Angela Stein, Pharm.D.PGY-1 Pharmacy ResidentSt. Johns Mercy Medical CenterSt. Louis College of Pharmacy

FDA Approved IndicationsEssential hypertension

Non-FDA Approved IndicationsAttention deficit hyperactivity disorderHot sweatsIschemic foot ulcer; AdjunctNicotine dependenceOpioid withdrawalTic disorder

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

Opioids activate opiate receptors in the locus coeruleus adenylate cyclase cAMP productionK+ efflux, Calcium influxOVERALL RESULT= NE release

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Once opioids is withdrawn, loss of inhibitory effect increase in NE release to well above normal levels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

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 warrentedSupportive 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

Clonidine Pharmacologic therapyEffectively reduces withdrawal signs in adults0.5-1 ug/kg in a single dose followed by a maintenance dose of 3 to 5 ug.kg/day, divided every 4 ti 6 hoursBlood levels 0.1-0.3 ng/mlPoor sleep only sign that seems refractoryLength 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.

Background: Treatment of NAS often prolongs hospitalizationStudy Design: Prospective, block-randomized, double-blind, placebo-controlled trialOutcomes:Total duration of pharmacotherapy for NASAmount of DTO required to treat NAS Treatment failuresSeizures weight gainBlood pressure, heart rate, hemoglobin saturation

Methods:TreatmentClonidine 1 ug/kg every 4 hours+ diluted tincture of opium (DTO) 0.4 mg/mlDTO aloneInclusion0-14 days oldPernatal exposure to opioidsModerate to severe NAS ExclusionGestational age 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 hoursDTO was de-escalated by 0.05 ml/dose for each 24 hour periodIf 2 consecutive MFSs of >12 during de-escalatio., the last controlled dose was re-initiated2 consecutive MFSs > 9 on the highest dose (0.9 ml Q3H were classified as treatment failuresTotal opioid dose, length of treatment, MFSs, and vital signs were collected

Additioanl AssessmentsTemperature, heart rate, respiratory rate, oxygen saturation, blood pressure, MFSs scores every 3 to 4 hoursBlood pressure every 4 hours for the first 48 hours and after stopping clonidine or placebo otherwise every 12 hours

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 groupLog-rank test reported for time-dependent dataFischers exact test is reported for categorical variablesT-test between group comparisons corrected for multiple comparisonsMann-Whitney U test used for continuous variables with non-normal distribution

PrimaryClonidne/DTO- median length was 27% shorter than for the placebo/DTO group (11 days [95%CI: 8-15] vs 15 days [95% CI 13-17]) P=0.02SecondaryNO difference in weight lossTotal dose of DTO for clonidine/DTO group was 19.4 ml (7.7 mg ME) vs 47.9 ml (19.2 mf ME) P

Scheduled morpinefailed scheduled morpine + clonidine

Background: clonidine is a potential benificial therapy for NAS due to safety profile, ease of administration, and lack of a requirement for taperingStudy Design: retrospectiveOutcomes:

Methods14 patients were identified11 patients were treated with fentanyl for sedation and 3 were born unto opioid-dependent mothersAll treated with clonidine 0.5-1 mcg/kg orally every 6 hoursNo 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 interventionVital signs and oxygen saturation were recorded hourlyNo exclusion criteria

ResultsMean 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

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

Opiates effect on nervous systemClonidine protective effect of nervous system

How do we d/c it?DoseAdverse effects to monitor

GauanfacineGuanabenzlofixidine

Angela Stein, Pharm.D.PGY-1 Pharmacy ResidentSt. Johns Mercy Medical CenterSt. Louis College of Pharmacy

NAS occurs in 55-94% of infants born to substance dependant womenSymptoms of NAS include: Neurologic hyperexcitability (insomnia, irritabilitym hypertonia, hyperflexia, tremors, and seizures) enteric symptoms (vomiting, diarrhea, feeding disturbances), and sympathetic/parasympathetic dysregulation (sweating, fever, tachypnea, and congestion) holding, swaddling, and minimal stimulation may alleviate mild and non progressive withdrawl, but is insuffucuent for severe NAS.Goals of NASAmeliorate hyperactivity and autonomic instabilityPromote normal patterns of sleep, feeding, and weight gain

