BJA Advance Access published online on July 17, 2008
British Journal of Anaesthesia, doi:10.1093/bja/aen213
Combination of opioid agonist and agonist–antagonist: patient-controlled analgesia requirement and adverse events among different-ratio morphine and nalbuphine admixtures for postoperative pain
Department of Anaesthesiology, National Taiwan University Hospital, No. 7, Chung San South Road, Taipei, Taiwan, Republic of China
* Corresponding author. E-mail: wzsun{at}ntu.edu.tw
Accepted for publication June 1, 2008.
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Abstract |
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Background: Nalbuphine, a mixed agonist–antagonist opioid, has a potential to attenuate the mu-opioid effects and to enhance the kappa-opioid effects. However, when morphine and nalbuphine are mixed together, the clinical interactions in different combining ratios on analgesic effect and adverse events are unknown.
Methods: This randomized, double-blind controlled study investigated five different combining ratios of morphine and nalbuphine in 311 patients undergoing gynaecologic operations. The concentrations [morphine (mg ml–1)]/[nalbuphine (mg ml–1)] were 1/0 in Group 1, 0.75/0.25 (ratio 1:3) in Group 2, 0.5/0.5 (ratio 1:1) in Group 3, 0.25/0.75 (ratio 3:1) in Group 4, and 0/1 in Group 5. Patient-controlled analgesia (PCA) requirement, postoperative pain, and adverse events were evaluated throughout the postoperative 24 h period.
Results: Twenty-four hour PCA requirements were similar among the five groups. Verbal rating scores for pain were statistically higher in Groups 2 and 4 than in Group 3. The incidences of pruritus were higher in Group 1 (15.6%) than in Group 2 (6.2%), Group 3 (3.4%), Group 4 (1.6%), and Group 5 (0%). The incidences and severity of dizziness, nausea, and vomiting were not significantly different.
Conclusions: The interaction between morphine and nalbuphine in PCA admixture on analgesia is additive. Combinations of morphine and nalbuphine in PCA can decrease the incidence of pruritus, and the antipruritus effect is ratio-dependent. This may provide a novel combination strategy of opioid agonist and agonist–antagonist for postoperative pain management after gynaecologic surgery.
Keywords: analgesia, patient-controlled; analgesia, postoperative; analgesics opioid, morphine; analgesics opioid, nalbuphine
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Introduction |
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Nalbuphine is a mixed agonist–antagonist opioid.12 Nalbuphine derives its analgesic and sleep-producing effects through agonism at the kappa-opioid receptor, and it also has the potential to attenuate the mu-opioid receptor-related adverse events.3 Although morphine is the most common opioid used in patient-controlled analgesia (PCA), it may induce many adverse events including pruritus, nausea, vomiting, constipation, urinary retention, respiratory depression, and drowsiness. Morphine binds most readily to the mu-opioid receptor and less well to the kappa-opioid receptor. This implies that the most undesirable adverse events of morphine are from agonism at the mu-opioid receptor.3 Comparative trials have shown that both nalbuphine and morphine are equally effective on pain relief.4 5
Many drugs have been combined with morphine in PCA to augment analgesic effect or to reduce the adverse events.6–10 For nalbuphine, in 1997, Parker and colleagues11 demonstrated that combination of morphine and nalbuphine in patient-controlled epidural analgesia produces a dose-dependent decrease in epidural morphine-related urinary retention, itching, and nausea. There is no previous report of the interaction between morphine and nalbuphine in i.v. PCA. Moreover, potency and clinical effect at the mu-opioid receptor and kappa-opioid receptor are different between morphine and nalbuphine. We hypothesized that the interaction between morphine and nalbuphine might be different in different combining ratios. The goal of this study was to evaluate the interaction of combining different ratios of morphine and nalbuphine in i.v. PCA.
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Methods |
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Patients
This randomized, double-blinded, controlled study enrolled 311 female patients aged between 18 and 65 yr with an ASA physical status I or II. They underwent gynaecologic surgery (total abdominal hysterectomy, myomectomy, and excision of ovarian tumour) with general anaesthesia. The protocol was approved by the Committee for Human Investigation of National Taiwan University Hospital, and informed consent was obtained from each patient. Patients who had a history of drug abuse, chronic pain, or psychiatric disorders were excluded. We also excluded pregnant women, and patients who took sedatives, antiemetics, or antipruritics within 24 h of operation.
