Substance Abuse (w/o fun illicit drugs)

Define addiction

A primary, chronic neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations

What are the 5C’s of addiction?

Chronicity, impaired control over drug use, compulsive use, continued use despite harm, craving

Define drug abuse

maladaptive pattern of substance use characterized by repeated adverse consequences related to the repeated use of the substance

Define dependence:

2 of the following within 12 months:

• tolerance

• withdrawal

• larger amounts or longer period of time than was intended

• persistent desire or unsuccessful effort to cut down or control

• time spent in activities necessary to obtain, use, or recover

• craving or strong desire to use

• social, occupational, or recreational activities given up or reduced

• recurrent use resulting in failure to fulfill major role obligations at work, school, and home

• continued despite persistent or recurrent social or interpersonal problem caused or exacerbated by substance

• recurrent use in situations in which it is physically hazardous

  • continued use despite having knowledge of having persistent or recurrent physical or psychological problem that it likely to have been caused or exacerbated by the substance

T/F: a patient taking opioids solely under medical supervision would not be considered dependent if they had tolerance and withdrawal symptoms (even though those are two of the symptoms)

true

what are opiate agonists

Drugs that activate opiate receptors on neurons — repeated administration leads to physical dependence and tolerance

What are opiate antagonists

Opiates that bind to opiate receptors but block them rather than activating them

what are opiate partial agonists

Drugs that bind to opiate receptors but not to the same degree as full agonists —→ ceiling effect

Define sensitization

Increased response to a drug with repeated use — shifts the dose response curve to the left 

Example of a drug that induces tolerance (euphoria) and sensitization (movement)

Cocaine

What can occur in cocaine-induced sensitization?

movement, cataplexy, and seizures

Define tolerance

A 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 — shifts dose response curve to the right

what are the two types of tolerance?

Metabolic and cellular.

What is meabolic tolerance

tolerance involving the liver enzymes that metabolism the drug

what is cellular tolerance?

tolerance involving receptor down-regulation (the receptor that drug targets)

How does acute tolerance diff from protracted?

Acute is within a single administration whereas protracted is over time

what is cross-tolerance

tolerance to one drug leads to tolerance of other drugs in the same class

What has to be done to the dose of a drug if the patient is sensitized to it?

Lower dose

What has to be done to the dose of a drug if the patient has tolerance to it?

Higher dose

T/F: physical dependence is associated with, but separate from, tolerance

true

How does physical dependence differ from tolerance?

Involves the patient needing the drug to function normally and to avoid withdrawal symptoms

What is physiological dependence

The body adapts to presence of drug and needs the drug on board to maintain homeostasis.

What can cause withdrawal symptoms for patients with physiological dependence?

Can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of a drug and/or administration of an antagonist.

Define withdrawal symptoms

Behaviors displayed by a user when a drug use ends — typically the opposite of the drug effect

What system do all abused drugs tend to activate?

The mesolimbic dopamine system

What are the 3 stages of repeated activation of the mesolimbic dopamine system?

pleasure —> associative learning through classical conditioning —→ incentive salience (craving to get DA released by cues/context alone)

What are the risk factors for SUDs?

Dysfunctional childhood, abuse, ADHD, school problems, conduct disorder, early onset of substance use (esp. before the age of 14), personal history of a SUD, genetic predisposition (positive family history)

facts regarding young patients and SUD:

Information about the risk and benefits of opioid use among those less than 18 years old is limited.

The long-term effects of opioids on the developing adolescent brain are not known.

Adolescents who misuse opioids often misuse their own prescription.

Use of opioids before high school graduation is associated with a 33% increase in the risk of later opioid misuse.

Marijuana use may be a marker for those at-risk for prescription misuse

What are the types of drug testing?

Hair, urine, blood, and saliva

Facts regarding hair drug tests:

Can tell if patient has used drug anywhere from 7 days - 3 months ago. Hair from the nape is the most recent, the crown is the oldest, and the scalp is the most reliable.

Advantages: Long observation period (observed)

Disadvantages:

• Few labs do this (Cordant)

• Need 150 strands, 3 sections at least 0.75” each thickness of a pencil

Facts regarding urine drug tests

Gold standard! Can tell if patient has used drugs anywhere from 1-30 days depending on the drug. Most drugs are detected for a few days to a few weeks.

Advantages: Reasonable detection limits, can/need to creatinine normalize to follow levels

Disadvantages: Patients can falsify or alter sample. Can observe but can still be falsified, monitor temperature and use blue tablets

Facts regarding blood drug tests

Detects most drugs from 0-3 days of drug use, unless they have a very long half-life.

