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Methadone versus morphine for treatment of neonatal abstinence syndrome: A prospective randomized clinical trial

Abstract

Objective:

Compare duration of treatment of neonatal abstinence syndrome between methadone and morphine.

Study design:

A prospective, double-masked, randomized trial at a single site. Randomization of methadone or morphine was stratified for maternal treatment with methadone or buprenorphine. Inclusion criteria were (i) maternal treatment with prescribed methadone or buprenorphine, (ii) withdrawal treatment criteria, (iii) adjusted gestational age 350/7 weeks and (iv) medically stable. Primary outcome was length of opioid treatment.

Result:

From January 2011 through October 2012, 78 infants were eligible for the study: 41 methadone-exposed and 37 buprenorphine-exposed. Consent was obtained from 31 mothers, 13/41 (32%) methadone-treated and 18/37 (49%) buprenorphine-treated. Length of opioid treatment was significantly shorter for methadone than morphine treatment, median 14 versus 21 days (P=0.008).

Conclusion:

Methadone had a shorter length of neonatal withdrawal treatment compared with morphine. Owing to the smaller sample size and single site, a larger randomized study is needed.

Introduction

The rise in births of opioid-exposed infants is a result of an increase in prescription opioid abuse and subsequent entry into replacement programs among reproductive-aged women.1, 2, 3 This increase has been fueled by superior pain control, diversion that increases availability of opioid medications and the strong dependency that often develops with continued use. Infants exposed to opioids during the prenatal period frequently have signs of withdrawal, termed neonatal abstinence syndrome (NAS). The initial approach to the treatment of NAS is a dedicated program of non-pharmacologic supportive care. The decision to begin drug therapy is based on the failure of supportive care to effectively control the escalation in signs of withdrawal which occurs in over half of opioid-exposed infants.4 To make treatment decisions, withdrawal signs are usually quantified by one of several abstinence scales.5, 6, 7 A number of different medications have been used to treat NAS including opioids such as dilute deodorized tincture of opium (dDTO), morphine, methadone and buprenorphine and non-opioids like the noradrenergic antagonist clonidine and phenobarbital.4 There is a lack of quality, evidence-derived information to guide the choice of one treatment over another, giving rise to heterogeneity in treatment approaches.

Recent surveys have enumerated the range and frequency of the more common treatment choices. In 2006, Sarkar and Donn8 published a survey regarding treatment for NAS from 102 neonatal intensive care units in the United States. There was a return of 75 surveys (73.5%). dDTO and morphine sulfate were most commonly used for opioid withdrawal (63%), followed by methadone (20%). Phenobarbital was the most common second-line drug in infants treated with opioids. In 2009, O’Grady and coworkers9 published a similar survey concerning treatment for NAS from 235 neonatal intensive care units in the United Kingdom and Ireland with a return of 211 (90%). Morphine was the most commonly used medication (92%) for NAS treatment and phenobarbital was the most common second-line drug.

The 1998 AAP guidelines on NAS recommended dDTO as the drug of choice for treating neonatal opioid withdrawal.6 This followed the concept of using a drug for treatment from the same class, opioids, as that causing withdrawal.10 After the release of these guidelines, there have been several studies published that have compared opioid treatments for NAS. Langenfeld and coworkers11 randomized treatment between dDTO and morphine in 38 infants. They did not find any differences in duration of treatment or length of stay. The opioid exposure that was identified in meconium, when available, was methadone and heroin, although this was not further linked to treatment efficacy or length of stay. Lainwala and coworkers12 reported a retrospective study of two different oral morphine preparations (dDTO or neonatal morphine solution) versus methadone for the treatment of NAS. Maternal drug exposure included opiates and methadone. There was no significant association between length of stay and treatment group or other factors including gestation, gender, nicotine use, polydrug use or opiate exposure. Increased length of stay was associated with maternal methadone dose, heavier birth weight and higher doses for NAS treatment although not broken down specifically by maternal treatment grouping. A recent randomized open-label trial compared sublingual buprenorphine with neonatal opium solution for the treatment of NAS in 26 infants. All infants had been prenatally exposed to methadone. There was no difference in length of treatment or hospitalization in buprenorphine-treated infants compared with morphine-treated infants.13 The 2012 update of AAP guidelines modified the NAS treatment recommendations to either methadone or neonatal morphine solution in part based on the high alcohol content of dDTO.4

In view of the above literature and recommendations, and in the absence of a randomized trial comparing methadone with morphine, this trial was set up to compare the treatment of NAS between methadone and morphine.

