ORIGINAL ARTICLE
A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery Y. Xiao1, L. Wu2, Q. Zhou1, W. Xiong1, X. Duan1 and X. Huang1 1
Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China Department of Anesthesiology, Cancer Institute and Hospital, National Cancer Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Peking, China 2
Correspondence X. Huang, Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China E-mail: [email protected] Ying Xiao and Linxin Wu have equally contributed to this study. Conflicts of interest The authors have no conflicts of interest. Funding Funded by Guangdong Natural Science Foundation (10151008901000119) and Zhongshan University’s Basic Scientific Research Foundation for Young Teachers Cultivation Project (10ykpy12). Submitted 5 April 2015; accepted 19 April 2015; submission 10 July 2014. Citation Xiao Y, Wu L, Zhou Q, Xiong W, Duan X, Huang X. A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery. Acta Anaesthesiologica Scandinavica 2015 doi: 10.1111/aas.12560
Background: Tolerance to remifentanil during sevoflurane anesthesia may increase postoperative analgesic requirements. Lowdose naloxone not only has been shown to block the development of acute opioid tolerance but also to ameliorate undesired opioidinduced side effects. We hypothesized that naloxone prevents the acute opioid tolerance produced by a large dose of remifentanil, and reduces the incidence of opioid-induced side effects. Methods: Seventy-two patients undergoing open colorectal surgery were randomly assigned to receive intraoperative remifentanil (1) small dose at 0.1 lg/kg/min; (2) large dose at 0.30 lg/kg/ min; or (3) large dose at 0.30 lg/kg/min combined with low-dose naloxone at 0.25 lg/kg/h just after the induction. Cumulative morphine consumption, postoperative pain scores, incidence of opioid-related side effects, time to recovery of bowel function, and length of hospital stay were recorded. Results: Cumulative morphine consumption at 24 h after surgery was higher in the large-dose remifentanil group (28 12 mg) compared with the small-dose remifentanil group (17 12 mg), and large-dose remifentanil–naloxone group (18 9 mg), (P < 0.001). The median time to return of bowel function was shorter in the large-dose remifentanil–naloxone group than the other two groups (P < 0.05). The median length of hospital stay was lower in the large-dose remifentanil–naloxone group (8 [interquartile range: 8–12] days) compared with the small-dose remifentanil group (12 [interquartile range: 9–15] days) and large-dose remifentanil group (12 [interquartile range: 10–13] days), (P < 0.001). Conclusion: Naloxone infusion prevented the acute opioid tolerance, provided a quicker recovery of bowel function, and reduced the length of hospital stay after open colorectal surgery.
Editorial comment: what this article tells us
A large dose of remifentanil during general anesthesia may generate postoperative opioid tolerance. Addition of an ultra-low dose of naloxone can ameliorate this effect, enhance recovery of bowel function, and decrease hospital stay.
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Remifentanil, a potent short-acting opioid analgesic, is widely used in the intraoperative period for its favorable pharmacokinetic characteristics, including the rapid and predictable onset and offset of the analgesic effect with little risk for delayed awakening or respiratory depression after surgery.1 Although considerable evidence suggests that intraoperative infusion of a large-dose remifentanil causes acute opioid tolerance, manifesting as increased postoperative analgesic requirements, the results of clinical trials are controversial.2–8 Naloxone, a selective l-opioid receptor antagonist, frequently used in clinical practice to counter the effects of opioid overdosage,9 has also been used at ultra-low doses in combination with opioids to enhance the analgesic effect,10–12 block the development of acute opioid tolerance,13–17 and decrease the incidence of opioidinduced side effects.18–20 Though all of these applications remain less well defined and disputable, a low-dose naloxone infusion may have a potential as adjuvant in painful surgical procedures where the anticipated opioid requirement is high. Among the adverse effects of opioids, the most clinically important for abdominal surgery is bowel dysfunction. However, there are few clinical trials demonstrating whether ultra-low-dose naloxone can prevent opioid-induced delay in bowel motility without affecting analgesia. A large number of studies have shown that naloxone has some relation with opioid-induced hyperalgesia and tolerance.21–24 However, there are no clinical studies regarding the effect of opioid antagonists on remifentanil-induced tolerance. In this study, we hypothesized that perioperative infusion of low-dose naloxone could prevent acute opioid tolerance induced by large dose of remifentanil, manifesting as decrease postoperative morphine consumption, and provide quicker recovery of bowel function and thus reduce the length of hospital stay after open colorectal surgery. Methods This prospective, randomized, double-blind, single-center study was approved by the Institutional Ethics committee (IRB NO. [2011]194, 30 June 2011)and written informed consent was
obtained from all patients. The trial was registered in the Chinese Clinical Trial Registry 201108-11 (Identifier : ChiCTR-TRC-11001461). Consecutive adult patients who were scheduled to undergo open colorectal surgery and refused to receive epidural analgesia were enrolled. The study included patients between the age 18 and 65 years, and with an ASA physical status I–III. Exclusion criteria were consent refusal, obesity (body mass index ≥ 30 kg/m2), pregnancy, and contraindications to any drug used during general anesthesia. We also excluded patients who needed an enterostomy, had previous chronic pain, received preoperative opioids within 12 h of surgery, were unable to understand the patient-controlled analgesia device, or participated in another research project in the previous 30 days. Postoperative exclusion criteria included reoperation, excessive bleeding, and prolonged ventilation (> 12 h). During the preoperative anesthetic evaluation in the evening before surgery, patients were instructed how to use the PCA pump (Pain management provider, Abbott, USA), a fourpoint verbal rating scale for pain assessment (0 = no pain, 1 = slight pain, 2 = moderate pain, 3 = intense or severe pain)4 and the 100 mm visual analog scale (VAS) for pain evaluation, with 0 mm identifying no pain and 100 mm being defined as the worst imaginable pain. All patients were unpremedicated and fasted for at least 8 h. Baseline heart rate and mean arterial pressure were defined as the mean of the two lowest measurements recorded during a 3- to 5-min interval just before induction of anesthesia. General anesthesia was induced with propofol (1.5 mg/kg), remifentanil (1 lg/kg), and cisatracurium (0.2 mg/kg) and was maintained with sevoflurane and remifentanil to target a Narcotrend (Monitor Technique, Hannover Medical School, Germany) stage between D2~E1, which means deep sedation. Before admission to the operating room, the patients were randomly assigned in a 1 : 1 : 1 ratio for three parallel arms using a concealed allocation approach (computer-generated codes) with sealed envelopes. There was no stratification or block randomization. Patients and the study investigators performing pain assessment were blinded to group allocation during the