Advantages: can use if you can’t get urine or saliva (observed)

Disadvantages: very short detection time, somewhat invasive, few labs do this (Cordant)

Facts regarding saliva drug tests

Detects most drugs from 0-3 days of drug use, unless they have a very long half-life.

Advantages: can use if you can get urine or blood? (observed)

Disadvantages: very short detection time

How is urine obtained for toxicology

Use cups with temperature strips, consider direct observation, qualitative immunoassays, quantitative CG/MS

Facts regarding qualitative immunoassays

Synthetic opioids (e.g., methadone, fentanyl) do not produce a positive test for opiates.

Some opiates (e.g., oxycodone, buprenorphine) typically will not produce a positive test for opiates

Some benzodiazepines (e.g., clonazepam) may not produce a positive test for benzodiazepines

Some OTC medications (e.g., pseudoephedrine) may produce a positive test for amphetamines

Environmental exposure to marijuana will not produce a positive test

Drugs with short half-lives (methamphetamine, lorazepam, cocaine, heroin) will cause urine toxicology tests to be positive for _____________________________

only a few days after last use

Drugs with long half-lives (buprenorphine, cannabinoids, diazepam, methadone) may cause urine toxicology tests to be positive for ________________________________

several days to a few weeks after last use

Creatinine Normalized Drug Level =

[urine drug level] / [urine creatinine] x 100

Why do we creatinine normalize urine drug tests?

Urine drug concentrations can vary widely depending on how dilute or concentrated the urine is. Normalizing creatinine will make drug concentration results more comparable across samples

What are diazepam’s metabolites?

Temazepam —> oxazepam

Desmethyldiazepam

What are quazepam’s metabolites?

desmethyldiazepam

What is temazepam’s metabolite

Oxazepam

What is buprenorphine’s metabolite?

norbuprenorphine

What are codeine’s metabolites?

morphine, norhydrocodone, hydrocodone, hydromorphone

What are hydrocodone’s metabolites?

norhydrocodone, hydromorphone

What is morphine’s metabolite?

hydromorphone

what is fentanyl’s metabolite?

norfentanyl

How are SUD treated?

using pharmacotherapy, outpatient/inpatient addiction treatment, counseling, groups (NA/AA), family groups (Nar-anon, Al-Anon), toxicology testing, identifying co-morbid conditions, laboratory testing to find deficits, psychiatric diagnosis, determine presence of other health issues

What are the concerns with sharing needles?

sexually transmitted diseases (HIV/AIDS), hepatitis, tetanus, anaphylaxis, nephrotic syndrome, abscesses (skin popping)

Which drug has risks of severe necrotic skin ulcerations from repeated exposure

Xylazine

Which depressants are typically abused?

Sedatives/hypnotics (benzos, flunitrazepam, barbiturates), GHB (Gamma-hydroxybutyrate), opiates, DM

MOA of benzos

Potentiate inhibitory action of GABA: binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system

Describe the PK of benzos

Extensively metabolized by the liver to both active and inactive metabolites. Active metabolites contribute to magnitude of effect. Long elimination half-lives with accumulation during chronic dosing. 

T/F: benzos have rapid tolerance with chronic dosing

true

Effects of benzos

decreased BP, memory impairment, drowsiness, confusion, anterograde amnesia GI, urinary retention, slurred speech, poor coordination, bloodshot eyes, respiratory depression

How does benzo withdrawal present?

anxiety, insomnia, restless, muscle tension, irritability, blurred vision, diaphoresis, nightmares, depression, paranoia, hallucinations, seizures, psychosis

How do you treat benzo overdose?

supportive care, flumazenil 0.2 mg/min up to 3 mg

CI with flumazenil

tricyclic (seizure) or dependent patients

MOA of flumazenil

Competitively inhibits the activity at the benzodiazepine receptor site on the GABA/benzodiazepine receptor complex

Describe the PK of flumazenil

Onset of 1-3 minutes (80% response within 3 minutes)

Peak effect of 6-10 minutes

ADRs of flumazenil

N/V, benzo withdrawal signs and symptoms

barbiturates have similar effects to ______________________

benzos and alcohol

describe intoxication of barbiturates

Occurs similarly to alcohol - disinhibition, mood lability, unsteady gait, slurred speech, nystagmus, amnesia, poor judgement

How do you treat barbiturate overdose?

supportive care

how does barbiturate withdrawal present?

can be life-threatening - anxiety, n/v, postural hypotension, seizures, delirium, insomnia, hyperpyrexia

how to treat withdrawal form barbiturates

taper, change to a longer acting barbiturate (phenobarb) and taper, substitute anticonvulsant

What is GHB?