Methods

Study design

This was a single-site, randomized, double-masked inpatient treatment trial conducted between January 2011 and October 2012 in infants treated for NAS to compare the days of treatment with either methadone or morphine. The primary outcome of this trial was to test the hypothesis that treatment of NAS with methadone would require fewer days of opioid treatment compared with morphine. This was based on the longer half-life of methadone which could provide less variation in blood levels during weaning compared with morphine.14 The secondary outcome was comparison of the proportion of infants between groups with treatment failure as evidenced by rescue treatment with a second drug.

Study inclusion criteria were: (i) prenatal exposure to prescribed methadone or buprenorphine, (ii) meeting our NAS treatment criteria, (iii) adjusted gestational age of 350/7 weeks assessed from best menstrual, obstetrical and physical exam criteria, and (iv) otherwise medically stable in the opinion of the attending neonatologist. Exclusion criteria were: (i) medical illness requiring continued stay in the Neonatal Intensive Care unit making intravenous treatment necessary and withdrawal difficult to assess, (ii) evidence of major congenital anomalies or genetic syndromes that would impact the neonatal course and (iii) mother also taking prescribed benzodiazepine at the time of delivery based on urine screen and confirmed self-report. The protocol was reviewed and approved by the Institutional Review Board for Eastern Maine Medical Center. Care was provided in the Neonatal Intensive Care and Pediatric inpatient units.

Procedure

Upon admission in labor, mothers who were in medication-assisted treatment for opioid dependence with either methadone or buprenorphine submitted urine for screening of illicit and prescription drugs. After delivery, infants were cared for using standard rooming in and nursery care, and infant meconium was similarly screened. Withdrawal severity was assessed using a modified Finnegan scoring scale, which is the customary tool to assess withdrawal at Eastern Maine Medical Center.7 All nursing staff had standardized training and met scoring competencies. Our policy has been to observe all prenatally opioid-exposed infants for a minimum of 5 days for severity of withdrawal meeting treatment criteria. Infants were scored every 4 h and treatment criteria was 2 out of 3 sequential scores of 9 or a single score 13.11, 12, 13,15

Study treatment

Randomization was computer-generated by the institutional pharmacy into blocks of six with masked assignment to either methadone or morphine. Randomization was stratified for maternal prescribed methadone or buprenorphine. Methadone was mixed from powder, dissolved in sterile water and mixed with syrup. Morphine injectable was used and mixed with syrup. To maintain masking, both treatment medications were clear and at a concentration of 1 mg ml−1. Infants were on cardiorespiratory monitors during the initiation of treatment.

Thirty-one infants were randomized to treatment with methadone or morphine. Starting dose for either treatment medication was based on the severity of qualifying scores and was either 0.05 (12) or 0.1 mg kg−1 (>12), given every 4 h. This treatment protocol was the one in current use for treating infants with NAS. Stabilization was assessed every 12 h and the dose was increased by 0.05 mg kg−1 dose−1 as needed to a maximum dose of 0.2 mg kg−1 dose−1 until the scores were stabilized 8. Maximum dose was not needed in any newborn enrolled in the study. Weaning was started when withdrawal stabilized with NAS scores 8 for 24 to 36 h. Weaning was assessed daily and decreased by 10% of stabilizing dose using a dated weaning schedule provided by the pharmacy to maintain NAS scores 8. After the last dose, there was a minimum of 36 h for the observation of rebound withdrawal before discharge.

