A GUIDELINE WEANING OPIATE DEPENDENT INFANTS 1

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1 A GUIDELINE WEANING OPIATE DEPENDENT INFANTS 1 A Guideline Weaning Opiate Dependent Infants Lyn England Standing RN, BSN University of Utah College In partial fulfillment of the requirements for the degree of Doctor of Nursing Practice, May 2013

2 2 Table of Contents Table of Contents 2 Table of Figures 2 Executive Summary 4 Introduction 4 Problem Statement 6 Project Significance 8 Project Objectives & Purpose 9 Literature Review 9 Clinical Presentation 10 NAS Scoring Tools 11 Non-Pharmacological Treatments 12 Pharmacological Treatment 12 Guideline for Opiate Dependent Infants 13 Use of the Weaning Guideline 16 Project Implementation 16 Review of Evidence-based Literature 17 Development of Clinical Guideline 17 Dissemination of the Clinical Guideline 18 Evaluation 19 Scholarly Project Implementation and Evaluation Table 20 Scholarly Project Limitations 21 Conclusion 21

3 3 References Table of Figures Figure 1: Literature Search Results 28 Figure2: NAS Weaning Algorithm 29

4 4 Executive Summary The scholarly project will provide an evidence-based guideline for the pharmacologic management of infants suffering from neonatal abstinence syndrome. Neonatal abstinence syndrome increases the infant s length of hospital stay, impairs maternal-infant relationships, and impairs neurodevelopment (Patrick et al., 2012; Velez & Jansson, 2008). Sixty to 80% of infants whose mother took illicit opiates during pregnancy display signs and symptoms of NAS and the rate of infants diagnosed with NAS has increased from 1.2% to 3.4% from the year 2000 to 2009 (Bio, Siu, & Poon, 2011; Patrick et al., 2012; N. S. Seligman et al., 2010). An initial evidence-based literature review was conducted to assess outcomes of infants with neonatal abstinence syndrome medically managed with different medications such as morphine, phenobarbital, methadone, clonidine, and buprenorphine. Further literature reviews will insure inclusion of all current relevant studies. In this project, I will provide an evidencebased guideline to provide a standardized approach to the medical treatment of NAS. This proposal includes the process of implementation, evaluation of the guidelines, and submission of a manuscript to a scholarly journal. Introduction Opiates are a class of drugs commonly used for pain. Infants with transplacental exposure to opiates in the antenatal period may cause physical dependency in the infant causing them to experience withdrawal when the opiates are removed at birth. Neonatal abstinence syndrome (NAS) consists of a myriad of symptoms including seizures, feeding difficulties and respiratory issues secondary to an opiate dependent infant experiencing withdrawal. An increasing number of infants with NAS are admitted to the neonatal intensive care unit (NICU) for treatment. NAS is comprised of a variety of symptoms caused by withdrawal

5 5 from opiate dependency. NAS symptoms vary depending on the drug, the dosage, and the length of exposure to the drug. Physical symptoms are classified as neurologic, gastrointestinal, and autonomic due to the concentration of the opioid receptors residing predominantly in the gastrointestinal and the central nervous systems (Bio, Siu, & Poon, 2011; Hudak & Tan, 2012; Kuschel, 2007). Additional negative outcomes secondary to NAS include increased length of hospital stay, increased financial costs, impaired mother- infant relationships, and neurodevelopmental impairment (Kuschel, 2007; Osborn, Jeffery, & Cole, 2010a; Patrick et al., 2012). The rate of infants diagnosed with NAS increased 1.2% to 3.4% between 2000 and 2009 (Patrick et al., 2012). In the state of Utah 4.7% of women delivering infants are positive for opiates (Buchi, Suarez, & Varner, 2012). The incidence rate of mothers using opiates at the time of their infant s birth was 5.6 per 1000 in 2009 (Patrick et al., 2012). Sixty to 80 percent of infants with mothers using opiates while pregnant display NAS symptoms (Bio et al., 2011; Patrick et al., 2012; Seligman et al., 2010). The treatment for NAS includes non-pharmacologic and pharmacologic treatment. Nonpharmacologic treatment modalities include: swaddling, pacifier use, holding, small high caloric feedings to optimize nutrition, consolidation of nursing care, and a quiet, dark environment to decrease stimulation. Pharmacologic treatment for NAS varies and can include opiates, phenobarbital, buprenorphine, methadone, clonidine, chlorpromazine, and diazepam (Bio et al., 2011; Kraft et al., 2008; Kraft & van den Anker, 2012; Lainwala, Brown, Weinschenk, Blackwell, & Hagadorn, 2005; Osborn et al., 2010a; Osborn, Jeffery, & Cole, 2010b). Assessment of neonates with NAS, pharmacological management, and outcomes are inconsistent; varying widely among clinicians. The purposes of this NAS guideline are to

