Published online April 14, 2008
PEDIATRICS Vol. 121 No. 5 May 2008, pp. e1363-e1371 (doi:10.1542/peds.2007-1468)
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ARTICLE

Effect of Low-Dose Naloxone Infusion on Fentanyl Requirements in Critically Ill Children

Cindy Maria Darnell, MDa, Jennifer Thompson, MD, LCDRb, Daniel Stromberg, MDa, Lonnie Roy, PhDc and Paul Sheeran, MDa

a Department of Pediatrics, University of Texas Southwestern, Dallas, Texas
b Naval Medical Center, Portsmouth, Virginia
c Children's Medical Center, Dallas, Texas


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Sedating critically ill patients often involves prolonged opioid infusions causing opioid tolerance. Naloxone has been hypothesized to limit opioid tolerance by decreasing adenylate cyclase/cyclic adenosine monophosphate activation. The study purpose was to investigate the effect of low-dose naloxone on the maximum cumulative daily fentanyl dose in critically ill children.

METHODS. We conducted a double-blinded, randomized, placebo-control trial from December 2002 through July 2004 in a university PICU. We enrolled 82 children age 1 day to 18 years requiring mechanical ventilation and fentanyl infusions anticipated to last for >4 days were eligible for enrollment. Those receiving additional oral analgesia or sedation, having a history of drug dependence or withdrawal, or having significant neurologic, renal, or hepatic disease were excluded. In addition to fentanyl infusions, patients received low-dose naloxone or placebo infusions. Medications were adjusted using the Modified Motor Activity Assessment Scale. Withdrawal was monitored using the Modified Narcotic Withdrawal Scale. Intervention was a low-dose naloxone infusion (0.25 µg/kg per hour) and the main outcome variable was the maximum cumulative daily fentanyl dose (micrograms per kilogram per day).

RESULTS. There was no difference in the maximum cumulative daily fentanyl dose between patients treated with naloxone (N = 37) or those receiving placebo (N = 35). Adjustment for the starting fentanyl dose also failed to reveal group differences. Total fentanyl dose received throughout the study in the naloxone group (360 µg/kg) versus placebo (223 µg/kg) was not statistically different. Placebo patients trended toward fewer rescue midazolam boluses (10.7 vs 17.8), lower total midazolam dose (11.6 mg/kg vs 23.9 mg/kg), and fewer rescue fentanyl boluses (18.5 vs 23.9).

CONCLUSIONS. We conclude that administration of low-dose naloxone (0.25 µg/kg per hour) does not decrease fentanyl requirements in critically ill, mechanically ventilated children.

Key Words: critically ill children • opiate dependent neonate • pain management • sedation • randomized • controlled trial

Abbreviations: Gs—G stimulatory • AC—adenylate cyclase • cAMP—cyclic adenosine monophosphate • Gi—G inhibitory • MMAAS—Modified Motor Activity Assessment Scale • MNWS—Modified Narcotic Withdrawal Scale • PELOD—pediatric logistic organ dysfunction • ANCOVA—analysis of covariance • DSMB—data and safety monitoring board • CI—confidence interval

Untreated pain and stress increase morbidity and mortality in critically ill children in the PICU.1 Thus, opioids are frequently administered by continuous infusion in the PICU to provide adequate sedation and analgesia.1,2 Patients receiving continuous opioid infusions commonly experience adverse effects of opioid dependence, withdrawal, and tolerance.3–5 Of these unwanted adverse effects, opioid tolerance not only complicates medical management but limits long-term opioid use.6

Opioid tolerance is an adaptation to prolonged opioid exposure clinically reflected by a decrease in opioid effect over time.4 The cellular and molecular mechanisms underpinning this phenomenon are complex and incompletely understood.6–10 It has been proposed that opioid tolerance may be because of loss of opioid surface receptors, desensitization of opioid receptors, functional antagonism, and/or increased alternative coupling to G-stimulatory (Gs) proteins.7,8,10 Of these possible mechanisms, there are considerable data supporting alternative coupling to Gs proteins resulting in upregulation of the adenylate cyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase A transduction system as a cause of opioid tolerance.

Opioid receptor binding leads to both analgesia and increased pain perception through activity of both Gs and G-inhibitory (Gi) proteins.11 Short-term opioid administration causes Gi binding, which decreases neuron action potential duration and neurotransmitter release, resulting in analgesia, the clinically desired outcome. However, chronic Gi binding, as occurs with long-term opioid administration, increases AC-cAMP accumulation by mechanisms that are unclear.12,13 Increased AC-cAMP leads to increased neuron action potential duration and increased neurotransmitter release, resulting in decreased analgesia. This phenomenon, known as AC-cAMP superactivation, is one of the possible mechanisms of opioid tolerance.6,14–16 Low-dose naloxone, an opioid antagonist, decreases Gi activity associated with chronic binding and causes AC-cAMP levels to return to normal, resulting in decreased neuron action potential duration, decreased neurotransmitter release, and improved analgesia.15,17

Chronic opioid administration also increases Gs binding, causing upregulation of AC-cAMP, leading to increased neuron action potential duration and increased neurotransmitter release. Clinically, this Gs binding results in decreased analgesia and may be related to hyperalgesia or "antianalgesia."11,17–20 Low-dose naloxone also decreases Gs binding, thus down regulating AC-cAMP, decreasing neuron action potential duration and neurotransmitter release, resulting in improved analgesia.19,21,22

