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Departments of *Anesthesiology and Orthopedic Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania
Address correspondence to Bruce Ben-David, MD, Department of Anesthesia, Allegheny General Hospital, 320 East North Ave., Pittsburgh, PA 15212. Address e-mail to b.bendavid{at}verizon.net Reprints will not be available from the authors.
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IMPLICATIONS: Droperidol in combination with nalbuphine enhances analgesia and is more effective than nalbuphine alone in preventing pruritus, nausea, and vomiting after minidose lidocaine-fentanyl spinal anesthesia.
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Introduction |
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Pruritus and nausea are well known side effects of intrathecal opioids. Nalbuphine is effective in treating pruritus after intrathecal or epidural morphine, and it accomplishes this with no increase in postoperative pain or other side effects (5,6). Although some reports suggest that nalbuphine has a similar beneficial effect on the associated nausea (6,7), other reports indicate only a modest benefit at best (5,8). Droperidol is effective for prophylaxis and treatment of postoperative nausea and vomiting (PONV) after general anesthesia (9) and likewise reduces the incidence of nausea and vomiting associated with epidural or intrathecal morphine (8,10). This study compares the prophylactic administration of nalbuphine with the prophylactic administration of nalbuphine in combination with droperidol for patients having spinal anesthesia for ambulatory surgery with the SABMLF technique.
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Methods |
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Patients received no premedication. On arrival in the operating room (OR), an IV infusion of lactated Ringer’s solution was begun, and patients were immediately given midazolam 0.02–0.03 mg/kg IV and fentanyl 0.75–1.0 µg/kg IV. Standard monitoring was applied and included continuous electrocardiogram (ECG), pulse oximetry, and automated blood pressure at 5-min intervals. All patients received supplemental oxygen via an oxygen mask.
Lumbar puncture was performed in the sitting position in all patients. Patients were immediately returned to supine position on completion of the spinal. Lumbar punctures were made with 25- or 26-gauge pencil-point needles positioned midline at the L2-3 or L3-4 interspace with the orifice directed cephalad. Injections were made over 10 to 15 s. The spinal injectate was prepared by drawing up a mixture of 5 mL of 1% lidocaine (50 mg), 1 mL of fentanyl (50 µg), and 4 mL of dextrose 10%. From this solution, 4 mL was used for the anesthetic. This yielded 20 mg of 0.5% lidocaine and 20 µg of fentanyl in dextrose 4%. All spinals were conducted by the same anesthesiologist (BB-D) and all surgeries by the same surgeon (PJD). Continuing intraoperative care was provided by a staff certified registered nurse anesthetist, who made the continuing determinations as to the need for further sedation or analgesia. Further sedation was allowed with midazolam 0.01–0.02 mg/kg IV, and further analgesia was allowed with fentanyl 0.75–1.0 µg/kg IV. If the patient still was unduly anxious or was still in pain, the protocol allowed for titration of additional propofol as needed. Intraarticular injection of 20 mL of 0.25% bupivacaine with 1:200,000 epinephrine was made at the conclusion of surgery.
Patients were randomized by the sealed-envelope technique to receive one of two prophylactic IV injections at the conclusion of surgery. The injections, both of which were 2 mL in volume, comprised either nalbuphine 4 mg IV (Group N) or nalbuphine 4 mg plus droperidol 0.625 mg (Group ND). These drugs were administered in a double-blinded manner such that neither the patient, nor the recovery room nurses, nor the investigator performing follow-up assessments and phone calls was aware of study group assignment.
All patients bypassed the postanesthesia care unit (Phase I recovery) and were transferred directly from the OR to the Phase II recovery area. Patients’ progress during recovery was observed, but no attempt was made to intervene in nursing decisions regarding medications or timing of discharge. Standard criteria were used to determine home readiness, including 1) vital signs within 20% of preoperative value, 2) fully awake and oriented, 3) able to stand up and remain standing for >1 min and in most circumstances able to ambulate with crutches, 4) minimal nausea, 5) minimal to moderate pain, 6) minimal bleeding, and 7) having had and tolerated fluids by mouth. Voiding was not a requirement for discharge. A change in the surgery center’s discharge policy (as a result of consumer feedback) was instituted before commencing this study. Specifically, this entailed asking patients if they felt ready to go home, in addition to simply declaring them ready for discharge.
