Opioid tapering and weaning protocols in pediatric critical care units: a systematic review

Bichaff, Pedro; Setani, Karina T; Motta, Emiliana H. G; Delgado, Artur F; Carvalho, Werther B; Luglio, Michele

doi:10.1590/1806-9282.64.10.909

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Revista da Associação Médica Brasileira

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Original Article • Rev. Assoc. Med. Bras. 64 (10) • Oct 2018 • https://doi.org/10.1590/1806-9282.64.10.909 copy

Opioid tapering and weaning protocols in pediatric critical care units: a systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

SUMMARY

OBJECTIVE:

Opioid abstinence syndrome is common in the pediatric intensive care environment because sedation is often needed during the children's treatment. There is no specific guideline regarding the management of these patients; and lately, methadone is an important drug for the prevention of abstinence symptoms during the weaning of opioids. This study gathers the available research to establish the initial dose of methadone, the rate of taper and tools to recognize this syndrome and act promptly.

METHODS:

A systematic review was made from data of four different databases. Forty-nine articles of observational and experimental studies were selected based on the inclusion criteria (critical pediatric patients in acute use of opioids) and exclusion criteria (previous chronic use of opioids, other medications). The data regarding specific themes were separated in sections: initial dose of methadone, use of protocols in clinical practice, abstinence scales and adjuvant drugs.

RESULTS:

The articles showed a great heterogeneity of ways to calculate the initial dose of methadone. The pediatric intensive care units of the study had different weaning protocols, with a lower incidence of abstinence when a pre-defined sequence of tapering was used. The Withdrawal Assessment Tool – 1 was the most used scale for tapering the opioids, with good sensitivity and specificity for signs and symptoms.

CONCLUSION:

There is still little evidence of other medications that can help prevent the abstinence syndrome of opioids. This study tries to promote a better practice during opioid weaning.

KEYWORDS:
Review; Critical Care; Analgesics, Opioid; Child; Substance Withdrawal Syndrome

Author	Study design (evidence)	Population	Initial dose	Withdrawal	Outcomes	Example (weight: 10kg, fentanyl 10mcg/h)
Bowens et al. (⁸8. Bowens CD, Thompson JA, Thompson MT, Breitzka RL, Thompson DG, Sheeran PW. A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions. Pediatr Crit Care Med. 2011;12(5):504-11.)	Prospective Randomized Trial (IB)	n=78, 1-36 mo	“low-dose” (0,1mg/kg/ dose) n=34 vs “high-dose” [0,1mg/kg/dose x recent fentanyl (mcg/ kg/h)] n=26	No difference of incidence between the groups	No significant difference of oversedation incidence. Patients that failed to complete the assigned taper (18/78) had longer PICU length of stay and more days of ventilation	Methadone dose: 1mg
Lugo et al. (⁹9. Lugo RA, MacLaren R, Cash J, Pribble CG, Vernon DD. Enteral methadone to expedite fentanyl discontinuation and prevent opioid abstinence syndrome in the PICU. Pharmacotherapy. 2001;21(12):1566-73.)	Retrospective (III)	n=22, 6,1 ± 5,4 yrs	0,5 ± 0,22 mg/kg/dia q6h. Group (1) n=15 no need of dose increase; Group (2) n=7 dose was increased to 0,91 ± 0,37 mg/kg/dia	There was no withdrawal	No significant difference regarding the duration of taper	Methadone dose: 1,25mg
Johnson et al. (¹⁰10. Johnson PN, Miller J, Harrison D. Evaluation of initial methadone dosing for prevention of iatrogenic opioid abstinence syndrome in children. J Pediatr Intensive Care. 2012;1(2):105-13.)	Retrospective (III)	n=55, 0,03-12,2 yrs	initial “low-dose” <0,84mg/kg/dia n=27 vs initial “high-dose” ≥ 0,84mg/kg/dia n=28	No difference of incidence between the groups	No significant difference regarding length of stay in PICU	Methadone dose: 2,1mg
Siddappa et al. (¹¹11. Siddappa R, Fletcher JE, Heard AM, Kielma D, Cimino M, Heard CM, et al. Methadone dosage for prevention of opioid withdrawal in children. Paediatr Anaesth. 2003;13(9):805-10.)	Retrospective (III)	n=30, 0,1 – 16,2 yrs	methadone (mg) = 3 x daily fentanyl dose (mg)	There was a significant difference of withdrawal incidence: 78% (7/9) of those who used ≤ 80% of the initial dose had symptoms in comparison with 14% (3/21) of the patients with the initial dose of >80%		Methadone dose: 0,72mg
Jeffries et al. (¹²12. Jeffries SA, McGloin R, Pitfield AF, Carr RR. Use of methadone for prevention of opioid withdrawal in critically Ill children. Can J Hosp Pharm. 2012;65(1):12-8.)	Retrospective (III)	n=43, 0,25-201 mo	methadone (mg) = morphine (mg)	42% had withdrawal symptoms
Meyer et al. (¹³13. Meyer MM, Berens RJ. Efficacy of an enteral 10-day methadone wean to prevent opioid withdrawal in fentanyl-tolerant pediatric intensive care unit patients. Pediatr Crit Care Med. 2001;2(4):329-33.)	Prospective (III)	n=29, 1 day – 19,8 yrs	enteral methadone (mg) = morphine IV (mg) x 2 = fentanyl (mcg/h) x 120	14% (4/29) had withdrawal symptoms		Methadone dose: 1,2mg
Robertson et al. (¹⁴14. Robertson RC, Darsey E, Fortenberry JD, Pettignano R, Hartley G. Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatr Crit Care Med. 2000;1(2):119-23.)	Prospective comparison of protocol vs control groups (III)	n=20, 6 mo – 18 yrs	enteral methadone (mg) = morphine (mg) = daily fentanyl (mcg) x 10	No difference of incidence between the groups (protocol vs control)		Methadone dose: 2,4mg

