Average 24-hour morphine consumption was 1.41 ± 0.08 mg/kg/d and ranged from 1.13 ± 0.22 to 1.64 ± 0.63 mg/kg/d across cohorts (Table 3). Female subjects consumed significantly more morphine than males (1.57 ± 0.10 vs 1.17 ± 0.12 mg/kg/24 h, P < 0.025). However, observing each gender individually, we found no significant difference in 24-hour morphine consumption as a function of naloxone infusion dose cohort (Table 4).
Whereas the overall average plasma morphine level was 31.8 ± 2.3 ng/mL (Table 3), interindividual variability was moderately high with morphine levels ranging between a minimum of 3.52 and a maximum of 172 ng/mL (Fig. 2). However, >75% of measured plasma morphine levels decreased between 16 and 46 ng/mL, whereas >90% ranged between 10.2 and 61.6 ng/mL. Comparing plasma morphine levels between responders and treatment failures, we found that at the time the second plasma morphine level was measured (>12 hours after initiation of PCA and naloxone infusion), mean plasma morphine levels did not differ significantly between the 2 groups (34.7 ± 5.1 vs 29.2 ± 3.2 ng/mL for responders and treatment failures, respectively). In addition, the slopes of the lines correlating morphine plasma level and morphine consumption were approximately equal to zero, suggesting that morphine level was generally stable and independent of morphine consumption for patients in both groups. Finally, beyond the initial postoperative period, the highest plasma morphine level measured in any patient who failed therapy was 41 ng/mL.
Comparing pain scores over the first 24 hours after surgery in those patients who did not fail treatment, we found that females reported significantly higher pain scores than males at 8, 20, and 24 hours after the start of the naloxone infusion (4.9 ± 0.5 vs 3.4 ± 0.5, P = 0.039, 4.7 ± 0.4 vs 2.9 ± 0.6, P = 0.023, and 5.0 ± 0.5 vs 2.5 ± 0.7, P = 0.002, respectively) (Fig. 3). However, we did not observe any difference in analgesia in female patients over time as the naloxone infusion rate was increased. In male patients, pain scores trended lower over time in the low- and moderate-dose infusion rate groups, but not in the high-dose group. This difference was statistically significant at 24 hours, but this observation is limited by the fact that pain scores were obtained on less than half of all patients at this time point.
In this prospective, dose finding study in children and adolescents being treated with IV PCA morphine after major surgery, we found that a naloxone infusion of ≥1 μg/kg/h significantly reduced, but did not eliminate, the incidence of opioid-induced side effects, and that this infusion rate was more effective than lower doses studied. We also found that patients who failed therapy generally had plasma naloxone and morphine levels that were comparable to those who had good symptom relief. This finding suggests that a specific naloxone plasma level is not correlated with therapeutic success or failure and should not be a target of therapy. Finally, comparing all doses studied here, we could not demonstrate either an opioid-sparing effect or a significant increase in opioid consumption in our study patients.
Opioids are the analgesics most frequently prescribed for the management of moderate to severe pain and, regardless of the method of administration, produce undesired side effects. Some of these side effects, such as nausea, vomiting, and pruritus are common and often so debilitating that patients would rather be in pain than experience them. Crain and Shen6 in a series of laboratory experiments demonstrated that when administered in combination with opioids, ultralow-dose opioid antagonists may decrease opioid-induced side effects, such as hyperalgesia and tolerance, and improve pain control. Possible explanations for this effect include the hypothesis that at very low doses, opioid antagonists inhibit μ-opioid receptor excitatory G-protein complexes (Gs) while leaving the inhibitory G-protein receptors (Gi) available for pain control.6,7 Subsequently, consistent with these results, Gan et al.1 showed that administration of a naloxone infusion of 0.25 μg/kg/h in combination with IV PCA morphine attenuated opioid-induced side effects and significantly reduced 24-hour opioid consumption in women after abdominal hysterectomies. However, results from other trials have been more variable, with some showing no improvement. From our review of the literature, we believe that one possible explanation for the failure of opioid antagonist prophylaxis in these studies may relate to how the opioid antagonist was prepared and administered. In some trials in which the antagonist was ineffective, morphine and naloxone were mixed together in saline and delivered via a PCA pump.8–10 Thus, patients received only small doses of naloxone intermittently when the PCA pump was triggered. How much naloxone was administered and how long it remained at its effector sites varied within and between patients. However, in studies in which an antagonist was effective, the opioid antagonist was often either a long-acting drug, such as nalmefene,11 or a shorter-acting drug, naloxone, administered as an independent, continuous infusion as was done here.1,2 Of note, however, opioid sparing has been inconsistently found even when the antagonist has been administered continuously.