6 6 provide an algorithm for the successful pharmacologic treatment of NAS, decrease the variability in treatment of infants with NAS, improve outcomes, and improved maternal-infant attachment. Problem Statement Opiates are a class of narcotics containing opium or a natural or synthetic derivative of opium. As a prescription medication opiates include: morphine, fentanyl, and oxycodone, and the most common illicit drug heroin. Infants exposed to opiates during pregnancy may become physically dependent and this leads to withdrawal when these drugs are removed at birth. An increasing number of infants with neonatal abstinence syndrome (NAS) are admitted to the neonatal intensive care unit (NICU) for treatment. NAS is comprised of a variety of symptoms caused by withdrawal from opiate dependency. The results from a national survey by the Substance Abuse and Mental Health Services Administration (2010) indicates that the highest use of illicit drugs during pregnancy in women aged 15 to 17 years of age. As the number of women using opiates during pregnancy increases so does the number of drug dependent infants requiring treatment for NAS. The rate of infants diagnosed with NAS increased from 1.2% to 3.4% from the year 2000 to 2009 (Patrick et al., 2012). In the state of Utah 4.7% of women delivering infants are positive for opiates (Buchi, Suarez, & Varner, 2012). Sixty to 80% of infants whose mother took illicit opiates while pregnant will display signs and symptoms of NAS ranging from irritability to seizures (Bio et al., 2011; Patrick et al., 2012; Neil S. Seligman et al., 2010). Negative outcomes from NAS include increased length of hospital stay, increased financial costs, feeding disorders and neurodevelopmental impairment (Patrick et al., 2012). The hospitalization cost for an infant with NAS is between $49,000 and $57,700 (Patrick et al.,

7 7 2012). Other costs related to NAS morbidities including neurodevelopmental impairment have not been estimated. NAS symptoms vary depending on the drug and the length of exposure to the drug. Physical symptoms of NAS are classified as neurologic, gastrointestinal, and autonomic due to the concentration of the opioid receptors in the gastrointestinal and the central nervous systems (Bio et al., 2011; Hudak & Tan, 2012; Kuschel, 2007). Neurological symptoms include sleep disturbances, irritability, hyperactive deep tendon reflexes, tremors, and seizures. Gastrointestinal symptoms include poor feeding, watery or loose stools, regurgitation, poor weight gain, and vomiting. The autonomic system symptoms include frequent yawning or sneezing, fever or diaphoresis, and mottling (Hudak & Tan, 2012). NAS negatively affects the maternal-infant attachment. The opiate exposed infant may develop dysregulation of behavioral, motor, and autonomic functions resulting in NAS symptoms. Mothers may interpret the NAS symptoms as being caused by poor mothering or failure to meet the infant s needs, thus increasing maternal guilt and anxiety (Velez & Jansson, 2008). Treatment for NAS includes non-pharmacologic and pharmacologic treatment. Nonpharmacological treatment modalities include swaddling and holding the infant, and providing a dark, quiet environment to keep the infant calm. Gastrointestinal symptoms are managed with providing adequate intake of fluid and electrolytes. Pharmalogical treatment for NAS varies and includes opiates, phenobarbital, buprenorphine, clonidine, chlorpromazine, and diazepam (Bio et al., 2011; Colombini et al., 2008; Kraft et al., 2008; Mazurier et al., 2008; Osborn, Jeffery, & Cole, 2010a, 2010b).

8 8 Assessment, pharmacological management, pharmacological drugs, and outcomes of infants with NAS are inconsistent; varying widely among individual clinicians. NAS causes multiple negative outcomes for the infant, the mother and other caregivers. NAS increases financial burden on individual families and society as a whole. The purpose of this project is to develop a clinical guideline for the successful pharmacologic treatment of NAS to reduce variability of treatment of infants with NAS to decrease negative outcomes and improve maternal-infant attachment. Project Significance Opiates are a class of drugs commonly used to treat pain. Prescription opiates include morphine, fentanyl, and oxycodone. Heroin is the main opiate that is an illicit drug. Exposure to opiates in the antenatal period may cause physical dependency that causes the infant to go through withdrawal when the opiates are removed. Neonatal abstinence syndrome (NAS) is a myriad of symptoms including seizures, feeding difficulties, and respiratory issues secondary to an opiate dependent infant experiencing withdrawal. The rate of infants diagnosed with NAS increased 1.2% to 3.4% from the year 2000 to 2009 (Patrick et al., 2012). In the state of Utah 4.7% of women delivering infants are positive for opiates (Buchi et al., 2012). The incidence rate of mothers using opiates at time of their infant s birth was 5.6 per 1000 in 2009 (Patrick et al., 2012). Sixty to 80 percent of infants with mothers using opiates while pregnant display NAS symptoms (Bio et al., 2011; Patrick et al., 2012; N. S. Seligman et al., 2010). NAS has many negative impacts that not only affect the infant and the infant s immediate family, but also society as a whole. Negative impacts from NAS include: physical symptoms affecting the neurologic, autonomic and gastrointestinal systems of the infant requiring an