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entire study period, except for the anesthesiologist in charge of the patient. The three treatment groups were as follows: 1. Small-dose remifentanil group (SR): Patients were given an infusion of remifentanil at a constant rate of 0.1 lg/kg/min throughout the operation while sevoflurane was maintained at 0.8 minimum alveolar concentration (MAC). If the Narcotrend (NT) stage was above D2 for at least 1 min or clinical signs of inadequate anesthesia such as patient movement, coughing, tearing, or sweating appeared, the inspired sevoflurane concentration was increased stepwise by 1% increments. If the NT stage was already in the given range, but the systolic arterial pressure or heart rate exceeded baseline values by 20%, nicardipine or esmolol was given. 2. Large-dose remifentanil group (LR): Patients were given an intraoperative infusion of remifentanil at an initial rate of 0.3 lg/kg/min and subsequently increased stepwise by 0.05 lg/kg/min increments if insufficient anesthesia was indicated while sevoflurane was constantly maintained at an end-tidal concentration of 0.6 MAC. 3. Large-dose remifentanil–naloxone group (LR– LN): Patients were given an intraoperative infusion of naloxone at a rate of 0.25 lg/kg/ h, an amount that reduces the incidence of opioid-induced side effects in postoperative patients receiving IV morphine with PCA.18– 20 Anesthesia maintenance was the same as in group LR. The naloxone infusion was continued for 72 h postoperatively and then PCA was discontinued. If hypotension (MAP < 60 mmHg) or bradycardia (HR < 45 beats/min) occurred more than 5 min, the patient was treated with ephedrine 10 mg or atropine 0.5 mg. Muscle paralysis was maintained with bolus doses of cisatracurium guided by train-of-four monitoring. Thirty minutes before the end of surgery, a 0.15 mg/kg bolus dose of morphine was administered intravenously. At skin closure, sevoflurane was discontinued while remifentanil was maintained at 0.1 lg/kg/min, and residual neuromuscular blockade was antagonized with 40 lg/kg neostigmine and 20 lg/kg atropine IV. Patients in
all groups received a preemptive antiemetic drug (0.25 mg palonosetron IV) 10 min before the end of the operation. Extubation was performed when the patient was able to open the eyes and take deep breaths on verbal command. Remifentanil infusion was stopped after tracheal extubation. Patients were transferred to the post-anesthesia care unit (PACU) within 10 min after tracheal extubation. They remained in the unit for at least 2 h and were given oxygen via a facemask at a rate of 5 l/min throughout this period. Pain was evaluated for the first 15 min after extubation with a behavioral score (0 = calm patient with no verbal or behavioral manifestation of pain, 1 = behavioral or verbal expression of pain, 2 = intense behavioral or verbal manifestation [crying or extreme agitation]).4 Postoperative pain was initially treated with morphine by nurses who were unaware of the patient’s group assignment when the patient’s behavioral pain score was more than 0 or the verbal rating scale score was more than 1. Boluses of morphine (3 mg) were given at 5min intervals until the patient was calm and with no verbal or behavioral manifestation of pain. However, morphine administration was discontinued when the four-point sedation score (0 = patient fully awake, 1 = patient somnolent and responsive to verbal commands, 2 = patient somnolent and responsive to tactile stimulation, 3 = patient asleep and responsive to painful stimulation) was greater than 2 or the respiratory rate was < 12 breaths/min. Patients were connected to a PCA device just before discharge from the PACU. The pump was set to deliver 1 mg morphine as bolus dose with an 8-min lockout interval, and no background infusion was provided. The PCA regimen was continued for 72 h after tracheal extubation. Values from all routine anesthetic monitors were recorded at 5-min intervals during surgery. Duration of anesthesia and surgery were recorded. Intraoperative variables included remifentanil dose and consumption of ephedrine, atropine, nicardipine, or esmolol. In the PACU, patients were observed by nurses who were blinded to the group assignment. The time interval from discontinuation of remifentanil to the first requirement of morphine and the total amount of morphine titration was also recorded. Acta Anaesthesiologica Scandinavica 59 (2015) 1194–1203
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Pain intensity at 30 min and 1 h after extubation was assessed by the patients utilizing a visual analog scale. Cumulative morphine consumption was also recorded. In the surgical ward, the cumulative consumption of morphine given by PCA and the pain intensity using the VAS were recorded at 24 h, 48 h, and 72 h after surgery. The time to return of bowel function (repeated passage of flatus and stools), nausea and vomiting requiring treatment with ondansetron, and analgesic technique-related side effects, especially respiratory depression were also recorded. Analgesicrelated postoperative respiratory depression in the surgical ward was defined by the combination of a sedation score greater than 1 and a respiratory rate < 10 breaths/min. Postoperative morbidity was assessed prospectively using defined criteria. Length of hospital stay was assessed from the start of surgery. All patients were evaluated for residual peri-incisional postoperative pain 3 months after surgery. Statistical analysis The initial postoperative 24-h morphine consumption was considered as our primary endpoint. The secondary endpoints were VAS pain scores, the time for the first morphine demand, cumulative morphine consumption over 72 h, and postoperative recovery parameters and complications. Our experience indicated that morphine consumption over the initial postoperative 24 h after major abdominal surgery is 30 15 mg. A sample size estimate indicate that 24 patients in each group would give a power of 80% at an a-level of 0.05 for detecting a difference in morphine consumption of at least 40%. The study size was thus prospectively set to 75 patients (25 patients/group). Duration of surgery and anesthesia, intraoperative remifentanil consumption, and morphine titration in the PACU were analyzed by oneway analysis of variance (ANOVA). Cumulative morphine consumption and VAS scale were analyzed by repeated-measures ANOVA for inter-group comparison. The chi-square test or Fisher’s exact test was used to compare the relative frequency of type of surgery, intraoperative atropine, ephedrine, nicardipine and esmolol use, requirement for antiemetic drugs, and
incidence of postoperative complications [postoperative nausea and vomiting (PONV) anastomotic leakage, wound abscess, intraabdominal abscess, and incidence of chronic pain]. Because the time to first morphine requirement, the time until return of bowel function and the length of hospital stay were not normally distributed (asymmetric distribution), the Kruskal–Wallis H test was used. For post hoc comparisons, we used the Bonferroni test, as needed. Statistical analysis was performed with SPSS software v. 17.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered statistically significant. Results During the time period, August 2011 until August 2013, 75 patients were enrolled, and three patients were excluded from analysis because of early reoperation for postoperative bleeding (n = 1), massive bleeding intraoperatively, and patients transferred to the SICU requiring postoperative mechanical ventilation (n = 2). Seventy-two patients were analyzed (Fig. 1). The groups did not differ regarding demographic data or surgical characteristics (Table 1). Anesthetic characteristics and postoperative care data are shown in Table 2. Intraoperative remifentanil consumption was twofold higher in the LR and LR–LN groups compared with the SR group (P < 0.001). Intraoperative atropine use was significantly higher in the LR group (16.7%) compared with the other two groups (P = 0.031), whereas there were no significant differences in ephedrine, nicardipine, or esmolol utilization (Table 2). Regarding time to first morphine demand, patients in the LR group requested morphine by titration significantly earlier (29.5 [20.0–39.5] min) than those in the SR group (39.0 [33.5–50] min) and the LR–LN group (40.0 [35.3–50] min; P = 0.004). The morphine dose given by titration in the PACU was larger in the LR group than in the SR and LR– LN group (Table 2). The VAS scores were higher in the LR group than the SR and LR–LN groups at the first 30 min after surgery, but did not differ thereafter, while cumulative morphine consumption was significantly higher in the LR group than the other two groups (Fig. 2).
