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PEDIATRIC ANESTHESIA

A Prospective Evaluation of Opioid Weaning in Opioid-Dependent Pediatric Critical Care Patients

Departments of Anesthesiology and Pediatrics, Medical College of Wisconsin, Children’s Hospital of Wisconsin; National Outcomes Center, Children’s Hospital and Health System; Jane B. Pettit Pain and Palliative Care Center, Children’s Hospital of Wisconsin; Department of Nursing, Children’s Hospital of Wisconsin; Department of Pharmacy, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin

Address correspondence and reprint requests to Richard J. Berens, MD, 9000 W Wisconsin Ave MS, 735 Wauwatosa, WI 53226. Address e-mail to rberens{at}chw.org.

	Abstract

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Critically ill children are treated with opioid medication in an attempt to decrease stress and alleviate pain during prolonged pediatric intensive care. This treatment plan places children at risk for opioid dependency. Once dependent, children need to be weaned or risk development of a withdrawal syndrome on abrupt cessation of medication. We enrolled opioid-dependent children into a prospective, randomized trial of 5- versus 10-day opioid weaning using oral methadone. Children exposed to opioids for an average of 3 wk showed no difference in the number of agitation events requiring opioid rescue (3 consecutive neonatal abstinence scores >8 every 2 h) in either wean group. Most of the events requiring rescue occurred on day 5 and 6 of the wean in both treatment groups. Patients may be able to be weaned successfully in 5 days once converted to oral methadone, with a follow-up period after medication wean to observe for a delayed withdrawal syndrome.

	Introduction

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Critically ill and injured children are exposed to opioids and benzodiazepines in an effort to lessen pain, anxiety, morbidity, and mortality. After prolonged exposure, physical dependence may develop, placing the patient at risk for withdrawal symptoms after abrupt discontinuation of these medications. To minimize symptoms of withdrawal, practitioners wean the dose or lengthen the interval between doses of these medications. The ideal procedure for the weaning process has not been effectively studied.

Withdrawal symptoms are nonspecific, hyper-adrenergic responses occurring after an abrupt dosage reduction of these medications. The cumulative fentanyl exposure of dose (1.5 mg/kg) or time (5 days) has been associated with a 50% chance of significant withdrawal symptoms when the drug was weaned over 2 days (1,2). The incidence approached 100% with a cumulative dose exposure of 2.5 mg/kg or time exposure of 9 days. A variety of clinical scoring tools have been used to follow the course of withdrawal. The Neonatal Abstinence Score (NAS) (Table 1), described by Finnegan et al. (3), ranks symptoms in neonates exposed to intra-uterine opiates and has subsequently been adopted through publication as a measure of withdrawal in opioid-exposed infants requiring extracorporeal membrane oxygenation (ECMO) (4) and in older children (2,5).

Pediatric opioid dependence and subsequent withdrawal symptoms have been reported with a 48-h wean (2), whereas none were reported in a 6-wk outpatient wean (5). A 2- to 4-wk wean protocol has been favored in a review article (6). However, a retrospective case series showed successful weaning from opioids over 10 days in 23 of 26 pediatric patients who had an exposure of 14.5 ± 9.2 days (7). Robertson et al. (8) used a strategy for children designed to limit the duration of weaning based on time of medication exposure. Patients with 7–14 days of exposure were weaned over a 5-day period and patients with >14 days of exposure were weaned over a 10-day period. Eighty percent of these opioid-dependent patients weaned successfully with minimal withdrawal symptoms regardless of the wean duration.

This study investigated whether opioid-dependent patients could be weaned with oral methadone as effectively in 5 days as in 10 days

	Methods

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This study was an IRB-approved, prospective, randomized, double-blind comparison of 5-day versus 10-day enteral methadone wean in opioid-dependent patients. The inclusion criteria were 18 yr of age and exposed to at least 120 h of continuous IV opioid infusion. Exclusion criteria were neonates <36 wk gestation, lack of attending physician consent, patient diagnosis of acute central nervous system injury (hypoxic ischemic injury, traumatic brain injury, postoperative craniotomies), the presence of an orotracheal, nasotracheal or tracheostomy tube, or the inability to transition to morphine or methadone based on present or past difficulties with either drug. Medication weaning was initiated at the discretion of the attending physician. Standard demographic data, a full psychoactive medication profile (as determined by the medication administration record), NAS (Table 1), and modified Ramsey sedation scores (Table 2) (9) were collected on each patient. These 2 scoring systems were selected because they are the standard scoring tools used at our facility. Informed consent was obtained from each patient’s parent or legal guardian by one of the investigators.