Recognition that G-protein activity may alter the desired outcome during opioid treatment has suggested that opioid tolerance and withdrawal could be limited by administering low-dose naloxone concomitantly with opioids.3 Support for this hypothesis has come from both in vitro studies of nociceptive types of dorsal root ganglion neurons23 and in vivo animal studies17,21,22,24 in which the use of the low-dose opioid antagonist decreased opioid tolerance and dependence. Furthermore, clinical studies in adults have shown that low doses of opioid antagonist can markedly enhance the analgesic effect of opioids, even reducing opioid dosing requirements by as much as 28% in some studies.25–27 In addition, a retrospective review of 26 PICU patients demonstrated a reduction in patient opioid requirements after concomitant opioid and low-dose naloxone therapy.28

Opioid tolerance is inevitable in critically ill children receiving chronic opioid infusions,5,29 and it is imperative that a safe and effective treatment for opioid tolerance is found. The effect of simultaneous low-dose naloxone and fentanyl administration on opioid tolerance in critically ill pediatric patients has not been explored in a prospective, randomized, placebo-controlled fashion. The need for such a study has recently been recognized.28


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
To evaluate the effect of low-dose naloxone on opioid requirements in the PICU, we conducted a double-blinded, randomized, placebo-controlled study. We hypothesized that mechanically ventilated PICU patients receiving continuous fentanyl infusion and concomitant low-dose naloxone would experience diminished opioid tolerance and enhanced analgesia as manifested by a 30% decrease in the maximum cumulative daily dose of fentanyl administered over the period of observation. PICU patients aged 1 day to 18 years requiring fentanyl infusions anticipated to last >4 days were screened from December 2002 through July 2004 (N = 337). Subjects were enrolled within 24 hours of initiation of fentanyl infusion. Institutional review board approval and parental consent for participation were obtained. Patients were not eligible if they were currently receiving oral analgesia or sedation, had a history of drug dependence or withdrawal, or had significant renal or hepatic disease. Patients were also excluded if they had significant or preexisting cardiovascular disease requiring class IV antiarrhythmics (secondary to adverse events in Food and Drug Administration studies using therapeutic doses of naloxone)30 or neurologic impairment that could complicate the accurate assessment of sedation and withdrawal.

Monitoring Tools
Sedation was assessed every 4 hours and as clinically indicated using the Modified Motor Activity Assessment Scale (MMAAS). This tool measures sufficiency of sedation, with scores ranging from +3 (undersedation) to –3 (oversedation). The MMAAS has been used for sedation monitoring in other PICU studies,31–33 and it was recently used to construct the State Behavioral Scale.34 Analgesia was assessed using the Faces, Legs, Activity, Cry, and Consolability (FLACC) score. The Faces, Legs, Activity, Cry, and Consolability score has been validated as a reliable pain assessment tool in multiple pediatric populations.35,36 Monitoring for withdrawal was performed using the Modified Narcotic Withdrawal Scale (MNWS). This represents a modified form of the Finnegan Neonatal Abstinence Syndrome monitoring tool, a validated withdrawal assessment tool for neonates. Scores >8 were indicative of withdrawal.37 The pediatric logistic organ dysfunction (PELOD) score was used to quantify baseline organ dysfunction.38

Study Protocol
Enrolled patients received, in addition to fentanyl infusion, infusion of either naloxone (0.25 µg/kg per hour concentrated to run at 1 mL per hour) or placebo (normal saline run at 1 mL per hour). The need for either continuous or intermittent supplementary doses of midazolam was established by the attending physician of the primary PICU service. Fentanyl and midazolam infusions were adjusted to provide appropriate sedation according to patient MMAAS scores. MMAAS scores were obtained every 4 hours, 1 hour after a change in the fentanyl or midazolam infusion rate, and as clinically indicated. For scores suggestive of oversedation, fentanyl and then midazolam infusions were decreased. For scores suggestive of undersedation, fentanyl and then midazolam infusions were increased. Medication dose adjustments followed standard practice, delineated as follows.30 Fentanyl was adjusted by 1.00 µg/kg per hour for children weighing ≤50 kg and by 0.50 µg/kg per hour for children weighing >50 kg. Midazolam was adjusted by 0.10 mg/kg per hour for children weighing ≤20 kg and by 0.05 mg/kg per hour for children weighing >20 kg. Bolus doses were administered in response to undersedation. Standardized fentanyl boluses were 1.00 to 2.00 µg/kg, and midazolam boluses were 0.05 to 0.10 mg/kg. First episodes of undersedation were treated with bolus medication. Recurrent episodes of undersedation were treated with increases in infusion of medication. Fentanyl and midazolam were the only sedative and analgesic medications administered to study patients during the period of observation. The use of agents other than fentanyl to provide analgesia (eg, additional opioids, acetaminophen, or nonsteroidal anti-inflammatory drugs) was not permitted during the study. The use of sedatives other than midazolam (eg, barbiturates, other benzodiazepines, or antihistamines) was not permitted. Patients requiring these additional agents to maintain adequate MMAAS scores were removed from the study and continued to receive sedation and withdrawal monitoring. Patients were allowed to receive acetaminophen and/or nonsteroidal anti-inflammatory drugs intermittently for treatment of fever only.

