Substance Use Disorders
Chapters 23 and 32
Pathophysiologic Approach to Pharmacotherapeutics 1
(MSPA 520)
Fall 2023
Learning Objectives
1. Describe the pharmacologic actions of nicotine, opiates, and
alcohol
2. Describe the biochemical and physiologic alterations common
to substance use disorders.
3. Identify the symptoms of acute intoxication and withdrawal
from drugs of abuse
4. Select an appropriate treatment regimen for the treatment of
intoxication and withdrawal effects from drugs of abuse
5. Select a pharmacologic treatment for the maintenance
treatment of substance dependence
6. Identify legislation that enables the use of prescribed
controlled substances for opioid use disorder.
Definitions
• Physical Dependence – develops when recurrent drug use
leads to a state where specific physical withdrawal symptoms
occur when an individual stops taking the drug
• Psychological Dependence – develops when recurrent drug
use is driven by powerful cravings to obtain the pleasurable
effects of the drug
• Tolerance – state of adaptation in which exposure to a drug
induces changes that result in a diminution of one or more of
the drug's effects over time
Substance Use Disorder (DSM-5)
• A cluster of cognitive, behavioral, and physiological
symptoms indicating that the individual continues using the
substance despite significant substance-related problems
• Underlying changes in brain circuits that may persist beyond
detoxification, particularly in individuals with severe
disorders
• Pathological pattern of behaviors related to use of the
substance.
Addiction
• Chronic brain disease
• Compulsive use of substance despite serious detrimental
consequences
• Impaired control over use of the drug
• Stages
• Experimental use
• Recreational use
• Early dependency/abuse
• Full dependence/compulsive use
Reward of Adaptive Behavior
• Humans evolved to have systems in place to mediate
behaviors involved in survival
• Sex
• Food
• Social interaction
• Avoidance of aversive events
• Three main regions in the brain
• Nucleus accumbens – positive reward
• Amygdala – negative/fear-motivated behavior
• Prefrontal cortex – assigns stimulus to behavioral response
Brain Pathways
Reward Pathway
• Natural rewarding behaviors and drugs of abuse increase
dopamine in the nucleus accumbens
• Causes an acute “high”
• Drugs of abuse increase dopamine to greater levels than with
natural rewards
• Short-term reinforcement is linked to rate of increase of
dopamine levels
• Faster acting drugs are more rewarding and produce more dependence
(injected opioids, snorted cocaine)
• Reward system becomes completely controlled by drug of abuse
over time
• Leads to continued drug seeking despite tolerance to positive effects to
drugs
Dopamine: The Common Neurotransmitter
• Direct increases – inhibition of reuptake or stimulation of release
at NAc
• Cocaine
• Amphetamine
• Indirect increases – from other transmitters affecting the
mesolimbic system
•
•
•
•
•
•
Natural rewards
Alcohol – via GABA and opioid system
Opioids – via mu-opioid receptor
Nicotine – nicotinic cholinergic receptor
Cannabis – via endocannabinoid and opioid system
NMDA antagonists (hallucinogens)
Reward Circuitry
Nicotine
Nicotine Pharmacology
• Cholinergic agonist
• Rapidly absorbed from mouth or respiratory tract
• Effects are dependent on dose
• May stimulate or depress CNS
• Skeletal muscle relaxation
• Peripheral vasoconstriction, ↑ bp, ↑hr
• Increased alertness and cognitive function
• Pleasure and relaxation
• Activates reward system
• Adaptation and tolerance with repetitive exposure
Neurochemical Related Effects
N
O
â Dopamine
â Norepinephrine
â Acetylcholine
â Glutamate
T
â Serotonin
I
C
I
N
E
â b-Endorphin
â GABA
Pleasure, appetite suppression
Arousal, appetite suppression
Arousal, cognitive enhancement
Learning, memory enhancement
Mood modulation, appetite
suppression
â Reduction of anxiety and tension
â Reduction of anxiety and tension
â
â
â
â
â
Nicotine reaches the brain
within 11 seconds!