Patients were enrolled into the study either while receiving a continuous opioid infusion (preemptive enrollment) or with an increase of NAS after cessation or decrease of opioids (rescue enrollment). Patients who demonstrated active opioid withdrawal symptoms (NAS 8 every 2 h for 3 consecutive scores) received "rescue therapy" with IV morphine, titrated to reduce the patient’s NAS to <8 while maintaining a modified Ramsey sedation score >4, before initiation of the methadone wean protocol.

All preemptive enrollment patients were transitioned from continuous fentanyl or morphine to enteral methadone. The methadone was given as a initial "loading dose" every 12 h for 3 consecutive doses titrated for a NAS of <8 and sedation score 4. The first dose was scheduled as an evening dose in an effort to both promote a peak effect overnight prompting sleep and to better transition to the subsequent routine administration of one nightly dose. Once steady-state was achieved the informed consent was obtained and the child was enrolled into one of two weaning arms.

After receiving informed consent, the pharmacist randomized enrolled patients to either a 5-day or 10-day enteral methadone wean protocol. The 5-day wean protocol was defined by a 20% reduction of the initial methadone dose each of 5-days, followed by a 5-day course of placebo. The 10-day wean protocol was defined by a 10% reduction of the initial methadone dose each of 10 days with no placebo course. Study drug was dispensed from pharmacy in amber Baxa® oral syringes, using the same size syringe throughout a patient’s methadone wean. The pharmacist prepared all medication doses by diluting commercial methadone syrup (1 mg/mL) to the volume equal to the initial methadone dose. Orange colored simple syrup was used to dilute the methadone 1 mg/mL syrup and for placebo doses. Each dose was labeled "methadone wean study," with the patient’s name, visit number, day and time each dose was to be administered. The study investigators determined the initial methadone doses for all patients but were blinded as to the protocols.

After the first 2 doses, methadone therapy was provided as a single, daily evening dose. NAS and modified Ramsey sedation scores were monitored throughout the duration of the study. Scores were obtained every 8 h until 48 h after the methadone study drug was finished. Scoring frequency was increased to every 2 h if the NAS increased to 8 on any occasion. If the NAS remained 8 for 3 scores, 2 h apart, the child was assessed by one of the investigators.

In our unit, many children are treated continuously with both opioids and lorazepam; these were allowed to participate in the study. Lorazepam was weaned if the child was continuously exposed for >5 days at the time of transitioning from morphine to methadone. Continuous exposure was defined as a dosing regimen designed to administer the medication in a shorter interval than the elimination half-life of the administered medication. For exposures <10 days, lorazepam was weaned over the same number of days of continuous exposure. If lorazepam exposure was >10 days, patients were weaned from lorazepam over 20 days.

Patients with an increased NAS were assessed for other causes of agitation (pain, infection, other medication administration) and treated accordingly before attributing symptoms to opioid withdrawal. On the basis of prior studies (2,3,5,7,10), the presence of a NAS of >8 for 3 consecutive scores performed 2 h apart would allow for routine variation of behavior initially and limit the duration of abnormality if withdrawal was the diagnosis of exclusion. Patients who had 3 consecutive NAS scores of >8 at 2-h intervals during their weaning period were placed in the rescue arm of the study.

Children who met rescue criteria were initially given an additional dose of the study medication equal to the dose administered the day before the rescue event. Children were reassessed in 1 h. If comfortable (NAS <8 and sedation score 4) the child continued with the weaning protocol as planned. If NAS remained 8, the child was given 0.025 mg/kg of IV morphine or 0.05 mg/kg of methadone incrementally every 30 min. Children were reassessed and treatment of agitation with opioids, benzodiazepines, or behavioral therapy continued until the child was comfortable. The child then continued on the same wean protocol as originally ordered.

