11/3/2014. To understand the neurobiology mediating the different types of withdrawal from illicit drugs: physical and psychological

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1 Estelle B. Gauda, M.D. Professor of Pediatrics Johns Hopkins School of Medicine To understand the neurobiology mediating the different types of withdrawal from illicit drugs: physical and psychological To understand why clonidine may be an effective adjunct treatment choice for individuals with moderate to severe withdrawal from opiates Opiates: methadone, buprenorphine, heroin, Prescription drugs: Vicodin, OxyContin, Percocet Benzodiazipenes Stimulants: cocaine, methamphetamine Cannabinoids Tobacco SSRI Past Month Illicit Drug Use among Persons Aged 12 or Older: 2012 Tennessee: INCIDENCE OF NAS ACROSS THE COUNTRY 10fold increase (12yrs) 0.7 per 1,000 live births 1999, 8.5 per 1,000 live births in % of total population 12 yrs Used drugs within the last month Kentucky : Florida: Vermont, Washington: 11fold increase (10yrs) 1.2 cases per 1,000 live births in cases per 1,000 live births in fold increase (6 yrs) 2.31 per 1,000 live births in per 1,000 live births in fold increase (8 yrs) 3 per 1,000 deliveries in per 1,000 deliveries in fold increase (8 yrs) 1.2 per 1,000 live births in per 1,000 live births in

2 National Survey on Drug Use and Health Shift from abuse of classical opioids such as heroin, morphine and methadone to abuse of prescription opioids such as hydrocodone, hydromorphone and oxycodone. Prescription of opioids in the U.S. during the last ten years million million Prescription drug abuse: Women 1517 years of age 23% of pregnant women 13% in nonpregnant women 2010, OPIOIDS: Vicodin OxyContin Codeine Fentanyl... Diminish perception of pain Addiction Euphoria Dependence Drowsiness Constipation Slow respiration Death DEPRESSANTS: Valium Xanax Ambien... Calming Drowsiness Addiction Dependence Uncoordinated Slow respiration Decrease heart rate Death STIMULANTS: Adderall Ritalin... Alertness Addiction Dependence Irregular heartbeat High body temp. High blood pressure Heart failure Seizures Paranoia Death O in FIVE Idaho students report taking a prescription drug without a physicians prescription at least once during their lifetime (Idaho Youth Risk Behavior Survey, 2011) In 2010, an Idaho citizen died every 45 HOURS because of a drug induced death caused by illicit, prescription, or over the counter druguse. 250% increase since (Idaho Vital Statistics, 2010) This rise is greatly attributed to the increase in prescription drug abuse. From 2005 to 2010, Idaho addiction treatment facilities experienced a SEVEN FOLD increase in percent of opioid admissions as the primary substance of abuse. (SAMHSA, Idaho Treatment Episode Data Set) In 2011, more Americans (6.1 MILLION) reported the nonmedical use of prescription drugs within the preceding month than had used cocaine, heroin, hallucinogens, and inhalants combined. (SAMHSA NSDUH 2011) 54% of prescription opioids being used for nonmedical purposes are obtained from a friend or relative for free, with these friends or relatives most often obtaining them from 1 physician (82%) (SAMHSA NSDUH 2011) IDAHO OFFICE OF DRUG POLICY PRESCRIPTION DRUG ABUSE WORKGROUP IDAHO OFFICE OF DRUG POLICY PRESCRIPTION DRUG ABUSE WORKGROUP 16.4 $53,400 EVERY HOUR, one baby in the US is born suffering from opiate withdrawal. (National Institute of Drug Abuse, 2012) 2

3 Oxycodone/morphine/codeine/hydromorphone 5 fold increase over ~12 years Kellogg. Narcotic use in pregnancy. Am J Obstet Gynecol Tobacco exposure toxicity vs withdrawal Only tobaccoexposed infants within 24 hrs of birth: excitable hypertonic, required more handling and More stress/abstinence signs specifically in the central nervous system (CNS), GI, and visual areas. Resolved with in 2448 hrs Law et al, Lester: PEDIATRICS Vol. 111 No. 6 June 2003 Increase Severity Past Month and Past Year Heroin Use among Persons Aged 12 or Older: Polymorphisms in ioid receptor OPRM1, variant A11AG and catecholomethyltransferase (COMT) Higher maternal dose methadone during last trimester (5.5mg increased LOS by 1 day) GA >36 wks Lower maternal weight at delivery High infant BW Benzodiazepines SSRI exposure Cigarettes smoke 24 hrs prior to delivery Reviewed in CLINICAL OBSTETRICS AND GYCOLOGY ; 56,, Addiction Nov;107 In utero exposure Opiate Exposure Presentation Incidence Heroin, Methadone oxycodone bupernorphine 2472 hours After birth 45 days for buprenorphine Heroin >90% Methadone 5090% Oxycodone 5.6% Buprenorphine 2070% Tolerance Loss of effect following repeated treatments such that a higher dose is required for equivalent effect Dependence Superactivation of Physical signs: withdrawal (autonomic and somatic signs associated with drug absence) Psychological (addiction) loss of control over drug use (impulsivity and compulsivity) 3

