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

Pharmacotherapy. 2001;21(12) 

In This Article

Discussion

Clinical and experimental evidence indicates that tolerance and physical dependence develop rapidly with continuous opioid exposure.[3,4,5,16] In children, continuous administration of fentanyl beyond 5-7 days increases the risk of opioid abstinence syndrome.[4,6,17] A striking neurologic syndrome characterized by movement disorders and agitation after discontinuing fentanyl occurred in five children who had received 7.8 ± 4.9 days of treatment.[17] All patients had myoclonus, ataxia, and choreoathetoid movements in various combinations. Neonatal abstinence syndrome occurred in 21 (57%) of 37 infants who received continuous fentanyl administration during extracorporeal membrane oxygenation.[4]Cumulative doses of fentanyl exceeding 1.6 mg/kg and continuous infusions longer than 5 days were associated with withdrawal. A cumulative fentanyl dose of 2500 µg/kg or higher or continuous infusion of 9 days or longer was 100% predictive of opioid abstinence syndrome.[6] Although the most appropriate rate of fentanyl discontinuation for these high-risk patients is not known, numerous investigators and clinicians recommended slow discontinuation to prevent development of the syndrome.[8,9,11] The weaning process for infusions may take 2-4 weeks in patients who have received prolonged fentanyl therapy.[8]

The results of this study suggest that low-dosage enteral methadone may be given to facilitate rapid fentanyl discontinuation without resulting in acute opioid abstinence syndrome, even in highest-risk patients who have received 9 or more days of continuous fentanyl infusion. In this study, only 1 of 22 children treated with methadone before fentanyl discontinuation developed the syndrome. It is noteworthy that our patients received fentanyl by continuous infusion for an average of 17.8 days and were therefore at very high risk for developing opioid abstinence syndrome.[6] We found that starting methadone approximately 1-2 days before beginning the fentanyl taper enabled us to discontinue fentanyl rapidly in a median of 2.6 days. Although there was no control group, experience dictates that a significantly longer taper is required to prevent manifestations of opioid abstinence syndrome in patients who have received fentanyl for this length of time.[8,9,11] The time to fentanyl discontinuation was strongly influenced by the duration of infusion, perhaps because prolonged exposure resulted in clinicians being less aggressive in discontinuing the agent. More recently, our experience suggests that all patients may be aggressively weaned from fentanyl, as long as methadone is begun first.

The optimal dosage of methadone to treat or prevent opioid withdrawal in the PICU is unknown. In several case reports 0.1 mg/kg administered every 12 hours effectively controlled the signs and symptoms of narcotic withdrawal in children.[13] However, in more recent publications, it was suggested that larger dosages might be required in some patients.[8,12] We concur with this observation, and our minimum methadone dosage in the fentanyl-weaning protocol was 0.1 mg/kg every 6 hours; however, in the subgroup of patients (group 2) who were seemingly at higher risk for withdrawal, the dosage was empirically increased from 0.53 to 0.91 mg/kg/day, although only one patient in this group experienced withdrawal. This patient ultimately required a dosage of 1.2 mg/kg/day to control the signs of opioid abstinence syndrome. This subgroup of high-risk patients received a significantly higher cumulative dose of fentanyl (2624 µg/kg) and a higher infusion rate (8.1 µg/kg/hr) than the rest of the patients. Although the trend was toward a longer time to fentanyl discontinuation in this group (4.9 days group 2, 2.7 days group 1), this still represents a relatively rapid discontinuation of fentanyl.

Some investigators suggested that the dosage of fentanyl be converted to an equipotent dosage of methadone either to prevent or treat opioid withdrawal in PICU patients.[8,12,18,19] However, our approach of empirically starting methadone at 0.1 mg/kg every 6 hours should not be viewed as a conversion from fentanyl to an equivalent dosage of methadone. Moreover, we recommend against using an "equivalent" dosage of methadone to treat or prevent withdrawal since this pharmacokinetic approach usually results in methadone dosages that are unnecessarily high for this indication. Furthermore, the half-lives of fentanyl and methadone in such calculations must be specific for a critically ill pediatric population, otherwise the dosage conversion is likely to be erroneous. For example, a dosage conversion using a fentanyl:methadone half-life ratio of 1:50-100 (based on a 30-minute fentanyl half-life) and a 100:1 fentanyl:methadone potency ratio was recommended.[18] Although these proposed ratios result in a relatively low and reasonable calculated dosage of methadone for prevention of withdrawal,[12,18] more accurate estimates of fentanyl and methadone half-lives in critically ill children result in a calculated equivalent dosage of methadone that is very large. For example, in perioperative children, methadone's half-life was 19 hours,[20] and in critically ill children, fentanyl's half-life after prolonged infusion was 21.1 hours,[21] which represents a 1:1 ratio of half-lives. Thus, if the daily dose of fentanyl is multiplied by 100 to account for the potency difference and divided by approximately 1 to account for the difference in half-lives, one arrives at an "equivalent" dosage of methadone (assuming similar distribution volumes) that greatly exceeds dosages necessary to prevent opioid withdrawal. This likely would result in prolonged opioid dependence and a longer opioid taper.