All data were compared by ²-test, Fisher’s exact test, or Student’s unpaired t-test. For all tests, P value <0.05 were considered statistically significant.

	Results

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During the study period, May 2001 to December 2003, there were 52 patients eligible for enrollment. Of these, 8 were not enrolled because of attending physician discretion, lack of parental consent, or initiation of methadone wean before the decision regarding enrollment. One patient agreed to participate if rescue therapy was deemed necessary but did not develop symptoms of opioid withdrawal syndrome and, consequently, required no methadone therapy. Six patients were enrolled and then withdrew from the study after initiation of methadone therapy. Of these, 3 patients required reinitiation of opioid infusions for changes in their clinical status, 2 patients were removed from the study at the parent’s request, and 1 patient was removed from the study when diagnosed with a chromosomal abnormality of unknown neurologic impact.

Thirty-seven patients were enrolled, randomized and completed the protocol. Of these, 16 were randomized to the 5-day wean and 21 to the 10-day wean protocol. The two groups did not differ significantly with respect to age, gender, race or admitting diagnosis (Table 3). Severity indices such as duration of mechanical ventilation, vasopressor therapy, pediatric intensive care unit (ICU) length of stay and pediatric risk of mortality scores did not differ between the two groups.

Table 4 defines medication exposures, initial NAS at start of methadone wean and number of patients in each group who required rescue therapy. The median (range) for duration of opioid exposures was 10.28 (5.8–24.9) days for the 5-day group and 13.58 (5–45.67) days for the 10-day wean group. Table 5 describes 17 patients with concomitant lorazepam and methadone weaning strategies. One of these patients in the 10-day wean group had withdrawal events attributed to opioid withdrawal. In addition, 1 patient had a withdrawal event not treatable by additional opioid, but symptoms diminished with additional benzodiazepines. We did not include this patient in the analysis of opioid withdrawal events.

Of the 37 patients enrolled, 21 were enrolled preemptively and 16 enrolled through a rescue path. There were no significant differences of rescue events based on enrollment.

The average NAS through the course of weaning and 2 days of postprotocol follow-up (Fig. 1) showed an increase in the NAS from days 4 through 7 for the 5-day group; however, there was no significant difference compared with the 10-day wean group. Seven patients required rescue therapy (Fig. 2). Of these, 6 patients received opioids to decrease the NAS to <8. One patient’s NAS decreased to <8 after placebo administration on wean day 7 after completing the 5-day wean.

View larger version (18K): [in this window] [in a new window]   Figure 1. Mean neonatal abstinence score (NAS) per wean day (11, 15).

View larger version (18K): [in this window] [in a new window]   Figure 2. Rescue events during wean.

	Discussion

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We found that opioid-tolerant patients were weaned with oral methadone as effectively in 5 days as in 10 days. The pediatric literature regarding iatrogenic opioid withdrawal syndrome mainly comprises individual case reports, case series, and retrospective chart reviews of accepted clinical practices. This is the first prospectively randomized, double-blind study to compare two systematic opioid weaning protocols in critically ill and injured children at high risk for opioid withdrawal. This study demonstrated that children at risk of opioid withdrawal could be effectively and safely transitioned to an enteral methadone weaning protocol of either 5 days’ or 10 days’ duration with minimal risk.

Intensive care therapy of critically ill children involves the use of analgesics and sedatives during both the acute stage of injury and prolonged stage of recovery. These medications decrease the physiologic "stress response" and provide analgesia and amnesia. Dependence may develop if medications are given continuously. This condition occurs as a result of modulation at local receptors as well as higher neural centers, such as the locus coeruleus, allowing the individual to respond in a normal fashion despite the presence of large doses of the sedative medication. Abrupt cessation of medications, once central change has taken place, leads one to a relatively dysfunctional, hyper-responsive and hyperirritable state. To prevent withdrawal syndrome, a strategy for weaning must be developed. Clinically driven weaning protocols have ranged from abrupt cessation of medications to weaning over many months (2,6,8,11). Weaning strategies are quite variable and are often determined by the length of exposure, the type of opioid, practitioner bias and preference, and whether there are continuing pain management needs. For instance, a patient with prolonged continuous fentanyl exposure, while receiving surgical and medical management for a diaphragmatic hernia, most likely has developed dependence and will develop withdrawal symptoms if the fentanyl is abruptly discontinued. In contrast, a patient managed by patient-controlled analgesia with IV morphine for 3–4 days after appendectomy is not likely to need any special weaning strategy.

