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Abstract |
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 Top Abstract IntroductionMethodResultsDiscussionReferences |
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We evaluated the effect of perioperative administration of two doses of morphine for postoperative analgesia after remifentanil-based anesthesia. The prospective, randomized study included 245 patients from 33 centers. All patients were scheduled for abdominal or urological surgery lasting more than 1 h. General anesthesia used remifentanil as the perioperative opioid (1 µg/kg as a bolus then, 0.5 µg/kg as a continuous infusion). A morphine bolus of 0.15 mg/kg (0.15-mg group) or 0.25 mg/kg (0.25-mg group) was administered 30 min before the end of surgery. In the postanesthesia care unit, pain scores for patients were evaluated by using behavioral pain scores of 1–3, verbal pain scores of 0–3, and visual analog scale scores of 0–10). Postoperative analgesia was obtained by a morphine titration (3 mg every 5 min). Demographic and surgery characteristics were similar in both groups. The delay for first demand of morphine was similar in the 0.15-mg and the 0.25-mg groups (26 [9–60] and 30 [10–60] min, respectively). The frequency of morphine titration was similar in both groups (75% and 66%, respectively). The amount of morphine used in the postanesthesia care unit was smaller in the 0.25-mg group (0.16 [0.0–1.25] vs 0.10 [0.0–0.56] mg/kg; P = 0.008). In the 0.25-mg group, the behavioral pain score was lower at 15 min, the verbal pain score was lower at 60 min (P < 0.001), and similar at 30 min. The visual analog scale pain score at 30 min and 60 min was similar in both groups. The incidence of minor side effects was similar in both groups. However, three cases of postoperative respiratory depression occurred in the 0.25-mg group compared with no cases in the 0.15-mg group. In conclusion, perioperative administration of morphine alone does not provide entirely adequate immediate postoperative pain control after remifentanil-based anesthesia in major surgery.
Implications: The administration of 0.15 or 0.25 mg/kg perioperative morphine during remifentanil-based anesthesia for major surgery does not preclude additional morphine administration in the postanesthesia care unit. The larger dose of 0.25 mg/kg slightly improves postoperative analgesia; however, it may be responsible for postoperative respiratory depression.
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Introduction |
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The immediate postoperative period is important for the control of pain after major surgery. Patient transition from total anesthesia to awake with adequate analgesia is sometimes difficult. This problem is even more acute for a new opioid such as remifentanil with a short context-sensitive half-life (1–4). In fact, this new opioid offers no residual analgesia (5,6). Therefore, one study (7) and several preliminary reports (8–11) have evaluated the benefit of intraoperative administration of morphine for analgesia after remifentanil- based anesthesia. Partial analgesia was obtained with 0.15 mg/kg morphine 20 min before the end of surgery (7). Other reports stated that perioperative morphine (dose range 0.15–0.20 mg/kg or bolus of 15 mg 20–25 min before the end of surgery) did not preclude additional morphine in the immediate postoperative period (8–11). This insufficient postoperative pain control may be related to the insufficient delay between morphine bolus and end of surgery (20–25 min) or the limited dose of morphine (0.2 mg/kg). Therefore, the purpose of this study was to evaluate the influence of perioperative administration of morphine 30 minutes before the end of surgery on the quality of postoperative pain in a large series of patients scheduled for major surgery and to define whether a larger dose of morphine (0.25 mg/kg) may enhance the quality of immediate postoperative pain control.
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Method |
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TopAbstractIntroductionMethodResultsDiscussionReferences |
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After institutional ethics committee approval and written, informed consent, 245 adults (ASA physical status I–III) >18 yr old, scheduled for major abdominal or urological procedures planned to last at least 1 h and requiring morphine for postoperative analgesia, were included in a prospective, randomized study. Exclusion criteria were day-surgery patients; patients with an uncontrolled disease, such as arrhythmia, asthma, hypertension, inflammatory bowel disease; chronic use of opioid or prescription of opioid within 12 h before surgery; obesity (weight >30% the ideal value); allergy to opioids or any other drug used in the study; psychiatric disorders; pregnant or breast feeding women; alcoholic intoxication; and participation in another research project.