4 Neurocircuitry: Reward Pathway Dopamine Chocolate/Excercise benzodiazepine DOPAMI (Ventral Tegmental Area) W I T H D R A W A L Clinical Signs Wakefulness Irritability Tremors, Temperature Instability, Tachypnea Hyperactive, High Pitch Cry, Hypertonia, Hyperreflexia Diarrhea, Dysfunctional Suck and Swallow Rub Marks, Respiratory Distress, Rhinorrhea, Reflux Apnea, Alkalosis (respiratory), Acidosis (metabolic) Weight Loss Autonomic Dysfunction (sneeze, yawn, sweating) Lacrimation Norepinephrine neurocircutry in the brain mediates the physical signs of withdrawal leading to Elevated Sympathetic Output Summation of cellular events: Acute responses to opiate exposure in a neuron in the LC Frontal Cortex Locus Ceruleus Norepinephrine Cerebellum Opiate receptors Locus ceruleus Gi/o Presynaptic Neuron LCneuron Increased vigilance Alertness Insomnia Stress Anxiety Prefrontal Frontal Cortex Limbic hypothalamus HPAxis CRF ACTH ADRENALSCORTISOLEPI and Postsynaptic Neuron LC neurons cellular adaptation after chronic exposure Gi/o + α 1 receptors, β 1 receptors Vasoconstriction smooth muscle, Diaphoresis, Tachycardia, Hypertension, GI irritability Myenteric plexus of gut constipation Tolerance to opiateinduced reduction in intestinal motility and increase in motility during withdrawal Dorsal horn of Spinal Cord hyperalagesia Tolerance to opiate induced analgesia Multiple Brain regions dysphoria, involved in psychological addiction 4

5 NALTREXO PRECIPITATED OPIATE WITHDRAWAL IN METHADO ADDICTED HUMAN SUBJECTS: EVIDENCE FOR NORADRERGIC HYPERACTIVITY Dennis S. Charney; D. Eugene Redmond, Jr.; Matthew P. Galloway; Herbert D. Kleber; George R. Heninger; Michelle Murberg; Robert H. Roth craving, anxiety,piloerection, hot and cold flashes, aching bones, anorexia, restlessness nausea, vomiting, diarrhea, spontaneous orgasm, yawning, perspiration, lacrimation, rhinorrhea, and tremors) on a Life Sciences 1984 Vol 35 pp five point rating scale (l=not at all, 2=mild, 3=moderate, 4=severe, 5=extremely severe) Direct correlation between the abstinence Scores and plasma MHPG levels (a biomarker for centrally released ) In adult humans during opiate withdrawal LC neurons cellular adaptation after chronic exposure Gi/o + Gi/o Methadone, Morphine, Burpernorphine Life Sciences 1984 Vol 35 pp α 1 receptors, β 1 receptors Vasoconstriction smooth muscle, Diaphoresis, Tachycardia, Hypertension, GI irritability Mechansism of Action Morphine Methadone Buprenorphine Mureceptor agonist Mureceptor NMDA antagonist Ethanol content 0% 8% 30% Bioavailability Variable, <40% % NA Halflife (t½, h) Preterm: 10 20, neonates: 7.6 ( ) Protein binding (%) Metabolic pathway (metabolites) Opioids used to treat NAS in infants Children: 19h (4 62) < Highly lipid soluble glucuronidation (morphine6glucuronide (active) and morphine3 glucuronide (inactive)) Hepatic N demethylation via CYP3A4 (2ethylidene1, 5 dimethyl3, 3 diphenylpyrrolidene (inactive) partial μopioid agonist; high affinity for and slow dissociation ceiling effect Premature neonates 20±8h Br J clin Pharmac 1993; 36: Hepatic Ndealkylation primarily via CYP3A4 (norbuprenorphine (active)) and glucuronidation of active metabolite Methadone: CON Half life ~26 h in neonates compared with 8 h with morphine, Drug accumulation prolongs hospitalization Metabolism rates vary by factor of 100 No single ratio for equianalgesic dosing can be found between morphine and methadone Difficult to convert to morphine. 5