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Enrollment
Assessed for eligibility (n = 206) at the first affiliated Hospital of Sun Yat-sen
Excluded (n = 131) ♦ Not meeting inclusion criteria (n = 111) ♦ Declined to participate (n = 20)
Randomized (n = 75)
Allocation
Allocated to SR (n = 25)
Allocated to LR (n = 25)
Allocated to LR - LN (n = 25)
Excluded (n = 1)
Excluded (n = 1)
Excluded (n = 1)
Reoperation postoperatively
Mechanical ventilation required postoperatively
Mechanical ventilation required postoperatively
Follow-Up 0 lost to follow-up
0 lost to follow-up
0 lost to follow-up
Analysis 24 included in analysis
24 included in analysis
24 included in analysis
Fig. 1. Flow diagram of patients in this study.
Postoperative complications are presented in Table 3. Although more patients in the LR group experienced PONV, there was no significant difference in the incidence of PONV among the groups (P = 0.094). The groups did not differ in postoperative complications including anastomotic leakage, wound abscesses and intraabdominal abscesses (Table 3). Two patients had residual peri-incisional postoperative pain 3 months after surgery in the LR group, while
one patient developed chronic pain in the SR group. The median time until flatus was shorter in the LR–LN group than in the other two groups, (P = 0.013 and P = 0.003 each, Fig. 3). The median time until stools was also shorter in the LR– LN group than the other two groups, (P = 0.008 and P = 0.003 each, Fig. 3). The median length of hospital stay was lower in the LR–LN group (8 [interquartile range: 8– Acta Anaesthesiologica Scandinavica 59 (2015) 1194–1203
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Table 1 Demographic and surgical characteristics.
Age, years Sex, M/F Height, m Weight, kg ASA Score, I/II/III Type of surgery (%) Left-side colectomy Right-side colectomy Dixon Duration of surgical procedure, min Duration of anesthesia, min
Group SR (n = 24)
Group LR (n = 24)
Group LR–LN (n = 24)
52 (25–65) 13/11 165 9 63 13 8/13/3
49 (25-65) 12/12 165 7 59 10 5/17/2
50 (23-64) 12/12 164 7 59 11 7/14/3
5 (21) 16 (67) 3 (13) 256 84 292 85
7 (29) 15 (63) 2 (8) 249 70 290 74
8 (33) 14 (58) 2 (8) 244 70 278 64
Values are mean (range), no. of patients, mean SD, or number (%). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group. There were no statistical differences between the Groups regarding duration of surgical procedure or anesthesia.
Table 2 Anesthetic characteristics and postoperative care data.
Remifentanil dose (mg) Ephedrine uses (No of patients/%) Atropine uses (No of patients/%) Nicardipine uses (No of patients/%) Esmolol uses (No of patients/%) Time to first postoperative morphine demand (min) Morphine titration in PACU (mg)
Group SR (n = 24)
Group LR (n = 24)
1.8 0.7 6 (25.0) 0 (0) 5 (20.8) 3 (12.5) 39 (34-50) 93
5.3 1.8* 4 (16.7) 4 (16.7)* 0 (0) 0 (0) 30 (20-40)* 10 2
Group LR–LN (n = 24) 5.1 2.1* 6 (25.0) 0 (0)† 4 (25) 0 (0) 40 (35-50)† 9 2†
Values are presented as mean SD, median (interquartile range), or number of patients (%). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group. *P < 0.05 compared with small-dose remifentanil group; †P < 0.05 compared with large-dose remifentanil group. PACU, post-anesthesia care unit.
11.5] days) compared with the SR group (12 [interquartile range: 9.3–14.5] days) and the LR group (12 [interquartile range: 10–13] days) (Fig. 4). Discussion This prospective, randomized study confirmed that remifentanil given during inhalational anesthesia was associated with increased postoperative morphine consumption after major abdominal surgery: the larger the remifentanil dose, the larger the morphine requirement by titration. Patients who received a large dose of remifentanil, all requested morphine by titration and significantly earlier than patients who received a small dose of remifentanil. Most
importantly, we confirmed our hypothesis that intraoperative administration of low-dose naloxone eliminated the increased morphine consumption that resulted from a large dose of remifentanil. Patients who received a large dose of remifentanil combined with low-dose naloxone had significantly less postoperative morphine requirements than those receiving the large dose of remifentanil only; in fact, the morphine dose was comparable to that of the small-dose remifentanil patients. The time to return to normal gastrointestinal function and length of hospital stay was also shortened in the large-dose remifentanil combined with low-dose naloxone group compared with the other two groups. Previous studies of acute opioid tolerance induced by remifentanil have shown differing
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A
B
Fig. 2. Cumulative morphine consumption (A) and visual analog pain scores (VAS) (B) during 72 postoperative hours. Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group. *P < 0.05, Group LR compared with Group SR and Group LR–LN.
Table 3 Postoperative complications.
0–72 h PONV (No of patients/%) Postoperative complications, n (%) Anastomotic leakage Wound abscess Intraabdominal abscess Chronic pain, n (%)
Group SR (n = 24)
Group LR (n = 24)
Group LR–LN (n = 24)
8 (33.3)
11 (45.8)
4 (16.7)
0 1 1 1
(0) (4.1) (4.1) (4.1)
2 1 2 2
(8.3) (4.1) (8.3) (8.3)
0 0 0 0
Data are presented as no. of patients (%). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group. There were no statistically significant differences among the groups.
results. Guignard and colleagues6 found that patients undergoing major abdominal surgery receiving the higher concentration of remifentanil had higher pain scores postoperatively, and these patients required morphine at an earlier
time and had a higher cumulative morphine consumption over 24 h. Cortinez et al8 failed to demonstrate any kind of acute opioid tolerance in patients undergoing gynecological surgery when the duration of anesthesia was shorter than 90 min. The higher doses and the longer duration of remifentanil were used to explain the discrepancies observed between both studies. In most clinical studies which failed to demonstrate acute opioid tolerance, the dose and duration of infused remifentanil were insufficient or the surgical procedure did not cause sufficient postoperative pain to demonstrate a difference in analgesic consumption.7,8 In our study, we chose the patients undergoing laparotomy, which is one of the most painful surgical procedures. The duration of anesthesia was more than 90 min, and thus confirmed the development of acute opioid tolerance after a large dose of remifentanil. Although we found that anesthesia with large-dose remifentanil would increase postoperative morphine requireActa Anaesthesiologica Scandinavica 59 (2015) 1194–1203
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A
B
Fig. 3. Time until flatus (A) and stools (B). Data are presented as median (horizontal line within the box), interquartile range (upper and lower edges of the boxes), maximum and minimum (upper and lower bars). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group.