When extubation of a study patient was expected, the fentanyl and midazolam infusions were decreased by 25% of the original dose every 12 hours until discontinuation. The naloxone-placebo infusion remained unchanged until the fentanyl infusion was discontinued, at which time it was also discontinued. Patients were monitored every 6 hours for withdrawal during and after weaning until 4 days after discontinuation of study medications. Because the half-life of fentanyl after long-term continuous infusion is 21 hours, with a range of 11 to 36 hours,30 it was felt that 4 days (96 hours) of monitoring would adequately allow for withdrawal symptoms to manifest. Patients who were assigned scores indicative of withdrawal and those who demonstrated significant withdrawal symptoms as judged by the primary PICU service despite normal MNWS scores received methadone and/or diazepam. These patients were removed from study protocol.

Outcome Variables
The main outcome variable was the maximum cumulative daily fentanyl dose. This parameter was calculated by summing the total dose of fentanyl infusion (micrograms per kilogram) received by each study patient within a 24-hour period. Secondary outcome variables, including the rate of the fentanyl and midazolam infusions, the duration of these infusions, and the number of fentanyl and midazolam supplemental boluses were recorded for each patient. Sedation and withdrawal scores were recorded. Unexplained adverse events, defined as changes in medical condition not related to the current medical illness, resulted in patient unblinding and/or withdrawal from the study.

Statistical Analysis
An SPSS software random number generator (SPSS Inc, Chicago, IL) was used to create a permuted block randomization schedule and allocation sequence. The randomized patient assignment was unknown to all of the investigators and medical team members, with the exception of the PICU pharmacist. The physician investigators enrolled study participants.

Sample size for the investigation was based on an assumed power of 80%, an effect size of 30% reduction in maximum cumulative daily fentanyl dose, and historical data for the maximum daily fentanyl dosing in our PICU (between January and August 2002, the cumulative maximum daily fentanyl dose of 428 PICU patients was 79 µg/kg with an SD of ±47 µg/kg). The effect size of 30% was chosen based on a 28.4% reduction of morphine use demonstrated in patients who received low-dose naloxone versus placebo in a previous study26 and the belief that a reduction of fentanyl use by 30% would be clinically significant. The sample size was determined to be 62 patients per group (total N = 124). The {alpha} criterion for significance was .05.

Hypothesis testing was done using independent samples t tests to compare means between the 2 groups for the primary and secondary outcome variables (nonparametric equivalent tests corroborated the t test findings and are not presented herein). Analysis of covariance (ANCOVA) modeling was used to test for between-group differences while controlling for fentanyl dose at the start of the study. It was necessary to log-transform the primary outcome variable for the ANCOVA modeling to meet the assumptions of homoscedasticity and normality. The ANCOVA statistical results were used for the interim monitoring decision given the model's ability to adjust for the covariate and the advantage of greater statistical power inherent to the use of normally distributed data rather than the nonparametric test.

All of the data were analyzed using SPSS for Windows (SPSS Inc) and Microsoft Excel (Redmond, WA) software packages. Interim monitoring at the midpoint of the study was performed by an independent data and safety monitoring board (DSMB), which consisted of both internal and external reviewers. O'Brien-Fleming stopping boundaries and Lan-DeMets spending functions were used in the analysis.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
From December 2002 until July 2004, there were 82 patients enrolled in the study, 72 of whom completed the investigational protocol. Of the 10 patients not completing the study, 2 were removed by their parents because of their perception of decreased comfort after starting the study, 1 septic oncology patient died from the underlying disease during the study, and 7 were excluded because of protocol violations. The death was reported to the institutional review board as an adverse event. Of the protocol violations, 3 patients had expired consent forms, 1 patient received neuromuscular blockade before receiving study medication, and 3 patients were administered a long-acting opioid to increase sedation (thereby precluding accurate determination of subsequent fentanyl infusion requirements). The 10 patients not completing the study were not included in the data analysis. Of these, 4 patients were never randomly assigned and did not receive study drug, and 3 patients were not analyzed because of the likelihood of additional opioid administration impacting subsequent fentanyl infusion requirements and the assessment of the primary outcome variable. The remaining 3 patients did not have sufficient data to analyze the primary outcome variable. At interim data analysis, there were 37 patients in the low-dose naloxone group and 35 patients in the placebo group. See CONSORT diagram (Fig 1).


Figure 1
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  		FIGURE 1 CONSORT diagram.

 
There were no differences in age, race, gender, PICU admission diagnostic category, or PELOD score between the naloxone and placebo groups (Table 1), nor were there group differences in length of PICU stay, number of ventilator days, fentanyl dose at the start of the study, total fentanyl dose received before the start of the study, and baseline sedation score. Requirement for drains (chest tubes and peritoneal drains), surgical procedures during or before the study, and midazolam dose before the start of the study were comparable, as were study completion rates between groups (Table 1). When classified by admitting diagnosis, there was no difference between groups (Table 2).


