Pediatric Satellite Pharmacy Supervisor McLeod Regional ... · the treatment of opioid use disorder...
Transcript of Pediatric Satellite Pharmacy Supervisor McLeod Regional ... · the treatment of opioid use disorder...
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Dr. Evelyn Fulmore, Pharm.D.
Clinical Pharmacy Specialist – Pediatrics/Women’s Health
Pediatric Satellite Pharmacy Supervisor
McLeod Regional Medical Center
Florence, SC
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No financial relationships or duality of interest to disclose
I will be discussing off-label use of agents (methadone and buprenorphine)
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Demonstrate an understanding of the pharmacologic differences between methadone vs buprenorphine in the treatment of opioid use disorder in pregnancy
Compare maternal and neonatal outcomes identified with the use of methadone vs buprenorphine in the treatment of opioid use disorder in pregnancy
Determine the most effect opioid agonist treatment (OAT): methadone vs buprenorphine that should be used to treat opioid use disorder in pregnancy in your community
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The prevalence of opioid use among pregnant women ranges from 1-2% to as high as 21%
Methadone maintenance has been the treatment of choice for opioid-dependent women since the 1970s
Buprenorphine
Prenatal methadone or buprenorphine exposure may result in neonatal opioid withdrawal syndrome
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30-60 MME = hydrocodone 5-10 mg
po q 4 hours90 MME = hydrocodone
15 mg q 4 hours120 MME =
hydrocodone 20 mg q 4 hours
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In just one decade, deaths from prescription pain killers (opioids) rose by more than 400% among women. (CDC, 2013)
Every 3 minutes, a woman goes to the emergency room for prescription painkiller misuse. (CDC, 2013)
The number of drug overdose deaths has never been higher, and the majority of these deaths (more than 6 out of 10 in 2014) involved opioids. (CDC, 2015d)
At least half of opioid deaths involve a prescription opioid. When pregnant women use opiates, the fetus can also become dependent on them. (CDC, 2016d)
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Active metabolites enter the CNS of the fetus causing neuronal cell injury or death
Studies have shown physiologic brain changes Impact on cognitive and behavioral
development Side effects of certain drugs can cause
vasoconstriction and decrease blood supply Result in complications of pregnancy
(placental abnormalities, IUGR, preterm delivery)
Drug abuse or chronic drug use can increase risk for NAS
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Tobacco Marijuana Stimulants OpiatesPregnancy complications No fetal growth effects Cocaine Stillbirth
Prematurity No physical abnormalities Prematurity Prematurity
Decreased birth weight Decreased birth weight Decreased birth weight
Decreased birth length Decreased birth length Decreased birth length
Decreased birth head
circumference
Decreased birth head
circumference
Decreased birth head
circumference
Sudden infant death
syndrome (SIDS)
Intraventricular
hemorrhage
Fetal and neonatal
abstinence syndrome
Increased infant mortality
rate
Methamphetamine Sudden infant death
syndrome (SIDS)
Small for Gestational Age
(SGA)
Decreased birth weight
Sonnia Minnes. Addict Sci Clin Pract. 2011 July; 6(1): 57–70
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Tobacco Marijuana Stimulants OpiatesDisturbed maternal-infant
interaction
Excitability
Hypertonia
Stress abstinence signs
Conduct Disorder
Reduced IQ
Aggression
Antisocial behavior
Impulsivity
ADHD
Tobacco use and dependence
Mild withdrawal symptoms
Delayed state regulation
Reading, spelling difficulty
Executive function
impairment
Early tobacco and marijuana
use
Cocaine
Neonatal/Infancy
Early neurobehavioral
deficits: orientation, state
regulation, autonomic
stability, attention, sensory,
and motor asymmetry,
jitteriness
Poor clarity of infant cues
during feeding interaction
Delayed information
processing
General cognitive delay
Abstinence syndrome
Less rhythmic swallowing
Strabismus
Possible delay in general
cognitive function
Anxiety
Aggression
Feelings of rejection
Disruptive/inattentive
behavior
Methamphetamine
Poor movement quality (3rd
trimester exposure)
Low arousal
Increased lethargy
Increased physiologic stress
No mental or motor delay
*Effects may be subtle and transientSonnia Minnes. Addict Sci Clin Pract. 2011 July; 6(1): 57–70.