6 Methadone: PRO Effective in treating opiate induced hyperalgesia, thus methadone may be useful in infants with iatrogenic NAS who also might have pain In 80% of cancer patients with uncontrolled pain or significant side effects, switching from morphine to methadone better pain control and reduced side effects J Clin Oncol. 2001;19: Prenatal Buprenorphine Versus Methadone Exposure and Neonatal Outcomes: Systematic Review and MetaAnalysis 12 studies infants born Design: randomeffects metaanalysis model evaluated for confounding, publication bias, and heterogeneity Subjects: 515 neonates CONFOUNDER mothers on BupMT 855 neonates mothers on MethMT OUTCOMES: Fewer The women unadjusted treated NAS Bup vs with Meth BMT treatment risk was lower (risk used ratio = 0.90, illicit 95% opioids (CI: 0.81, 0.98) near delivery mean length of hospital stay shorter (7.23 days, 95% risk CI: 10.64, ratio 3.83). = 0.44, NAS treatment duration was shorter (95% CI: 0.28, 0.70). (8.46 days, 95% CI: 14.48, 2.44) morphine dose lower (3.60 mg, 95% CI: 7.26, 0.07) Higher mean GA, BW, and Head Circ Brogly SB,. Am J Epidemiol Bupernorphine for treatment of NAS in methadone exposed infants On going RCT Jefferson medical College, Thomas Jefferson Given sublingual dissolved in ETOH Randomized Not blinded 1339 mcg/kg/day Kraft et al 2008 Pediatrics Bupernorphine N=12 Morphine N=12 Length of treatment days 12 (1147) Mean (range) Exclusion Criteria 32 (1460) LOS 27 (1751) 38 (1966) Phenob, adjunct 3 1 Infants exposed to 1660mcg/kg/day Bupernorphine Morphine Kraft 2011 N=12 N=12 Addiction benzodiazepines Length of treatment 23±12 38±14 Infants who have severe NAS May need 2 nd agent to control symptoms What about Phenobarbital as adjunct treatment for NAS LOS 32 ± ±13 Phenob, adjunct 3 1 MOR LC neuron Phenobarbital as adjunct treatment for NAS based study with an N of 10 infants!! Coyle MG, et al J Pediatr 2002; 140(5): GABA GABA Hyperpolarization Gi/o DESIGN: Partially randomized, controlled trial: infants exposed to methadone and/or heroin in utero. Finnegan scoring system used. Treatment groups: DTO and placebo (n = 10) vs DTO and phenobarbital (n = 10) DOSE: DTO 0.02 mg/kg (morphine equivalents) dose Q 34 hrs; Phenobarbital LD: 30 mg/kg divided in three oral 10 mg/kg given q 12 hrs. Main: 2.5 mg/kg Q 12 hr target plasma level 20 to 30 mcg/ml OUTCOMES: LOS: (hospital) DTO with phenobarbital group 38 days DTO alone 79 days ( DTO+phen vs DTO alone) P<0.001). Phenobarb and benzo prolongs and potentiates the action of GABA on GABAA receptors TOTAL DURATION OF TREATMENT: On average the infants in the Phenobarbital group continued phenobarbital therapy 3.5 months (range 2 9 months), after the DTO was discontinued 6

7 Phenobarbital in therapeutic dosages causes apoptosis in developing neurons in newborn rats Pediatric Neurologist avoid exposing neonates to phenobarbital longer than for treatment of the acute seizure episode Because data from human and animal studies implicating cognitive delays and apoptosis, respectively PETRA BITTIGAU, Ann. N.Y. Acad. Sci. 993: (2003). FARWELL, J.R., Y.J. LEE, et al Phenobarbital for febrile seizures effects on intelligence and on seizure recurrence. N. Engl. J. Med. 322: REINISCH, J.M., S.A. SANDERS, et al In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 274: SULZBACHER, S., J.R. FARWELL, et al Late cognitive effects of early treatment with phenobarbital. Clin. Pediatr. Philad. 38: THORP, J.A., M. O CONNOR, et al Does perinatal phenobarbital exposure affect developmental outcome at age 2? Am. J. Perinatol. 16: DESSENS, A.B., P.T. COHENKETTENIS, et al Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems. Acta Paediatr. 89: For these reasons, at Johns Hopkins, we do not use Phenobarbital as adjunct therapy for treatment of NAS But we do use CLONIDI to directly target LC neuronal hyperactivity Summation of cellular events: Role of 2 noradrenergic stimulation during superactivation of systems induced by chronic opioid exposure Review of the literature Adverse effects of phenobarbital on outcome in humans Gi/o + Clonidine 2 Clonidine 2 Gi/o Clonidine decrease sympathetic overactivity in response to withdrawal in adults Plasma epi levels Plasma levels α 1 receptors, β 1 receptors on postsynaptic neurons Vasoconstriction smooth muscle, Diaphoresis, Tachycardia, Hypertension, GI irritability Representative recording of a patient addicted to opioids undergoing detoxification demonstrating the effects of opioid receptor blockade by naloxone during propofol anesthesia, and the effects of clonidine on efferent sympathetic activity to muscle and on arterial blood pressure. 7