Intervals were recorded from the time of Phase II recovery arrival until first oral intake and until actual discharge. Pain in the recovery unit was treated with ketorolac 30 mg IV. Additional analgesia was provided with hydrocodone 5–10 mg by mouth with acetaminophen 500–1000 mg by mouth. Nausea was treated with dolasetron 12.5 mg IV. Pruritus was treated at patient request with diphenhydramine 12.5 mg IV. All medication requirements were recorded. At the time of discharge, patients were queried as to their postoperative experience of pain, nausea, pruritus, headache, or dizziness. Patients were asked to score positive responses on a verbal analog scale of 0 (none) to 10 (worst imaginable). Before discharge, it was recorded whether or not the patient had been able to void.
A telephone interview was conducted the evening of surgery, an interval no less than 6 h since discharge home. Patients were asked whether they had had any difficulty with voiding at home and, if so, the degree of difficulty and whether it had continued or been only on the first void. Patients were queried as to their at-home postoperative experience of pain, nausea, pruritus, headache, or dizziness. Patients were asked to score positive responses on a verbal analog scale of 0 (none) to 10 (worst imaginable). If patients had pain suggestive of TNS (back pain radiating to buttocks or legs), they were contacted again until resolution of their symptoms.
Power analysis was conducted before the study to determine the necessary study size. To show a reduction in the incidence of nausea from 22% to 5% at an 
of 0.05 and ß of 0.80 required 58 patients per group. To show a 10-min reduction in discharge time from an average of 75 min (
of 20 min) at an of 0.05 and ß of 0.80 required 62 patients per group. Therefore, a study of 62 patients per group was planned.
Statistical analysis was conducted with Statview 5 (SAS Institute, Cary, NC). Data were analyzed with analysis of variance, the Mann-Whitney U-test, 
2 analysis, or expanded contingency table analysis, as appropriate. Results were considered significant at a P value of 0.05.
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Discussion |
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Pruritus is a well recognized and common side effect of neuraxial opiates whose mechanism remains poorly understood (8). The incidence of pruritus after intrathecal fentanyl is typically reported in the range of 60%–80% (1,8,11,12). The incidence of pruritus after intrathecal fentanyl in outpatient orthopedic surgery has been reported as 66% (13) and 68% (4).
A variety of drugs have been studied for their ability to prevent or treat pruritus resulting from neuraxial opiates. Kjellberg and Tramer (8) reviewed this literature and concluded that the only drugs of proven efficacy were the µ-receptor antagonists naloxone and naltrexone, nalbuphine (a mixed agonist/antagonist), and droperidol. Nalbuphine appears to offer an advantage over the pure µ antagonists in that the latter cause a dose-dependent reversal of analgesia. Whereas titration to effect with the pure µ antagonists may be difficult in nalbuphine, even in large doses, it is unlikely to diminish analgesia (7,14–16). In one study of epidural morphine’s side effects, patients who received an IV nalbuphine infusion of 15 µg · kg-1 · h-1 had analgesia comparable to a control group but had less nausea and/or vomiting (13% vs 62%), had less pruritus (7% vs 62%), and were less likely to have an increased PaCO2 (6).
Our results in Group N are somewhat surprising and contrast with these prior reports. Our results also contrast with studies of single-dose IV nalbuphine administered for treatment of established pruritus after intrathecal morphine (5,17). In those reports, 3 mg of nalbuphine IV was 83% (17) and 97% (5) effective, and 4 mg of nalbuphine IV was 100% (5) effective. Our results do not suggest this degree, if any, of nalbuphine’s efficacy as a prophylactic antipruritic. Although we did not, for perceived ethical reasons, include a control group, our previous study of SABMLF, using essentially an identical technique with the same personnel, produced a similar (68%) incidence of pruritus.
