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* From the Department of Anesthesiology, Kangnam Saint Mary's Hospital, 505 Banpo-dong, Seocho-gu, Seoul, Korea and the Puget Sound Veterans Affairs Medical Center and the University of Washington School of Medicine, Seattle, Washington.
Address correspondence to: Dr. Jaimin Lee, 137-040, Department of Anesthesiology, Kangnam Saint Mary's Hospital, 505 Banpo-dong, Seocho-gu, Seoul, Korea. Phone: 82-2-590-1545; Fax: 82-2-537-1951; E-mail: jmlee{at}cmc.cuk.ac.kr
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Abstract |
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Methods: Eighty patients undergoing combined epidural and general anesthesia for hysterectomy were randomly assigned to one of four groups. All received 2 mg epidural morphine bolus one hour before the end of surgery and a continuous epidural infusion was started containing 4 mg morphine in 100 ml bupivacaine 0.125% with either no naloxone (Group 1, n=20), 0.083 µg•kg–1•hr–1 of naloxone (Group 2, n=20), 0.125 µg•kg–1•hr–1 of naloxone (Group 3, n=20) or 0.167 µg•kg–1•hr–1 of naloxone (Group 4, n=20). Analgesia and side effects were evaluated by blinded observers.
Results: The combination of epidural morphine and bupivacaine provided good analgesia. Eight hours after the end of surgery, the pain score in the group receiving the highest dose of naloxone was lower than in the control group (VAS 1.2 vs 2.0, P < 0.05) but there was less pruritus in the high-dose naloxone group (itching score 1.3 vs 1.9, P < 0.05). Pain scores were no different in any of the naloxone groups from the control group. Itching was less in both of the higher dose naloxone groups (P < 0.05 at 8, 16, and 32 hours). The incidence of vomiting in the control group was 40% vs 5% for high dose naloxone group (P < 0.05).
Conclusions: Epidural naloxone reduced morphine-induced side effects in dose-dependent fashion without reversal of the analgesic effect.
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Introduction |
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Small doses of the opioid antagonist naloxone administered intravenously maintain analgesia and reduce epidural morphine-induced side effects effectively.2 In rabbits, intraspinal naloxone effectively inhibits visceromotor responses to morphine.3 The analgesic effects of epidural morphine can be inhibited in rats by epidural naloxone.4 So far, however, clinical experiments have not established the effect of epidural naloxone on analgesic effect of morphine and the incidence of side effects.
We hypothesized that there was a relationship between the epidural naloxone doses that would minimize side effects in patients receiving epidural pain control with morphine and bupivacaine without reversing analgesia.
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Methods |
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After identification of the epidural space using the loss of resistance technique, a 20 gauge epidural catheter was placed between the 3rd and 4th lumbar vertebrae and fixed three centimeters into the epidural space. An initial dose of 10 ml bupivacaine 0.33% was then injected. Patients underwent anesthetic induction and tracheal intubation after 4 mg•kg–1 thiopental and 1 mg•kg–1 succinylcholine. Muscle relaxation was induced with 0.08 mg•kg–1 vecuronium and general anesthesia was maintained with enflurane <0.5% end-tidal and nitrous oxide 60%.
Five minutes after induction, 5 ml bupivacaine 0.33% were again administered via the epidural catheter and, at ten minutes after induction, an additional 3 - 5 ml bupivacaine were administered. Patients then received between 1/2 and 1/3 of the initial dosage (15 ml) at one hour intervals until the end of the surgery.
As the surgeons started to close the abdominal cavity, each patient was given 2 mg morphine into the epidural catheter. A continuous epidural infusion was then initiated by attaching Two-day InfusorsTM (Baxter, USA), containing 4 mg morphine in 100 ml bupivacaine 0.125%.
Patients were randomly allocated into four groups, each of which received a different medication mixture via the Two-day Infusors. Group 1 received 80 µg morphine in 2 ml bupivacaine 0.125% per hour. Group 2 received the same mixture, but with the addition of 0.083 µg•kg–1•hr–1 of naloxone. Groups 3 and 4 were identical to Group 2 except that the naloxone infusion rate was 0.125 µg•kg–1•hr–1 for Group 3, and 0.167 µg•kg–1•hr–1 for Group 4.
Visual Analog Scales (VAS)5 were employed to assess postoperative pain at 2, 4, 8, 16, 32, and 48 hr. Nausea, itching, somnolence and respiratory depression were assessed using the evaluation scores noted in Table I
. The assessment was carried out by anesthesiologists who had not been involved in care of the patients and who were blinded to the group assignment.
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). The outcome of data analyses for each group at each time point is shown in Table III.
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). Group 4, the highest naloxone dose, had lower VAS scores compared with Group 1 at 8, 16 and 32 hr postoperatively (P < 0.05).
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) (P < 0.05 at 8, 16, 32 hr for Groups 3 and 4 vs Group 1). Even at the lowest dose of naloxone (Group 2), some benefit was derived in relieving the itching (P < 0.05 at 32 hr vs Group 1).
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). The incidence of vomiting or retching at some point in the postoperative course was 40%, 25%, 15%, and 5% for groups 1 through 4 respectively (P < 0.05 for Group 4 vs Group 1 by Fisher's exact test).
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) (P < 0.05 at two and four hours).
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Discussion |
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Not surprisingly, pain scores were low in all of the patients since the combination of bupivacaine plus morphine is an effective analgesic. We found no reduction in efficacy in patients receiving naloxone and epidural naloxone actually improved analgesia at the highest dose. We speculate that this is due to reduced side effects producing greater comfort. The beneficial effects of naloxone were dose related with higher doses reducing itching more than lower doses.