Fig. 4. Length of hospital stays among the groups. Data are presented as median (horizontal line within the box), interquartile range (upper and lower edges of the boxes), maximum and minimum (upper and lower bars). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group.
ments, we failed to find an increase in pain scores. The VAS pain scores were comparable in all three groups except during the first 30 min
after surgery. This may either be explained as the development of acute tolerance or hyperalgesia induced by the large-dose remifentanil which would lead to a potential increase in pain scores which was counteracted by an increased PCA morphine utilization. We found that acute opioid tolerance appeared in the large-dose remifentanil group, while it did not occur in the large-dose remifentanil–naloxone group, which may suggest an inhibitory effect of naloxone on acute opioid tolerance. This effect has been observed both in animal experiments13,14,17,25 and in clinical trials.26 Recently, drug combinations of the l receptor antagonist naltrexone or naloxone with oxycodone or buprenorphine have been used to enhance the antinociceptive effect of the opioids and block the development of physical tolerance.27 Several mechanisms of action have been proposed to explain the effects of ultra-low-dose naloxone when coadministered with remifentanil. In animal experiments, naloxone was reported to inhibit microglia activation and superoxide generation, thus protecting neurons from injury. Given that neuronal apoptosis is a pathological process occurring in opioid tolerance, the neuroprotective effect of naloxone may inhibit opioid tolerance development.28 Furthermore, naloxone binds a pentapeptide segment of the scaffolding protein, filamin A, preventing a G-protein coupling switch (Gi/o to Gs) by the l opioid receptor.15 This mechanism of action may explain the inhibition of opioid tolerance perhaps as a result of the desensitization of the antinociceptive opioid system.25 In addition, naloxone acts on toll-like receptor 4, inhibiting neuroinflammation, which is implicated in blocking the development of opioid-induced tolerance.24,29 We also found that, compared with the other two groups, the large-dose remifentanil–naloxone group showed a shortened recovery time for bowel function, which is pivotal for early rehabilitation after surgery.30 Postoperative ileus has been identified as one of the most important causes of patient discomfort, prolonging convalescence and length of hospital stay.31 This indicated that the addition of low-dose naloxone benefited the patients after colorectal surgery by shortening the time for recovery of postoperative
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bowel movement. Interestingly, the mechanism of this action was not related to its opioid-sparing effect by inhibition of acute opioid tolerance, as the morphine consumption was similar to that in the SR group. The most reasonable explanation for this phenomenon is that naloxone as an opioid antagonist can alleviate opioidinduced bowel dysfunction.32,33 There are several limitations in this study. The first limitation is that we did not perform measurements of hyperalgesia such as mechanical detection thresholds using von Frey filaments to evaluate the changes in the threshold value for pain. As a second limitation, we only recruited patients who refused to receive epidural analgesia in this study for an ethical responsibility to achieve better analgesia and recovery, which is prone to introduce selection bias. In conclusion, our findings show that, intraoperative administration of a relatively large dose of remifentanil triggered acute opioid tolerance postoperatively. The use of low-dose naloxone not only prevented acute opioid tolerance, but also improved functional recovery and reduced length of hospital stay after open colorectal surgery when relatively large intraoperative remifentanil doses were administered. The addition of low-dose naloxone to remifentanil-based anesthesia seems to be most beneficial in surgical procedures, where high postoperative pain is expected and enhanced gastrointestinal functional recovery is especially important.
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5. Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000; 93: 409–17. 6. Shin SW, Cho AR, Lee HJ, Kim HJ, Byeon GJ, Yoon JW, Kim KH, Kwon JY. Maintenance anaesthetics during remifentanil-based anaesthesia might affect postoperative pain control after breast cancer surgery. Br J Anaesth 2010; 105: 661–7. 7. Lee LH, Irwin MG, Lui SK. Intraoperative remifentanil infusion does not increase postoperative opioid consumption compared with 70% nitrous oxide. Anesthesiology 2005; 102: 398–402. 8. Cortınez LI, Brandes V, Mu~ noz HR, Guerrero ME, Mur M. No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth 2001; 87: 866–9. 9. Olofsen E, van Dorp E, Teppema L, Aarts L, Smith TW, Dahan A, Sarton E. Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: a mechanism-based pharmacokineticpharmacodynamic modeling study. Anesthesiology 2010; 112: 1417–27. 10. Taylor R Jr, Pergolizzi JV Jr, Porreca F, Raffa RB. Opioid antagonists for pain. Expert Opin Investig Drugs 2013; 22: 517–25. 11. Imasogie NN, Singh S, Watson JT, Hurley D, Morley-Forster P. Ultra low-dose naloxone and tramadol/acetaminophen in elderly patients undergoing joint replacement surgery: a pilot study. Pain Res Manag 2009; 14: 103–8. 12. Gan TJ, Ginsberg B, Glass PS, Fortney J, Jhaveri R, Perno R. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology 1997; 87: 1075–81. 13. Tuerke KJ, Beninger RJ, Paquette JJ, Olmstead MC. Dissociable effects of ultralow-dose naltrexone on tolerance to the antinociceptive and cataleptic effects of morphine. Behav Pharmacol 2011; 22: 558–63. 14. Lin SL, Tsai RY, Shen CH, Lin FH, Wang JJ, Hsin ST, Wong CS. Co-administration of ultralow dose naloxone attenuates morphine tolerance in rats via attenuation of NMDA receptor neurotransmission and suppression of neuroinflammation in the spinal cords. Pharmacol Biochem Behav 2010; 96: 236–45. 15. Wang HY, Friedman E, Olmstead MC, Burns LH. Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor-G protein coupling and Acta Anaesthesiologica Scandinavica 59 (2015) 1194–1203
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Gbetagamma signaling. Neuroscience 2005; 135: 247–6. Crain SM, Shen KF. Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment. Proc Natl Acad Sci USA 1995; 92: 10540–4. Mattioli TA, Milne B, Cahill CM. Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats. Mol Pain 2010; 6: 22. Cepeda MS, Alvarez H, Morales O, Carr DB. Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects. Pain 2004; 107: 41–6. Monitto CL, Kost-Byerly S, White E, Lee CK, Rudek MA, Thompson C, Yaster M. The optimal dose of prophylactic intravenous naloxone in ameliorating opioid-induced side effects in children receiving intravenous patient-controlled analgesia morphine for moderate to severe pain: a dose finding study. Anesth Analg 2011; 113: 834–42. Maxwell LG, Kaufmann SC, Bitzer S, Jackson EV Jr, McGready J, Kost-Byerly S, Kozlowski L, Rothman SK, Yaster M. The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: a double-blind, prospective, randomized, controlled study. Anesth Analg 2005; 100: 953–8. Lin SL, Tsai RY, Tai YH, Cherng CH, Wu CT, Yeh CC, Wong CS. Ultra-low dose naloxone upregulates interleukin-10 expression and suppresses neuroinflammation in morphine-tolerant rat spinal cords. Behav Brain Res 2010; 207: 30–6. Abul-Husn NS, Sutak M, Milne B, Jhamandas K. Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists. Br J Pharmacol 2007; 151: 877–87. Movafegh A, Shoeibi G, Ansari M, Sadeghi M, Azimaraghi O, Aghajani Y. Naloxone infusion and post-hysterectomy morphine consumption: a double-blind, placebo-controlled study. Acta Anaesthesiol Scand 2012; 56: 1241–9.