9 9 increased length of hospital stay, increased financial costs, impaired mother infant relationships, and neurodevelopmental impairment (Kuschel, 2007; Patrick et al., 2012; Velez & Jansson, 2008). Project Objectives Review the evidence-based literature on opiate dependence in infants and management strategies for weaning. Identify and develop a clinical guideline for the neonatal intensive care unit to wean opiate dependent infants. Disseminate the clinical guideline to NNPs and neonatologist at Primary Children Medical Center. To prepare and submit a manuscript for publication. Purpose of the Guideline The purpose of this clinical guideline is to provide a standardized approach to pharmacological care of opiate dependent infants that can be individualized to control symptomatology associated with NAS. Control of the symptoms of NAS may allow for better nutrition, growth, sleeping patterns and maternal-infant relationships. Review of Literature The incidence of mothers who used opiates at the time of their infant s birth was 5.63 per 1000 in 2009 (Patrick et al., 2012). In Utah 4.7% of mothers are positive for opiates at the time of infant delivery (Buchi et al., 2012). Infants exposed to opiates during fetal life may develop physical dependency resulting in withdrawal symptoms when the opiates are removed. Neonatal abstinence syndrome (NAS) is the cluster of symptoms exhibited by infants experiencing opiate withdrawal (Bio et al., 2011; Patrick et al., 2012). Infants diagnosed with NAS require increased

10 10 length of hospital stay and neonatal intensive care unit (NICU) specialty care. The care needed by these infants increases cost of care, impairs the mother-infant relationship, and leads to dysfunction of the infant s neurologic, autonomic, and gastrointestinal systems (Bio et al., 2011; Kuschel, 2007; Patrick et al., 2012; Velez & Jansson, 2008). Sixty to 80% of the infants born to mothers who used opiates during pregnancy, present with NAS and require medical treatment (Bio et al., 2011; Patrick et al., 2012; N. S. Seligman et al., 2010). The infant s gestational age and metabolism, the opiate pharmacokinetics, the timing of the last opiate dose, and the duration of opiate exposure determine the onset and severity of symptoms experienced by an opiate dependent infant (Bio et al., 2011; D' Apolito, 2009; Dominguez, Lomako, Katz, & Kelly, 2003; Hudak & Tan, 2012; Thajam, Atkinson, Sibley, & Lavender, 2010). Differential diagnoses of illnesses that present with similar signs and symptoms include: central nervous system hemorrhage, hyperthyroidism, hypoglycemia, anoxia, hypocalcemia, hypomagnesemia, and infection. Clinical Presentation of NAS Neonatal Abstinence Syndrome (NAS) is a cluster of symptoms exhibited by infants experiencing opiate withdrawal (Bio, Siu, & Poon, 2011; Finnegan & MacNew, 1974; Patrick et al., 2012). The infant s gestational age and metabolism, the opiate pharmacokinetics, the timing of the last opiate dose, and the duration of opiate exposure determine the onset and severity of symptoms experienced by an opiate dependent infant (Bio et al., 2011; Dominguez, Lomako, Katz, & Kelly, 2003; Thajam, Atkinson, Sibley, & Lavender, 2010). Differential diagnoses of illnesses presenting with similar signs and symptoms include: central nervous system hemorrhage, hyperthyroidism, hypoglycemia, anoxia, hypocalcemia, hypomagnesemia, and infection.

11 11 NAS symptoms appear secondary to the action of opiates on noradrenaline synaptic terminals. Opiates bind to G protein-coupled delta, kappa, and mu receptors. The neurologic and gastrointestinal systems of the infant contain high concentrations of opiate receptors leading to the myriad of symptoms occurring with NAS. Neurological symptoms include: sleep disturbances, irritability, hypertonicity, high pitched crying, excessive sucking, hyperactive deep tendon reflexes, tremors, and seizures. Gastrointestinal symptoms include poor feeding and weight loss, watery or loose stools, regurgitation, poor weight gain, and vomiting. Additionally the infant s autonomic system is overactive causing frequent yawning, sneezing, fever or diaphoresis, and mottling (Dominguez et al., 2003; Katzung, Masters, & Trevor, 2009). NAS Scoring Tools Multiple scoring tools are available as a method to quantify the signs and symptoms of NAS, evaluate symptoms to determine if pharmacological treatment is required, and to titrate medications used for NAS. NAS scoring tools available include: the National Drug Withdrawal Scoring System by Lipsitz, the Neonatal Abstinence Scoring System by Finnegan, the Neonatal Narcotic Withdrawal Index, the Ostrea System, and the Neonatal Withdrawal Inventory. The American Academy of Pediatrics (AAP) recommended the Lipsitz scoring system in 1998 due to the ease of scoring, however in the latest clinical report on neonatal drug withdrawal the AAP no longer recommended one scoring tool over another (Hudak & Tan, 2012). The most comprehensive scoring tool is the Finnegan s Neonatal Abstinence Scoring System, but a modified Finnegan scoring tool is most commonly used to evaluate infants with NAS (Jansson, Velez, & Harrow, 2009; Sarkar & Donn, 2006; Zimmermann-Baer, Nötzli, Rentsch, & Bucher, 2010). Cumulative scores of 8 or greater while using the Finnegan s scoring system are indicative of neonatal withdrawal (Zimmermann-Baer et al., 2010). The evaluation and scoring