Our study builds on other efforts to limit the side effects of epidural morphine while maintaining good analgesia. These have included administering non-steroidal anti-inflammatory drugs plus morphine, ß-2 adrenergic agonists plus morphine, and low concentrations of local anesthetics plus morphine.6 Klahsen et al.7 and Isosu et al.8 found that epidural droperidol could reduce morphine-induced nausea and vomiting. However, continuous epidural administration of droperidol may trigger such side effects as dystonia and akathisia.9
Epidural administration of the agonist-antagonist butorphanol, which acts as an antagonist at mu receptors but as an agonist at kappa receptors, reduced itching and nausea, and maintained analgesia without causing somnolence or respiratory depression.10,11 However, an increased incidence of altered consciousness rather than reduced side effects was noted in another report among patients who had Cesarean section and were given morphine and butorphanol.12 Cohen et al.13 found that intravenous administration of nalbuphine was more effective than naloxone in reducing morphine-induced side effects such as itchiness and nausea, but its effects were of short duration and it also resulted in increased sedation.
The efficacy of naloxone in reducing nausea and vomiting while preserving the analgesic effects of epidural morphine is well documented.2 However, titration of the dose is critical since excess naloxone may reverse analgesia and is capable of inducing hyperalgesia.14,15 Little is known about the dose-response relationship of naloxone when administered into the epidural space. Epidural administration of naloxone in mice reverses the analgesic effect of epidural morphine, but the effects on other actions of morphine are not known nor are the effects in humans documented.3 Our study found a dose range for epidural naloxone that preserves analgesia while minimizing side effects.
We were surprised to find better analgesic effects in Group 4 patients despite the higher dose of naloxone. Although this could be the result of some partial agonist effect from naloxone,16,17 it may also be a reflection of greater overall comfort in the patients because of less nausea and itching.
We conclude that epidural administration of naloxone can preserve analgesia while minimizing itching, nausea, pruritus and somnoloence. The highest dose used - 0.167 µg•kg–1•hr–1 - gave the best results, but we cannot be certain whether this is the ideal dose or whether higher doses might produce fewer side effects without interfering with analgesia.
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Footnotes |
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Accepted for publication September 26, 1999.
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References |
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2 Vedrenne JB, Esteve M, Guillaume A. Preventing the adverse effects of epidural morphine analgesia for cancer pain by naloxone. (French) Ann Fr Anesth Reanim 1991; 10: 98–103.[Medline]
3 Borgbjerg FM, Frigast C, Madsen JB. Tonic endogenous opioid inhibition of visceral noxious information in rabbits. Gastroenterology 1996; 111: 78–84.[Medline]
4 Kaneko M, Saito Y, Kirihara Y, Collins JG, Kosaka Y. Synergistic antinociceptive interaction after epidural coadministration of morphine and lidocaine in rats. Anesthesiology 1994; 80: 137–50.[Medline]
5 Huskisson EC. Measurement of pain. Lancet 1974; 2: 1127–31.[Medline]
6 Bonnet F, Vésinet C. How can we improve the efficacy of morphine analgesia without increasing adverse effects? (French) Cah Anesthesiol 1994; 42: 191–4.[Medline]
7
Klahsen AJ, O'Reilly D, McBride J, Ballantyne M, Parlow JL. Reduction of post-operative nausea and vomiting with the combination of morphine and droperidol in patient-controlled analgesia. Can J Anaesth 1996; 43: 1100–7.
8 Isosu T, Katoh M, Okuaki A. Continuous epidural droperidol for postoperative pain. (Japanese) Masui 1995; 44: 1014–7.
9 Shimada J, Akama Y, Tase C, Okuaki A. Problems of epidural droperidol administration. (Japanese) Masui 1994; 43: 1248–50.
10
Wittels B, Glosten B, Faure EAM, et al. Opioid antagonist adjuncts to epidural morphine for postcesarean analgesia: maternal outcomes. Anesth Analg 1993; 77: 925–32.
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Lawhorn CD, McNitt JD, Fibuch EE, Joyce JT, Leadley RJ Jr. Epidural morphine with butorphanol for postoperative analgesia after Cesarean delivery. Anesth Analg 1991; 72: 53–7.
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Gambling DR, Howell P, Huber C, Kozak S. Epidural butorphanol does not reduce side effects from epidural morphine after Cesarean birth. Anesth Analg 1994; 78: 1099–104.
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Cohen SE, Ratner EF, Kreitzman TR, Archer JH, Mignano LR. Nalbuphine is better than naloxone for treatment of side effects after epidural morphine. Anesth Analg 1992; 75: 747–52.
14 Jacob JJ, Tremblay EC, Colombel M-C. Enhancement of nociceptive reactions by naloxone in mice and rats. Psychopharmacologia 1974; 37: 217–23.
15 Chesher GB, Chan B. Footshock induced analgesia in mice: its reversal by naloxone and cross tolerance with morphine. Life Sci 1977; 21: 1569–74.[Medline]
16 Cattaneo I, Kayser V, Guilbaud G. Differential effects of specific delta and kappa opioid receptor antagonists on the bidirectional dose-dependent effect of systemic naloxone in arthritic rats, an experimental model of persistent pain. Brain Res 1993; 623: 201–7.[Medline]
17 Kayser V, Besson JM, Guilbaud G. Further evidence for a bidirectional effect of naloxone on the pain threshold in tolerant and non-tolerant arthritic rats. Neuropeptides 1984; 5: 49–52.[Medline]
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