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PETER J. DAVIS

A Prospective Evaluation of Opioid Weaning in OpioidDependent Pediatric Critical Care Patients

Richard J. Berens, MD, Michael T. Meyer, MD, Theresa A. Mikhailov, MD,
Krista D. Colpaert, RN, Michelle L. Czarnecki, RN, MSN, CPNP, Nancy S. Ghanayem,
George M. Hoffman, Deborah J. Soetenga, RN, MSN, CNS, Thomas J. Nelson, RPh,
and Steven J. Weisman, MD

MD,

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

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

ritically 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, hyperadrenergic 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
Accepted for publication December 6, 2005.
Supported, in part, through the Jane B. Pettit Pain and Palliative
Care Center.
Address correspondence and reprint requests to Richard J. Berens, MD, 9000 W Wisconsin Ave MS, 735 Wauwatosa, WI 53226.
Address e-mail to rberens@chw.org.
DOI: 10.1213/01.ane.0000202395.94542.3e
2006 by the International Anesthesia Research Society
0003-2999/06

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.
(Anesth Analg 2006;102:104550)

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 714 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.
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Table 1. Neonatal Abstinence Score

Sign/Symptom
Cry
Excessive
Continuous
Sleep
1 h
2 h
3 h
Moro Reflex
Hyperactive
Marked
Tremors
Mild (disturbed)
Mod-severe
Mild (undisturbed)
Mod-severe
Hypertonia
Frequent yawning
Excoriation
Seizures

Score

2
3
3
2
1
2
3
1
2
3
4
2
1
1
5

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Table 2. Modified Ramsey Sedation Score

Sign/
Symptom

Score

Sweating
Fever
37.2C38.4C
38.4C
Mottling
Nasal Stuffiness
Sneezing
Nasal flaring
Respiratory rate
60
60 (retractions)
Excessive sucking
Poor feeding
Regurgitation
Projectile vomiting
Stools
Loose
Watery

1
1
2
1
1
1
2
1
2
1
2
2
3
2
3

For all signs and symptoms, other causes must be eliminated. Score 0 7
indicates mild withdrawal, 8 11 indicates moderate withdrawal, and 1215
indicates severe withdrawal.

This study investigated whether opioid-dependent

patients could be weaned with oral methadone as
effectively in 5 days as in 10 days

Methods
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 patients 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

Activity

Score

Unresponsive to painful stimuli

Arouses, but not conscious, to pain stimuli
Arouses slowly to painful tactile stimuli
Drowsy, arouses with light tactile/verbal
stimuli
Spontaneously awake without stimulus
Agitated, anxious, or pain baseline

1
2
3
4
5
6

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 patients 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 10day 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 patients 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 patients
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

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Table 3. Demographics, Pre-enrollment Variables and Severity Indices: 5- versus 10-Day Wean Groups
Variable

5-day wean (n 16)

10-day wean (n 21)

Age (mo)
Gender
Race

9.45 16.69
10 boys, 6 girls
10 white
2 native American
1 Hispanic
3 African-American
8 CHD
5 HLHS, 1 Fontan,
1 TAPVR, 1 VSD
4 Respiratory failure
1 ENT
3 trauma

9.80 26.17
15 boys, 6 girls
17 white
1 native American
1 African-American
1 other
7 CHD
5 HLHS, 1 critical AS
1 TGA
7 Respiratory failure
3 ENT Surgery
3 PHN
2 ECMO
1 Shock
337.83 272.76
183.31 337.86
13.05 6.52
19.14 15.11
36.95 25.75

Admitting Diagnosis

Mechanical Ventilation (h)

Vasopressor Therapy (h)
Admission PRISM
Pediatric intensive care unit length of stay
Hospital length of stay

268.53 144.01
140.10 173.90
9.63 4.70
20.81 16.84
36 20.36

Values are mean sd. P not significant. CHD congenital heart disease; TAPVR total anomalous pulmonary venous return; HLHS hypoplastic left
heart syndrome; VSD ventricular septal defect; ENT ear, nose and throat; AS aortic stenosis; TGA transposition great arteries; PHN pulmonary
hypertension; ECMO extracorporeal membrane oxygenation; PRISM pediatric risk of mortality.

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, Fishers exact
test, or Students unpaired t-test. For all tests, P value
0.05 were considered statistically significant.

Results
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 parents 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

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Table 4. Magnitude of Medication Exposures, Dosages, Effects on Neonatal Abstinence Score (NAS) and Need for Rescue
Variable

5 Day (n 16)

10 Day (n 21)

Total fentanyl dose (g/kg)

Fentanyl exposure (days)
Last fentanyl dose (g/kg/h)
First methadone dose (g/kg)
Starting NAS at initiation of methadone wean
Number of patients rescued during study

1415.7 780.1
11.38 5.25
4.53 .58
235 24
5.37 2.11
3

2210.6 1728.9
15.54 10.74
4.05 .42
277 38
4.98 2.94
4

Values are mean sd. P not significant.

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 patients NAS decreased to 8 after placebo administration on wean day 7 after completing the 5-day
wean.

Discussion
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

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Table 5. Description of Lorazepam Exposure, Number of Patients and Duration of Exposure to Both Methadone and
Lorazepam Weans and Number of Rescue Events
Variable

5-day wean

10-day wean

Number of patients weaned from lorazepam

Pre-wean lorazepam exposure (mg/kg)
Number of days sd of lorazapam exposure prior to wean
Mean days sd on combined methadone and lorazepam wean
Number of patients on combined lorazepam and methadone wean on day 5 of study
Number of patients on combined lorazepam and methadone wean on day 10 of study
Number of patients rescued during study

7
3.57 2.39
9.57 5.9
6.7 3.9
5
3
0

10
4.25 4.89
14.4 12.5
7 3.4
6
5
1

Values are mean sd. P not significant.

Figure 1. Mean neonatal abstinence score (NAS) per wean day (11,
15).

Figure 2. Rescue events during wean.

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

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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.

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