12 12 is performed by the bedside RN and is subjective. Inter-rater variability is high depending on the training of caregivers and their exposure with infants experiencing NAS. No research studies could be found determining the reliability and validity of the modified Finnegan scoring tool. Non-pharmacological Treatments Non-pharmacological treatments are indicated with all opiate-exposed infants to provide optimal support for improving comfort and minimizing symptoms of withdrawal (Velez & Jansson, 2008). Non-pharmacological treatments commonly used with infants exposed to opiates include swaddling, rocking, small high caloric feedings to optimize nutrition, consolidation of nursing interventions, and providing a quiet, dark environment to decrease stimulation (Jansson et al., 2009; Kuschel, 2007; Osborn, Jeffery, & Cole, 2010). Decreased NAS scores are associated with a prone sleeping position and breastfeeding. However, infants with NAS who are prone sleeping are at an increased risk for sudden infant death syndrome (SIDS) and must be carefully monitored (Dwyer & Ponsonby, 2009). Other therapies attempted in the past include rocking beds, relaxing baths, and waterbeds (Kuschel, 2007; Liu, Bjorkman, Stewart, & Nanan, 2011; Osborn et al., 2010). Pharmacological Treatment NAS symptoms undiminished by these non-pharmacological treatments require pharmacological treatment. Opiates and non-opiate medications that have been used or are currently used to treat infants with NAS include: morphine, methadone, paregoric, camphor, tincture of opium, diazepam, clonidine, phenobarbital, and chlorpromazine. In the formulation of this guideline paregoric, and diluted tincture of opium were excluded because they (1) are not available in the hospital formulary or (2) they have adverse effects making them inappropriate for use in infants. Paregoric solution contains the central

13 13 nervous system depressant ethanol and benzoic acid. Camphor contains benzyl alcohol which is converted to benzoic acid by the body. Benzoic acid can cause hypotension, central nervous system depression, renal failure, seizures, gasping syndrome, and mortality ("Benzyl alcohol: toxic agent in neonatal units," 1983; Gershanik, Boecler, Ensley, McCloskey, & George, 1982; "Neonatal drug withdrawal. American Academy of Pediatrics Committee on Drugs," 1998). Diluted tincture of opium is contains due to unstandardized amounts of alkaloid contents, significant dilution required increasing the chance of medication error, and after dilution it contains ethanol 0.19% (Bio, Siu, & Poon, 2011; "Neonatal drug withdrawal. American Academy of Pediatrics Committee on Drugs," 1998). Diazepam and chlorpromazine are not frequently used for NAS and have been found to increase sedation, late-onset seizures, poor sucking, and increased failure rate (Finnegan, Connaughton, Kron, & Emich, 1975; Kuschel, 2007). Diazepam contains sodium benzoate that increased jaundice by causing bilirubin to be dislodged and benzyl alcohol known to cause gasping syndrome, hypotension, CNS depression, mortality, and seizures (Gershanik et al., 1982; "Neonatal drug withdrawal. American Academy of Pediatrics Committee on Drugs," 1998). Further testing is required for chlorpromazine. Guideline for Opiate Dependent Infants The guideline to wean opiate dependent infants was produced to provide an algorithm for the successful pharmacologic treatment of NAS, decrease the variability in treatment of infants with NAS and improve outcomes by decrease the symptoms of withdrawal, increase the infants feeding tolerance and growth, and promote maternal-infant bonding (See Figure 2). Pharmacologic treatment for opiate dependency should be use only if NAS symptoms are unresponsive to non-pharmacological supportive treatments as evidenced by NAS scoring >8 via

14 14 the modified Finnegan s scoring tool, or >4 on the Lipsitz scoring tool. The guideline is based on the modified Finnegan scoring tool due to its prevalence (Sarkar & Donn, 2006). The initial medication used to control the symptoms of NAS is morphine, an opiate derivative and is metabolized in the liver via hepatic glucuronidation (Taketomo, Hodding, & Kraus, 2011). In a randomized, double blind, control trial involving 33 infants morphine measured the effectiveness of morphine drops versus diluted tincture of opium (Langenfeld et al., 2005). The results found morphine was as effective as diluted tincture of opium with similar Finnegan scores and better weight gain (Langenfeld et al., 2005). The use of morphine drops decreases the chances for error during dilution and morphine does not contain alcohol or alkaloids with potential side effects (Langenfeld et al., 2005). In a survey of neonatology divisions chiefs for fellowship neonatal- perinatal medicine programs 75 of 102 indicated opiates are most often the first line medication for opiate withdrawal (Sarkar & Donn, 2006). A randomized control trial involving 75 infants randomized oral morphine and oral phenobarbital (29). The group of infants receiving morphine had a shorter length of stay and better suppression of NAS symptoms than the infants receiving phenobarbital in infants with NAS and opiate positive mothers (L. Jackson, Ting, McKay, & al., 2004). Clonidine is the second medication used in this guideline that is initiated when NAS is unresponsive to Morphine. Clonidine is an alpha-2-adrenergic receptor antagonist metabolized in the liver. Alpha-2 adrenergic receptor antagonists decrease central catecholamine release, leading to decreased heart rate and vasomotor tone due to activating brain stem inhibitory neurons (Agthe et al., 2009; Taketomo et al., 2011). A retrospective study involving 14 infants receiving clonidine for management of NAS found a lower mean arterial pressure, heart rate, and core temperature in these infants however it remained within the normal acceptable ranges