Once the "at-risk" patient was identified, withdrawal symptoms were monitored using the Finnegan NAS (2,3) with modifications (5,12). We chose the NAS to quantify the severity of symptoms, as well as to follow the effectiveness of therapy (6,10,13,14) because our nurses were familiar with this measure, it has good reported interrater reliability (3,14), and it is an effective clinical tool in older children (2,5). One of the limitations in using this tool is that one-time increased scores may reflect withdrawal but also could be a marker for other etiologies of agitation. Unremitting agitation at a level 8 for 3 scores, 2 hours apart, was previously used as a reasonable marker for withdrawal (3).

Figure 1 demonstrates mean NAS scores as well as the number of events treated as withdrawal episodes. The line chart shows the mean NAS per wean day of study by wean groups and the bar chart identifies patients who met the NAS time and intensity criteria to be categorized as experiencing a withdrawal event and the day that the event occurred. Both groups clearly have an average score below the threshold identified as indicating withdrawal. In our study, the timing of breakthrough withdrawal symptoms occurred between 5 and 7 days of weaning regardless of the weaning regimen.

Our study population experienced an average 3-week pediatric ICU stay along with 2 weeks of continuous opioid exposure. A review of the literature demonstrates many suggested methods for opioid weaning (2,11,14,15) and/or conversion to enteral medications such as methadone (7,8), clonidine (16), or barbiturates (17).

Children at risk can be prospectively identified for opioid withdrawal, or they can have active withdrawal symptoms treated as they emerge. In pediatric patients, several risk factors, such as cumulative fentanyl dose, duration of fentanyl exposure (2), and duration of extracorporeal membrane oxygenation therapy (4), have been identified that may predict opioid withdrawal. The adult literature suggests that mechanical ventilation 7 days, acute respiratory distress syndrome, use of neuromuscular blocking drugs, or propofol infusions for longer than 1 day increase the risk of withdrawal syndromes (18). In the current study, the at-risk population was defined as children exposed to more than 5 days of continuous fentanyl infusion, which has been associated with a >50% chance of developing opioid withdrawal (2).

The main confounding factor in any study evaluating opioid withdrawal is the concomitant administration of other sedative medications in the pediatric ICU. These drugs in our unit, primarily lorazepam, also have been associated with withdrawal syndromes. We attempted to control this by standardizing a weaning protocol for prolonged lorazepam exposure. Only 1 of 17 patients on concurrent lorazepam wean had withdrawal events that were treated effectively with opioids. We found no increase in rescue events during concomitant weaning of methadone and lorazepam. Weaning psychotropic medication has been clinically recommended (19,20) and shown to be successful; however, there is no universally accepted protocol for duration of therapy or identification of risk factors. In addition, even though the goal of our study was to compare the efficacy of two different methadone-weaning protocols, a potential source of bias was that the nurses and physicians who evaluated the study patients were not blinded as to the dose or duration of fentanyl exposure. Also, the study size was small, possibly limiting the true significance of some of the findings.

In summary, it appears that there were minimal differences between a 5-day and a 10-day opioid weaning schedule in critically ill opioid-tolerant children. This study demonstrated that children at risk for opioid withdrawal can be prospectively safely transitioned to an enteral methadone weaning protocol of either 5 days’ or 10 days’ duration with minimal risk of opioid withdrawal. Although mean NAS scores were slightly higher in the 5-day regimen, the observed scoring was well below the clinically recognized threshold for withdrawal of an NAS score of 8. The use of a 5-day weaning protocol has the potential to decrease ICU days as well as total hospital days. Our findings support consideration of shorter opioid weaning schedules so that patients may be transitioned more rapidly from the critical care environment to a less intensively monitored setting.

	Footnotes

 
Accepted for publication December 6, 2005.

Supported, in part, through the Jane B. Pettit Pain and Palliative Care Center.

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