Nicotine Withdrawal
• Can last 2-4 weeks after quitting
• Increased skin temperature
• Anxiety
• Cravings (for cigarettes and food)
• Difficulty concentrating
• Frustration
• Irritability and impatience
• Hostility
• Insomnia and restlessness
• Cravings (psychological dependence) can last months-years
Health Risks of Smoking
• CV disease
• Stroke
• MI
• Lung disease
• Asthma
• Chronic bronchitis
• Emphysema
• Cancer
•
•
•
•
Lung
Head and neck
Leukemia
Others
• Reproductive effects
• Reduced fertility
• Poor pregnancy outcomes
• Infant mortality
• Other
•
•
•
•
Cataract
Osteoporosis
Periodontitis
Poor surgical outcomes
Compounds in Tobacco Smoke
An estimated 4,800 compounds in tobacco smoke,
including 11 proven human carcinogens
Gases
n
n
n
n
n
Carbon monoxide
Hydrogen cyanide
Ammonia
Benzene
Formaldehyde
Particles
n
n
n
n
n
Nicotine
Nitrosamines
Lead
Cadmium
Polonium-210
• Nicotine is the addictive component of tobacco products, but it does NOT cause the ill
health effects of tobacco use.
• These compounds are responsible for CYP450 1A2 induction effects of smoke
Nonpharmacologic Strategies
Cognitive
• Thinking about cigarettes
doesn’t mean you have to
smoke.
• Tell yourself, “It’s just a
thought,” or “I am in control.”
• Say the word “STOP!” out loud,
or visualize a stop sign.
• As soon as you get up in the
morning, look in the mirror
and say to yourself “I am
proud that I made it through
another day without tobacco.”
Behavioral
• Control the environment
• Tobacco-free home and
workplace
• Remove cues to tobacco use;
actively avoid trigger situations
• Substitutes for smoking
• Take a walk, diaphragmatic
breathing, self-massage
• Actively work to reduce stress,
obtain social support, and
alleviate withdrawal
symptoms
Pharmacologic Strategies
• Nicotine replacement
• Reduces physical withdrawal
• Eliminates immediate, reinforcing effects of nicotine
• Allows for focus on behavioral and psychological aspects
• Bupropion – NE/DA reuptake inhibitor
• Dopamine = mimics rewarding effects
• Norephinephrine = reduces withdrawal symptoms
• Varenicline (Chantix) – selective nicotinic agonist
• Greater affinity than nicotine – blocks binding
• Stimulates release of dopamine to mimic rewarding effects
Nicotine Replacement
• Gum
• Nicorette and generics
• Lozenge
• Commit
• Nicorette and generics
• Patch
• NicoDerm and generics
• Nasal spray
• Nicotrol (Rx)
• Inhaler
• Nicotrol
• E-cigarettes
NRT General Guidelines
• Avoid in recent (≤ 2 weeks) post-MI patients or serious
angina pectoris
• Avoid in pregnancy (category D)
• Not available OTC for adolescents
• Therapy typically begins on the patient’s quit day
• Preloading strategy may reduce satisfying effects of smoking
Nicotine Gum/Lozenge
• Available in 2- and 4-mg doses
• Gum – chew until peppery/minty taste, then
park between cheek and gum
• Lozenge – allow to dissolve in mouth for 2030 min
• Dose every 1-2 hrs initially, then increase
interval to 2-4, then 4-8 hours over
several weeks
• May self-titrate as needed
• Satisfies oral cravings
Nicotine Patch
• Available in 21-, 14-, and 7-mg/day strengths
• For >10 cigs/day: start 21-mg patch for 4-6 wks, then use 14- and
7-mg patches for 2 wks each
• For <10 cigs/day: start 14 mg/day for 6 wks, then 7 mg for 2 wks
• May wear patch for 16 hrs and remove at bedtime if pt has
sleep disturbance
• Can supplement with gum/lozenge for acute management of
symptoms
Nicotine Nasal Spray/Inhaler
• NS: 0.5 mg nicotine/spray
• 1 spray given in each nostril 1-2 times/hr
• Fastest delivery of nicotine
• Inhaler: 4 mg nicotine vapor/cartridge
• Each cartridge (10 mg) used over 20 minutes
• Delivery method simulates smoking
• Recommended to be used for 3-6 months
• Patients may self-titrate dose
E-cigarettes
• Utilizes liquid nicotine containing solutions
• Devices heat solution producing a vapor that
is inhaled, delivering nicotine via the
respiratory tract
• Solution pods may also contain flavoring and
other inert chemicals