Randomization and grouping
Patients were allocated randomly into one of the five groups by using a computer-generated randomized number table. Patients and the investigators who collected the postoperative data were blinded to the randomization. Before the surgery, patients were instructed in the 0–10 verbal rating score (VRS) of pain and the use of PCA. The scale of 0 represented no pain and the scale of 10 represented the worst pain imaginable. The goal of PCA analgesia was to maintain the VRS at rest 
4 between the 4th and 24th hour after surgery. The PCA solutions were prepared by a nurse anaesthetist. On the basis of isobolographic investigations of interaction between two drugs,12 13 we chose five different combining ratios (Fig. 1). In Group 1, 100 mg preservative-free morphine was added into normal saline to a total of 100 ml (concentration of [morphine]/[nalbuphine]=1/0 mg ml–1; pure morphine). In Group 2, 75 mg preservative-free morphine and 25 mg nalbuphine were added into normal saline to a total of 100 ml (concentration of [morphine]/[nalbuphine]=0.75/0.25 mg ml–1; ratio of morphine:nalbuphine=3:1). In Group 3, 50 mg preservative-free morphine and 50 mg nalbuphine were added into normal saline to a total of 100 ml (concentration of [morphine]/[nalbuphine]=0.5/0.5 mg ml–1; ratio of morphine:nalbuphine=1:1). In Group 4, 25 mg preservative-free morphine and 75 mg nalbuphine were added into normal saline to a total of 100 ml (concentration of [morphine]/[nalbuphine]=0.25/0.75 mg ml–1; ratio of morphine:nalbuphine=1:3). In Group 5, 100 mg nalbuphine were added into normal saline to a total of 100 ml (concentration of [morphine]/[nalbuphine]=0/1 mg ml–1; pure nalbuphine).
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Anaesthesia, postoperative analgesia, and PCA setting
Patients did not receive any drug for premedication. Anaesthesia was induced with thiopental (3–5 mg kg–1) and fentanyl (1.5–3 µg kg–1), and maintained with sevoflurane 1.2–1.5% in oxygen. Rocuronium (0.8 mg kg–1) was given to facilitate endotracheal intubation and maintained with 0.2 mg kg–1 every 30 min. At the end of surgery, atropine (0.015 mg kg–1) and neostigmine (0.05 mg kg–1) were administered for reversal of neuromuscular block. After the trachea was extubated, patients were transported to the post-anaesthesia care unit. During the 1 h stay in post-anaesthesia care unit, vital signs were monitored every 5 min and oxygen saturation was monitored continuously by pulse oximetry. The patients were attached to a PCA machine (Lifecare 5500 PCA; Abbott Laboratories). Postoperative analgesia was commenced with a loading dose of 3 ml PCA solution i.v. given by a nurse. After the patients were responsive, they were allowed to use the PCA machine by themselves. The setting for PCA was 1 ml bolus with a 5 min lockout. There was no background continuous infusion throughout the postoperative period.
Postoperative evaluation
After transfer back to the general ward, all patients were observed for 24 h after surgery. The cumulative PCA requirements were recorded in PCA machines, and data were transferred to a computer for interpretation. Pain intensity was evaluated with a 0–10 VRS at rest and upon movement (during coughing or changing body position from supine to lateral on bed). The following adverse events were evaluated: nausea, vomiting, pruritus, and dizziness. Nausea was recorded by incidence and severity. The severity of nausea was defined as mild (discomfort noticed, but no disruption of anticipated normal activity), moderate (discomfort sufficient to reduce or affect anticipated normal activity), or severe (inability to perform anticipated normal daily activity).14 Vomiting episodes were defined as the events of vomiting that occurred in a rapid sequence (<1 min between events), and retching (same as vomiting but without expulsion of gastric content) was considered as vomiting. If events of vomiting were separated by longer than 1 min, they were considered as separate episodes. The total number of episodes of vomiting was recorded. Vomiting that occurred more than four times within 24 h was considered as severe vomiting.15 A rescue antiemetic (Prochlorperazine mesylate 10 mg i.v.) was given at patient's request. Pruritus was reported by incidence. Dizziness was reported by incidence and severity. The severity of dizziness was defined as mild, moderate, or severe as the same grading system for nausea. Drowsiness was reported using the Ramsay sedation score.16 17 All data were collected at 1, 2, 4, and 24 h after operation by direct questioning by the investigators.7
Definitions of treatment failure and severe adverse events
Treatment failures were considered to be insufficient analgesia, intolerable nausea and vomiting, and pruritus. Insufficient analgesia was defined as VRS >4 at rest during 4–24 h after operation.8 Adjunctive analgesic with i.v. meperidine 50 mg or ketorolac 30 mg would be administered for insufficient analgesia. Intolerable nausea and vomiting were defined as persistent nausea or vomiting episodes that required more than three administrations of antiemetics (Prochlorperazine mesylate). In this situation, the patient could decide to continue with the PCA or receive non-steroidal anti-inflammatory drugs (NSAIDs) (ketorolac) for postoperative pain management. Intolerable pruritus was defined as persistent pruritus which requiring more than three administrations of antipruritics (diphenhydramine). In this situation, the patient could decide to continue with the PCA or receive NSAIDs (ketorolac) for postoperative pain management.