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  		TABLE 1 Patient Characteristics

 

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  		TABLE 2 Admitting Diagnosis Classification

 
Low-dose naloxone infusion did not affect the maximum cumulative daily fentanyl dose between the naloxone and placebo groups (61.6 µg/kg per day vs 51.1 µg/kg per day; P = .3; 95% confidence interval [CI] for the difference: –30.84 to 9.82; Fig 2). Additional ANCOVA analysis, using the log-transformed maximum daily dose, adjusting for fentanyl dose at the beginning of the study, also failed to demonstrate a statistically significant difference between groups (3.79 µg/kg per day vs 3.75 µg/kg per day; P = .82; 95% CI: –0.33 to 0.26; Fig 2). Furthermore, the secondary analyses of average fentanyl dose per day (54.3 µg/kg per day vs 44.8 µg/kg per day; P = .19; 95% CI: –23.79 to 4.88) was not significantly different between the naloxone and placebo groups, nor was there a significant difference in the highest fentanyl infusion dose received during the study (2.9 µg/kg per hour vs 2.4 µg/kg per hour; P = .28; 95% CI: –1.34 to 0.39) or in the total fentanyl dose received (359.7 µg/kg vs 223.1 µg/kg; P = .26; 95% CI for the difference: –378.65 to 105.32). Finally, there was no significant difference in the amount of fentanyl escalation required within 48 hours of starting the study between the naloxone and placebo groups (0.98 µg/kg per hour vs 0.95 µg/kg per hour; P = .75; 95% CI: –0.24 to 0.17).


Figure 2
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  		FIGURE 2 Maximum cumulative daily dose of fentanyl. Top, Highest total daily fentanyl dose unadjusted for fentanyl received before starting the study. Bottom, Highest total daily fentanyl dose adjusted for fentanyl received before starting the study. There was no difference between groups in the highest cumulative daily dose of fentanyl (measured in micrograms per kilogram) received.

 
The use of low-dose naloxone did not significantly alter the average sedation score between the naloxone group and placebo group. The mean MMAAS score was 0.14 in the naloxone group and 0.17 in the placebo group (P = .81; 95% CI: –0.24 to 0.31; Fig 3). Both scores fell within a range suggestive of adequate sedation. This demonstrated the ability to maintain adequate sedation in both groups. The mean highest MMAAS score, indicating undersedation, was not significantly different between groups (+1.8 vs +2.1; P = .24; 95% CI: –0.20 to 0.81). The mean number of times that patients were undersedated, as measured by the MMAAS, was also similar between the naloxone and placebo groups (16.7 vs 14.6; P = .61; 95% CI: –9.93 to 5.89).


Figure 3
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  		FIGURE 3 Average sedation score. The average MMAAS scores in both groups were within the range of adequate sedation for the instrument. There was no difference in sedation score between groups.

 
Although not statistically significant, the low-dose naloxone group required more medication administration to maintain MMAAS scores in an adequate sedation range. The average number of midazolam boluses received in the naloxone group was 17.8 vs 10.7 in the placebo group (P = .08; 95% CI: –15.10 to 0.97; Fig 4). The low-dose naloxone group also had a higher total midazolam dose required versus the placebo group (mean: 23.9 mg/kg vs 11.6 mg/kg; P = .13; 95% CI: –28.46 to 3.85; Fig 5). The average number of fentanyl boluses received in the naloxone group was 23.9, and in the placebo group was 18.5 (P = .34; 95% CI: –16.59 to 5.73; Fig 4). The study did not demonstrate any significant difference in the incidence of withdrawal between the naloxone and placebo groups, as determined by MNWS, or demonstration of withdrawal symptoms as judged by the primary ICU service (22.9% vs 13.5%; P = .37). Using the MNWS, the mean withdrawal score received in the naloxone group was 3.0 and in the placebo group was 3.2, both less than the score of 8 indicative of withdrawal (P = .82; 95% CI: –1.93 to 2.41).


Figure 4
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  		FIGURE 4 Supplemental fentanyl and midazolam bolus doses. The figure depicts the average number of supplemental bolus doses of fentanyl and midazolam administered in each group. There was no significant difference between the groups, although there was a trend toward fewer bolus doses in the placebo group.

 

Figure 5
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  		FIGURE 5 Total midazolam dose. This figure depicts the average total dose of midazolam administered while on the study. There was no difference between groups, although a trend exists toward lower midazolam dosing in the placebo group.

 
Of the 72 patients completing the study, 10 patients were not receiving midazolam before starting the study, 5 patients were initiated on midazolam infusions after starting the study, 2 patients received only intermittent midazolam boluses after starting the study, and 3 patients never received midazolam throughout the course of the study. The 10 patients not included in the data analysis did not have significant differences in fentanyl requirements, midazolam requirements, sedation scores, or withdrawal scores compared with the naloxone or placebo groups. The 3 patients who were not analyzed because they received additional medications had maximum cumulative daily fentanyl doses of 39, 54, and 102 µg/kg per day.