24. Li Q. Antagonists of toll like receptor 4 maybe a new strategy to counteract opioid-induced hyperalgesia and opioid tolerance. Med Hypotheses 2012; 79: 754–6. 25. Powell KJ, Abul-Husn NS, Jhamandas A, Olmstead MC, Beninger RJ, Jhamandas K. Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats. J Pharmacol Exp Ther 2002; 300: 588–96. 26. Chindalore VL, Craven RA, Yu KP, Butera PG, Burns LH, Friedmann N. Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex. J Pain 2005; 6: 392–9. 27. Hay JL, La Vincente SF, Somogyi AA, Chapleo CB, White JM. Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects. Eur J Pain 2011; 15(3): 293–8. 28. Hu S, Sheng WS, Lokensgard JR, Peterson PK. Morphine induces apoptosis of human microglia and neurons. Neuropharmacology 2002; 42: 829–36. 29. Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR. Evidence that opioids may have toll-like receptor 4 and MD2 effects. Brain Behav Immun 2010; 24: 83–95. 30. Lassen K, Soop M, Nygren J, Cox PB, Hendry PO, Spies C, von Meyenfeldt MF, Fearon KC, Revhaug A, Norderval S, Ljungqvist O, Lobo DN, Dejong CH. Enhanced Recovery After Surgery (ERAS) Group: consensus review of optimal perioperative care in colorectal surgery: enhanced Recovery After Surgery (ERAS) Group recommendations. Arch Surg 2009; 144: 961–9. 31. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg 2000; 87: 1480–93. 32. Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol Res Pract 2014; 2014: 141737. 33. Leppert W. New treatment possibilities for opioid-induced bowel dysfunction. Pain 2013; 154: 1491–2.
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A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery Y. Xiao1, L. Wu2, Q. Zhou1, W. Xiong1, X. Duan1 and X. Huang1 1
Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China Department of Anesthesiology, Cancer Institute and Hospital, National Cancer Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Peking, China 2
Correspondence X. Huang, Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China E-mail: [email protected] Ying Xiao and Linxin Wu have equally contributed to this study. Conflicts of interest The authors have no conflicts of interest. Funding Funded by Guangdong Natural Science Foundation (10151008901000119) and Zhongshan University’s Basic Scientific Research Foundation for Young Teachers Cultivation Project (10ykpy12). Submitted 5 April 2015; accepted 19 April 2015; submission 10 July 2014. Citation Xiao Y, Wu L, Zhou Q, Xiong W, Duan X, Huang X. A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery. Acta Anaesthesiologica Scandinavica 2015 doi: 10.1111/aas.12560
Background: Tolerance to remifentanil during sevoflurane anesthesia may increase postoperative analgesic requirements. Lowdose naloxone not only has been shown to block the development of acute opioid tolerance but also to ameliorate undesired opioidinduced side effects. We hypothesized that naloxone prevents the acute opioid tolerance produced by a large dose of remifentanil, and reduces the incidence of opioid-induced side effects. Methods: Seventy-two patients undergoing open colorectal surgery were randomly assigned to receive intraoperative remifentanil (1) small dose at 0.1 lg/kg/min; (2) large dose at 0.30 lg/kg/ min; or (3) large dose at 0.30 lg/kg/min combined with low-dose naloxone at 0.25 lg/kg/h just after the induction. Cumulative morphine consumption, postoperative pain scores, incidence of opioid-related side effects, time to recovery of bowel function, and length of hospital stay were recorded. Results: Cumulative morphine consumption at 24 h after surgery was higher in the large-dose remifentanil group (28 12 mg) compared with the small-dose remifentanil group (17 12 mg), and large-dose remifentanil–naloxone group (18 9 mg), (P < 0.001). The median time to return of bowel function was shorter in the large-dose remifentanil–naloxone group than the other two groups (P < 0.05). The median length of hospital stay was lower in the large-dose remifentanil–naloxone group (8 [interquartile range: 8–12] days) compared with the small-dose remifentanil group (12 [interquartile range: 9–15] days) and large-dose remifentanil group (12 [interquartile range: 10–13] days), (P < 0.001). Conclusion: Naloxone infusion prevented the acute opioid tolerance, provided a quicker recovery of bowel function, and reduced the length of hospital stay after open colorectal surgery.
Editorial comment: what this article tells us
A large dose of remifentanil during general anesthesia may generate postoperative opioid tolerance. Addition of an ultra-low dose of naloxone can ameliorate this effect, enhance recovery of bowel function, and decrease hospital stay.