• Typically only contain trace amounts of
carcinogenic chemicals
• Risks
• Burns
• Nicotine dependence in youth – potential
‘gateway’ for cigarette use
• Unclear risks of lung disease (E-cigarette or
Vaping use-Associated Lung Injury-EVALI) and
cancer
Bupropion SR (Zyban)
• Reduces withdrawal and cravings by inhibiting DA and NE
reuptake
• Dose: 150 mg PO daily × 3 days, then 150 mg BID
• Start 1-2 weeks prior to quit date
• Duration: 3-6 months
• May be used in conjunction with NRT
• AE: Agitation, nausea, insomnia, weight loss, lowering of
seizure threshold
• Contraindicated in seizure disorders, eating disorders
Varenicline (Chantix)
• Partial agonist at α4β2 nicotinic receptor
• Reduces withdrawal symptoms
• Prevents full agonist binding – blocks effects of nicotine from
smoking
• Titration – started 1 week prior to quit date
• 0.5 mg daily for 3 days
• Increase to 0.5 mg twice daily for 3 days
• Increase to 1 mg twice daily for 12-weeks
• May repeat a 12-week course if not fully abstinent
Varenicline (Chantix)
• Common Adverse Effects
• Nausea
• Constipation
• Insomnia, abnormal dreams
• Headache
• Warnings
• Increased effects of alcohol
• Seizures
• Psychiatric Adverse Effects
• Mood changes – depression or
mania
• Psychosis – hallucinations,
paranoia, delusions, homicidal
ideation,
• Aggression, hostility, agitation
• Anxiety and panic
• Suicidal ideation, suicide
attempts, or completed suicide
Alcohol Use Disorder
Alcohol
• A CNS depressant affecting gamma amino-butyric acid
(GABA), glutamate, and dopamine
• Dose-dependent CNS depression
• Euphoria, disinhibition
• Impaired judgment, reasoning
• Ataxia, vision impairment; slurred speech
• Sedation, sleep
• Unconsciousness
• Coma
• Respiratory depression and cardiovascular collapse
Dosing
• Equivalent amounts (14 g alcohol)
• 1 12-oz can of beer
• 4 oz of wine
• 1 shot (1.5 oz) whiskey
• Increases BAL 20-25 mg/dL in a healthy 70-kg male
• Lethal dose varies, but generally seen with BAL >400-500
mg/dL
Alcohol PK – Absorption
• 5-10 min: Absorption begins in the stomach.
• 30-90 min: Peak blood ethanol levels after oral consumption
in fasting subjects.
• Food slows absorption.
Alcohol PK – Metabolism
• Occurs in stomach and liver (>90% in liver).
• ADH is main pathway for metabolism.
• Gastric metabolism accounts for gender and ethnic differences.
• Nonlinear elimination=higher doses saturates enzymes.
• Zero-order elimination kinetics
• Chronic heavy drinkers metabolize at 2x normal rate – associated
with behavioral tolerance
Wernicke’s Encephalopathy
• Associated with thiamine deficiency from prolonged alcohol
consumption
• Medical emergency – 10-20% mortality
• CNS depression: mental sluggishness, restlessness, confusion,
coma
• Ambulatory difficulties: wide-based ataxic gait
• Ocular problems: horizontal nystagmus, pupillary abnormalities,
retinol hemorrhages, papilledema
• Other: hypothermia, hypotension, polyneuropathy
Korsakoff’s Psychosis
• Often a progression from Wernicke’s Encephalopathy
• 80% who survive but do not recover in 48 to 72 hr will progress.
• Symptoms: psychosis, retrograde amnesia (inability to recall
info), anterograde amnesia (inability to assimilate new info),
confabulation.
• Slow and incomplete recovery in most
• 25-50% do not recover and require long-term care
Alcohol Withdrawal
• Stage 1 (6-8 hr): tremulousness, anxiety, hyperreflexia,
hypertension, tachycardia, diaphoresis, hyperthermia,
nausea, vomiting, insomnia, and craving due to moderate
autonomic hyperactivity
• Stage 2 (24 hr): auditory and visual hallucinations, anxiety,
tremor, continued autonomic hyperactivity
• Stage 3 (7-48 hr): generalized seizures
• Stage 4 (3-5 d): Delirium Tremens (DTs)
Delirium Tremens
• Symptoms: confusion, hallucinations, agitation, tachycardia,
mydriasis, fever.
• 5-15% mortality in those left untreated.
• Mortality from aspiration, shock, trauma, hyperthermia,
arrhythmias, and infection
• Risks
• Prior history of DTs.