Unless a patient requires continued sedation or treatment of pain, our experience is that the low dosage of methadone reported here, followed by titration if necessary, is reasonable and sufficient for treatment and prevention of withdrawal, regardless of the dosage or duration of fentanyl treatment. Our regimen is also more consistent with the recommendation of methadone 0.05-0.1 mg/kg every 6 hours to treat withdrawal, with increases of 0.05 mg/kg until symptoms are controlled.[9]

We found that methadone was tapered in an average of 18 days. This is significantly faster than the 5-6 weeks reported in a similar PICU population.[12] However, a faster 10-day taper was reported in PICU patients who received an average of 18 days of opiate infusion,[19] although those patients apparently received lower dosages of fentanyl (median 2.5 µg/kg/hr) than patients in our study.[22] Nevertheless, that report causes us to speculate whether our methadone weaning schedule may be accelerated. Additional research is necessary to determine the minimum time to taper and discontinue methadone.

Aside from inherent biases associated with a retrospective design, limitations of this study include the potential for incomplete docu-mentation of withdrawal in medical records and lack of a validated scoring tool for defining abstinence syndrome in critically ill children. We attempted to minimize the former by thoroughly evaluating all sources of medical documentation, including nurses' progress notes, which often provide a detailed hour-to-hour account of the patient's condition. Regarding the latter, other investigators used the Finnegan rating scale[15] in evaluating patients in the PICU.[6,12] However, this tool was designed for use in newborns and its validity in older children has not been determined. Accordingly, we defined opioid abstinence syndrome as the presence of any number of signs that may have interfered with the comfort or care of patients and that occurred within 72 hours of fentanyl or methadone dosage reduction. Although it is possible that subtle signs of mild abstinence syndrome may have been missed as a result of retrospective analysis, we are confident that moderate-to-severe withdrawal requiring treatment was effectively assessed.

The final limitation of this study is that benzodiazepine withdrawal theoretically may have confounded the analysis of opioid abstinence syndrome. However, the potential for benzodiazepine withdrawal was minimized by slowly tapering drugs over an average of 15 days, which extended well beyond the period during which fentanyl was rapidly discontinued. Since benzodiazepines are known to attenuate opioid abstinence syndrome, we speculate that the slow taper of enteral benzodiazepines may have reduced the chance of developing opioid withdrawal while at the same time minimizing the development of benzodiazepine withdrawal. This should not be viewed as methodologically problematic since administration of concomitant benzodiazepines for sedation is common in the PICU. Finally, we attempted to minimize the confounding nature of benzodiazepine withdrawal by requiring that the definition of opioid abstinence syndrome include attenuation or reversal of signs and symptoms with additional or increased dosages of opioids. In the only patient with the syndrome, signs and symptoms were significantly improved after reinstituting fentanyl and increasing the dosage of methadone. Accordingly, we are confident that this patient had opioid abstinence syndrome and not benzodiazepine abstinence syndrome.

Methadone is clearly not the only treatment of opioid abstinence syndrome. Barbiturates, benzodiazepines, clonidine, chlorpromazine, and tincture of opium have been given with variable success to treat neonatal abstinence syndrome.[9] In the PICU, it is often convenient and intuitive to treat fentanyl withdrawal with additional doses of fentanyl and an increased rate of infusion. However, in many institutions, prolonged taper of intravenous fentanyl may delay transfer from the PICU. Subcutaneous administration of fentanyl is effective in preventing withdrawal in high-risk PICU patients.[23] However, this method of administration may not be as convenient or as cost effective as administering methadone orally or enterally. In addition, much experience has been gathered with methadone, as it is widely administered for opioid detoxification in adults and for treating fentanyl-dependent children.[8,9,12]

Whereas some may think that methadone sends an undesired message to parents,[24] we believe that appropriate parental education easily overcomes concerns about addiction. The advantages of methadone include its long serum half-life permitting infrequent administration, its low cost, and its availability in both parenteral and liquid dosage forms.

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