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Remifentanil, a potent short-acting opioid analgesic, is widely used in the intraoperative period for its favorable pharmacokinetic characteristics, including the rapid and predictable onset and offset of the analgesic effect with little risk for delayed awakening or respiratory depression after surgery.1 Although considerable evidence suggests that intraoperative infusion of a large-dose remifentanil causes acute opioid tolerance, manifesting as increased postoperative analgesic requirements, the results of clinical trials are controversial.2–8 Naloxone, a selective l-opioid receptor antagonist, frequently used in clinical practice to counter the effects of opioid overdosage,9 has also been used at ultra-low doses in combination with opioids to enhance the analgesic effect,10–12 block the development of acute opioid tolerance,13–17 and decrease the incidence of opioidinduced side effects.18–20 Though all of these applications remain less well defined and disputable, a low-dose naloxone infusion may have a potential as adjuvant in painful surgical procedures where the anticipated opioid requirement is high. Among the adverse effects of opioids, the most clinically important for abdominal surgery is bowel dysfunction. However, there are few clinical trials demonstrating whether ultra-low-dose naloxone can prevent opioid-induced delay in bowel motility without affecting analgesia. A large number of studies have shown that naloxone has some relation with opioid-induced hyperalgesia and tolerance.21–24 However, there are no clinical studies regarding the effect of opioid antagonists on remifentanil-induced tolerance. In this study, we hypothesized that perioperative infusion of low-dose naloxone could prevent acute opioid tolerance induced by large dose of remifentanil, manifesting as decrease postoperative morphine consumption, and provide quicker recovery of bowel function and thus reduce the length of hospital stay after open colorectal surgery. Methods This prospective, randomized, double-blind, single-center study was approved by the Institutional Ethics committee (IRB NO. [2011]194, 30 June 2011)and written informed consent was
obtained from all patients. The trial was registered in the Chinese Clinical Trial Registry 201108-11 (Identifier : ChiCTR-TRC-11001461). Consecutive adult patients who were scheduled to undergo open colorectal surgery and refused to receive epidural analgesia were enrolled. The study included patients between the age 18 and 65 years, and with an ASA physical status I–III. Exclusion criteria were consent refusal, obesity (body mass index ≥ 30 kg/m2), pregnancy, and contraindications to any drug used during general anesthesia. We also excluded patients who needed an enterostomy, had previous chronic pain, received preoperative opioids within 12 h of surgery, were unable to understand the patient-controlled analgesia device, or participated in another research project in the previous 30 days. Postoperative exclusion criteria included reoperation, excessive bleeding, and prolonged ventilation (> 12 h). During the preoperative anesthetic evaluation in the evening before surgery, patients were instructed how to use the PCA pump (Pain management provider, Abbott, USA), a fourpoint verbal rating scale for pain assessment (0 = no pain, 1 = slight pain, 2 = moderate pain, 3 = intense or severe pain)4 and the 100 mm visual analog scale (VAS) for pain evaluation, with 0 mm identifying no pain and 100 mm being defined as the worst imaginable pain. All patients were unpremedicated and fasted for at least 8 h. Baseline heart rate and mean arterial pressure were defined as the mean of the two lowest measurements recorded during a 3- to 5-min interval just before induction of anesthesia. General anesthesia was induced with propofol (1.5 mg/kg), remifentanil (1 lg/kg), and cisatracurium (0.2 mg/kg) and was maintained with sevoflurane and remifentanil to target a Narcotrend (Monitor Technique, Hannover Medical School, Germany) stage between D2~E1, which means deep sedation. Before admission to the operating room, the patients were randomly assigned in a 1 : 1 : 1 ratio for three parallel arms using a concealed allocation approach (computer-generated codes) with sealed envelopes. There was no stratification or block randomization. Patients and the study investigators performing pain assessment were blinded to group allocation during the
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entire study period, except for the anesthesiologist in charge of the patient. The three treatment groups were as follows: 1. Small-dose remifentanil group (SR): Patients were given an infusion of remifentanil at a constant rate of 0.1 lg/kg/min throughout the operation while sevoflurane was maintained at 0.8 minimum alveolar concentration (MAC). If the Narcotrend (NT) stage was above D2 for at least 1 min or clinical signs of inadequate anesthesia such as patient movement, coughing, tearing, or sweating appeared, the inspired sevoflurane concentration was increased stepwise by 1% increments. If the NT stage was already in the given range, but the systolic arterial pressure or heart rate exceeded baseline values by 20%, nicardipine or esmolol was given. 2. Large-dose remifentanil group (LR): Patients were given an intraoperative infusion of remifentanil at an initial rate of 0.3 lg/kg/min and subsequently increased stepwise by 0.05 lg/kg/min increments if insufficient anesthesia was indicated while sevoflurane was constantly maintained at an end-tidal concentration of 0.6 MAC. 3. Large-dose remifentanil–naloxone group (LR– LN): Patients were given an intraoperative infusion of naloxone at a rate of 0.25 lg/kg/ h, an amount that reduces the incidence of opioid-induced side effects in postoperative patients receiving IV morphine with PCA.18– 20 Anesthesia maintenance was the same as in group LR. The naloxone infusion was continued for 72 h postoperatively and then PCA was discontinued. If hypotension (MAP < 60 mmHg) or bradycardia (HR < 45 beats/min) occurred more than 5 min, the patient was treated with ephedrine 10 mg or atropine 0.5 mg. Muscle paralysis was maintained with bolus doses of cisatracurium guided by train-of-four monitoring. Thirty minutes before the end of surgery, a 0.15 mg/kg bolus dose of morphine was administered intravenously. At skin closure, sevoflurane was discontinued while remifentanil was maintained at 0.1 lg/kg/min, and residual neuromuscular blockade was antagonized with 40 lg/kg neostigmine and 20 lg/kg atropine IV. Patients in
all groups received a preemptive antiemetic drug (0.25 mg palonosetron IV) 10 min before the end of the operation. Extubation was performed when the patient was able to open the eyes and take deep breaths on verbal command. Remifentanil infusion was stopped after tracheal extubation. Patients were transferred to the post-anesthesia care unit (PACU) within 10 min after tracheal extubation. They remained in the unit for at least 2 h and were given oxygen via a facemask at a rate of 5 l/min throughout this period. Pain was evaluated for the first 15 min after extubation with a behavioral score (0 = calm patient with no verbal or behavioral manifestation of pain, 1 = behavioral or verbal expression of pain, 2 = intense behavioral or verbal manifestation [crying or extreme agitation]).4 Postoperative pain was initially treated with morphine by nurses who were unaware of the patient’s group assignment when the patient’s behavioral pain score was more than 0 or the verbal rating scale score was more than 1. Boluses of morphine (3 mg) were given at 5min intervals until the patient was calm and with no verbal or behavioral manifestation of pain. However, morphine administration was discontinued when the four-point sedation score (0 = patient fully awake, 1 = patient somnolent and responsive to verbal commands, 2 = patient somnolent and responsive to tactile stimulation, 3 = patient asleep and responsive to painful stimulation) was greater than 2 or the respiratory rate was < 12 breaths/min. Patients were connected to a PCA device just before discharge from the PACU. The pump was set to deliver 1 mg morphine as bolus dose with an 8-min lockout interval, and no background infusion was provided. The PCA regimen was continued for 72 h after tracheal extubation. Values from all routine anesthetic monitors were recorded at 5-min intervals during surgery. Duration of anesthesia and surgery were recorded. Intraoperative variables included remifentanil dose and consumption of ephedrine, atropine, nicardipine, or esmolol. In the PACU, patients were observed by nurses who were blinded to the group assignment. The time interval from discontinuation of remifentanil to the first requirement of morphine and the total amount of morphine titration was also recorded. Acta Anaesthesiologica Scandinavica 59 (2015) 1194–1203
