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Department of Anesthesiology, the Clinical Epidemiology Unit, and the Department of Preventive Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Address correspondence and reprint requests to Charuluxananan Somrat, MD, Department of Anesthesiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Rama IV Rd., Pathumwan, Bangkok 10330, Thailand.
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Abstract |
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Implications: Nalbuphine was superior to propofol for the treatment of intrathecalmorphine-induced pruritus after cesarean delivery.
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Introduction |
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Methods |
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Without premedication, all parturients were hydrated with 500 to 1000 mL of normal saline before the administration of spinal anesthesia. The block was then performed with the patient in the left lateral position at either the L2-3 or the L3-4 interspace by use of a 25- or 27-gauge Quincke spinal needle. Once free flow of clear cerebrospinal fluid had been demonstrated, 2.2 mL of 0.5% hyperbaric bupivacaine and 0.2 mL (0.2 mg) of preservative-free morphine, mixed in the same syringe, were injected. The parturients were then immediately placed in the supine position with left uterine displacement, and supplemental oxygen was delivered through a face mask at 5 L/min. IV fluid and ephedrine were administered as needed to maintain the systolic blood pressure within 30% of its preoperative value, or systolic blood pressure 
100 mm Hg. After a satisfactory spinal block was verified by loss of sensation to cold or pinprick, cesarean delivery was performed.
In the postanesthesia care unit, vital signs were recorded every 15 min, according to the institutional monitoring protocol, for 4 h. The degree of pruritus was evaluated by asking about the presence of pruritus and whether treatment was desired (1 = no pruritus; 2 = mild pruritus, treatment not requested; 3 = moderate pruritus, treatment requested; 4 = severe pruritus). Patients whose pruritus score was 3 were randomly assigned to receive 1 mL of 2% lidocaine and two syringes of intervention drugs with a double-dummy technique (one white fluid syringe and one clear fluid syringe). The patients in Group 1 (Nalbuphine group) received 2 mL of intralipid (Pharmacia & Upjohn AB, Stockholm, Sweden) as placebo (white fluid syringe) and 2 mL of 3-mg nalbuphine (Nubain®; Dupont Pharma, Manati, Puerto Rico), whereas patients in Group 2 (Propofol group) received 2 mL of 20-mg propofol (Diprivan®; Zeneca, Macclesfield Chesshire, UK) and 2 mL of normal saline (clear fluid syringe). The randomization sequence was selected according to a random number table and was written on a paper enclosed in a sealed envelope. Randomly-allocated coded syringes were prepared by a nurse anesthetist not involved in the study and were administered in a double-blinded fashion. At the same time, the patients were evaluated for pruritus, blood pressure, and pulse rate. A verbal numeric pain score (0 = no pain, 10 = worst imaginable pain), a four-point sedation score (1 = fully awake; 2 = somnolent, responds to call; 3 = somnolent, responds to tactile stimulation; 4 = asleep, responds to painful stimulation), and a four-point rating score for nausea and vomiting (1 = no nausea or vomiting, 2 = queasy, 3 = severe nausea, 4 = vomiting) were also recorded before and 10 min after the administration of the study drugs. Parturients whose pruritus score decreased to 1 or 2 after treatment were considered a treatment success and were then evaluated every 15 min for up to 4 h to determine the duration of the antipruritic response. The patients who continued to have pruritus scores 3 were considered treatment failures. Patients with treatment failure and those whose pruritus score continued to be 3 were treated with divided doses of IV 0.4-mg naloxone. Nausea and vomiting were treated with 5 or 10 mg IV metoclopramide upon patient request. Sedation, the presence of pain on injection, dizziness, hallucination, respiratory depression, other adverse effects during the perioperative period, and the onset of pruritus were also recorded.
Power analysis was performed to determine the size of the treatment groups. Allowing for the probability of a type II error of 0.1 and a type I error of 0.05 (considering the success rate of the Nalbuphine group of 90% and the success rate of the Propofol group of 70% from a pilot study), a sample size of 84 in each group was calculated as being required. Statistical analysis of the results was performed with the 
2 test (Fisher’s exact test as appropriate) for categorical data and Student’s t-tests for continuous data, with a 95% confidence interval as appropriate. P < 0.05 was considered significant.
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Results |
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3) were allocated to the Nalbuphine or Propofol groups. Both groups were comparable regarding demographic characteristics and onset of intrathecal morphine-induced pruritus, as shown in Table 1. The onset of pruritus appeared 25 to 180 min after the neuraxial administration of morphine.