8 Funding: NIDA Clonidine as an Adjunct Therapy to Opioids for Neonatal Abstinence Syndrome: A Randomized, Controlled Trial Investigators: Alex G. Agthe, M.D, George Kim, M.D., Kay Mathias, NNP, Raul ChavezValdez, M.D. Tamorah Lewis, Lauren Jansson, M.D., Craig W. Hendrix, M.D., Ph.D., and Myron Yaster, M.D, Estelle B. Gauda, M.D Pediatrics 123(5):e849e856, Primary Endpoints: Length of treatment, defined as the need for any pharmacological treatment for NAS Amount of DTO (Diluted tincture of opium) needed to treat NAS DTO: 0.4mg/ml of morphine Inclusion Criteria: All newborns age 0 to 14 days who were prenatally exposed to opioids (methadone and/or heroin) NAS (moderate to severe) defined by two consecutive NASscores of 9 on the adapted Finnegan Scale, INFANT CHARACTERISTICS CLONIDIDTO GROUP (N=40) PLACEBODTO GROUP (N=40) Birthweight g 2863 ± ± 415 Gestational age wk 38.5 ± ± 2.0 Prenatal exposure no. (%) Methadone 35 (87.5%) 35 (87.5%) Morphine 26 (65) 29 (72.5) Cocaine with opioids 25 (62.5) 24 (60) Percent of infants on DTO Median length of treatment CLONIDI+DTO = 11 days PLACEBO + DTO = 15 days 27% shorter with clonidine Clonidine decreased the median length of pharmacotherapy by 4 days Clonidine Placebo Days on DTO P=0.02 log rank Clonidine Placebo DTO (ml) 19.4 (20.1) 47.9 (89.2) Morphine Equivalents (mg) 7.7 (8.0) 19.2 (3.3) Mean DTO (ml/kg/day) Day of treatment PLACEBO No. of infants CLONDI No. of infants Infants in the clonidne group required less opiate after first 3 days of therapy clonidne Day of treatment Summary of Study Clonidine combined with DTO (oral morphine) is effective in treating infants with NAS. Clonidine combined with DTO at dosage of 1mcg/kg every 4 hours was not associated with adverse cardiovascular outcomes in this newborn population Infants with the worst signs of NAS benefited most from the addition of clonidine. PERCENT Concurrent drug exposures in women on Methadone Maintenance Therapy 88 FACTORS THAT INCREASED LOS Maternal BZD Use And Bottle feeding More treatment failures were observed in the placebo+dto group (5 vs 0) and seizures (3 vs 0). 3 Deaths in the overall cohort: Myocarditis, Homicide, SIDS all after discharge to home. One infant developed SVT resolved Tobacco Alcohol SSRIs BZD Marijuana Opioids Retrospective; Eastern Maine Medical Center, Bangor Maine ( ) Pritham et al: JOGNN 41, n=136 8