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Pain intensity at 30 min and 1 h after extubation was assessed by the patients utilizing a visual analog scale. Cumulative morphine consumption was also recorded. In the surgical ward, the cumulative consumption of morphine given by PCA and the pain intensity using the VAS were recorded at 24 h, 48 h, and 72 h after surgery. The time to return of bowel function (repeated passage of flatus and stools), nausea and vomiting requiring treatment with ondansetron, and analgesic technique-related side effects, especially respiratory depression were also recorded. Analgesicrelated postoperative respiratory depression in the surgical ward was defined by the combination of a sedation score greater than 1 and a respiratory rate < 10 breaths/min. Postoperative morbidity was assessed prospectively using defined criteria. Length of hospital stay was assessed from the start of surgery. All patients were evaluated for residual peri-incisional postoperative pain 3 months after surgery. Statistical analysis The initial postoperative 24-h morphine consumption was considered as our primary endpoint. The secondary endpoints were VAS pain scores, the time for the first morphine demand, cumulative morphine consumption over 72 h, and postoperative recovery parameters and complications. Our experience indicated that morphine consumption over the initial postoperative 24 h after major abdominal surgery is 30 15 mg. A sample size estimate indicate that 24 patients in each group would give a power of 80% at an a-level of 0.05 for detecting a difference in morphine consumption of at least 40%. The study size was thus prospectively set to 75 patients (25 patients/group). Duration of surgery and anesthesia, intraoperative remifentanil consumption, and morphine titration in the PACU were analyzed by oneway analysis of variance (ANOVA). Cumulative morphine consumption and VAS scale were analyzed by repeated-measures ANOVA for inter-group comparison. The chi-square test or Fisher’s exact test was used to compare the relative frequency of type of surgery, intraoperative atropine, ephedrine, nicardipine and esmolol use, requirement for antiemetic drugs, and
incidence of postoperative complications [postoperative nausea and vomiting (PONV) anastomotic leakage, wound abscess, intraabdominal abscess, and incidence of chronic pain]. Because the time to first morphine requirement, the time until return of bowel function and the length of hospital stay were not normally distributed (asymmetric distribution), the Kruskal–Wallis H test was used. For post hoc comparisons, we used the Bonferroni test, as needed. Statistical analysis was performed with SPSS software v. 17.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered statistically significant. Results During the time period, August 2011 until August 2013, 75 patients were enrolled, and three patients were excluded from analysis because of early reoperation for postoperative bleeding (n = 1), massive bleeding intraoperatively, and patients transferred to the SICU requiring postoperative mechanical ventilation (n = 2). Seventy-two patients were analyzed (Fig. 1). The groups did not differ regarding demographic data or surgical characteristics (Table 1). Anesthetic characteristics and postoperative care data are shown in Table 2. Intraoperative remifentanil consumption was twofold higher in the LR and LR–LN groups compared with the SR group (P < 0.001). Intraoperative atropine use was significantly higher in the LR group (16.7%) compared with the other two groups (P = 0.031), whereas there were no significant differences in ephedrine, nicardipine, or esmolol utilization (Table 2). Regarding time to first morphine demand, patients in the LR group requested morphine by titration significantly earlier (29.5 [20.0–39.5] min) than those in the SR group (39.0 [33.5–50] min) and the LR–LN group (40.0 [35.3–50] min; P = 0.004). The morphine dose given by titration in the PACU was larger in the LR group than in the SR and LR– LN group (Table 2). The VAS scores were higher in the LR group than the SR and LR–LN groups at the first 30 min after surgery, but did not differ thereafter, while cumulative morphine consumption was significantly higher in the LR group than the other two groups (Fig. 2).
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Enrollment
Assessed for eligibility (n = 206) at the first affiliated Hospital of Sun Yat-sen
Excluded (n = 131) ♦ Not meeting inclusion criteria (n = 111) ♦ Declined to participate (n = 20)
Randomized (n = 75)
Allocation
Allocated to SR (n = 25)
Allocated to LR (n = 25)
Allocated to LR - LN (n = 25)
Excluded (n = 1)
Excluded (n = 1)
Excluded (n = 1)
Reoperation postoperatively
Mechanical ventilation required postoperatively
Mechanical ventilation required postoperatively
Follow-Up 0 lost to follow-up
0 lost to follow-up
0 lost to follow-up
Analysis 24 included in analysis
24 included in analysis
24 included in analysis
Fig. 1. Flow diagram of patients in this study.
Postoperative complications are presented in Table 3. Although more patients in the LR group experienced PONV, there was no significant difference in the incidence of PONV among the groups (P = 0.094). The groups did not differ in postoperative complications including anastomotic leakage, wound abscesses and intraabdominal abscesses (Table 3). Two patients had residual peri-incisional postoperative pain 3 months after surgery in the LR group, while
one patient developed chronic pain in the SR group. The median time until flatus was shorter in the LR–LN group than in the other two groups, (P = 0.013 and P = 0.003 each, Fig. 3). The median time until stools was also shorter in the LR– LN group than the other two groups, (P = 0.008 and P = 0.003 each, Fig. 3). The median length of hospital stay was lower in the LR–LN group (8 [interquartile range: 8– Acta Anaesthesiologica Scandinavica 59 (2015) 1194–1203
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Table 1 Demographic and surgical characteristics.
Age, years Sex, M/F Height, m Weight, kg ASA Score, I/II/III Type of surgery (%) Left-side colectomy Right-side colectomy Dixon Duration of surgical procedure, min Duration of anesthesia, min
Group SR (n = 24)
Group LR (n = 24)
Group LR–LN (n = 24)
52 (25–65) 13/11 165 9 63 13 8/13/3
49 (25-65) 12/12 165 7 59 10 5/17/2
50 (23-64) 12/12 164 7 59 11 7/14/3
5 (21) 16 (67) 3 (13) 256 84 292 85
7 (29) 15 (63) 2 (8) 249 70 290 74
8 (33) 14 (58) 2 (8) 244 70 278 64
Values are mean (range), no. of patients, mean SD, or number (%). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group. There were no statistical differences between the Groups regarding duration of surgical procedure or anesthesia.
Table 2 Anesthetic characteristics and postoperative care data.
Remifentanil dose (mg) Ephedrine uses (No of patients/%) Atropine uses (No of patients/%) Nicardipine uses (No of patients/%) Esmolol uses (No of patients/%) Time to first postoperative morphine demand (min) Morphine titration in PACU (mg)
Group SR (n = 24)
Group LR (n = 24)
1.8 0.7 6 (25.0) 0 (0) 5 (20.8) 3 (12.5) 39 (34-50) 93
5.3 1.8* 4 (16.7) 4 (16.7)* 0 (0) 0 (0) 30 (20-40)* 10 2
Group LR–LN (n = 24) 5.1 2.1* 6 (25.0) 0 (0)† 4 (25) 0 (0) 40 (35-50)† 9 2†
Values are presented as mean SD, median (interquartile range), or number of patients (%). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group. *P < 0.05 compared with small-dose remifentanil group; †P < 0.05 compared with large-dose remifentanil group. PACU, post-anesthesia care unit.