15 15 (Leikin et al., 2009). The study also showed that clonidine did not cause respiratory depression, sedative effects, or seizures in these infants (Leikin et al., 2009). A randomized control trial involving 80 infants greater than 35 weeks gave 40 infants morphine with clonidine and 40 infants morphine with a placebo (Agthe et al., 2009). The results showed the amount of morphine required to control NAS symptoms was decreased, the severity of NAS scores were lower, and the length of stay is decreased when clonidine 1 mcg/kg every four hours is given in conjunction with tincture of opium equivalent to 0.4 mg/ml of morphine (Agthe et al., 2009). An initial study randomized control trial involving 26 infants indicated a non-significant difference between an oral opium solution and buprenorphine (Kraft et al., 2008). A follow up randomized study also involving 26 patients increased the initial buprenorphine doses to provide therapeutic serum levels. The results of the second study indicated an increased length of stay and treatment with morphine when compared to buprenorphine (Kraft et al., 2011). Methadone trials in infants have been done in the pediatric intensive care unit population including infants 6 months of age to 18 years (Robertson, Darsey, Fortenberry, Pettignano, & Hartley, 2000). The numbers of infants included in these studies were small and further studies with larger populations are needed. Phenobarbital is a barbiturate, sedative metabolized via glucuronide conjugation and hydroxylation in the liver. The microsomal enzymatic function of phenobarbital increases the excretion of opiates in opiate dependent infants at birth. A randomized, double blind control trial involving 75 infants whose mothers were taking methadone found that infants taking morphine had a decreased length of stay than phenobarbital, and phenobarbital required a second line of medication treatment (I. D. Jackson, Heidemann, Wilson, Power, & Brown, 2004). Phenobarbital is beneficial as an adjunct therapy for opiate treatment to minimize CNS

16 16 symptoms including irritability, insomnia and seizures. The average duration of outpatient treatment is 3.5 months (Coyle, Ferguson, Lagasse, Oh, & Lester, 2002). Use of the Weaning Guideline The NAS weaning guideline is not suitable for infants being treated for NAS at home. Morphine may cause respiratory depression, bradycardia, hypotension, and over-sedation. Clonidine does not exhibit respiratory depression or sedation, but it has been shown to decrease mean blood pressure and heart rate in infants even though these vital signs remained within normal ranges. Respiratory and blood pressure monitoring are required while the infant is receiving pharmacological treatment for NAS. Maternal history and drug testing is necessary to determine if opiates are the cause of NAS symptoms. The differential diagnoses of hyperthyroidism, hypocalcemia, hypoglycemia and sepsis must be ruled out to ensure the appropriate care of the infant. Non-pharmacological treatments should be initiated with the appearance of signs and symptoms of NAS, and should continue throughout the course of treatment. The lack of reliability and validity of the NAS scoring tools is problematic for providers caring for these infants. The current scoring tools available require psychometric testing and are a gap in the current care and management of NAS infants. Control trials testing the effectiveness of this guideline are required. Implementation The purpose of this scholarly project is to produce a clinical pharmacologic treatment guideline. I proposed four objectives including: a thorough review of evidence-based literature on opiate dependent infants and management strategies for weaning, development of a clinical guideline with an algorithm for weaning opiate dependent infants, dissemination of this guideline

17 17 to the NNPs and neonatologist in a local hospital, and to prepare and submit a manuscript for publication. The implementation of these objectives is described below. Review of Evidence-based Literature A search for evidence-based literature was performed in the CINAHL and PubMed databases from 1975 to March The search terms use to find relevant research on the management of opiate dependent infants included: neonatal abstinence syndrome, NAS, infants, opiate withdrawal, and management. All randomized control trials, retrospective and prospective trials found in peer-reviewed journals reporting management for NAS were included. Additional sources were found by examining the reference lists of retrieved articles. Articles using medications that are alcohol based or not available in the current formulary were excluded. The algorithm for weaning opiate dependent infants was produced using articles classified as level-one evidence per the Centre for Evidence Based Medicine from Oxford University. The articles located and included in this review are shown on Figure 1. A review of literature was synthesized and submitted to my scholarly project chair Professor Janice Morse for approval on October 1, An updated review of literature was submitted in December An updated and specifically focused literature review was developed and sent to Professor Janice Morse the scholarly project chair for approval on March 18, Further revisions were made with the recommendations of Professor Morse and the editor. The final revision of the evidence-based literature review was submitted with my manuscript on April 1, Development of a Clinical Guideline The development of a clinical guideline to wean opiate dependent infants was accomplished by integration new evidence-based literature with the initial results of the