• Early signs of withdrawal.
• Significant drinking history-equivalent of 1 pint of whiskey/d for
10-14 days
• Alcohol induced hepatic dysfunction.
Goals of Treatment
• Nutritional support
• Fluids and vitamins
• Symptomatic management of withdrawal
• Prevention of seizures and DTs
• Long-term abstinence after detoxification
Treatment of Nutritional Deficits
• Thiamine – for prevention of Wernicke-Korsakoff syndrome
• Must be given prior to glucose-containing solutions in suspected
cases of WE
• Initial: 500 mg IV or IM
• Continue to give 100-250 mg daily for 3-5 days
• Hydration – to correct dehydration
• Electrolytes
• Oral potassium
• Magnesium and phosphorous may correct gradually with
adequate diet
• Multivitamin supplementation
Management of Alcohol Withdrawal
• Drug of choice – benzodiazepines
• Cross-tolerant with alcohol
• Prevents seizures and DTs
• Dosing regimens – Scheduled vs. Symptom-triggered dosing
• Alternatives
• Divalproex
• Carbamazepine
• Gabapentin
Benzodiazepines used in AUD
• Chlordiazepoxide (Librium) – PO
• Diazepam (Valium) – PO, IV
• Lorazepam (Ativan) – PO, IM, IV
• Oxazepam (Serax) – PO
Benzodiazepine Pharmacology
• A large group of CNS depressant drugs with
similar chemical structure and pharmacologic
effects
• Facilitate activity of GABA – main CNSdepressant neurotransmitter
• Acts as a positive allosteric modulator at the
chloride channel
• Increases affinity of GABA at binding site
• Chloride entry leads to hyperpolarization
• Produces hypnosis, anxiolytic, anticonvulsant,
and muscle relaxant effects
• Cross-tolerant with alcohol
Benzodiazepine PK
• Onset – determined by absorption and entry into CNS
• Very fast with parenteral agents: lorazepam, diazepam
• Fast with oral lipophilic agents: diazepam, chlordiazepoxide
• Slower with oral hydrophilic agents: lorazepam
• Duration of action – determined by elimination half-life,
presence of active metabolites, and redistribution from CNS
• Long: chlordiazepoxide, diazepam
• Shorter: lorazepam, oxazepam
Benzodiazepines: Symptom-Triggered Therapy
• Current standard of care in alcohol detox
• Medication given only when patient has symptoms
• Generally leads to shorter treatment course and less
oversedation
• Use objective measure (e.g. CIWA scale) to assess symptom
and determine dosing
• Sample regimen: chlordiazepoxide 25-100 mg q1hr PRN CIWA-Ar
score>8
Benzodiazepines: Scheduled Dosing
• Examples of standing protocols:
• Chlordiazepoxide 50 mg q2-4h
• Diazepam 10 mg q2-4h
• Oxazepam 60 mg q2h
• Lorazepam 1 mg q2h
• PRN dosing x 24 hrs to suppress autonomic hyperactivity and
CNS irritability
• Total dose is then given the next day in 4 divided doses
• Taper over 3-5 days.
• Maximum dose: equivalent of 600 mg/d of chlordiazepoxide.
Anticonvulsants for Withdrawal
• May be useful for less severe cases of withdrawal in
ambulatory patients
• Not effective for reducing risk of DT’s and seizures
• Gabapentin
• Comparable efficacy to benzos with less sedation
• Start at 900-1200 mg, then taper over 4 days
• Carbamazepine
• Comparable efficacy to gabapentin and benzos, but more nausea
and CNS depression
• Start at 600-800 mg, then taper over 4 days
Maintenance Therapy
• Intended for chronic treatment of AUD for relapse
prevention
• Treatment works best after withdrawal symptoms have
subsided
• FDA Approved
• Disulfiram (Antabuse)
• Naltrexone PO (ReVia) and LAI (Vivitrol)
• Acamprosate (Campral)
• Alternatives (Currently off-label)
• Topiramate
• Gabapentin
Disulfiram (Antabuse)
• Irreversible acetaldehyde dehydrogenase inhibitor
• Can take up to 14 days for new enzymes to be produced
• Produces a severe aversive reaction after alcohol intake
• flushing, nausea, vomiting, tachycardia
• Potentially cardiovascular collapse and death.
X
Disulfiram
• Efficacy is highest in highly motivated patients or those
legally mandated to take it
• Adherence is a strong predictor of positive outcome.