Author	Study (evidence)	Population	Protocol	Rescue	Abstinence score	Groups	Incidence of abstinence	Secondary outcomes
Berens et al. (¹⁵15. Berens RJ, Meyer MT, Mikhailov TA, Colpaert KD, Czarnecki ML, Ghanayem NS, et al. A prospective evaluation of opioid weaning in opioid-dependent pediatric critical care patients. Anesth Analg. 2006;102(4):1045-50.)	Clinical trial (IB)	n=37, ≤ 18 yrs	Switch over fentanyl or morphine to enteral methadone using an initial dosage (“attack dosage ”) and a maintenance daily dosage. Comparison between 5 day weaning protocol reducing 20% of initial dosage + 5 days of placebo vs. 10 days weaning protocol reducing 10% of initial dosage.	Additional dose of methadone equal to the same dose administered the day before or 0,025mg/kg of morphine IV or 0,05mg/kg of methadone incrementally every 30 minutes	Neonatal Abstinence Score - Finnegan (NAS), modified Ramsay.	5 days (n=16) vs. 10 days (n=21)	No difference in incidence of abstinence between groups.	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
Steineck et al. (¹⁶16. Steineck KJ, Skoglund AK, Carlson MK, Gupta S. Evaluation of a pharmacist-managed methadone taper. Pediatr Crit Care Med. 2014;15(3):206-10.)	Case - control (III)	n=52, 1m – 16 yrs	Weaning protocol based on the risk of development of abstinence by the duration of opioid and by the accumulate dose of fentanyl. Initial dose ranges from 0,05 to 0,2mg/ kg/dose every 8 or 6 hours with reduction rate of 10% to 33% per day.	Additional dose of 0,05mg/kg of morphine IV every 2 hours if abstinence score between 9-11 or 0,1mg/kg if score ≥ 12	Modified Neonatal Abstinence Score - Finnegan (NAS)	pharmaceutic guided protocol (n=20) vs. regular protocol (n=32)	No difference in incidence of abstinence between groups.	A shorter weaning time of methadone (24,7 days vs. 15 days; p=0,003) and shorter length of hospital stay (38%) in the intervention group
Neunhoeffer et al. (⁴4. Neunhoeffer F, Kumpf M, Renk H, Hanelt M, Berneck N, Bosk A, et al. Nurse-driven pediatric analgesia and sedation protocol reduces withdrawal symptoms in critically ill medical pediatric patients. Pediatric Anesth. 2015;25(8):786-794.)	Clinical trial (IIB)	n=337, 0-18 yrs	Taper based on duration of opioid exposure: < 5 day - decrease of 50% of initial dose every 24hours; > 5 days - decrease of 10 to 20% every 24hours.	Dose of morphine, fentanyl and midazolam is adjusted according to COMFOT-B and NISS scale. The reduction is suspended for 24 hours if SOS ≥ 4	COMFORT-B, Nurse Interpretation Sedation Scale (NISS), Sophia Observation Withdrawal (SOS).	before protocol (n=165) vs. after protocol (n=172)	Lower incidence of abstinence after implementation of protocol (12,8% vs. 23,6%, p=0,005)	No difference in duration of mechanical ventilation, in days in ICU or total dosage of opioid.
Best et al. (¹⁷17. Best KM, Asaro LA, Franck LS, Wypij D, Curley MA; Randomized Evaluation of Sedation Titration for Respiratory Failure Baseline Study Investigators. Patterns of sedation weaning in critically ill children recovering from acute respiratory failure. Pediatr Crit Care Med. 2016;17(1):19-29.)	Prospective cohort (III)	n=145, 2 wks – 17 yrs	Group comparisons were made between patients with an intermittent weaning pattern, defined as a 20% or greater increase in daily opioid dose after the start of weaning, and the remaining patients defined as having a steady weaning pattern.	Not specified in the study	FLACC, Wong-Baker Faces, numerical scales to evaluate analgesia; State Behavior Scale; WAT-1.	intermittent pattern (n=66) vs. steady pattern (n=79)	Lower incidence of abstinence (WAT-1 ≥ 3) in the steady group: 46% vs. 85%, p<0,001. The tapering time of steady group was also shorter.	Comparison between protocol group and non-protocol group: lower length of mechanical ventilation (5,9 vs. 9,1 days, p<0,001), lower length of ICU stay (9,3 days vs. 12,8 days, p<0,001) and lower length of hospital stay (14 days vs. 21,5 days, p<0,001).
Robertson et al. (¹⁴14. Robertson RC, Darsey E, Fortenberry JD, Pettignano R, Hartley G. Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatr Crit Care Med. 2000;1(2):119-23.)	Clinical trial (III)	n=20, 6 m – 18 yrs	Weaning protocol based on duration of opioid exposure: 7 to 14 days: decrease of 20% every day (taper time of 5 days) > 14 day: decrease of 20% every 2 days (taper time of 10 days)	Not specified in the study	Scale based on signs and symptoms from Neonatal Abstinence Score.	protocol (n=10) vs. non protocol (n=10)	No difference in incidence of abstinence between groups.	Lower weaning time in protocol group (9 days vs. 20 days, p<0,001).

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[1] CORRESPONDING AUTHOR: Pedro Bichaff, Av. Dr Enéas Carvalho de Aguiar, 647 Sao Paulo - São Paulo - Brasil – 05403-000. E-mail: bichaff@gmail.com