In our previous prospective study, a continuous 0.25 μg/kg/h naloxone infusion significantly ameliorated pruritus and, to a lesser degree, nausea and vomiting in two-thirds of the children and adolescents studied.2 Why it failed in one-third of patients, however, was unclear. Because we did not know whether a higher or lower infusion rate might be more effective or might, conversely, be unsuccessful, we undertook this dose finding study. We found that plasma naloxone levels increased in a linear fashion with increasing infusion rate, and that naloxone infusion rates ≥1 μg/kg/h reduced the treatment failure rate to <10%. Moreover, patients who failed therapy had comparable or higher plasma naloxone levels than those levels measured in patients who did not fail treatment, suggesting that a strategy to target IV infusions to achieve an effective plasma level would fail.
Other investigators have reported side effect amelioration at naloxone doses as low as 0.006 to 0.065 μg/kg/h, with worsening of analgesia at higher doses.8,9,12 Although we also found side effect amelioration at lower doses in our study, higher doses (≥1 μg/kg/h) were more consistently effective. A possible explanation for these different results may simply be related to how IV PCA was provided in this study. Specifically, all pediatric patients in our institution are treated with a continuous basal opioid infusion. The use of a continuous infusion may be associated with increased total opioid consumption13 as well as opioid-related side effects including respiratory depression.14–16 Although the use of a continuous basal opioid infusion is not universal in pediatric pain management, it is more frequently used2,14,17 than in adult practice.1,8,9,12,16 Our findings that a higher naloxone infusion rate more effectively reduced pruritus in children receiving basal/bolus IV PCA than the lower doses reported to be effective in adult patients receiving bolus-only PCA are similar to those reported in a small pilot study of patients with sickle cell anemia who received morphine via continuous infusion in combination with naloxone.18
Maxwell et al.2 found in their placebo-controlled trial that low-dose naloxone was more effective in ameliorating pruritus than nausea and vomiting. Our results support this. Indeed, in our study, increasing the naloxone infusion rate did not affect the overall incidence of gastrointestinal side effects as opposed to pruritus. This may be explained in part by the fact that pruritus is a more purely opioid-related side effect than nausea and vomiting. Postoperative nausea and vomiting are due only in part to the impact of opioids on central nervous system vomiting centers and gut motility.19 After surgery, other factors including the release of neurogenic, hormonal, inflammatory, and pharmacologic mediators can also contribute to disturbed gastrointestinal motility.20 As a result, nausea and vomiting may not be effectively reversed by opioid antagonism alone and will require, as in our treatment algorithm, other antiemetics, such as serotonin (5-HT3) receptor antagonists and/or antihistamines.
Although we did find moderate variability in plasma morphine levels between patients, success or failure of low-dose naloxone could not be explained by these differences. Plasma morphine levels ranged between a minimum of 3.52 and a maximum of 172 ng/mL, and >90% of levels ranged between 10.2 and 61.6 ng/mL, well within the range reported to be therapeutic in patients during or after surgery (between 10 and 65 ng/mL).21–23 However, levels were comparable between patients who failed therapy and those patients who achieved symptom control. Only 1 patient who developed intractable symptoms demonstrated an increased plasma morphine level (83.1 ng/mL). However, that level was obtained within 1.5 hours of the completion of surgery, at a time when the patient may have been in the midst of being “loaded” with opioid. A subsequent level was almost 4-fold lower and consistent with levels measured in other patients who had consumed similar amounts of morphine, suggesting that a diminished capacity to metabolize opioid was not the cause of treatment failure in this case.