• May reduce drinking, but does not significantly achieve total
abstinence, delay relapse, or improve employment status
• Adverse effects: dermatitis, garlic-like or metallic after-taste,
hepatitis, optic neuritis, peripheral neuropathy, psychotic
reactions, nausea, headache.
• Drug Interactions:
• Inhibits CYPP450 3A4
• Topical and OTC products containing alcohol
Naltrexone
• Mechanism: opioid antagonist – reduces reinforcing effect of
alcohol consumption
• Efficacy
• Small to moderate benefit depending on study outcomes
• Benefit for binge drinkers
• Significant effect on the maintenance of abstinence and
prevention of heavy drinking
• Dosing – can be initiated while patient is still drinking
• Oral (ReVia): 50 mg daily
• IM (Vivitrol inj): 380mg once every 4 weeks deep into gluteal
muscle.
Naltrexone
• Precaution: acute hepatitis, liver failure, cirrhosis.
Hepatoxicity is dose-related.
• Adverse Effects: GI pain/nausea, constipation, anxiety,
headache, hepatotoxicity, opioid-withdrawal syndrome.
• Patient education
• Limit nausea by starting after sufficient abstinence, with low dose,
titrate slowly
• Patient should be opioid-free for 7-14 days before starting
• Pain management: opioid doses given to overcome naltrexone
may result in fatal OD. Non-opioid such as NSAID should be used,
if possible.
Acamprosate (Campral)
• Glutamate modulator at NMDA receptor – reduces alcohol
craving
• Supports overall abstinence; no effect on consumption after first
drink
• May have improved outcome in combination with naltrexone
• Dosing: 666 mg (2 333mg tablets) tid.
• No titration on initiation.
• Poor bioavailability. Takes several days to achieve therapeutic blood
levels.
• Therapy should be continued regardless of relapse.
• Decrease dose to 333mg tid for CrCl 30-50ml/min. Do not use with
CrCl<30ml/min.
Acamprosate
• Adverse Effects: diarrhea most commonly reported
• Drug Interactions:
• Does not interact with alcohol.
• Coadministration with naltrexone resulted in 33% inc Cmax and 25%
inc AUC of acamprosate. No dosage adjustment necessary.
• Acamprosate may decrease effects of tetracyclines.
Topiramate (Topamax)
• Believed to antagonize glutamate receptors, inhibiting
dopamine release in the reward center
• Outcomes
• Reduced drinks per drinking day
• Reduced % of drinking days and heavy drinking days
• Dosing
• Initial: 50 mg PO daily
• May need 100 mg PO BID
• Maximum: 300 mg daily – titrate over several weeks
• Dose adjustments in renal (CrCl<70) and hepatic impairment
Topiramate
• Adverse Effects
• Cognitive dulling
• Sedation
• Paresthesia
• Abdominal pain, anorexia
• Should be gradually tapered when stopping therapy
• May decrease efficacy of oral contraceptives
Gabapentin (Neurontin)
• Likely mechanism is through modulation of GABA activity in the
amygdala
• Outcomes
•
•
•
•
Increased rates of abstinence
Decreased heavy drinking
Possible useful in co-occurring neuropathic pain
Possible adjunct to naltrexone
• Dosing
•
•
•
•
Initiate at 300 mg PO daily
Increase by 300 mg daily, as tolerated
Target dose: 1800 mg PO daily in three divided doses
Limit dose in renal impairment (CrCl < 60)
Gabapentin
• Adverse Effects
• Dizziness
• Drowsiness
• Somnolence
• Ataxia
• May cause additive CNS depression with alcohol, opioids,
and benzos
Opioid Use Disorder
Definitions
• Opiates: All naturally occurring alkaloids derived from opium
(the sap from the immature Papaver Somniferum) and semisynthetic
• Opioids: All drugs (natural & synthetic) with morphine like
activity.
• Narcotics: Legal term for this group of drugs.
