The use of Clonidine for Neonatal Abstinence Syndrome

1. The use of Clonidine for Neonatal Abstinence Syndrome Angela Stein, Pharm.D. PGY-1 Pharmacy Resident St. Johns Mercy Medical Center St. Louis College of Pharmacy

2. Practical uses FDA Approved Indications • Essential hypertension Non-FDA Approved Indications • Attention deficit hyperactivity disorder • Hot sweats • Ischemic foot ulcer; Adjunct • Nicotine dependence • Opioid withdrawal • Tic disorder

3. MOA of Clonidine • Stimulates the presynaptic alpha-2 receptor in the brain and imidazoline receptor • leading to inhibition of norepinephrine release • Inhibitory effects on NE release in the locus coeruleus

4. Opioids activate opiate receptors in the locus coeruleus • ↓ adenylate cyclase→ ↓ cAMP production • K+ efflux↑, Calcium influx↓ OVERALL RESULT= ↓ NE release

5. Chronic Opioid Use • NE release gradually ↑ to normal levels as tolerance develops • Once opioids is withdrawn, loss of inhibitory effect increase in NE release to well above normal levels • Increase NE leads to withdrawal symptoms • Administration of opioids results in ↓ in neuronal activity and ↓ withdrawal symptoms

6. AAP • Initial treatment of a neonate experiencing drug withdrawal should be supportive, since pharmacologic therapy prolongs hospitalization and subject the infant to exposure to drugs that may not be warrented • Supportive care: swaddeling, frequent small feedings of hypercaloric (24 cal.oz) formula o suppl additioanl caloric requirements, observation of sleeping patterns, temperature stability, weight gain or loss, or change in clinical status • Assess infants of drug abusing mothers includes Heatitis B and C and sexually transmitted diseases including HIV

7. Clonidine Pharmacologic therapy Effectively reduces withdrawal signs in adults 0.5-1 ug/kg in a single dose followed by a maintenance dose of 3 to 5 ug.kg/day, divided every 4 ti 6 hours Blood levels 0.1-0.3 ng/ml Poor sleep only sign that seems refractory Length of therapy for infants treated with clonidine was significantly shorter when compared to phenobarbital (13 vs 27 days (P=0.05) Larger controlled trials and pharmacokintic data is needed before clonidine can be avocated as routine treatment.

8. AAP

9. Clonidine as an Adjunct Therapy to Opioids for Neonatal Abstinence Syndrome: A Randomized, Controlled Trial • Background: Treatment of NAS often prolongs hospitalization • Study Design: Prospective, block-randomized, double-blind, placebo-controlled trial • Outcomes: • Total duration of pharmacotherapy for NAS • Amount of DTO required to treat NAS • Treatment failures • Seizures • weight gain • Blood pressure, heart rate, hemoglobin saturation

10. Methods: • Treatment • Clonidine 1 ug/kg every 4 hours+ diluted tincture of opium (DTO) 0.4 mg/ml • DTO alone • Inclusion • 0-14 days old • Pernatal exposure to opioids • Moderate to severe NAS • Exclusion • Gestational age <35 weeks • Intrauterine growth retardation (birth weight below 5th percentile • Congenital anomalies • Illness requiring oxygen • breastfeeding • 3 baltimore hospitals • 80 patients were eligible and randomized • 0.2 ml DTO was started on all infants (0.08 mg ME) Q4H • Uncontrolled if 2 consecutive MFS > 9. DTO dose escalation to 0.3, 0.4, 0.5 ml every 4 hours then 0.5, 0.7, . 0.9 ml every 3 hours untill withdrawal syptoms were controlled (MFS < 9) • Once controlled, infants were maintained on that dose for 48 hours • DTO was de-escalated by 0.05 ml/dose for each 24 hour period • If 2 consecutive MFSs of >12 during de-escalatio., the last controlled dose was re-initiated • 2 consecutive MFSs > 9 on the highest dose (0.9 ml Q3H were classified as treatment failures • Total opioid dose, length of treatment, MFSs, and vital signs were collected Additioanl Assessments Temperature, heart rate, respiratory rate, oxygen saturation, blood pressure, MFSs scores every 3 to 4 hours Blood pressure every 4 hours for the first 48 hours and after stopping clonidine or placebo otherwise every 12 hours

11. Results To demonstrate a 25% reduction in primary outcome, a power of 0.8 and a 2-sided alpha value of 0.05 were needed for each study group Log-rank test reported for time-dependent data Fischer’s exact test is reported for categorical variables T-test between group comparisons corrected for multiple comparisons Mann-Whitney U test used for continuous variables with non-normal distribution

13. Trials Scheduled morpine…failed scheduled morpine + clonidine

16. Use of Clonidine in the prevention and management of neonatal abstinence syndrome Background: clonidine is a potential benificial therapy for NAS due to safety profile, ease of administration, and lack of a requirement for tapering Study Design: retrospective Outcomes:

17. Methods • 14 patients were identified • 11 patients were treated with fentanyl for sedation and 3 were born unto opioid-dependent mothers • All treated with clonidine 0.5-1 mcg/kg orally every 6 hours • No patients received opioids • Stability of patients and NAS scores were assessed at 24-48 hours • NAS scoring system was done every 3 to 4 hours during pharmacologic intervention and every 48 hours after discontinuation of intervention • Vital signs and oxygen saturation were recorded hourly • No exclusion criteria

18. Results Mean duration of treatment was 6.8 days (range 4-15) Mean abstinence scores were 6.4 pretreatment (range 0-20) and 1.9 posttreatment (range 0-5) No patient suffered from adverse events from clonidine

19. Mean GA 30.1 weeks Treatment started in 10 patients in anticipation of withdrawal and 4 after NAS scores were optained Clonidine was stopped abruptly in 12 patients and tapered (by 0.25 mcg/kg every 6 hours) in 2 patients without adverse effects

20. Rat studies Opiates effect on nervous system Clonidine protective effect of nervous system

21. Practial use How do we d/c it? Dose Adverse effects to monitor

22. Barriers

23. Future medications Gauanfacine Guanabenz lofixidine

24. References

26. The use of Clonidine for Neonatal Abstinence Syndrome Angela Stein, Pharm.D. PGY-1 Pharmacy Resident St. Johns Mercy Medical Center St. Louis College of Pharmacy