In our initial data analysis, we did observe a trend toward increased opioid consumption as naloxone infusion rate increased. Further examination of our data suggested that this finding was attributable in part to gender-based differences within cohorts. Therefore, we next focused on our female patients because they were our largest and most homogeneous population subgroup. Combining naloxone infusion cohorts into low, moderate, and high infusion rate groups, we found that total daily opioid consumption did not increase significantly with increasing naloxone infusion rate in our female subjects. Consumption varied by only 7% between moderate- and high-dose naloxone groups and by only 3% between low- and high-dose groups. Thus, although this study was not designed or powered to detect whether opioid sparing did occur, this result suggests that little if any opioid sparing could have occurred in the cohorts receiving the lowest naloxone infusion rates. Similarly, at the higher infusion rates, we did not observe a need for significantly higher opioid doses to combat opioid antagonism. These findings are similar to those reported by Darnell et al.24 who studied low-dose naloxone infusions in combination with fentanyl infusions in critically ill children in an intensive care unit setting and did not observe a difference in opioid consumption.
Interestingly, however, we did observe a significant difference in 24-hour opioid consumption in female compared with male study participants. While this finding may be gender-based, it may also reflect unappreciated differences between the patients enrolled in this study, or may be related to differences in the distribution of surgical procedures between female and male subjects. Although we did not find a significant association between type of surgery and opioid consumption, it is important to note that a larger percentage of female as compared with male patients underwent posterior spinal fusion repair. It is possible that severity of pain varied between the 2 procedures over the course of the observation period and this could have affected cumulative opioid consumption.
In addition to higher opioid consumption, female subjects also reported significantly higher pain scores than male subjects at multiple times during the observation period. However, we did not observe any differences over time in analgesia in female patients as a function of naloxone infusion rate. In male patients, however, pain scores did trend lower over time in the low and moderate infusion rate groups, but not in the high-dose group. Whether this association, which is suggestive of a differential sensitivity to low-dose opioid antagonism between males and females, would achieve significance if a larger, more homogeneous group of male postoperative patients was studied is unknown.
Although we cannot be certain that gender was, or was not, a critical factor in these observed differences, it has been reported that females may demonstrate increased pain sensitivity compared with males.25 Furthermore, gender-related differences in analgesic sensitivity and opioid consumption have also been described.26 A possible explanation for gender-related differences in pain perception involves sex hormone variability.27 In this study, few, if any, prepubescent subjects were enrolled. Thus, hormonal differences may have affected our findings. Finally, it should be noted that in other studies, differences between male and female subjects have also been related to differences in treatment regimen. For example, some studies suggest that women experience better pain relief than men in response to butorphanol, a weak μ agonist, but strong κ agonist.28 Focusing on μ agonists, such as morphine, Chia et al.29 reported that female patients had a lower postoperative opioid requirement, whereas others have concluded that females experience more intense postoperative pain and require more opioid to experience a similar degree of analgesia.30,31
This study has several limitations. Because it was primarily designed to be a dose finding study, sample groups at each infusion rate tended to be small, nonhomogeneous, and of variable size. Hence, we could not always discern differences between individual groups and instead had to evaluate dose ranges to increase group size and power. Even so, group makeup may have limited our ability to discern statistical significance in some settings. For example, although our female population was very homogeneous in terms of type of surgery, male patients were divided almost evenly between pectus surgery and spine surgery, which limited our ability to clearly distinguish differences based on gender versus surgery performed.
In addition, intraoperative analgesic and antiemetic management was not standardized across patients. This approach may have resulted in differences in early opioid consumption and side effect profiles. However, in general, side effect management failure occurred >8 hours after institution of IV PCA and naloxone, at a time when patients were receiving a standardized pain and side effect management regimen.