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3) within 4 h after the administration of study drug (P = 0.76). Other side effects, such as changes in analgesia, nausea or vomiting, and sedation, are shown in Table 2. A pain score decreased by 2 points or more on the verbal rating score was not different between groups (5% vs 2%; P = 0.45 for the Nalbuphine and Propofol groups, respectively). Pain on injection was mild in both groups and not significantly different. Hallucinations, mood change, and respiratory depression were not observed in either group.
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Discussion |
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3), and this is consistent with previously reported values (5,9,10). The parturients were observed for four hours in the postanesthesia care unit, because pruritus usually occurs within a few hours of intrathecal morphine injection (11,12). The onset of pruritus in this study ranged from 25 to 180 minutes, which is also consistent with the previous results (10). The mechanism of pruritus after the neuraxial administration of opioids is not fully understood. It is probably not related to histamine release, because histamine blockers are ineffective in the therapy of pruritus caused by spinal morphine (13). Another theory is that the opioid receptors in the central nervous system are activated by morphine. Opioid receptors are located both supraspinally and at the spinal cord level. Spinal opioids activate the opioid receptors in the substantia gelatinosa of the spinal cord’s dorsal horn (14). The µ receptor is responsible for pain modulation and some side effects, especially pruritus (14). This would explain the antipruritic effect of nalbuphine or naloxone, specific µ antagonists (3,5). A third theory is that the pruritus from neuraxial opioids may be related to the excitatory effects of opioids on the nocifensive and nonnocifensive neurons in the anterior and posterior spinal horns (15). Propofol may relieve pruritus related to neuraxial opioids because it has an inhibitory effect on the dorsal horn of the spinal cord (15). Recently, there has been evidence that opioids and the serotoninergic system interact closely in the central nervous system; ondansetron, a specific 5-hydroxytryptamine-3 receptor antagonist, has an antipruritic effect (10,16).
In this study, we were able to demonstrate that the success rate after treatment with 3 mg of nalbuphine was significantly greater than with 20 mg of propofol (83% vs 61%) (P < 0.001). In the subgroup of moderate pruritus (initial pruritus score = 3), nalbuphine was more effective than propofol (P = 0.01). In the subgroup of severe pruritus (initial pruritus score = 4), the difference in success rate was not statistically significant (P = 0.139); this may be because of the small sample size in this subgroup. A dose of 3 mg of nalbuphine was chosen because this dose had been previously proved successful in similar patients (5). The 20-mg dose of propofol was chosen according to the regimen of Borgeat et al. (4), which started with 10 mg of propofol and repeated this dose up to 20 mg if necessary.
A limitation of this study is that the extent and sites of the pruritus were not recorded. However, most of the patients whose initial pruritus score was 2 (mild pruritus not requiring treatment) had pruritus only in the facial area. The infrequent recurrence rates within four hours after successful treatment by nalbuphine and propofol were not significantly different and demonstrated a considerably long duration of antipruritic effect. There was no evidence that either nalbuphine or propofol had a deleterious effect on the analgesia, nor was there evidence that nalbuphine altered nausea or vomiting compared with those patients who received propofol. Our findings are consistent with those of Alhashemi et al. (17) and Borgeat et al. (4), who found nalbuphine and propofol, respectively, to be effective in the treatment of neuraxial morphine-induced pruritus. In contrast to our findings and those of Borgeat, there have been reports that subhypnotic doses of propofol do not relieve or prevent intrathecal morphine-induced pruritus after cesarean delivery (8,18,19).1 Possible explanations for these contradictory findings include different types of narcotic administered (demerol versus morphine), different times of propofol administration (treatment versus prevention), and different doses of propofol (20 vs 10 mg). Another difference is that the sample size in previous studies was smaller than in our study.
The sedative effect of nalbuphine is thought to be mediated by its agonist activity at certain 
receptors throughout the brain (20), whereas propofol can also cause sedation by central nervous system suppression (21). However, sedation in both groups was mild and of short duration, and it did not interfere with breast-feeding or general care of the infant. We chose to administer 20 mg IV lidocaine before the administration of both propofol and nalbuphine (22,23) because we have also observed the reduction of pain on injection of nalbuphine by 20 mg IV lidocaine in our institution. However, pain on injection in both groups was mild and not significantly different. Few patients developed dizziness. No patients had hallucinations or respiratory depression.
In conclusion, this study showed that nalbuphine was superior to propofol in the treatment of intrathecal morphine-induced pruritus after cesarean delivery.
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Acknowledgments |
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The authors express their appreciation to Professor Edgar J. Love, Professor Charles H. Goldsmith, Professor Chitr Sitthi-amorn, and Assistant Professor Bandit Thinkamrob for their helpful advice and to Mr. Orlich Robert for reviewing the manuscript.
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Footnotes |
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