11.5] days) compared with the SR group (12 [interquartile range: 9.3–14.5] days) and the LR group (12 [interquartile range: 10–13] days) (Fig. 4). Discussion This prospective, randomized study confirmed that remifentanil given during inhalational anesthesia was associated with increased postoperative morphine consumption after major abdominal surgery: the larger the remifentanil dose, the larger the morphine requirement by titration. Patients who received a large dose of remifentanil, all requested morphine by titration and significantly earlier than patients who received a small dose of remifentanil. Most
importantly, we confirmed our hypothesis that intraoperative administration of low-dose naloxone eliminated the increased morphine consumption that resulted from a large dose of remifentanil. Patients who received a large dose of remifentanil combined with low-dose naloxone had significantly less postoperative morphine requirements than those receiving the large dose of remifentanil only; in fact, the morphine dose was comparable to that of the small-dose remifentanil patients. The time to return to normal gastrointestinal function and length of hospital stay was also shortened in the large-dose remifentanil combined with low-dose naloxone group compared with the other two groups. Previous studies of acute opioid tolerance induced by remifentanil have shown differing
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A
B
Fig. 2. Cumulative morphine consumption (A) and visual analog pain scores (VAS) (B) during 72 postoperative hours. Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group. *P < 0.05, Group LR compared with Group SR and Group LR–LN.
Table 3 Postoperative complications.
0–72 h PONV (No of patients/%) Postoperative complications, n (%) Anastomotic leakage Wound abscess Intraabdominal abscess Chronic pain, n (%)
Group SR (n = 24)
Group LR (n = 24)
Group LR–LN (n = 24)
8 (33.3)
11 (45.8)
4 (16.7)
0 1 1 1
(0) (4.1) (4.1) (4.1)
2 1 2 2
(8.3) (4.1) (8.3) (8.3)
0 0 0 0
Data are presented as no. of patients (%). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group. There were no statistically significant differences among the groups.
results. Guignard and colleagues6 found that patients undergoing major abdominal surgery receiving the higher concentration of remifentanil had higher pain scores postoperatively, and these patients required morphine at an earlier
time and had a higher cumulative morphine consumption over 24 h. Cortinez et al8 failed to demonstrate any kind of acute opioid tolerance in patients undergoing gynecological surgery when the duration of anesthesia was shorter than 90 min. The higher doses and the longer duration of remifentanil were used to explain the discrepancies observed between both studies. In most clinical studies which failed to demonstrate acute opioid tolerance, the dose and duration of infused remifentanil were insufficient or the surgical procedure did not cause sufficient postoperative pain to demonstrate a difference in analgesic consumption.7,8 In our study, we chose the patients undergoing laparotomy, which is one of the most painful surgical procedures. The duration of anesthesia was more than 90 min, and thus confirmed the development of acute opioid tolerance after a large dose of remifentanil. Although we found that anesthesia with large-dose remifentanil would increase postoperative morphine requireActa Anaesthesiologica Scandinavica 59 (2015) 1194–1203
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A
B
Fig. 3. Time until flatus (A) and stools (B). Data are presented as median (horizontal line within the box), interquartile range (upper and lower edges of the boxes), maximum and minimum (upper and lower bars). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group.
Fig. 4. Length of hospital stays among the groups. Data are presented as median (horizontal line within the box), interquartile range (upper and lower edges of the boxes), maximum and minimum (upper and lower bars). Group SR, small-dose remifentanil group; Group LR, large-dose remifentanil group; Group LR–LN, large-dose remifentanil–naloxone group.
ments, we failed to find an increase in pain scores. The VAS pain scores were comparable in all three groups except during the first 30 min
after surgery. This may either be explained as the development of acute tolerance or hyperalgesia induced by the large-dose remifentanil which would lead to a potential increase in pain scores which was counteracted by an increased PCA morphine utilization. We found that acute opioid tolerance appeared in the large-dose remifentanil group, while it did not occur in the large-dose remifentanil–naloxone group, which may suggest an inhibitory effect of naloxone on acute opioid tolerance. This effect has been observed both in animal experiments13,14,17,25 and in clinical trials.26 Recently, drug combinations of the l receptor antagonist naltrexone or naloxone with oxycodone or buprenorphine have been used to enhance the antinociceptive effect of the opioids and block the development of physical tolerance.27 Several mechanisms of action have been proposed to explain the effects of ultra-low-dose naloxone when coadministered with remifentanil. In animal experiments, naloxone was reported to inhibit microglia activation and superoxide generation, thus protecting neurons from injury. Given that neuronal apoptosis is a pathological process occurring in opioid tolerance, the neuroprotective effect of naloxone may inhibit opioid tolerance development.28 Furthermore, naloxone binds a pentapeptide segment of the scaffolding protein, filamin A, preventing a G-protein coupling switch (Gi/o to Gs) by the l opioid receptor.15 This mechanism of action may explain the inhibition of opioid tolerance perhaps as a result of the desensitization of the antinociceptive opioid system.25 In addition, naloxone acts on toll-like receptor 4, inhibiting neuroinflammation, which is implicated in blocking the development of opioid-induced tolerance.24,29 We also found that, compared with the other two groups, the large-dose remifentanil–naloxone group showed a shortened recovery time for bowel function, which is pivotal for early rehabilitation after surgery.30 Postoperative ileus has been identified as one of the most important causes of patient discomfort, prolonging convalescence and length of hospital stay.31 This indicated that the addition of low-dose naloxone benefited the patients after colorectal surgery by shortening the time for recovery of postoperative
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bowel movement. Interestingly, the mechanism of this action was not related to its opioid-sparing effect by inhibition of acute opioid tolerance, as the morphine consumption was similar to that in the SR group. The most reasonable explanation for this phenomenon is that naloxone as an opioid antagonist can alleviate opioidinduced bowel dysfunction.32,33 There are several limitations in this study. The first limitation is that we did not perform measurements of hyperalgesia such as mechanical detection thresholds using von Frey filaments to evaluate the changes in the threshold value for pain. As a second limitation, we only recruited patients who refused to receive epidural analgesia in this study for an ethical responsibility to achieve better analgesia and recovery, which is prone to introduce selection bias. In conclusion, our findings show that, intraoperative administration of a relatively large dose of remifentanil triggered acute opioid tolerance postoperatively. The use of low-dose naloxone not only prevented acute opioid tolerance, but also improved functional recovery and reduced length of hospital stay after open colorectal surgery when relatively large intraoperative remifentanil doses were administered. The addition of low-dose naloxone to remifentanil-based anesthesia seems to be most beneficial in surgical procedures, where high postoperative pain is expected and enhanced gastrointestinal functional recovery is especially important.
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