Interim Analysis
Interim analysis was performed after enrollment of the aforementioned 72 subjects, representing 58% of total planned enrollment. Evaluation of the primary end point, the maximum cumulative daily fentanyl dose, between groups yielded a standardized test statistic of –0.235 (repeated CI: –0.445 to 0.375). This test statistic and the associated 95% CIs were all within the O'Brien-Fleming stopping boundaries of 0.495 to –0.495, thereby meeting stringent futility criteria. This suggested that the probability of achieving a statistically significant difference in favor of the low-dose naloxone group for the primary outcome variable if patient accrual were to continue to completion of planned enrollment was extremely unlikely (P = .004). The β value for this analysis remained < .20. Furthermore, examination of secondary end point trends suggested improved outcomes for the placebo group (in terms of total midazolam dose administered and the number of fentanyl and midazolam boluses). Therefore, the DSMB halted further enrollment in the investigation on the grounds of futility in demonstrating that concomitant low-dose naloxone would decrease opioid requirement, diminish opioid tolerance, and enhance analgesia, as originally hypothesized. An external reviewer concurred with the conclusion of the DSMB.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This study demonstrates that low-dose naloxone (0.25 µg/kg per hour) administered to critically ill children receiving fentanyl infusions does not decrease the maximum cumulative daily fentanyl dose compared with similar infusions of fentanyl and placebo. Moreover, the implication of a greater requirement for total fentanyl infusion, more supplemental bolus dosing of fentanyl and midazolam, and a higher total midazolam dose requirement concurrent with receiving naloxone infusions is of interest. These findings provide evidence that simultaneous infusion of low-dose naloxone and opioids does not clinically affect opioid tolerance experienced in critically ill pediatric patients. To further confirm the lack of clinical benefit associated with fentanyl and low-dose naloxone coadministration, we evaluated average daily fentanyl dose, highest fentanyl dose while in the study, total dose of fentanyl while in the study, and the amount of escalation in fentanyl dose while on the study. These comparisons showed no differences between groups.

Although clinical trials evaluating low-dose naloxone given simultaneously with opioids have been done in the past, the results are conflicting, and none of the investigations seem to be directly applicable to the treatment of critically ill children requiring continuous opioid infusions. Levine et al27 found that 0.4 mg of naloxone in conjunction with pentazocine demonstrated more potent and prolonged analgesia than either high-dose morphine or pentazocine alone in adult patients after tooth extraction. Gan et al26 investigated the effect of low-dose naloxone on morphine-related adverse effects in postoperative hysterectomy patients and found that the cumulative morphine dose was lower in the low-dose naloxone group (0.25 µg/kg per hour). Cepeda et al39 demonstrated that intermittent low-dose naloxone (0.19–0.57 µg/kg per hour) given with intermittent morphine patient-controlled analgesia did not decrease postoperative morphine requirements or pain scores. These studies demonstrate the controversial nature of concomitant naloxone administration. Furthermore, a recent pediatric retrospective analysis28 of the effect of low-dose naloxone on opioid therapy suggested that further prospective clinical trials were needed. Thus, we designed this prospective, randomized, blinded trial to rigorously assess the effect of low-dose naloxone on opioid requirements in critically ill children.

It is possible that the previously demonstrated effects of short-term, low-dose naloxone on opioid tolerance are different after prolonged high-dose opioid therapy. Previous favorable investigations administered opioid therapy for considerably shorter time periods, 5 hours27 and 24 hours,26 than the average of 5 days in the present study. It is also notable that, compared with this study, patients in the study by Gan et al26 received considerably less opioid equivalents with morphine doses ranging from 42.3 to 64.7 mg per day (0.60–0.92 mg/kg per day of morphine based on the average 70-kg adult), whereas in this study, patients received average daily fentanyl doses of 44.8 to 54.3 µg/kg per day (the equivalent of 5.4 to 6.1 mg/kg per day of morphine).40 In the study of Cheung et al,28 in which patients received morphine equivalent doses ranging from 3 to 4 mg/kg per day for at least 4 days, no difference in opioid requirement during the low-dose naloxone infusion was found. Therefore, it is possible that low-dose naloxone loses its ability to affect opioid requirements after long-term higher-dose opioid administration.

Of note, the majority of clinical data using low-dose naloxone to treat opioid tolerance has been done in adults. It is possible that the effect of low-dose naloxone to treat opioid tolerance is somehow different in children compared with adults. This concern is demonstrated by the results shown in the Cheung et al28 study, where no difference in opioid requirement was found during low-dose naloxone administration. Because there are very few data on the effects of low-dose naloxone to treat opioid tolerance in children, it is difficult to determine the importance of this observation, but it must be considered as we continue to examine the mechanisms of opioid tolerance.

The naloxone dose chosen for this study at the time of protocol design mimicked that of the only other human clinical trial that used low dose naloxone as a continuous infusion simultaneously with an opioid infusion26 and was the lowest dose administered to humans published at the time.26,27,39,41–44 It is known that the effect of naloxone on opioid tolerance is dose dependent,17,20 with lower naloxone doses being more effective. Although some may consider the dose used in this investigation high,45 our dose was smaller than that used in the study by Levine et al,27 equal to the naloxone dose of the study by Gan et al,26 and equivalent to the dose suggested for further study in the retrospective review by Cheung et al.28

It is unclear whether the use of fentanyl in this investigation versus morphine, as used in previous investigations,21,22,26 could have contributed to the results of this study. Fentanyl was chosen because it is a commonly used opioid for the treatment of critically ill pediatric patients.46–48 Known differences in pharmacokinetics between morphine and other opioids6,49 are unlikely to explain the differing results of this study compared with previous investigations, because both fentanyl and morphine have the same pharmacologic activity at the µ-opioid receptor.50–52 However, it is possible that other pharmacologic differences, such as additional {kappa}-opioid receptor binding of morphine53 or differing µ-opioid receptor sodium channel activity between morphine and fentanyl,54 could have influenced the results of this investigation. While possible, it is unlikely that the use of fentanyl in this investigation versus morphine accounts for the differing results given that recent studies using morphine simultaneously with low-dose naloxone versus placebo showed no difference in opioid requirement.39,55