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Derived fully or partially from Opium
➢ Codeine Morphine
➢ Heroin
➢ Hydromorphone
➢ Hydrocodone (Vicodin™, Lortab™, Norco™)
➢ Oxycodone (Percocet™, Oxycontin™)
➢ Fentanyl
➢ Methadone
➢ Meperidine (Demerol™)
➢ Buprenorphine (Subutex™)- agonist/antagonist
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codeine
heroinmorphine
methadone
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codeine
heroinmorphine
Buprenorphine
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Mayo Clin Proc 2009; July, 84(7):613-624
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Methadone
Buprenorphine (Subutex)
Buprenorphine + naloxone (Suboxone™)
Naltrexone (Revia™)
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Transfer occurs ◦ passive diffusion
◦ protein transport
Transfer dependent ◦ Molecular size
(<500)
◦ pH
◦ Protein binding
◦ Lipid solubility
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Opiate drugs are highly lipophilic and have relatively low molecular weights
Cross the placenta by simple diffusion from mother to fetus
Tend to accumulate in the fetus
Longer half-life in the fetus (enzymes of glucuronidation and oxidation not fully developed, immature renal function)
Babies at increased risk of low birth weight and poor growth. May have smaller head size and be born pre-term
Chasnoff, NeoReviews 2003
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Improve outcomes for mother and baby◦ Minimize prenatal risks
◦ Increase participation in prenatal care
◦ Minimize opiate withdrawal
◦ Decrease illicit drug use
◦ Assist mother in transition to a safe and stable lifestyle
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➢ C-II narcotic (opioid) μ receptor agonist
➢ a “substitute” for opiate drugs of abuse - heroin
➢ produces similar effects and reduces withdrawal symptoms
methadone
heroin
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➢ 40 mg dispersible tab -must be dissolved in water/juice
➢ 5 and 10 mg regular tablets
➢ 1 mg/ml or 10 mg/mlconcentrate – note: concentrate must be mixed in water/juice5 and 10 mg tablets
40 mg tab
10 mg/ml oral conc1 mg/ml oral soln
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➢ Bioavailability = 80-95%
➢ T ½ = 15- 55 hours
➢ Does not create euphoria, sedation, or analgesia
➢ Endpoint: cravings stop
➢ Establish individualized dosing
➢ Usually require 60 to 120 mg/day
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Anderson IB et.al. Use of Methadone; WJM 2000; 172: 43-46
➢ Long t-1/2 may result in overdose
➢ Potential for apnea, respiratory failure, seizures
➢ Be aware of multiple drugs that can potentiate effects
➢ Other: sweating, constipation, weight gain, urinary retention
➢ Caution: Noncardiogenic pulmonary edema has resulted from therapeutic doses
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Anderson IB et.al. Use of Methadone. WJM, 2000; 172: 43
➢ Accelerated clearance in 3rd trimester
➢ Increase doses often required as gestation nears term
➢ Divided daily doses may keep maternal plasma levels stable
➢ Enhances fetal growth
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Jansson LM et.al. Methadone Maintenance and Breastfeeding Pediatrics, 2008; 121(1):106-114
➢ Crosses the placenta
➢ Does not cause fetal abnormalities
➢ Not associated with premature and LBW
➢ Infant can be weaned (if needed)
➢ Capatible with breastfeeding
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➢ C-III narcotic (opioid) agonist/antagonist (partial μ agonist and Κantagonist)
➢ High affinity for μ opioid receptors
➢ Less abuse potential than methadone
➢ Rx can be filled by regular pharmacy (covered by insurance)
methadone
buprenorphine
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C-III narcotic
Subutex® = buprenorphine
2 mg and 8mg sublingual tablets brand names: Belbuca®buccal film,
Butrans® transdermal patch, Sublocade®prefilled subQ syringe, Probuphine® subQ implant kit, Buprenex®injection
Suboxone® = buprenorphine
+ naloxone 2 mg/0.5, 4 mg/1,
8 mg/2, 12 mg/3 sublingual tabs
or sublingual/buccal filmbrand names: Bunavail®film or Zubsolv® tab
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C-III narcotic
Buprenex® injection is NOT INDICATED FOR TREATMENT OF OPIATE ADDICTION!!!!
Buprenex® injection is indicated for the treatment of pain!
