Enteral Methadone to Expedite Fentanyl Discontinuation and Prevent Opioid Abstinence Syndrome in the PICU

Pharmacotherapy. 2001;21(12) 

In This Article

Results

During the 3 years, there were 5243 admissions to the PICU and 704 patients received fentanyl by continuous infusion. Of these, 632 patients did not meet inclusion criteria since they did not receive concomitant scheduled methadone and continuous fentanyl infusion for a minimum of 9 days. Fifty patients were excluded due to a previous course of fentanyl and/or other opioid analgesic. Twenty-two mechanically ventilated children (12 boys, 10 girls) met inclusion and exclusion criteria and were included in the final analysis (Table 1). Fifteen patients received fentanyl for sedation during mechanical ventilation and seven for sedation and analgesia.

Fentanyl therapy is reported in Table 2. Methadone was started 1.6 ± 1.9 days before tapering fentanyl. The rate of fentanyl administration in the 24 hours before beginning the taper was 5.0 ± 3.6 µg/kg/hour. Once the taper was begun, the drug was discontinued in a median 2.6 days (Figure 1). A comparison between the duration of fentanyl infusion and the length of the fentanyl taper for each patient is illustrated in Figure 2. One patient, who received 16 days of fentanyl, had the drug turned off from 1.5 µg/kg/hour. This is represented in Table 2 and Figure 2 as zero days to fentanyl discontinuation.

Figure 1. Box plots illustrating hourly rate of fentanyl administration during 2 days before beginning fentanyl taper (days -2 and -1), immediately before beginning the fentanyl taper (day 0), and the first 4 days thereafter. The lower boundary of the box indicates the 25th percentile, the line in the box marks the median, and upper boundary of the box indicates the 75th percentile. Whiskers below and above the box indicate the 10th and 90th percentiles, respectively. *p<0.001, days 1-4 vs day 0, Friedman's repeated-measures analysis of variance on ranks (Dunnett's post hoc test).

Figure 2. Duration of fentanyl infusion (gray bars) and fentanyl taper (black bars) for each patient in study.

Twenty-one patients had no opioid abstinence syndrome during fentanyl taper, after discontinuation of fentanyl, or during methadone taper. In the single case of opioid abstinence syndrome, a 9-year-old girl was treated for pulmonary hemorrhage and received 16 days of fentanyl by continuous infusion (maximum dosage 7 µg/kg/hr and cumulative dose 1847 µg/kg). Sedation also was maintained with continuous midazolam infusion (maximum dosage 0.3 mg/kg/hr). The patient was started on enteral methadone 0.15 mg/kg every 6 hours on day 8 and diazepam 0.1 mg/kg every 8 hours on day 7. Intravenous midazolam was tapered and discontinued over the next 7 days and sedation was maintained with enteral diazepam 0.1 mg/kg every 6 hours. Fentanyl was rapidly tapered from 6 µg/kg/hour beginning on day 12 and was discontinued on day 16. One day after fentanyl discontinuation, the patient developed extreme diaphoresis, tachypnea, agitation, disorientation, tremulousness, hypertension (mean arterial pressure 90-100 mm Hg), liquid stools, and abdominal pain. Her clinical condition significantly improved on day 18 after fentanyl was reinstituted at 2 µg/kg/hour and the dosage of methadone was increased to 0.30 mg/kg every 6 hours. The dosage of diazepam (0.1 mg/kg every 6 hrs) remained unchanged during this time. Fentanyl was continued for an additional 48 hours and was abruptly discontinued; thereafter, the patient remained calm and stable with no clinical manifestations of withdrawal. Diazepam and methadone were tapered over the next 13 and 29 days, respectively, without further patient compromise.

Time to fentanyl discontinuation correlated with the duration (days) of fentanyl infusion (r = 0.812, p<0.001; Figure 3) and cumulative dose of fentanyl (r = 0.796, p<0.001). Multicollinearity existed between variables and a best subsets regression analysis indicated that time to fentanyl discontinuation was best predicted by duration of fentanyl infusion. The computed model was as follows: time to fentanyl discontinuation (days) = -2.997 + (0.323 duration of fentanyl exposure in days) (r2 = 0.74).

Figure 3. Relationship between the duration of fentanyl infusion (days) and time to fentanyl discontinuation (r = 0.812, p<0.001, Pearson product moment correlation). Time to fentanyl discontinuation (days) = -2.997 + (0.323 duration of fentanyl exposure in days) (r2 = 0.74)

The starting dosage of methadone -- 0.50 ± 0.22 mg/kg/day -- was administered by nasojejunal tube most commonly in four divided doses. Fifteen patients required no further increase in the dosage (group 1). Seven patients (group 2) had the dosage empirically increased from 0.53 ± 0.27 mg/kg/day to a maximum 0.91 ± 0.37 mg/kg/day over 8.3 ± 5.2 days. The single patient with documented withdrawal was part of group 2, but no other patient in that group had evidence of opioid abstinence syndrome or pain that would have prompted increasing the dosage of methadone. Although group 2 was not statistically different in demographics from group 1, those patients had a higher rate of fentanyl administration immediately before starting the fentanyl taper, 8.1 ± 4.1 and 3.6 ± 2.4 µg/kg/hour, respectively (p=0.004). Group 2 had greater cumulative fentanyl exposure than group 1, 2624 ± 2357 µg/kg and 1164 ± 857 µg/kg, respectively (p=0.043); however, there was no significant difference in the duration of fentanyl administration (20.1 ± 13.6 days group 2, 16.7 ± 4.8 days group 1, p=0.38). Group 2 showed a trend toward a longer time to taper and discontinue fentanyl (4.9 ± 3.9 days) compared with group 1 (2.7 ± 1.9 days), but the difference was not significant (p=0.086).

Nineteen patients had the methadone dosage tapered and discontinued before discharge. The mean time to methadone discontinuation was 18.2 ± 11.9 days after discontinuation of fentanyl. The remaining three patients were discharged after 16.7 ± 7.8 days, and no follow-up information was available regarding completion of the methadone taper. Groups 1 and 2 did not differ significantly in time to taper and discontinue methadone. No patient developed opioid abstinence syndrome during the methadone wean.

All 22 patients received midazolam by continuous infusion. The mean duration was 16.6 ± 8.5 days with a cumulative dose of 63.9 ± 49.9 mg/kg. All patients had the benzodiazepine dosage tapered slowly. After the drug was discontinued, 20 patients received a tapered regimen of an oral or enteral benzodiazepine (lorazepam or diazepam) for an additional 15.1 ± 12.8 days. In the remaining two patients, intravenous midazolam was tapered slowly without administering an oral benzodiazepine.

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