Drugs
• Agonists
• Natural: Morphine, Codeine
• Semisynthetic: Heroin, Hydromorphone, Hydrocodone,
Oxymorphone, Oxycodone, Dextromethorphan
• Synthetic: Methadone, Meperidine, Fentanyl, Propoxyphene,
Tramadol; Diphenoxylate
• Partial agonist: Buprenorphine
• Agonist-antagonist: Pentazocine, Butorphanol,Nalbuphine
• Antagonists: Naloxone, Naltrexone, Nalmefene
Opioid Mechanism of Action (MOA)
• *Mu (μ) receptor: analgesia, euphoria, respiratory
depression, pupillary constriction, constipation
• Kappa (κ) receptor: analgesia, dysphoria, diuresis
• Delta (δ) receptor: analgesia
Clinical Effects
• Analgesia
• Euphoria
• CNS Depression
• Drowsiness, lethargy, stupor, or coma
• Respiratory Depression
• Apnea, hypoxia, non-cardiogenic pulmonary edema (NCPE)
• Pin-point pupils
• May be normal or dilated if hypoxic or if coingestants are involved
(scopolamine and cocaine)
Other Clinical Effects
• Cardiac: hypotension, bradycardia
• GI: *constipation, nausea, vomiting
• GU: Urinary retention
• Histamine release à pruritis and flushing
• Hypothermia
Medical Complications - IVDA
• HIV/AIDS
• Endocarditis
• Pneumonia
• Hepatitis
• Embolism
• Abscess
Heroin
• Horse, smack, antifreeze, China White, dust, H, Harry, junk,
Mexican brown
• Use is rising - price has ¯ by 2/3; purity has ­ from <10% to
96%
• Snorted, smoked, injected
• Adulterants always present
• Fentanyl
• Caffeine
• Quinine
• Talc
Codeine Equivalents
Codeine
Equivalents
Codeine
Meperidine
Pentazocine
Morphine
Oxycodone
Dihydrocodeine
Hydromorphone
Oxymorphone
Mg
100
150
100
30
15
10
3.75
3
Conversion
factor
1
0.7
1
3.3
6.7
10
26.7
33.3
Goals of Opioid Dependence Treatment
1. Crisis intervention for resuscitation in event of overdose
2. Stable abstinence
• Evaluation of motivation for recovery
• Detoxification
• Relapse prevention
3. Reduction or discontinuation of illicit opioids and
improvement of health and social function
• Maintenance treatment
• Harm avoidance
• Rehabilitation
Managing Opioid Overdose
• Call for emergency assistance
• Support respiration
• Ventilate with 100% oxygen before naloxone is administered to
reduce the risk of acute lung injury
• When 100% oxygen is not available, rescue breathing very
effective in supporting respiration
• Administer naloxone
Naloxone
• Opioid antagonist available OTC via standing order
• Can be administered intranasal, IM, IV, SC
• Usually intranasal or IM outside of hospital
• Only produces effect when administered to someone who has
used opioids so relatively safe
• Few side effects but can precipitate withdrawal
• Response within 3-5 minutes; duration of action 30-90 minutes
• Dosing
• Intranasal: 2mg/2ml. Administer 1ml per nostril. Can readminster in 35 minutes, if necessary
• IM: 0.4mg/ml. Inject 1ml IM. Can readminster in 3-5 minutes, if
necessary
• Monitor for >4 hours for reemerging symptoms
Rescue Breathing
• Verify that the airway is clear
• Tilt the head back and pinch the nose closed
• Place your mouth over the patient's mouth to make a seal
and give 2 slow breaths
• Continue with one breath every 5 seconds.
