrathecal morphine as bolus dose or infusion providedbetter analgesia than fentanyl infusions.38 Reuben et al.9

found that 40 mg fentanyl injected through spinal cath-eters at the end of lower-extremity revascularizationprocedures provided excellent pain relief within 10 minlasting nearly 5 h. The investigators did not see respira-tory depression or oxygen desaturation, and the cardio-vascular stability was good. Thus, fentanyl appears tohave advantages over morphine and even sufentanil,which is more expensive. However, only 10 patientswere examined in each group with adequate analgesia,and the number of patients might have been too small inthis trial to observe rare events such as respiratory de-pression with this opioid. The longer-lasting analgesiceffect of fentanyl in comparison to sufentanil in ourstudy can possibly be explained by a lower intensity ofpain after vascular surgery than after major orthopedicoperations.

However, all clinical studies have not allowed conclu-sions to be drawn on long-term application of fentanyl orsufentanil with regard to toxicity until now. Althoughrepetitive subarachnoid sufentanil applications in largedoses caused severe inflammatory changes such as men-ingitis and myelitis in sheep,39 more clinically relevantdoses of 5–50 mg/day injected over a period of 15 or 28days did not reveal evidence of neurotoxicity in a dog

Table 4. Incidence of Postoperative Side Effects and Oxygen Administration after Repetitive Subarachnoid Sufentanil Application

Nausea Vomiting Pruritus Dizziness RD O2 Shivering

1st application of 10 mg sufentanil (time 1; n 5 10) 1 1 7 0 3 4 02nd application of 10 mg sufentanil (time 2; n 5 10) 0 0 7 0 0 4 03rd application of 10 mg sufentanil (time 3; n 5 10) 1 1 8 0 0 4 14th application of 10 mg sufentanil (time 4; n 5 6) 1 1 3 0 0 4 1Total incidence 2 2 9 0 3 4 1

Data are number of patients. Chi-square test.

RD 5 respiratory depression , 8 min21; O2 5 patients with oxygen insufflation; time 1 5 end of surgery until 1st injection (162 6 79 min); time 2 5 1st until 2ndinjection (198 6 70 min); time 3 5 2nd until 3rd injection (115 6 72 min); time 4 5 3rd until 4th injection (114 6 55 min).




model.40 In conclusion, we believe that postoperativepain relief with a maximum of 40 mg sufentanil in frac-tions of 10 mg administered through 28-gauge spinalcatheters represents an effective technique for earlypostoperative pain management in patients after majorlower-limb surgery. Although repetitive sufentanil injec-tions appear not to increase the risk of early respiratorydepression, monitored surveillance of these patients re-mains mandatory.

The authors thank Monika Weber, Technical Assistant-in-Chief, Department ofAnesthesiology; Frank Kugler and Karoline Fuchs, Research Fellows, Departmentof Anesthesiology; and the staff of the Postanesthesia Care Unit, OrthopedicDepartment and the Intensive Care Unit (all from the University Hospital Ham-burg-Ependorf, Hamburg, Germany).

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