Injection used to compound neonatal buprenorphine oral solution 75 mcg/ml
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FDA approved 2002
Treatment of opioid addiction
Relieves withdrawal, reduces cravings, and blocks the effects of heroin and other opiates
Bioavailability (sublingual)=30-40%; t ½ = 37 hours
Peak concentrations 30-60 mins after sublingual dose
Maintenance doses: 12 to 32 mg/day (sublingually)
**equivalent to 30-70 mg oral methadone**
Doses must be individualized (like Methadone)
Suboxone™ – contains naloxone (hard to overdose)
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Reckitt and Benckiser Pharmaceuticals,Inc. Product Info, 2007
➢ Prescribers must be “trained”
➢ Internet or one day course
➢A directory of prescribers can be found at
http://buprenorphine.samhsa.gov/bwns_locator
➢Almost 14,000 physicians have been authorized to
prescribe
➢REMS Program
➢ Subutex sublingual film: Medication Guide sheet
➢ https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020732s018lbl.pdf#page=27
➢ Suboxone sublingual film: Medication Guide sheet
➢ http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022410s026s027lbl.pdf#page=30
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Limited experience in pregnancy
Women must be willing to take med
Minimal side effects (sedation) following a dose
Fewer drug-drug interactions
Less chance for overdose
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Crosses the placenta
Less frequent NAS
Symptoms of NAS may be less severe
Fetal risk not greater than methadone
Compatible with breastfeeding
Jones HE, Finnegan LP, and Kaltebach K. Drugs 2012;72(6):747-757
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Few controlled trials comparing methadone and buprenorphine
Most case series or small comparative trials
Results often confounded by◦ Cigarette smoking
◦ Other substance abuse
◦ Psychiatric disorders
◦ Lack of prenatal care
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Methadone and Buprenorphine ➢NOT FDA approved
➢Methadone is considered standard of care
➢Buprenorphine shows promise
➢Both are Pregnancy Category C
➢Opiate antagonists are NOT recommended
➢Pharmacotherapy should be used with psychosocial support
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Those whom benefits outweigh risk
Lack of access to a methadone clinic
Those who do not tolerate methadone
Those who refuse methadone treatment
Women who become pregnant while on therapy should stay on it
Women on buprenorphine+naloxone(suboxone) should be switched to buprenorphine (subutex) alone
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Randomized, double-blind controlled trial that compared methadone-exposed neonates vs buprenorphine-exposed neonates
Similar maternal treatment and delivery outcomes between the medications
Compared to methadone-exposed infants, buprenorphine-exposed infants:
◦ Required 89% less morphine to treat NAS
◦ Spent 43% less time in the hospital
◦ Spent 58% less time in hospital being medicated for NAS
NAS treatment rates did not differ significantly between the groups
Women on buprenorphine were more likely to discontinue treatment (28/86 vs 16/89)
Jones HE, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010; 363: 2320-31.
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Jones HE, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010; 363: 2320-31.
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Unionized state
High lipid solubility
Low protein binding
Weak base
Low molecular weight
Maternal serum concentrations
Milk composition – pH
Infant feeding behaviors
Drug factors
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The amount of methadone in the breast milk will vary with the fat content of the sample:◦ Foremilk (less fat) less methadone
◦ Hindmilk (more fat) more methadone
◦ Peak milk methadone levels 4 hours after oral
◦ Average amount of methadone reported in breast milk 2.2% of the daily dose taken by the mother
◦ Frequent small doses can prevent Neonatal Withdrawal Syndrome (NWS)
Ballard et. al J Perinatal Neonatal Nurs 2002
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Small amount of methadone found in breast milk (not related to maternal methadone dose)
Limited data suggest breastfeeding may decrease NWS symptoms
Gradual weaning from breast is recommended to prevent NWS
Women who are HIV positive and/or continuing to use illicit drugs should not breast feed
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Excreted in breast milk with milk:plasma ratio of 1
Given the low bioavailability, infant exposure is approximately 1/5 to 1/10 of total buprenorphine
Buprenorphine levels in breast milk may have little effect on NWS
Jones HE, Martin PR, Heil SH et.al. J Subst Abuse Treat 2008;35;245-59
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Internet◦ U.S. National Library
of Medicine. LactMed(http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?)/LACT)
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“Methadone can increase serum prolactin. However prolactin level in a mother with established lactation may not affect her ability to breastfeed.”
“ Most infants receive an estimated dose of methadone ranging from 1 to 3% of the mother’s adjusted weight-adjusted methadone dosage.”
“The absolute dose in breast milk is less than the dosage used for treating NWS…”
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“Buprenorphine can increase serum prolactin. However prolactin level in a mother with established lactation may not affect her ability to breastfeed.”
“ Because of the low levels of buprenorphine in breast milk, its poor oral bioavailability in infants, and the low drug concentrations found in the serum and urine of breastfed infants, its use is acceptable in nursing mothers”
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Establish early collaboration/intervention between OB/GYN practitioner and OAT specialist and others
Address concerns/barriers for outpatient treatment of NWS in the community ◦ Breast feeding
◦ Availability of medications
◦ Risk for diversion of medication
◦ Assessments of the infant (reliable)
◦ Loss to followup
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Opioid use in pregnancy is an ever increasing problem
Neonatal withdrawal secondary to intrauterine exposure is associated methadone or buprenorphine
Non-pharmacologic and pharmacologic interventions with methadone or buprenorphine are indicated
Long term neurodevelopmental effects need to be determined
Transition of care issues need to be addressed
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1. Center for Substance Abuse Treatment. Medication-assisted treatment of opioid addiction in opioid treatment programs. Treatment Improvement Protocol Series 43. Rockville, MD: US Department of Health and Human Services 2005.
2. American Academy of Pediatrics Policy Statement: Breastfeeding and the Use of Human Milk. Pediatrics 2012;129:e827-e841.
3. Hudak ML, Tan RC. Committee on Drugs. Committee on Fetus and Newborn. American Academy of Pediatrics. Neonatal Drug Withdrawal. Pediatrics 2012; 129(2):e540-60, Feb 2012.
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Dr. Evelyn Fulmore, Pharm.D.
Clinical Pharmacy Specialist – Pediatrics/Women’s Health
Pediatric Satellite Pharmacy Supervisor
McLeod Regional Medical Center
Florence, SC