These results demonstrate a significant reduction in pruritus, both early and late, with the addition of droperidol 0.625 mg IV to nalbuphine 4 mg IV. Droperidol, a butyrophenone with -2 agonist, dopamine receptor antagonist, and serotonin (5HT3) receptor antagonist properties has been used both IV (18,19) and epidurally (20) to inhibit neuraxial opiate-induced pruritus. An added element to the question of IV droperidol’s antipruritic efficacy regards the dose-response relationship. Horta and Horta (19) showed that 2.5 mg of droperidol IV inhibited pruritus after epidural morphine but that 5.0 mg was ineffective. The antipruritic dose-response relationship of IV droperidol at doses <2.5 mg remains undefined. However, given the drug’s dose-related side effects, which include sedation, agitation, and dysphoria, and our own emphasis on speedy discharge, we believed that it was important to examine the usefulness of droperidol at this very small dose of 0.625 mg. Even at that dose, there was a sedating effect notable in the early recovery phase. Sedation was still evident at the time of discharge, as indicated by the 92% vs 65% of patients who still felt sleepy.
From the perspective of the patient, PONV is an important outcome to avoid (21). Wang et al. (7) found that a nalbuphine infusion in conjunction with epidural morphine decreased the total 24-hour incidence of nausea from 52% to 17% and of vomiting from 35% to 4%. Kjellberg and Tramer (8) combined the results from a number of trials with opioid antagonists to yield an average reduction in the incidence of neuraxial opioid-induced nausea from 54% (controls) to 44%. Our 18% incidence of early-onset (before discharge home) nausea in Group N as compared with the 22% incidence in our historical controls suggests only a minor benefit. However, the evidence of droperidol’s effect on neuraxial opiate-induced nausea is compelling. Studies uniformly show significant reductions in nausea and vomiting regardless of whether the drug is given IV (8,10) or epidurally (22,23). In our study, the addition of droperidol to nalbuphine produced a significant benefit over that of nalbuphine alone. The incidence of predischarge nausea was reduced from 18% to 5% and of postdischarge nausea from 32% to 13%.
The reductions in both pruritus and nausea achieved with the addition of droperidol to the nalbuphine prophylaxis were also accompanied by a significant analgesic benefit. The ND group had both lower pain scores and a longer delay until first use of analgesic. Although there are few data available on the specific analgesic potential or opiate-sparing effect of IV droperidol, there has been such work with epidural droperidol. These studies of epidural droperidol have yielded mixed results. Sanansilp et al. (10) saw no effect of either IV or epidural droperidol on the analgesia of epidural morphine. Others have found enhanced analgesia with epidural droperidol in both acute pain (22) and chronic pain (24).
As to side effects of the drugs, none were observed with nalbuphine and only a mild sedating effect with the droperidol. Of particular concern, since completion of this study a "Box Warning" has been added to droperidol’s labeling cautioning as to QT prolongation and the possibility of life threatening arrhythmia. The new labeling recommends continued electrocardiogram (ECG) monitoring for two to three hours after drug administration. One solution might be to give the droperidol at the start of the case to take advantage of the sedation during surgery and to achieve the requisite time of ECG monitoring without delaying discharge.
The results of this study are potentially confounded by the use of propofol in 6% of patients. Propofol itself may have some antipruritic and antiemetic effects. However, these patients were equally divided between the two study groups. Moreover, its use did not seem to, in these several patients, alter the incidence or severity of either side effect. Mulroy et al. (13) also found that intraoperative use of propofol did not affect the frequency of pruritus.
In conclusion, this study indicates that the prophylactic treatment of pruritus and nausea after SABMLF is superior with droperidol in combination with nalbuphine than with nalbuphine alone. The combination regimen provided for significant reductions in postoperative nausea, pruritus, and pain—benefits that persisted after discharge home. The combination also avoided isolated cases of extreme delay in discharge. Such continuing improvements in anesthetic technique may make spinal anesthesia more attractive to use in the ambulatory surgical setting.
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This article has been cited by other articles:
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  J. L. Parlow, I. Costache, N. Avery, and K. Turner Single-Dose Haloperidol for the Prophylaxis of Postoperative Nausea and Vomiting After Intrathecal Morphine Anesth. Analg., April 1, 2004; 98(4): 1072 - 1076. [Abstract] [Full Text] [PDF]
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M. Silvanto, P. Tarkkila, M.-L. Makela, and P. H. Rosenberg The Influence of Ambulation Time on the Incidence of Transient Neurologic Symptoms After Lidocaine Spinal Anesthesia Anesth. Analg., March 1, 2004; 98(3): 642 - 646. [Abstract] [Full Text] [PDF]
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