Intolerance of weaning of opioid medication was defined as 2 out of 3 sequential Finnegan scores of 9 in the 12 h prior to the next dose to be weaned. The wean was held at the current level unless scores remained 9 for 12 h, at which time an extra dose of study drug was given. If withdrawal re-emerged after this dose, the maintenance dose was increased to the previous dose. Weaning schedule was resumed when scoring criteria were reached again. Failure to wean twice in a 4-day period was the criterion to add a second drug. If rescue drug failed, the infant was removed from the study and treated with standard hospital protocol. Analysis was by intention-to-treat.

Clonazepam or phenobarbital was added as a rescue medication when infants were not able to be weaned on study drug. Clonazepam has been our first-line adjunct treatment16 although phenobarbital was used if parents were concerned about over sedation with clonazepam. The second drug protocol was as follows: clonazepam was begun at 0.005 mg kg−1 dose−1 every 8 h. When stabilized, opioid study medication was weaned and stopped per weaning schedule. Clonazepam was then weaned over 72 h and the infant was observed for 36 h before discharge. Phenobarbital was begun using two loading doses of 10 mg kg−1 given 8 h apart followed by maintenance of 2.5 mg kg−1 dose−1 12 h afterwards. After stabilization on phenobarbital, the study drug was weaned and the infant discharged on phenobarbital to be weaned as an outpatient.

Sample-size estimation

Sample size was estimated using the PASS program (version 2000, J Hintze, Cruncher Statistical Systems, Kaysville, UT, USA). Estimates of variability were based on our historical data. We felt that a 4-day difference in treatment time would be clinically meaningful. The number of infants was 21 per group to provide power of 0.8 and alpha of 0.05 for two-sided comparison. Using current admission rate, mix of buprenorphine- and methadone-exposed infants, treatment rates, and consent rate of 50%, the estimated study period was 18 months. This was planned as a pilot study for a multi-centered trial that would include developmental follow-up.

Statistical analysis

Group comparisons of continuous data were made using Student’s t-test or Wilcoxon rank-sum test where appropriate. Categorical variables were compared using Chi square or Fisher’s exact test. Primary outcome measure was length of study drug treatment rather than length of hospital stay as the latter would be influenced by social evaluations and, in some cases, by infants discharged on phenobarbital which was tapered after discharge.

Results

During the study period from January 2011 through October 2012, 198 methadone-exposed and buprenorphine-exposed infants were admitted to the NICU service on either NICU or Pediatric inpatient units and screened for withdrawal as shown in Figure 1. All were singleton pregnancies. Ninety-four of these infants, 47%, had withdrawal severe enough to meet treatment criteria. One infant was 344/7 weeks by obstetrical dates, 353/7 by menstrual and exam dates and was entered based on menstrual dates and exam. Those excluded were as follows: clinical instability requiring continued NICU care when treatment was begun (n=13), major congenital anomalies (n=2) and failure to consent for social reasons (n=1).

Figure 1
figure1

Screening, exclusion, consent rate, randomization and rate of treatment completion by study group—methadone or morphine.

Consent was declined by 47 of the parents of eligible infants (60%) most citing that they wanted to know what medication was used to treat their infant. This rate of consent is consistent with other studies we have done in this population. There were no significant differences between those who consented or declined study entry for maternal age, parity or when they had entered treatment; the majority of mothers were in medication-assisted treatment at the time they discovered they were pregnant, 90% of those on methadone and 83% of those on buprenorphine. Table 1 shows infant and maternal characteristics. There were no significant differences between those assigned to methadone or morphine treatment groups for maternal age, parity, breast feeding rates or illicit exposures based on urine drug screens upon admission or infant meconium. One mother in the methadone-exposed group was treated with an selective serotonin reuptake inhibitor and another was on Adderall. Median maternal dose of buprenorphine was not different between treatment groups although median maternal methadone dose was lower in the methadone treatment group compared with the morphine group (P=0.03).

Table 1 Baseline characteristics of study groups

At 21 months, study entry was stopped with an enrollment of 31 participants as shown in Figure 1. Study consent was obtained from 32% (13/41) of parents of methadone-exposed infants and 49% (18/37) of buprenorphine-exposed infants. The study was closed because of the longer estimated length of time to accrue projected enrollment.