It is also possible that unrecognized differences in concentrations of morphine's active metabolite morphine-6-glucuronide may have had a role in the differences in analgesia or side effect profiles observed. Given the limitations in the amount of blood that could be obtained from our study subjects, we were unable to measure plasma morphine metabolites along with plasma morphine, naloxone, and naloxone metabolites. Therefore, we chose to focus primarily on naloxone's primary metabolite, naloxone-3-glucuronide, because we were concerned that its presence might affect our observed response. When administered enterally, naloxone-3-glucuronide has been shown to act as an active metabolite, reversing morphine-associated delays in gastrointestinal transit time.32,33 Hence, differences in naloxone metabolism related to genetic polymorphisms could have had a role in explaining the variable responses observed among patients. However, we found that plasma naloxone-3-glucuronide levels were below the limit of quantification in all patients studied, making this possibility unlikely.
A number of side effects that are associated with opioid administration, such as urinary retention, constipation, development of tolerance, and respiratory depression could not be evaluated in this study. Given the nature of the surgery performed in our study population, the majority of our patients had bladder catheters and poor bowel function in the observational immediate postoperative period. Additionally, because patients were treated with IV therapy for only 2 to 3 days, we could not discern the development of tolerance. Finally, our study sample size was too small to observe any difference in the development of respiratory depression, an event that occurs rarely in our clinical population.
In conclusion, although some patients achieved symptom relief at all doses studied, we found that naloxone infusion rates ≥1 μg/kg/h significantly reduced, but did not eliminate, the incidence of opioid-induced side effects, primarily pruritus, in children and adolescents after major surgery. This effect was not associated with a significant increase in opioid consumption or impairment of analgesia. Patients who failed therapy generally had plasma naloxone and morphine levels that were comparable to those who had good symptom relief, suggesting that absolute plasma drug levels do not have a prominent role in treatment failure.
Name: Constance L. Monitto, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Constance L. Monitto has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Sabine Kost-Byerly, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Sabine Kost-Byerly has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Elizabeth White, RN.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Elizabeth White has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Carlton K. K. Lee, PharmD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Carlton Lee has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Michelle A. Rudek, PharmD, PhD.
Contribution: This author helped design the study and analyze the data.
Attestation: Michelle A. Rudek has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Carol Thompson, MS, MBA.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Carol Thompson has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Myron Yaster, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Myron Yaster has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Peter J. Davis, MD.
The Importance of FAER Funding to Career Development.
When I finished my residency/fellowship in pediatric anesthesia and critical care medicine (1981), newborns undergoing surgery were anesthetized with paralysis, oxygen, and a “whiff” of vapor. We weren't cruel; rather, the newborn undergoing emergency surgery was thought to be akin to the gunshot wound to the chest, because of the widely held beliefs that the newborn could not hemodynamically tolerate anesthesia and did not experience pain. I was sure that there must be an alternative, and based on the adult work of Ted Stanley and a preliminary report by George Gregory in the newborn, thought that high-dose fentanyl anesthesia might be the answer. But was it safe and would it work in the newborn? Using a FAER grant and under the guidance of my mentor, Dr. Richard Traystman, I studied the hemodynamic and central nervous system effects of high-dose fentanyl alone and in combination with other anesthetic agents (nitrous oxide, ketamine, barbiturates) in a newborn lamb model. These studies led to several discoveries and ultimately helped change how anesthesia is delivered to newborn infants today. Furthermore, it was also clear that pain, anxiety, and discomfort (both physical and psychological) were not limited to the newborn and did not begin and end with the induction and conclusion of surgery. This understanding helped launch my academic career and allowed me to start the pediatric pain service and set up a research laboratory at the Johns Hopkins University, which have served as the source of extensive clinical and translational research as well as practice policy. None of this would have been possible without my FAER starter grant. —Myron Yaster, MD.
While also a pediatric anesthesiologist with an interest in pediatric acute pain management, my FAER Research Starter grant focused on molecular mechanisms of cachexia. The goal of the research was to identify candidate genes responsible for the development of cachexia in a murine cancer cachexia model. At the time that this work was undertaken in 1998, cDNA expression arrays were just being developed and the human genome had not been sequenced. How times have changed! Receipt of a FAER grant sent me forward on a path that has allowed me to expand my laboratory skills with a focus on molecular biology, genomics, and epigenetics at a time when these disciplines and their relevance to clinical practice have undergone a dramatic transformation. —Constance L. Monitto, MD.
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© 2011 International Anesthesia Research Society
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