Reliable, consistent, objective monitoring of critically ill children is a worldwide challenge, as noted in recently published consensus guidelines for sedation and analgesia of critically ill children.56,57 The use of a sedation scoring tool, the MMAAS, which has not been validated in children to adjust fentanyl and midazolam dose, could detract from accurate assessment of the total fentanyl requirements. The MMAAS was created by enhancing the Motor Activity Assessment Scale, a valid measure of sedation of mechanically ventilated surgical adults ({kappa} = .83; 95% CI: 0.72 to 0.94),31 to better fit pediatrics. The MMAAS was the basis for the derivation of the State Behavioral Scale, which, although not validated, has good interrater reliability with an interclass coefficient of 0.79.34 In the present study, the MMAAS was applied uniformly to patients of both experimental groups, which should eliminate confounding of study results. Therefore, we believe that the MMAAS served as a reliable sedation assessment methodology.

In the present study, serum naloxone concentrations were not obtained. However, the concentration of naloxone needed to decrease opioid tolerance is unknown. Therefore, monitoring such concentrations would be of little clinical use. In addition, a trial to evaluate the effectiveness of naloxone infusion for the reversal of high-dose fentanyl demonstrated that there was no correlation between plasma fentanyl levels and naloxone concentrations.58

Although this study was not designed or powered to evaluate the effect of low-dose naloxone on midazolam requirements, it is interesting to note that the placebo group used less total midazolam and fewer midazolam supplemental boluses to maintain adequate sedation. The arbitrary use of supplemental midazolam (as determined by the PICU team) complicates the interpretation of this finding.


   CONCLUSIONS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
In conclusion, low-dose naloxone infusion (0.25 µg/kg per hour) given concomitantly with continuous infusion of fentanyl did not decrease fentanyl requirements in PICU patients. In fact, patients who received fentanyl plus naloxone had a tendency toward greater opioid and benzodiazepine requirements compared with patients who received fentanyl plus placebo. The results of this study, in combination with more recent investigations,28,39,55 suggest that opioid and naloxone coadministration may not be clinically beneficial for critically ill patients requiring prolonged high-dose opioid therapy.


   ACKNOWLEDGMENTS
 
We thank Julio Pérez Fontán, MD, with the University of Texas Southwestern for assistance in article revision. We thank John Rose, MD, from the Children's Hospital of Philadelphia, for reviewing and confirming the results of the interim analysis for which no funding was provided. We thank the clinical research department at Children's Medical Center of Dallas for assistance with data collection and management for which compensation was provided from the Children's Medical Center Foundation. We also thank the Children's Medical Center of Dallas PICU pharmacists for their participation in the trial, for which no funding was provided. Finally, we thank the Children's Medical Center Foundation for overall sponsorship of this investigation.


   FOOTNOTES
 
Accepted Nov 13, 2007.

Address correspondence to Cindy Maria Darnell, MD, Children's Medical Center, Dallas, Critical Care Services, 1935 Motor St, Dallas, TX 75235. E-mail: cindy.darnell{at}childrens.com

The authors have indicated they have no financial relationships relevant to this article to disclose.

This trial has been registered at www.clinicaltrials.gov (identifier NCT00286052).

The views expressed in this article are those of the author(s) and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government.

Dr Thompson is a military service member. This work was prepared as part of her official duties. Title 17 U.S.C. 105 provides that "copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a United States Government work as "a work prepared by a military service member or employee of the United States Government as part of that person's official duties."

Dr Darnell had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


What's Known on This Subject

The mechanism of opioid tolerance is unknown. Currently there is substantial evidence that alternative coupling to G-stimulatory proteins resulting in upregulation of the adenylate cyclase-cAMP-protein kinase A transduction system is a major cause of opioid tolerance.

 

What This Study Adds

The effect of low-dose naloxone to disrupt the alternative coupling that occurs with the G-stimulatory proteins has never before been explored in a prospective pediatric clinical trial.

 