18 18 evidence-based literature search. The algorithm for weaning opiate dependent infants was produced using articles classified as level-one evidence per the Centre for Evidence Based Medicine from Oxford University (OCEBM Levels of Evidence Working Group, 2013). The initial algorithm was submitted to the content experts for review on March 16, Revisions were made upon recommendations of the content experts and the project chair and the final guideline was submitted on April 14, Two content experts were secured for this project Dr. Walter Kraft and Dr. Karen Buchi who provided their CV and signed an agreement. My content experts provided critical feedback and recommendations through April Content experts are both actively interested in opiates and management strategies for weaning infants and were approved by the project chair, Janice Morse. Dr. Kraft has several research articles published regarding the pharmacological treatment for NAS. Each of the content experts provided a signed agreement and CV. Dissemination of the Clinical Guideline The clinical guideline for weaning opiate dependent infant was completed and sent to my project chair and content experts on April 1, Dissemination was achieved by submitting a manuscript to The Journal of Perinatology. A poster was created, and approved by the scholarly project chair, Janice Morse. A poster presentation was completed on April 18, A presentation has not been scheduled with the Neonatologists and NNPs at McKay Dee Hospital but will occur at a future date. The Journal of Perinatology was chosen to publish the clinical guideline for weaning opiate dependent infants. The manuscript was written per the scholarly journal s guidelines, edited, and approved by the scholarly project chair prior to submission. The manuscript was

19 19 submitted to The Journal of Perinatology on April 14, 2013 and is currently being reviewed by the Editorial Board. below. Evaluation The criteria for evaluation and successful completion of the objectives are discussed 1. The objective to review the evidence-based literature on opiate dependent infants and management strategies for weaning was fulfilled when the comprehensive evidencebased literature search was successfully completed and a thorough literature review integrating the evidence-based literature obtained was completed, edited, and approved by the scholarly project chair in March The objective to develop a clinical guideline for the neonatal intensive care unit for the pharmacologic treatment of opiate dependent infants was successfully completed by identifying content experts, obtaining their CV and agreement documentation, continuing communication via personal meetings and , and integrating their recommendations into a completed clinical guideline with an algorithm for opiate dependent infants. The clinical guideline was submitted and approved by the scholarly chair, Janice Morse in April The objective to disseminate the clinical guideline through a presentation to the Neonatologists and NNPs at a local hospital is scheduled for July The completion of this goal does not correspond to the implementation of this clinical guideline into their clinical practice. A presentation is in the process of being scheduled. 4. The objective to prepare a manuscript and submit for publication was successfully completed when The Journal of Perinatology was selected, a manuscript was prepared

20 20 according to the scholarly journals criteria and guidelines, approved by the scholarly chair, and the manuscript was submitted in April The Acceptance for publication by the scholarly journal of this manuscript is not required for successful completion of this objective. Scholarly Project Implementation and Evaluation Table Objective Implementation Evaluation 1. Review the evidence-based literature on opiate dependence in infants and management strategies for weaning. - Perform a systematic evidencebased literature search, and integrate information into a thorough literature review. - Continue to integrate new literature into the literature review as it becomes available. - The comprehensive literature search was performed. - A literature review integrating evidence-based literature was completed, edited, and approved by the scholarly project chair. 2. Develop a clinical guideline for the neonatal intensive care unit for the pharmacologic treatment of opiate dependent infants. 3. Disseminate the clinical guideline to NNPs and Neonatologists at Primary Children s Medical Center. 4. Prepare a manuscript and submit for publication to a scholarly journal. - Integrate information from the literature review into creating a clinical guideline for opiate dependent infants. - Ascertain content experts to provide recommendations and clinical experience to the scholarly project. - Create a presentation of the clinical guideline and obtain approval by the scholarly project chair. - Schedule a presentation with the Neonatologists and the NNPs prior to May Search scholarly journals and identify the scholarly journal for submission a manuscript. - Prepare the manuscript per the scholarly journals submission criteria and guidelines. - Submit manuscript after editing and approval of the scholarly project chair prior to May Content experts were identified and their CV and agreements were documented and obtained. - Recommendations from the content experts were integrated into the development of a clinical guideline. - A clinical guideline for the pharmacologic treatment of opiate dependent infants with an algorithm was completed and approved by the scholarly chair. - A presentation to the NNPs and Neonatologist in a local hospital is scheduled for July Although adoption of the clinical guideline is the desire, implementation of the clinical guideline is not required for the completion of this goal. - The Journal of Perinatology was selected. - A manuscript was prepared according to the scholarly journals criteria and guidelines, and approved by the scholarly project chair prior in April The manuscript was submitted for publication in April Acceptance for publication prior

21 21 to May 2013 is not required for the completion of this objective. Scholarly Project Limitations The guideline to wean opiate dependent infants has limitations including deficiency in available research and the absence of a trial of the guideline. There is limited level 1 research done on the pharmacological treatment of infants. Another limitation in the research with good external validity of the studies due to insufficient sample sizes. Insufficient sample sizes make it difficult to generalize the results to other populations. The second limitation to the guideline is the lack of testing for validity and reliability. Evaluation of the clinical guideline was not done due to the time constraints of the project and being a student. Convincing clinicians to implement this guideline without testing is difficult. Conclusion The increasing number of infants requiring pharmacological treatment for NAS exposes the necessity for an evidence-based, consistent approach to provide optimal care. The guideline to treat infants with NAS was produced to decrease the variability in the clinician approach, improve outcomes by decreasing the withdrawal symptoms, increase the feeding tolerance and growth of the infant, and promote maternal-infant bonding. The guideline is intended for use in a NICU with hemodynamic monitoring and nursing staff trained in the use of the facility s choice of scoring tool.