PCA-related hypotension, allergic reactions, bronchospasm, unconsciousness, and respiratory depression were considered as severe adverse events. Hypotension was defined as systolic arterial pressure <90 mm Hg at any investigated time. Respiratory depression was defined as ventilatory frequency <8 min–1 or hypoxaemia (SpO2<90%). If a severe adverse event occurred, the use of PCA was stopped immediately and the patient was closely observed. Naloxone and oxygen supplement were administered for respiratory depression.
Statistics
The sample size of 60 in each group chosen to give power to detect a 25% difference in 24 h PCA requirement among the groups, with an 
level of 0.05 (two-tailed) and β level of 0.2 (80% power), assuming a 24 h PCA requirement of 24.7 (12.4) ml. Parametric data were presented as mean (SD). One-way analysis of variance (ANOVA) was conducted to examine differences among the five groups with respect to parametric variables. The Tukey procedure was used for post hoc comparisons. A P-value of <0.05 was considered significant. The Kruskal–Wallis test was used to determine differences among the five groups with respect to non-parametric variables. If a significant difference was detected by Kruskal–Wallis test, Mann–Whitney U-test was used for intergroup comparison. A P-value of <0.05 was considered significant. The incidence of nausea, vomiting, pruritus, dizziness, use of antiemetics, and use of antipruritics were analysed by using 
2 tests or Fisher's exact test. Bonferroni corrections were used to correct for multiple hypothesis testing. A P-value of <0.01 was considered significant.
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Results |
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A total of 311 patients were recruited in this study. Five patients discontinued the investigation due to fever (n=1, in Group 1), severe dizziness [n=1, in Group 3; the dizziness was attributed to anaemia (Hb 8.9 g dl–1)], severe abdominal distention not related to PCA use (n=1, in Group 4), PCA machine dysfunction (n=1, in Group 4), and severe headache not related to PCA use (n=1, in Group 5) (Fig. 1). Three hundred and six patients completed the study: 64 in Group 1, 65 in Group 2, 58 in Group 3, 61 in Group 4, and 58 in Group 5. All patient characteristics were not significantly different among the five groups (Table 1).
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PCA requirements and pain intensity
Cumulative PCA requirements were not significantly different among the five groups (Table 2). Both at rest and with exertion, the VRS of pain in Groups 2, 3, 4 and 5 was not significantly different from the score in Group 1 during the observation period. At the 24th hour after surgery, the VRS of pain both at rest and upon movement was higher in Groups 2 and 4 than in Groups 3 and 5 (Table 3). Nine patients experienced insufficient analgesia and received adjunctive analgesics in this study: one in Group 1, one in Group 2, one in Group 3, three in Group 4, and three in Group 5. The incidence of insufficient analgesia was not significantly different among the five groups.
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PCA-related adverse events
The incidence and severity of nausea were not significantly different among the five groups. The incidence and episodes of vomiting were not significantly different among the five groups. The requirement for antiemetics was less in Group 3 (5.2%) than the other groups (10.8–20.7%), but the difference was not statistically significant (Table 4). The incidence of pruritus was significantly higher in Group 1 than in the other groups (Table 4). There was no event of intolerable nausea, vomiting, or pruritus. Ramsey scores were similar among the five groups. No severe adverse event occurred in this study.