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. McArdle P. Intravenous analgesia. Crit Care Clin. 1999;15 (1):89 –104[CrossRef][Web of Science][Medline]
  2. Golianu B, Krane EJ, Galloway KS, Yaster M. Pediatric acute pain management. Pediatr Clin North Am. 2000;47 (3):559 –587[CrossRef][Web of Science][Medline]
  3. Anand KJ, Arnold JH. Opioid tolerance and dependence in infants and children. Crit Care Med. 1994;22 (2):334 –342[Web of Science][Medline]
  4. Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000;28 (6):2122 –2132[CrossRef][Web of Science][Medline]
  5. Arnold JH, Truog RD, Orav EJ, Scavone JM, Hershenson MB. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology. 1990;73 (6):1136 –1140[Web of Science][Medline]
  6. Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem. 2004;73 :953 –990[CrossRef][Web of Science][Medline]
  7. Kieffer BL, Evans CJ. Opioid tolerance-in search of the holy grail. Cell. 2002;108 (5):587 –590[CrossRef][Web of Science][Medline]
  8. Suresh S, Anand KJ. Opioid tolerance in neonates: a state-of-the-art review. Paediatr Anaesth. 2001;11 (5):511 –521[CrossRef][Web of Science][Medline]
  9. Ueda H, Inoue M, Mizuno K. New approaches to study the development of morphine tolerance and dependence. Life Sci. 2003;74 (2–3):313 –320[CrossRef][Web of Science][Medline]
  10. Raith K, Hochhaus G. Drugs used in the treatment of opioid tolerance and physical dependence: a review. Int J Clin Pharmacol Ther. 2004;42 (4):191 –203[Web of Science][Medline]
  11. Crain SM, Shen KF. Modulatory effects of Gs-coupled excitatory opioid receptor functions on opioid analgesia, tolerance, and dependence. Neurochem Res. 1996;21 (11):1347 –1351[Web of Science][Medline]
  12. Avidor-Reiss T, Nevo I, Levy R, Pfeuffer T, Vogel Z. Chronic opioid treatment induces adenylyl cyclase V superactivation. Involvement of Gbetagamma. J Biol Chem. 1996;271 (35):21309 –21315[Abstract/Free Full Text]
  13. Nevo I, Avidor-Reiss T, Levy R, Bayewitch M, Heldman E, Vogel Z. Regulation of adenylyl cyclase isozymes on acute and chronic activation of inhibitory receptors. Mol Pharmacol. 1998;54 (2):419 –426[Abstract/Free Full Text]
  14. Nestler EJ, Hope BT, Widnell KL. Drug addiction: a model for the molecular basis of neural plasticity. Neuron. 1993;11 (6):995 –1006[CrossRef][Web of Science][Medline]
  15. Avidor-Reiss T, Bayewitch M, Levy R, Matus-Leibovitch N, Nevo I, Vogel Z. Adenylylcyclase supersensitization in mu-opioid receptor-transfected Chinese hamster ovary cells following chronic opioid treatment. J Biol Chem. 1995;270 (50):29732 –29738[Abstract/Free Full Text]
  16. Sharma SK, Klee WA, Nirenberg M. Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proc Natl Acad Sci USA. 1975;72 (8):3092 –3096[Abstract/Free Full Text]
  17. Crain SM, Shen KF. Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability. Pain. 2000;84 (2–3):121 –131[CrossRef][Web of Science][Medline]
  18. Shen KF, Crain SM. Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture. Brain Res. 1989;491 (2):227 –242[CrossRef][Web of Science][Medline]
  19. Crain SM, Shen KF. Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 ganglioside-regulated opioid receptor functions. Trends Pharmacol Sci. 1998;19 (9):358 –365[CrossRef][Medline]
  20. Woolf CJ. Analgesia and hyperalgesia produced in the rat by intrathecal naloxone. Brain Res. 1980;189 (2):593 –597[CrossRef][Web of Science][Medline]
  21. 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 (23):10540 –10544[Abstract/Free Full Text]
  22. Shen KF, Crain SM. Ultra-low doses of naltrexone or etorphine increase morphine's antinociceptive potency and attenuate tolerance/dependence in mice. Brain Res. 1997;757 (2):176 –190[CrossRef][Web of Science][Medline]
  23. Crain SM, Shen KF, Chalazonitis A. Opioids excite rather than inhibit sensory neurons after chronic opioid exposure of spinal cord-ganglion cultures. Brain Res. 1988;455 (1):99 –109[CrossRef][Web of Science][Medline]
  24. Crain SM, Shen KF. Opioids can evoke direct receptor-mediated excitatory as well as inhibitory effects on sensory neuron action potentials. NIDA Res Monogr. 1990;105 :34 –39[Medline]
  25. Joshi GP, Duffy L, Chehade J, Wesevich J, Gajraj N, Johnson ER. Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous patient-controlled analgesia. Anesthesiology. 1999;90 (4):1007 –1011[CrossRef][Web of Science][Medline]
  26. 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 (5):1075 –1081[CrossRef][Web of Science][Medline]
  27. Levine JD, Gordon NC, Taiwo YO, Coderre TJ. Potentiation of pentazocine analgesia by low-dose naloxone. J Clin Invest. 1988;82 (5):1574 –1577[CrossRef][Web of Science][Medline]
  28. Cheung CL, van Dijk M, Green JW, Tibboel D, Anand KJ. Effects of low-dose naloxone on opioid therapy in pediatric patients: a retrospective case-control study. Intensive Care Med. 2007;33 (1):190 –[CrossRef][Web of Science][Medline]
  29. Katz R, Kelly HW, Hsi A. Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion. Crit Care Med. 1994;22 (5):763 –767[Web of Science][Medline]
  30. Murray L. Physicians' Desk Reference 2005. 59th ed. Montvale, NJ: Thomson PDR; 2005
  31. Devlin JW, Boleski G, Mlynarek M, et al. Motor Activity Assessment Scale: a valid and reliable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit. Crit Care Med. 1999;27 (7):1271 –1275[CrossRef][Web of Science][Medline]