**Micromedex drug class: Alpha-2 Adrenergic AgonistMicromedex: Clonidine reduces sympathetic outflow from the brain secondary to direct stimulating effects on alpha-receptors in the vasomotor center of the medulla. Decreases in blood pressure are associated with reductions in peripheral vascular resistance and decreases in heart rate (secondary to increased vagal tone). Reduced renal vascular resistance is not associated with reduced renal blood flow or glomerular filtration rates

Micromedex Pharmacology: Clonidine stimulates the presynaptic alpha-2 receptor in the brain leading to inhibition of norepinephrine release, and it also stimulates the imidazoline receptor; both of these actions decrease sympathetic outflow. TOXICOLOGY: Stimulation of peripheral postsynaptic alpha-2 receptors after overdose can cause initial transient hypertension. Excessive stimulation of presynaptic alpha-2 receptors in the lower brainstem and medulla decreases plasma norepinephrine concentrations causing hypotension and bradycardia.

Morphine, diamorphine, and methadone activate opiate receptor in the locus ceruleus (one of the major clusters of noradrenergic cells in the in the brain). Their action decreases the activity of adenylate cyclase, resulting in a reduction in cAMP production. As a consequence, potassium efflux is increased and calcium influx into the cell is decreased, resulting in a decrease in noradrenaline (NE) release. During chronic opiate use, NE release gradually increases towards its normal level as tolerance develops. Once opioids are withdrawn this is a los of inhibitory effect, and significant increase in NE release with well above normal. The increase in NE activity coincides with the appearance of withdrawal symptoms in experimental models. Administration of opioids results in a reduction in neuronal activity and hence a decrease in withdrawal symptoms.

Clonidine also has inhibitory effects on NE release in the locus ceruleus, as it is an alpha 2 adrenoreceptor agonist.

Chloral hydrate exerts an hypnotic effect through its active metabolite trichloroethanol

Chlorpromazine is a neuroleptic which acts in the hypothalamus on hypothalamus and the brainstem.

Benzodiazepines have a variety of effects but in NAS they are given for sedation purposes, which results from binding to the inhibitory GABA amionbutyric acid receptor in the brain.

Phenobarbitone is a central; nervous system depressant and also acts on the GABA receptor complex, but has less specific effects on the brain than diazepam

*Morphine, diamorphine, and methadone activate opiate receptor in the locus ceruleus (one of the major clusters of noradrenergic cells in the in the brain). Their action decreases the activity of adenylate cyclase, resulting in a reduction in cAMP production. As a consequence, potassium efflux is increased and calcium influx into the cell is decreased, resulting in a decrease in noradrenaline (NE) release.

During chronic opiate use, NE release gradually increases towards its normal level as tolerance develops. Once opioids are withdrawn this is a loss of inhibitory effect, and significant increase in NE release with well above normal. The increase in NE activity coincides with the appearance of withdrawal symptoms in experimental models. Administration of opioids results in a reduction in neuronal activity and hence a decrease in withdrawal symptoms.

*During chronic opiate use, NE release gradually increases towards its normal level as tolerance develops. Once opioids are withdrawn this is a loss of inhibitory effect, and significant increase in NE release with well above normal. The increase in NE activity coincides with the appearance of withdrawal symptoms in experimental models. Administration of opioids results in a reduction in neuronal activity and hence a decrease in withdrawal symptoms.

*The CNS irritability is accompanied by seizuresin 2% to 11% of infants withdrawing fromopioids;1719 however, abnormal electroencephalogramswithout overt seizure activity have been reportedin 30%.20,21 Seizures also may be associatedwith nonnarcotic (barbiturates,22,23 alcohol,24 sedativehypnotics25) withdrawal. The mechanism andsignificance of withdrawal-associated seizures areUnclear

offspring exposed to opioids or heroin in utero, withdrawal signs will develop in 55% to 94%The clinical presentation of neonatal drug withdrawal is variable, depending on the drug(s), timing and amount of the last maternal use, maternal and infant metabolism and excretion, and other unidentifiablefactors*83**Hypothesis: Clonidine in combination with an opioid would ameliorate withdrawal more rapidly than an opioid alone.

*2 consecutive Finnegan scores MFSs of >=9Johns Hopkins, Johns hopkins Bayview medical centerBorn at JHH or JHBMCRebound HTN was defined as an increase of blood pressure above the 95th percentile of age specific normsOxygen saturation