All patients received lorazepam 2.5 mg the night before surgery. General anesthesia was induced with thiopental (5 mg/kg), the trachea was intubated, anesthesia was maintained with O2/NO2 (60%/40%), and isoflurane was started at an inspired concentration of 0.6%. Remifentanil was administered after the induction of anesthesia with thiopental as a bolus of 1 µg/kg over 30 to 60 s and then, as an infusion at 0.5 µg · kg-1 · min-1. The dose of the infusion was reduced 0.25 µg · kg-1 · min-1 for patients >65 yr old. Both isoflurane and remifentanil administration were discontinued at the end of surgery. Before intubation, a bolus of atracrium 0.5 mg/kg was administered followed by an infusion of 10–15 µg · kg-1 · min-1. Depending on the randomization, a bolus of 0.15 mg/kg (0.15-mg group) or 0.25 mg/kg (0.25-mg group) of morphine was administered 30 min before the anticipated end of surgery. Muscle relaxant effects were antagonized with neostigmine 40–60 µg/kg and atropine 15–20 µg/kg. The trachea was extubated when ETCO2 
5.5% and a respiratory rate 
12 breaths/min.
The primary endpoint was defined as the interval between the discontinuation of the remifentanil infusion and the request for morphine in the postanesthesia care unit (PACU). Pain was evaluated for the first 15 min after arrival in the PACU with a behavioral score defined as: zero = calm patient with no verbal or behavioral manifestation of pain; one = behavioral or verbal expression of pain; two = intense behavioral or verbal manifestation of pain (cry, extreme agitation). This behavioral pain score (BPS) was performed at 5, 10, and 15 min after the discontinuation of the remifentanil infusion. A BPS of one was considered adequate analgesia; BPS 2 was considered as a failure of analgesia. The verbal pain scale (VPS) was used at 15, 20, 25, 30, 45, and 60 min after discontinuation of the remifentanil infusion. This VPS score was defined as zero = no pain: one = light pain; two = moderate pain; three = severe pain. A VPS score was then, taken every 30 min until discharge from the PACU. A 10-cm visual analog scale (VAS) pain score (with endpoints labeled "no pain" and "worst possible pain") was also used to assess pain intensity when at rest. Evaluation was performed at 30, 45, 60 min after discontinuation of the remifentanil infusion and then, every 30 min until discharge from the PACU. The VPS 1 or the VAS = 40 mm was considered as adequate analgesia; VPS 2 or VAS > 40 mm was considered as a failure of analgesia.
Titration of morphine was started when BPS or VPS were 2 or VAS was 40 mm. This morphine titration in the PACU consisted of repeated boluses of 3 mg of morphine every 5 min until the pain score was reported by the patient as VAS 40 mm or VPS 1.
Sedation was monitored by using the following scale: zero, patient fully alert; one, patient with intermittent sedation; two, patient sedated, however, responsive to verbal stimuli; three, patient unresponsive to verbal stimuli. The sedation score was evaluated at 5, 10, 15, 20, 25, 30, 45, and 60 min and then, every 30 min until discharge from the PACU.
Blood pressure, heart rate, respiratory rate, and SaO2, were evaluated at 5, 10, 15, 20, 25, 30, 45, and 60 min, and then, every 30 min until discharge from the PACU. Side effects (nausea, vomiting, pruritus, urinary retention) were recorded when present. Respiratory side effects included apnea, hypoxia, and respiratory depression. Respiratory depression was considered present when the patient required the administration of naloxone or mechanical ventilation. Mental problems, such as dysphoria and hallucinations, were recorded when present.
Patients were discharged from the PACU when the Aldrete score was 9, SaO2 was 95% without oxygen, and the sedation score was 1 at two successive evaluations, 30 min apart. The time to reach these discharge criteria was noted.
Delay for the first demand of morphine was compared by using the log rank test. The Wilcoxon test was used to compare morphine cumulative doses. The percentage of patients receiving morphine or patients with a VPS 1 were compared with a 
2 test. The VAS score was compared with the Wilcoxon test. The percentage of BPS and VPS were compared with a Mantel-Haenszel test. Frequency of side effects and sex distribution were compared by using a 2 test. A value of P < 0.05 was considered significant. Data were expressed as median (range).
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Results |
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Included in the study were 248 patients (Table 1). One patient in the 0.15-mg and two patients in the 0.25-mg groups were excluded from the study for major violation of the protocol (two patients did not receive perioperative morphine, one patient had no evaluation in the PACU). Therefore, efficacy results are presented for 245 patients (121 and 124 patients for the 0.15-mg and the 0.25-mg groups, respectively). There was no difference between the groups for sex, age, weight, duration of surgery, type of surgery, and the cumulative perioperative dose of remifentanil.