Primary outcome

Figure 2 shows the length of opioid treatment which was significantly shorter for the methadone-treated infants, 14 days, compared with morphine-treated infants, 21 days, (P=0.008) (Table 2). In a simple contrast in the methadone-exposed infants, those treated with methadone had shorter median length of treatment, 14.5 days, compared with those treated with morphine, 25 days (P=0.004) (Table 2).

Figure 2
figure2

Comparison of length of opioid treatment (days) between methadone-treated and morphine-treated infants. Each individual infant’s length of treatment with either methadone or morphine is represented by a black dot. The horizontal black line represents the median for each group which is significantly different between groups (P=0.008).

Table 2 Outcomes of opioid treatment for study groups

Secondary outcome

As shown in Table 2, the use of rescue drug occurred less often in methadone-treated infants, n=6, than in morphine-treated, n=9, although this was not significant (P=0.64). In buprenorphine-exposed infants, this rate was essentially the same between groups, whereas in methadone-exposed infants, most of those treated with rescue drug were in the morphine-treated infants. One of the morphine-treated infants failed weaning and did not respond to treatment with phenobarbital. This infant was removed from the study and treated with methadone, which was our current standard treatment. The length of opioid treatment was analyzed according to the intent to treat. Ad hoc analysis excluding this infant showed that the length of opioid treatment remained significant (14.5 versus 22 days, P=0.007).

Discussion

In this randomized, double-masked trial, we found that NAS treatment with methadone was more effective in our population than treatment with morphine. These findings suggest that the choice of medication treatment can influence outcomes of NAS treatment which may have some specificity to the prenatal opioid exposure. It can be difficult to isolate treatment effects, such as for NAS, even in a randomized, double-masked study because other sources of variability may not distribute evenly in a smaller sample size. Other sources of variability associated with the infant’s response to NAS treatment have included maternal opioid exposure,17 breast-feeding,18, 19, 20 rooming-in21 and genetic variations in opioid metabolism.22,23 To address maternal opioid exposure, we stratified the randomization by prenatal methadone or buprenorphine exposure; the number of mothers who initiated breast-feeding was similar in both groups; rooming-in was variable during the inpatient stays because of our unit configurations and was not tracked. Exposure to illicit drugs, assessed by urine screen and meconium toxicology testing, showed a small amount of exposure to other opioids or illicit drugs. Single nucleotide polymorphisms in the μ opiate receptor and catechol-o-methyltransferase genes as well as methylation may impact the severity of NAS and response to treatment,22,23 and we have to speculate that genetic factors may have had some influence on our results although we were unable to evaluate their contribution in this study.

In a subgroup of infants treated inpatient for NAS, the treatment process is more complex and monotherapy is not as effective despite trying to minimize sources of variation. In these infants, combination drug therapy may be used.24 This underscores the variability of NAS where combination therapy can have the advantage of shortening the treatment period and the inpatient stay. Our study criterion for beginning rescue drug during failed weaning was targeted to minimize the inpatient stay. There were fewer infants in the methadone-treated group who were treated with a rescue drug consistent with our primary treatment effect, although this trend did not reach statistical significance.

There are several differences between methadone and morphine that are important in the context of this study. Methadone has a higher bioavailability, longer half-life and is metabolized by the P450 cytochrome enzyme pathway.25 It is a synthetic opioid agonist that selectively binds to the μ receptor exerting morphine-like effects. In adults, half-life estimates are 20 to 35 h with a wide range in variability.25 In newborns, there have been a limited number of pharmacokinetic studies with methadone and clearance rates have been similar to adults.26,27 In contrast, morphine is metabolized by glucuronidation in the liver and excreted by kidney. It has been studied more extensively in newborns than methadone, and its clearance, volume of distribution and half-life varies along gestation and postnatal age lines; half-life in term newborns is estimated to be 6.5 h and decreases with postnatal age.28,29 Pharmacokinetics of enteral administration for either drug has not been well studied nor has the bioavailability of the formulations we used. For purposes of masking and to minimize the effect of difference in half-life on duration of treatment, a 4-h dosing interval was used for both methadone and morphine treatment. Despite this, because of the substantial half-life differences, we may not have been able to achieve an equivalence effect even with this short treatment interval. For pain control, the mean dose ratio for oral methadone to oral morphine equivalence is 1:4.7 (confidence interval, 3.0 to 6.5).30 This type of equivalence ratio between methadone and morphine for withdrawal treatment in infants may exist and account for our findings; however, this approach has not been studied.