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Discussion |
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This study shows that combination of morphine and nalbuphine does not significantly increase PCA requirements. When achieving our goal in maintaining the VRS of pain at rest
4 between the 4th and the 24th hour after operation, the interaction between morphine and nalbuphine on analgesia is additive. The VRS of pain both at rest and upon movement was statistically higher in Groups 2 and 4 than in Group 3. We suggest that the optimal combining ratio of morphine and nalbuphine is 1:1. We found a ratio-dependent antipruritus effect. However, the combination of morphine and nalbuphine in PCA did not decrease the incidence and severity of nausea, the incidence and episodes of vomiting, or the requirement for antiemetics.
The analgesic effects of nalbuphine derive mainly from binding to the kappa-opioid receptor, and nalbuphine also has the potential to attenuate the mu-opioid receptor-related effects. The analgesic effect of morphine derives mainly from binding to the mu-opioid receptor and less to the kappa-opioid receptor. When combining morphine and nalbuphine together, the analgesic effect from mu-opioid receptor decreases, but the analgesic effect from kappa-opioid receptor increases. In this study, our results support that the attenuated analgesic effect at the mu-opioid receptor can be compensated by the increased analgesic effect at the kappa-opioid receptor. The potency of opioid receptor competition between morphine and nalbuphine is different at each opioid receptor.1 Agonism at the mu1-opioid receptor produces analgesia, and the potency at mu1-opioid receptor is morphine
nalbuphine. Agonism at the mu2-opioid receptor produces respiratory depression, and the potency at mu2-opioid receptor is nalbuphine>morphine. Agonism at the kappa1-opioid receptor produces sedation and analgesia, and potency at kappa1-opioid receptor is nalbuphine>>morphine.1 Moreover, the comparative potency of the analgesic effects between the mu1- and the kappa-opioid receptor is not clear. On the basis of the results of our study, the clinical interaction between nalbuphine and morphine on analgesia is additive. In this study, more patients suffered from insufficient analgesia in Groups 4 and 5, but the events of insufficient analgesia were not significantly different among the five groups. We should be aware that nalbuphine is a partial agonist and has its effect at the kappa receptor. This is important as it suggests a ceiling effect will be present in the response produced.18 19 Furthermore, the interaction between nalbuphine and morphine needs to be investigated for other populations or more advanced surgery.
The reduction of incidence of pruritus is the major benefit of combining morphine and nalbuphine in PCA. Opioid-related pruritus derives from agonism at the mu-opioid receptor.20 21 Nalbuphine does not induce pruritus and it can antagonize morphine-related pruritus.3 Although nalbuphine antagonizes the effect of mu-opioid receptor, however, we did not find that the severity and incidence of nausea, vomiting, or requirement of antiemetics was less in patients receiving this drug. There are possible explanations to these findings. First, in Group 5 (pure nalbuphine PCA), the incidence and severity of nausea, the incidence and episodes of vomiting, and requirement of antiemetics were similar to the other groups. Beside the opioid-related effect, the nausea and vomiting of the population in our study could derive from other mechanisms, such as the effect of pain on vomiting centre, the residual effect of anaesthetic on chemoreceptor trigger zone, or the effect of surgery. Secondly, the types of surgery, the methods of anaesthesia, and the population in our study were different from the studies which report that nalbuphine can reduce the incidence of morphine-induced nausea and vomiting.11 22 23
A sex-difference in analgesic requirement had been reported by Aubrun and colleagues.24 They found that women experienced more severe pain and required a greater dose of morphine than men. Moreover, kappa-opioids produce significantly greater analgesia in women than in men.25 Because our results were based on the population of women after gynaecologic surgery, further study is required to investigate the combining effect of morphine and nalbuphine on men. For the purposes of this study, we chose to achieve postoperative pain relief through PCA alone. Current recommendations for postoperative analgesia are multimodal methods. Multimodal protocols are also suggested to reduce morphine PCA-related adverse events.
In conclusion, the PCA requirements were not significantly different among the five groups. It suggests that interaction between morphine and nalbuphine on analgesia is additive. The optimal combining ratio of morphine and nalbuphine in PCA is 1:1. Combination of morphine and nalbuphine in PCA can decrease the incidence of pruritus, and the antipruritus effect is ratio-dependent.
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