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Emergence from anesthesia was rapid for all patients, and delay for extubation after remifentanil infusion discontinuation was 15 (2–70) and 15 (0–125) min in the 0.15-mg and the 0.25-mg groups, respectively (Table 2). The time to the first sedation score
1 after discontinuation of the remifentanil infusion was 20 (5–240) and 20 (5–360) min in the 0.15-mg and the 0.25-mg groups, respectively. During the first 15 min after arrival in the PACU, the maximum BPS was more frequently 1 in the 0.25-mg group than in the 0.15-mg group (P = 0.02). The VPS at 30 min after discontinuation of remifentanil was similar in the 0.25-mg group as compared with the 0.15-mg group (VPS 2; P = 0.31); however, it was significantly less important in the 0.25-mg group at 60 min (P < 0.001) (Figure 1). The VAS pain score at 30 min and 60 min was similar in both groups (P = 0.64 and P = 0.05, respectively) (Figure 2).
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All data concerning morphine administration in the PACU are listed in Table 2. Delay for the first administration of morphine in the PACU was similar in the 0.25-mg group and the 0.15-mg group (30 [10–60] vs 26 [9–60] min, respectively; P = 0.11). The frequency of morphine administration during the first one-half hour after surgery was similar in both groups (66% vs 75% for the 0.25-mg group and the 0.15-mg group, respectively; P = 0.12). However, immediate postoperative analgesia was obtained in the 0.15-mg group with larger cumulative doses of morphine administered in the PACU than in the 0.25-mg group (0.16 [0.00–1.25] vs 0.10 [0.00–0.56] mg/kg, respectively; P = 0.008). The total morphine dose received by patients, including the randomized study drug, was larger in the 0.25-mg group than in the 0.15-mg group (0.35 [0.25–0.81] vs 0.31 [0.15–1.40] mg/kg, respectively; P = 0.001).
Few patients stayed beyond 6 h in the PACU (11 in the 0.15-mg group and 9 in the 0.25-mg group). The time to eligibility for PACU discharge was similar in both groups (0.15-mg group: 116 ± 73 [60–535] min, and 0.25-mg group: 120 ± 92 [57–559] min). The effective duration of stay in the PACU was similar in both groups (0.15mg group: 183 ± 236 [64–1465] min, and 0.25-mg group: 188 ± 201 [72–1310] min; P = 0.11).
During the perioperative period, some patients had side effects probably related to remifentanil administration (23% in the 0.15mg group and 24% in the 0.25mg group) (Table 3). Hypotension occurred in 16% of the 0.15-mg group and 17% of the 0.25-mg group; and bradycardia occurred in 7% of the 0.15-mg group and 6% of the 0.25-mg group. Other side effects, possibly related to remifentanil infusion, were quite rare (<1%). During the postoperative period, side effects have been described in the 0.15- and 0.25-mg groups with a similar global incidence of 33% and 32%, respectively. The most frequent side effects had a similar incidence (nausea, 16% and 13%, and vomiting, 11% and 12%, in the 0.15-mg and the 0.25-mg groups, respectively). Respiratory side effects occurred in 2% and 8% of the patients in the 0.15-mg and the 0.25-mg groups, respectively. Three cases of respiratory depression occurred in the 0.25-mg group with two cases occurring at 60 and 106 min after discharge from the PACU. No cases of respiratory depression occurred in the 0.15-mg group. Respiratory depression was considered related to morphine administered perioperatively, and patients’ characteristics of the depression are listed in Table 4.
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Discussion |
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TopAbstractIntroductionMethodResultsDiscussionReferences |
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The perioperative morphine administration at two doses of 0.15 and 0.25 mg/kg does not preclude additional doses of morphine after surgery. The larger dose of 0.25 mg/kg slightly improved immediate postoperative pain; however, the total dose of morphine required for analgesia was increased. In the group receiving the larger dose of intraoperative morphine, we observed three cases of severe, delayed respiratory depression.
Although morphine used alone does not reflect contemporary postoperative analgesic care, we chose to evaluate the perioperative administration of two doses of morphine to improve immediate postoperative pain control after remifentanil-based anesthesia, because pain control is not satisfactory in the immediate postoperative period (5,6). In fact, postoperative infusion of small doses of remifentanil can offer pain control; however, it appears responsible for an incidence of 4% to 11% of apnea (7,12,13). Postoperative patient-demand IV remifentanil is effective (14); however, safety was not specifically evaluated in one preliminary study including a small number of patients (14). Therefore, the anticipation of postoperative pain treated with perioperative bolus of morphine is another proposed strategy (7). Doses of intraoperative morphine (0.15 and 0.25 mg/kg) used were chosen according to previous studies showing that the perioperative administration of a single bolus of morphine (0.1 mg/kg) does not modify the awakening concentration of isoflurane or sevoflurane (15,16) and that a bolus of 0.15 mg/kg-1 of intraoperative morphine is not sufficient after remifentanil-based anesthesia (7). We did not monitor patient satisfaction and some postoperative data, such as shivering or agitation, which partially limits the appreciation of the overall quality of recovery in both groups.