22 References WEANING OPIATE DEPENDENT INFANTS 22 Agthe, A. G., Kim, G. R., Mathias, K. B., Hendrix, C. W., Chavez Valdez, R., Jansson, L.,... Gauda, E. (2009). Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: A randomized, controlled trial. Pediatrics, 123 (5), e849-e856. doi: /peds Benzyl alcohol: toxic agent in neonatal units. (1983). Pediatrics, 72(3), Bio, L. L., Siu, A., & Poon, C. Y. (2011). Update on the pharmacologic management of neonatal abstinence syndrome. [Review]. Journal of Perinatology, 31(11), doi: /jp Buchi, K. F., Suarez, C., & Varner, M. W. (2012). The prevalence of prenatal opioid and other drug use in utah. American Journal of Perinatology. doi: DOI: /s Colombini, N., Elias, R., Busuttil, M., Dubuc, M., Einaudi, M.-A., & Bues-Charbit, M. (2008). Hospital morphine preparation for abstinence syndrome in newborns exposed to buprenorphine or methadone. Pharmacy World & Science: PWS, 30(3), D' Apolito, K. (2009). Neonatal Opiate Withdrawal: Pharmacologic Management. Newborn & Infant Nursing Reviews, 9(1), Dominguez, K. D., Lomako, D. M., Katz, R. W., & Kelly, H. W. (2003). Opioid withdrawal in critically ill neonates. The Annuals of Pharmacotherapy, 37(4), Dwyer, T., & Ponsonby, A. L. (2009). Sudden infant death syndrome and prone sleeping position. Ann Epidemiol, 19(4), doi: /j.annepidem Ebner, N., Rohrmeister, K., Winklbaur, B., Baewert, A., Jagsch, R., Peternell, A.,... Fischer, G. (2007). Management of neonatal abstinence syndrome in neonates born to opioid

23 23 maintained women. Drug Alcohol Dependence, 87(2-3), doi: /j.drugalcdep Finnegan, L. P., Connaughton, J. F., Jr., Kron, R. E., & Emich, J. P. (1975). Neonatal abstinence syndrome: assessment and management. Addict Dis, 2(1-2), Finnegan, L. P., Michael, H., Leifer, B., & Desai, S. (1984). An evaluation of neonatal abstinence treatment modalities. NIDA Res Monogr, 49, Gershanik, J., Boecler, B., Ensley, H., McCloskey, S., & George, W. (1982). The gasping syndrome and benzyl alcohol poisoning. New England Journal of Medicine, 307(22), doi: /NEJM Hudak, M. L., & Tan, R. C. (2012). Neonatal drug withdrawal. Pediatrics, 129(2), e doi: /peds Isemann, B., Meinzen-Derr, J., & Akinbi, H. (2011). Maternal and neonatal factors impacting response to methadone therapy in infants treated for neonatal abstinence syndrome. Journal of Perinatology, 31(1), doi: /jp Jackson, L., Ting, A., McKay, S., & al., e. (2004). A randomized controlled trial of morphine versus phenoparbitone for neonatal abstinence syndrome. Archives of Disease in Childhood: Fetal & Neonatal Edition, 89, F300-F304. doi: /adc Jansson, L. M., Velez, M., & Harrow, C. (2009). The opioid-exposed newborn: assessment and pharmacologic management. Journal Of Opioid Management, 5(1), Katzung, B. G., Masters, S. B., & Trevor, A. J. (2009). Basic & clinical pharmacology (11th ed.). New York: Lange Medical Books/McGraw Hill. Kraft, W. K., Dysart, K., Greenspan, J. S., Gibson, E., Kaltenbach, K., & Ehrlich, M. E. (2011). Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid

24 24 abstinence syndrome. Addiction, 106(3), doi: /j x Kraft, W. K., Gibson, E., Dysart, K., Damle, V. S., Larusso, J. L., Greenspan, J. S.,... Ehrlich, M. E. (2008). Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial. Pediatrics, 122(3), e doi: /peds Kuschel, C. (2007). Managing drug withdrawal in the newborn infant. Seminars In Fetal & Neonatal Medicine, 12(2), doi: /j.siny Langenfeld, S., Birkenfeld, L., Herkenrath, P., Muller, C., Hellmich, M., & Theisohn, M. (2005). Therapy of the neonatal abstinence syndrome with tincture of opium or morphine drops. Drug Alcohol Dependence, 77(1), doi: /j.drugalcdep Leikin, J. B., Mackendrick, W. P., Maloney, G. E., Rhee, J. W., Farrell, E., Wahl, M., & Kelly, K. (2009). Use of clonidine in the prevention and management of neonatal abstinence syndrome. Clinical Toxicology, 47, doi: / Liu, A., Bjorkman, T., Stewart, C., & Nanan, R. (2011). Pharmacological treatment of neonatal opiate withdrawal: between the devil and the deep blue sea. Internaltional Journal of Pediatrics, 2011, doi: /2011/ Maichuk, G. T., Zahorodny W, & Marshall, R. (1999). Use of positioning to reduce the severity of neonatal narcotic withdrawal syndrome. Journal of Perinatology, 19, Mazurier, E., Cambonie, G., Barbotte, E., Grare, A., Pinzani, V., & Picaud, J. C. (2008). Comparison of chlorpromazine versus morphine hydrochloride for treatment of neonatal abstinence syndrome. [Article]. Acta Paediatrica, 97(10), doi: /j x