  32. Curley MA, Hibberd PL, Fineman LD, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA. 2005;294 (2):229 –237[Abstract/Free Full Text]
  33. Clemmer TP, Wallace JC, Spuhler VJ, Bailey PP, Devlin JW. Origins of the Motor Activity Assessment Scale score: a multi-institutional process. Crit Care Med. 2000;28 (8):3124[Web of Science][Medline]
  34. Curley MA, Harris SK, Fraser KA, Johnson RA, Arnold JH. State Behavioral Scale: a sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatr Crit Care Med. 2006;7 (2):107 –114[CrossRef][Web of Science][Medline]
  35. Manworren RC, Hynan LS. Clinical validation of FLACC: preverbal patient pain scale. Pediatr Nurs. 2003;29 (2):140 –146[Medline]
  36. Voepel-Lewis T, Merkel S, Tait AR, Trzcinka A, Malviya S. The reliability and validity of the Face, Legs, Activity, Cry, Consolability observational tool as a measure of pain in children with cognitive impairment. Anesth Analg. 2002;95 (5):1224 –1229[Abstract/Free Full Text]
  37. Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management. Addict Dis. 1975;2 (1–2):141 –158[Medline]
  38. Leteurtre S, Martinot A, Duhamel A, Proulx F, Grandbastien B, Cotting J, et al. Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study. Lancet. 2003;362 (9379):192 –197[CrossRef][Web of Science][Medline]
  39. Cepeda MS, Africano JM, Manrique AM, Fragoso W, Carr DB. The combination of low dose of naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period. Pain. 2002;96 (1–2):73 –79[CrossRef][Web of Science][Medline]
  40. Facts & Comparisons 4.0: Administration and dosage. Available at: http://online.factsandcomparisons.com/printsection.aspx?id=662859&section=admin-dosage. Accessed March 17, 2008
  41. Kendrick WD, Woods AM, Daly MY, Birch RF, DiFazio C. Naloxone versus nalbuphine infusion for prophylaxis of epidural morphine-induced pruritus. Anesth Analg. 1996;82 (3):641 –647[Abstract]
  42. Rolly G, Poelaert J, Mungroop H, Paelinck H. A combination of buprenorphine and naloxone compared with buprenorphine administered intramuscularly in postoperative patients. J Int Med Res. 1986;14 (3):148 –152[Web of Science][Medline]
  43. Stoller KB, Bigelow GE, Walsh SL, Strain EC. Effects of buprenorphine/naloxone in opioid-dependent humans. Psychopharmacology (Berl). 2001;154 (3):230 –242[CrossRef][Medline]
  44. Rawal N, Schott U, Dahlstrom B, et al. Influence of naloxone infusion on analgesia and respiratory depression following epidural morphine. Anesthesiology. 1986;64 (2):194 –1201[Web of Science][Medline]
  45. Mehlisch DR. The combination of low dose of naloxone and morphine in patient-controlled (PCA) does not decrease opioid requirements in the postoperative period. Pain. 2003;101 (1–2):209 –211, author reply 211–212[CrossRef][Web of Science][Medline]
  46. Tobias JD. Sedation and analgesia in the pediatric intensive care unit. Pediatr Ann. 2005;34 (8):636 –645[Web of Science][Medline]
  47. Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J Med. 2002;347 (14):1094 –1103[Free Full Text]
  48. Kress JP, Hall JB. Sedation in the mechanically ventilated patient. Crit Care Med. 2006;34 (10):2541 –2546[CrossRef][Web of Science][Medline]
  49. Ummenhofer WC, Arends RH, Shen DD, Bernards CM. Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology. 2000;92 (3):739 –753[CrossRef][Web of Science][Medline]
  50. Narita M, Imai S, Itou Y, Yajima Y, Suzuki T. Possible involvement of mu1-opioid receptors in the fentanyl- or morphine-induced antinociception at supraspinal and spinal sites. Life Sci. 2002;70 (20):2341 –2354[CrossRef][Web of Science][Medline]
  51. Clark MJ, Furman CA, Gilson TD, Traynor JR. Comparison of the relative efficacy and potency of mu-opioid agonists to activate Galpha(i/o) proteins containing a pertussis toxin-insensitive mutation. J Pharmacol Exp Ther. 2006;317 (2):858 –864[Abstract/Free Full Text]
  52. Saidak Z, Blake-Palmer K, Hay DL, Northup JK, Glass M. Differential activation of G-proteins by mu-opioid receptor agonists. Br J Pharmacol. 2006;147 (6):671 –680[CrossRef][Web of Science][Medline]
  53. Pasternak Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Molinoff PB, Ruddon RW, Gilman AG, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: The McGraw-Hill Companies, Inc; 1996:521–556
  54. Haeseler G, Foadi N, Ahrens J, Dengler R, Hecker H, Leuwer M. Tramadol, fentanyl and sufentanil but not morphine block voltage-operated sodium channels. Pain. 2006;126 (1–3):234 –244[CrossRef][Web of Science][Medline]
  55. 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 (1–2):41 –46[CrossRef][Web of Science][Medline]
  56. Playfor S, Jenkins I, Boyles C, et al. Consensus guidelines on sedation and analgesia in critically ill children. Intensive Care Med. 2006;32 (8):1125 –1136[CrossRef][Web of Science][Medline]
  57. Prins S, van Dijk M, Tibboel D. Sedation and analgesia in the PICU: many questions remain. Intensive Care Med. 2006;32 (8):1103 –1105[CrossRef][Web of Science][Medline]
  58. Takahashi M, Sugiyama K, Hori M, Chiba S, Kusaka K. Naloxone reversal of opioid anesthesia revisited: clinical evaluation and plasma concentration analysis of continuous naloxone infusion after anesthesia with high-dose fentanyl. J Anesth. 2004;18 (1):1 –8[CrossRef][Web of Science][Medline]
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