Opioid Withdrawal
• Signs and Symptoms
• Agitation, anxiety, myalgia, rhinorrhea, insomnia, diarrhea,
mydriasis, nausea, vomiting
• Time Course
• Onset: 8-14 hr
• Peak: 36-72 hr
• Duration: 5-10 days
Opiate Dependence Treatment
• Acute Withdrawal – symptomatic management of discomfort
• Inpatient setting
• Detoxification – to end drug use and reduce relapse
• Inpatient or outpatient
• Maintenance – suppress withdrawal, reduce cravings, and
promote psychosocial integration
• Outpatient
Methadone
• Synthetic CNS μ-opioid receptor agonist
• Pharmacokinetics
• Absorption: 85-100% oral bioavailability
• Distribution:
• ~80% protein bound
• Distribution to lung, liver, spleen, kidney, brain
• Metabolism: CYP 3A4, 2B6, 2C19 > 2C9, 2D6
• Elimination:
• Parent – t½ = 23 hr
• Metabolite – t½ = 42 hr
Methadone
• Black Box Warnings
• Respiratory depression
• QTc prolongation by inhibition
of cardiac potassium channels
• Tablets are for oral
administration only
• Adverse Effects
•
•
•
•
•
Constipation
Sweating
Sexual Dysfunction
Sedation
Respiratory depression
• Contraindications
• Respiratory depression (without
ventilatory support)
• Acute bronchial asthma
• Paralytic ileus
• Hypersensitivity
Methadone
• Drug Interactions
• Additive increase in sedation: benzodiazepines, alcohol, other opioid
agonists and CNS depressants
• CYP450 inhibitors or inducers (3A4, 2B6, 2C19)
• Concomitant QTc prolonging agents
• Selegiline
• Monitoring Parameters
• Mental status and respiratory status
• Baseline electrocardiogram (ECG) within 30 days of initiation, annually
thereafter
• Additional ECG monitoring if methadone dose >100 mg or if seizures or
syncopal events occur
• Potassium (hypokalemia)
Methadone: Practical Considerations
• Schedule II Controlled Substance
• Narcotic Addict Treatment Act of 1974 first established
parameters for methadone treatment in OUD
• Must be dispensed from opioid treatment program, approved by
Substance Abuse and Mental Health Services and state authority
• Treatment can be continued in hospitalized patients after verification
from methadone program
• Diversion Risk: liquid < tablet
• Pregnancy
• May allow for priority treatment in MMT programs
• Monitor for abstinence in newborn
Buprenorphine
• Partial μ-receptor agonist with greater affinity than opioids
• Pharmacokinetics
• Absorption: 30-35% sublingual (SL) bioavailability
• Distribution
• 96% protein bound
• Distribution to blood, cerebrospinal fluid
• Metabolism: CYP3A4 and hepatic glucuronidation
• Elimination: t½ = 24-42 hr
Buprenorphine
• Dosage forms
• SL tablet (Subutex) – for induction therapy
• SL film as combination product with naloxone (Suboxone, Zubsolv)
• Naloxone in formulation is for abuse deterrence, very low PO and SL absorption
• Implant (Probuphine) – for long term use in stable patients
• Adverse Effects
• Relatively well tolerated, possible respiratory depression with large
doses
• Constipation
• Drowsiness
• Headache
• Nausea
• Reduced libido
Buprenorphine
• Contraindications: hypersensitivity
• Drug Interactions
• CYP 3A4 inhibitors or inducers
• Additive increase in sedation: benzodiazepines, alcohol, other
opioid agonists and CNS depressants
• Monitoring Parameters
• Mental status and respiratory status
Management of Withdrawal
• Methadone
• 40-60 mg daily
• Taper over 3-7 days
• Buprenorphine/naloxone
• 4-8 mg initially, tapering over 5 days
• Clonidine (not cross tolerant with opioids)
• Dose: 0.1 mg PO TID
• Duration: 4-6 days for short acting opioids, longer as needed for
long acting opioids
Opioid Detoxification
• Buprenorphine/naloxone
• Stabilization Dose: Buprenorphine 8-32 mg/day
• Taper: Every 10-14 days
• Methadone
• Up to 80 mg/day initially
• Slow taper
Maintenance Therapy
• Engage patient in full array of substance abuse rehab
treatment
• Methadone – within certified treatment program
• Use liquid formulation
• Dose: 60-100 mg daily
• Potentially long-term or life long treatment
• Buprenorphine/naloxone – office-based
• Sublingual tablets or film
• 4/1 to 32/8 mg daily
• Potentially long-term or life long treatment
DATA Waiver
• SAMHSA is federal government body that regulates
treatment for opioid use disorder
• DATA 2000 (Drug Addiction Treatment Act) was original
legislation that allowed of office-based management of
opioid addiction
• Certified physicians originally limited to 30 patients/practice
• Later increased to 100, then 275 patients per physician with
SAMHSA approval
• Prescribers used an ‘X’ DEA number (e.g. XB1234567)
CARA Act
• Comprehensive Addiction and Recovery Act was signed into
law by Pres. Obama in July 2016
• Expanded privilege of office-based prescribing
buprenorphine maintenance to qualifying PAs and NPs
• Can treat up to 30 patients with a standard waiver
• May increase to 100 after one year and with additional training
Waiver Elimination Act (2023)
• Law that removed federal requirement for practitioners to
have a waiver for prescribing buprenorphine
• All DEA-registered prescribers may prescribe buprenorphine
as permitted by state law
• No patient limits or counseling certifications requirements
• Opioid disorder training required for DEA registration
Questions?
85