9 Ativan (lorazepam) Valium (diazepam) Klonopin (clonazepam) TranxeneSD (clorazepate) Xanax (alprazolam) Restoril (temazepam) Dalmane (flurazepam) GABA MOR GABA HYPERPOLARIZATION Hyperpolarization Phenobarb and benzo prolongs and potentiates the action of GABA on GABAA receptors Clonidine 2 Gi/o Withdrawal associated with BZD exposure later onset and protracted Neonates exposed to benzodiazepines > LOT than those unexposed ~14 days Am J Obstet Gynecol 2008;199:396.e1 396.e7. Neonates exposed to BZD have a later presentation of NAS that is bimodal Case report: (2 infants) Clin Pediatr (Phila) 1990;29: Diazepam use by pregnant women can be associated with a later presentation of withdrawal symptoms in the neonate than that induced by the use of other drugs. Intensification of symptoms after 7 14 days of therapy BZD exposures effects on infant: floppy infant syndrome, or marked neonatal withdrawal symptoms mild sedation, hypotonia, and reluctance to suck, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress, movement disorders Why Highly lipophilic High intake in animal fat tissue Easy penetration into brain white matter Long retention in neural tissue High concentrations brain, the lungs, heart Fetal maternal ratio of 1.2 to 2 T1/2 in the neonate about 31 hours Tissues act as depot for BZD (diazepam worst) Daily or Almost Daily Marijuana Use in the Past Year and Past Month among Persons Aged 12 or Older: Marijuana smoke contains higher levels of certain toxins than tobacco smoke Acute effects of THC exposure adults problems with memory and learning neurons in the information processing system of the hippocampus and the activity of the nerve fibers are suppressed by THC distorted perception difficulty in thinking and problemsolving loss of coordination increased heart rate anxiety panic attacks 9

10 Cannabis use during pregnancy psychosocial effects on children Anxiety, irritability, physical tension, depression, and loss of appetite. Long T1/2 30 hrs Worse during the first 10 days of abstinence Prospective longitudinal assessments can increase the risk for ill behaviors (Goldschmidt et al, 2004; Day et al, 2011), Cognitive deficit (Huizink & Mulder, 2006), Drug seeking (Day et al, 2006) Attention deficit (Leech et al, 1999) Anxiety and depression (Leech et al,2006) Growth retardation (El Marroun et al, 2009), Review: Morris et al, Eur J Neurosci November ; 34(10): Psychological dependence vs Physical Dependence Increase Severity Polymorphisms in ioid receptor OPRM1, variant A11AG and catecholomethyltransferase (COMT) While essentially all drugs of abuse share similar signs and symptoms of psychological dependence (NAc Dopamine) this is not the case for physical dependence (LC) Higher maternal dose methadone during last trimester (5.5mg increase LOS by 1 day) GA >36 wks Lower maternal weight at delivery High infant BW Benzodiazepines SSRI exposure Cigarettes smoke 24 hrs prior to delivery Decrease Severity Breastfeeding/Rooming In Quiet environments Buprenorphine COCAI Reviewed in CLINICAL OBSTETRICS AND GYCOLOGY ; 56,, Addiction Nov;107 NAS from opiates is mediated by over activation of the sympathetic nervous system with a large contribution from excessive release of from LC neurons. LC neurons contain opioid receptors and alpha 2 adrenergic receptors both of which cause reduction in output from LC neurons, making both receptors therapeutic targets for the treatment of NAS 10

11 What I hope your remember Alpha 2 adrenergic receptors have a restricted distribution in the brain Clonidine binds to these receptorsreducing the release of GABAreceptors are widely distributed throughout the brain BZD and phenobarbital bind to these receptors throughout the brain Phenobarbital similar to BZD, enhance the binding of GABA to the GABA A receptor Depresses neuronal activity throughout the entire brain accounting during period of development Overall neuronal depression throughout the brain may be contributing to adverse effects on the developing nervous system What I hope you will consider Using this information to help guide targeted pharmacological therapies for the treatment NAS Advocate for properly conducted clinical trials in vulnerable populations to provide evidence When evidence is lacking use biology and physiology as a guide. Pharmacological treatment of NAS: 1) Opiate replacement alone (morphine) followed by clonidine when adjunct therapy is required. Clonidine is added when infant is requiring 0.2 mg (flat dose) of morphine every 4 hours ( 0.06mg/kg q 4) Clonidine dose 612mcg/kg/day divided q 36 hrs (may take 12 days to see full effect of clonidine) 2) Phenobarbital as adjunct therapy for the treatment of NAS should be avoided unless symptoms can not be controlled with opiate/clonidine because of concurrent benzodiazepine withdrawal. 3) When phenobarbital is used for treatment of benzodiazepine withdrawal in neonates, it should be used at the lowest effective dose for the shortest period of time. Thank you for your Attention SUMMARY 11

12 Positive urine toxicology screens in mothers and infants n= wks prior to delivery Drug use last 30 days: BZD 38%; cocaine 3.4%; marijuana 35% Percent Maternal Infant N=107 samples for mothers N=61 samples for infants Other Opiate BZD Cocaine 9.8 Prospective cohort study: 114 mother/infant dyads; Cleary et al: Addiction :