In addition to pharmacokinetics that may explain some of our findings, receptor affinities may contribute to a better response to methadone. Opioids, including morphine and methadone, have different opioid receptor affinities for each of the subgroups of opiate receptors—μ, δ and κ.31, 32, 33 One implication is that the broad opioid receptor action of methadone is generally more effective than morphine, which is specific to the μ receptor and more rapidly metabolized than methadone.34 Another implication is that because methadone and certain other opioids, excluding morphine, have NMDA antagonist effects in addition to their μ opioid effects, the difference in response of withdrawal between methadone and morphine may also, in part, be due to an NMDA antagonist effect by methadone.35 Further, the suggestion of better response of NAS treatment with methadone in methadone-exposed infants is of particular interest. This suggests that withdrawal in methadone-exposed infants might respond better to treatment with methadone because it has the same opiate receptor profile associated with prenatal opioid exposure. This is consistent with the possibility that specificity between exposure and treatment could extend to treatment of NAS from other opioid exposures.

There are important limitations to our study. First, this was a pilot study from a single site in which recruitment was lower than expected, particularly in the methadone-prescribed group (32%) compared with the buprenorphine-prescribed group (49%). This may limit the ability to generalize our findings to treating all infants with NAS. Second, the median maternal dose of methadone at delivery was significantly lower in the mothers of the methadone-treated infants. The information we have from retrospective studies suggests there may be a modest effect of higher maternal methadone dose on increased NAS severity although this has not held true in prospective studies such as ours.36 As this represents an association mostly from retrospective studies, dose could be a marker of other maternal severity factors such as genetic contributions to treatment severity. This needs further study to separate methadone dose effect from treatment effect in a larger sample. Finally, the ability to generalize our findings is limited because of the sample feature of our population which was primarily a European American sample, because opioid genetics varies by ethnicity.22

In conclusion, our findings are consistent with a more favorable response to treatment of neonatal opioid withdrawal with methadone compared with morphine. To some extent, these findings may be driven by differences in pharmacokinetics and pharmacology between methadone and morphine. Post hoc analysis suggests an interesting finding that treatment of neonatal withdrawal may be more responsive when individualized to prenatal opioid drug exposure. The limitations of single center and population require confirmation of these findings in a multicenter trial.

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Acknowledgements

We thank the infants and their families who participated in this trial, providers of EMMC NICU Professional Services (Ann Boomer NNP, Janice Gilbert NNP, Dave M. Roberts NNP, Deonne Thibodeau NNP, and Drs Kumar Akilesh, Mary Connolly, Jay Hagerty, and Alison Faulkingham) for their help with enrollment and conducting this trial, the EMMC Nursing Staff of NICU and Pediatrics for caring for these infants and families, and Ms. Sharon LaBrie for assistance with data collection. No external funding was secured for this study.

Author Contributions

Mark S. Brown: Dr Brown conceptualized and designed the study, carried out the initial analysis, drafted the initial manuscript and approved the final manuscript as submitted.

Marie J. Hayes: Dr Hayes’ work in the past has been funded by the NIH. She reviewed the design of the study and the analysis, critically reviewed the manuscript and approved the final manuscript as submitted.

Lynn M. Thornton: Dr Thornton handled the randomization processes, supervised the study assignments and medication preparation, collected data, reviewed and revised the manuscript, and approved the final manuscript as submitted.

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Brown, M., Hayes, M. & Thornton, L. Methadone versus morphine for treatment of neonatal abstinence syndrome: A prospective randomized clinical trial. J Perinatol 35, 278–283 (2015). https://doi.org/10.1038/jp.2014.194

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