Our study suggests that intraoperative morphine administration, even at a dose as large as 0.25 mg/kg 30 minutes before the end of surgery, cannot totally preclude the need for morphine in the immediate postoperative period. The dose of 0.25 mg/kg is slightly more efficient because the BPS during the first 15 minutes and the VPS at 60 minutes are lower in this group as compared with those of the 0.15-mg group. An agitated behavior in the immediate postoperative period may not be caused by pain. BPS was used because VPS or the VAS pain scale are difficult to measure when patients are still sedated or tracheally intubated. The benefit of BPS is limited because the delay for the first demand of morphine is similar and short in both groups and the mean VAS pain score at 30 minutes and 60 minutes as the percentage of patients needing morphine over the first postoperative hour is similar in both groups. We did not use a control group receiving a more conventional opioid, such as sufentanil during surgery, which probably weakens our conclusions and does not allow comparison with another regimen of peroperative analgesia.
Despite the slight reduction of morphine doses used in the PACU, cumulative doses of morphine, including the intraoperative morphine bolus, were larger in the 0.25-mg group. The incidence of minor side effects, such as nausea and vomiting was similar in both groups. However, cases of severe, delayed respiratory depression requiring the administration of naloxone or mechanical ventilation occurred in the 0.25-mg group—one in the PACU and two after discharge from the PACU (60 and 106 minutes after discharge), both of whom had adequate Aldrete scores. For these two patients, the large doses of morphine administered in the PACU (25 and 17.5 mg) as the total morphine dose including perioperative bolus (37 and 26.5 mg, respectively) contribute to these cases of respiratory depression. Possible additional risk factors for opioid-induced respiration depression were obesity for one patient and a large blood loss in the other. This type of respiratory depression is difficult to manage because, in both cases, it occurred after discharge from the PACU in patients with an adequate Aldrete score. The occurrence of these severe side effects further suggests that large doses of morphine as the sole drug to control severe postoperative pain after remifentanil-based anesthesia are not adequate, especially when perioperative administration is not titrated to patient need. Delay between morphine administration and respiratory depression may be caused by the long half-life of morphine when compared with the reduction of nociception hours after surgery. In any event, this suggests that patients receiving large doses of morphine in the postoperative period after remifentanil-based anesthesia should be monitored during a long period in the PACU despite the apparent adequate criteria for discharge.
To limit the deficit in postoperative analgesia we observed, despite large doses of intraoperative morphine, the use of a multimodal approach (17) is probably of interest. The combination of synergistic analgesic drugs as nonsteroidal antiinflammatory drugs associated with morphine may offer a more intense analgesia and limit the amount of morphine necessary in the postoperative period (18).
In conclusion, the intraoperative administration of morphine at doses up to 0.25 mg/kg did not eliminate the need for morphine in the PACU after remifentanil-based anesthesia and led to three patients having postoperative respiratory depression.
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Acknowledgments |
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We thank all of the following staff and the centers they represent for their involvement in the study: Prof. François, Prof. Egreteau, Prof. Malledant, Prof. Fischler, Prof. Auboyer, Prof. Marty, Prof. Wilkening, Dr. Boillot, Prof. Manelli, Prof. Martin, Prof. Gouin, Prof. Grimaud, Dr. Mongin-Long, Prof. Petit, Dr. Avon, Dr. Petris, Prof. Feiss, Dr. Beaulaton, Prof. Ecoffey, Prof. Safran, Dr. Bryssine, Prof. Schoeffler, Dr. Carry, Dr. Wagner, Dr. Brule, Prof. Bonnet, Dr. Rocherieux, Dr. Madras. We also thank the following CRAs for monitoring the study: Marie-José Theus, Patrice Masseboeuf, Christine Pétilaire, Jacques Di-Guardo, Philippe Gougé, Florence Garnier, Claudine Ruellan, Marc Colin, Rémi Morin, Isabelle Lessinnes, Camille Laconfourque, Nicolas Trolonge, and Claude Doëglé.
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Footnotes |
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Sponsored by Glaxo Wellcome Laboratory.
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References |
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[Abstract/Free Full Text] - Katoh T, Suguro Y, Kimura T, Ikeda K. Morphine does not affect the awakening concentration of sevoflurane. J Anaesth 1993;40:825–8.
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Kehlet H, Dahl JB. The value of "multimodal or "balanced analgesia" in postoperative treatment. Anesth Analg 1993;77:1048–56.
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