25 25 Meyer, M. M., & Berens, R. J. (2001). Efficacy of an enteral 10-day methadone wean to prevent opioid withdrawal in fentanyl-tolerant pediatric intensive care unit patients. Pediatric Critical Care Medicine, 2(4), Neonatal drug withdrawal. American Academy of Pediatrics Committee on Drugs. (1998). Pediatrics, 101(6), OCEBM Levels of Evidence Working Group. (2013). The oxford levels of evidence 2. Oxford Retrieved from Oei, J., & Lui, K. (2007). Management of the newborn infant affected by maternal opiates and other drugs of dependency. Journal of Paediatrics and Child Health, 43(1-2), doi: /j x Osborn, D. A., Jeffery, H. E., & Cole, M. J. (2010a). Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database System Review(10), CD doi: / CD pub3 Osborn, D. A., Jeffery, H. E., & Cole, M. J. (2010b). Sedatives for opiate withdrawal in newborn infants. Cochrane Database System Review(10), CD doi: / CD pub3 Patrick, S. W., Schumacher, R. E., Benneyworth, B. D., Krans, E. E., McAllister, J. M., & Davis, M. M. (2012). Neonatal abstinence syndrome and associated health care expenditures: United States, JAMA: The Journal of the American Medical Association, 307(18), doi: /jama Robertson, R. C., Darsey, E., Fortenberry, J. D., Pettignano, R., & Hartley, G. (2000). Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatric Critical Care Medicine, 1(2),

26 26 Sarkar, S., & Donn, S. M. (2006). Management of neonatal abstinence syndrome in neonatal intensive care units: a national survey. Journal of Perinatology, 26, Seligman, N. S., Almario, C. V., Hayes, E. J., Dysart, K., Berghella, V., & Baxter, J. K. (2010). Relationship between maternal methadone dose at delivery and neonatal abstinence syndrome. The Journal of Pediatrics, 157, Seligman, N. S., Almario, C. V., Hayes, E. J., Dysart, K. C., Berghella, V., & Baxter, J. K. (2010). Relationship between maternal methadone dose at delivery and neonatal abstinence syndrome. The Journal of Pediatrics, 157(3), 428. Substance Abuse and Mental Health Services Administration. (2010). Results from the 2010 national survey on drug use and health: summary of national findings. In The Center for Behavioral Health Statistics and Quality, U.S. Department of Health and Human Services, (Ed.). Taketomo, C. K., Hodding, J. H., & Kraus, D. M. (2011). Pediatric and neonatal dosage handbook. Hudson, OH: Lexicomp, Inc. Thajam, D., Atkinson, D. E., Sibley, C. P., & Lavender, T. (2010). Is neonatal abstinence syndrome related to the amount of opiate used? JOGNN: Journal of Obstetric, Gynecologic & Neonatal Nursing, 39, doi: DOI: /j x Tobias, J. D., Schleien, C. L., & Haun, S. E. (1990). Methadone as treatment for iatrogenic narcotic dependency in pediatric intensive care unit patients. Critical Care Medicine, 18(11),

27 27 Velez, M., & Jansson, L. (2008). The opioid dependent mother and newborn dyad: nonpharmacologic care. Journal of Addiction Medicine, 2(3), doi: /ADM.0b013e31817e6105 Zimmermann-Baer, U., Notzli, U., Rentsch, K., & Bucher, H. U. (2010). Finnegan neonatal abstinence scoring system: normal values for first 3 days and weeks 5-6 in non-addicted infants. Addiction, 105(3), doi: /j x

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30 16th Apr 2013 Dear Mrs. Standing: Title: A Guideline Weaning Opiate Dependent Infants Corresponding Author: Mrs Standing Your manuscript has been received and is currently being reviewed by the Editorial Board. You will be notified as soon as this process is completed. Your manuscript has been allocated the number Please refer to the manuscript number cited above when making inquiries. You can now use a single sign-on for all your accounts, view the status of all your manuscript submissions and reviews, access usage statistics for your published articles and download a record of your refereeing activity for the Nature journals. Please check your account regularly and ensure that we have your current contact information. In addition, NPG encourages all authors and reviewers to associate an Open Researcher and Contributor Identifier (ORCID) to their account. ORCID is a community-based initiative that provides an open, non-proprietary and transparent registry of unique identifiers to help disambiguate research contributions. Sincerely, Edward E. Lawson, M.D. Editor-in-Chief the Journal of Perinatology Johns Hopkins Medicine Division of Neonatology Baltimore, MD This has been sent through the NPG Manuscript Tracking System NY-610A-NPG&MTS Confidentiality Statement: This is confidential and subject to copyright. Any unauthorised use or disclosure of its contents is prohibited. If you have received this in error please notify our Manuscript Tracking System Helpdesk team at Details of the confidentiality and pre-publicity policy may be found here