Similar to GABA (homemade) - Xyrem/Lumryz (ER) and Xywav

• controlled substance CIII

what is GHB used for?

treatment of cataplexy and daytime sleepiness in patients with narcolepsy

MOA of GHB

Sodium oxybate / oxybate salts are derived from gamma aminobutyric acid (GABA) and acts as an inhibitory chemical transmitter in the brain. May function through specific receptors for gamma hydroxybutyrate (GHB, a metabolite of GABA) and GABA (B) at noradrenergic, dopaminergic and thalamocortical neurons.

PK of GHB

Half-life elimination of 30-60 minutes

Time to peak is 30-75 minutes

No active metabolites

effects of GHB

amnesia and hypotonia

s/s of GHB toxicity

coma, seizures, respiratory depression, vomiting.

s/s of GHB withdrawal

agitation, mental status changes, elevated BP, HR, tachycardia

How do you treat GHB overdose?

supportive care, ventilation/O2/intubate, fluids, thiamine

T/F: xylazine causes major toxicity in humans

true

T/F: routine toxicology screens do not detect xylazine and overdoses are underdiagnosed d/t rapid elimination of 23-50 minutes

true

What should be considered if a patient does not respond to naloxone?

xylazine exposure (should provide appropriate supportive measures)

What is xylazine?

Xylazine is a non-opioid agent that FDA originally approved in 1972
as a sedative and analgesic for use in veterinary medicine. Structurally, xylazine is similar to levamisole, clonidine, and tizanidine and may share some clinical effects.

Like clonidine, xylazine acts as a central alpha-2- adrenergic receptor agonist in the brainstem, causing a rapid decrease in the release of NE and DA in the CNS. Xylazine is not approved for use in humans

s/s of xylazine withdrawal

agitation or severe anxiety

MOA of opiates

Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression

Examples of opiates:

heroin, morphine, codeine, hydrocodone, hydromorphone, fentanyl, oxycodone, tramadol, tapentadol, meperidine

effects of opiates:

euphoria, dysphoria, apathy, motor retardation, sedation, slurred speech, attention impairment, miosis, constipation

s/s of opiate withdrawal

not fatal/not delirious s/s: lacrimation, rhinorrhea, mydriasis, piloerection, diaphoresis, diarrhea, yawning, fever, insomnia, muscle ache/pain

describe the MOA of full opioid agonists

The opioid receptor is filled with full agonist. The receptor is fully active and drugs such as heroin and painkillers can cause euphoria and stop withdrawal for some time

Why do patients experience opioid withdrawals?

as patients become more tolerant, they become less sensitive to the medications which is when patients will experience pain (this is when withdrawal happens)

How do you treat opioid overdose

Supportive care and give naloxone 0.4-2 mg IV/IM/SQ every 2-3 minutes if unconscious and respiratory depressed. Administer 2 or 4 mg as a single dose in one nostril and may repeat every 2-3minutes in alternating nostrils until medical assistance becomes available

MOA of naloxone

pure opioid antagonist that competes with and displaces narcotics at opioid receptor sites

Which meds are utilized for withdrawal symptoms during detox?

Methadone, Buprenorphine (4-32 mg/day), Clonidine, Lofexidine (lucemyra), LAAM (d/c in 2003)

Which opiates are utilized as maintenance to prevent relapse

Methadone, Buprenorphine, LAAM (d/c in 2003)

Which opiates are used to maintain a complete opioid-free state after detox?

Naltrexone PO or IM

Role of methadone

Detox or maintenance.

MOA of methadone

Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain - produces generalized CNS depression

PK of methadone

Substrate of CYP2C9 (minor), 2C19 (minor), 2D6 (minor), 3A4 (major)

Inhibits CYP2D6 (moderate) and 3A4 (weak)

Half-life elimination of 4-91 hours but may be prolonged with alkaline pH and is decreased during pregnancy

Risk of QTc prolongation

Dosing of methadone for withdrawal s/s

20-80 mg — taper by 5-10 mg daily

what are the 3 objectives for methadone maintenance?

suppress s/s of opiate withdrawal, extinguish opiate craving, and block the reinforcing effects of illicit opiates

How is methadone maintenance dosing done?

Induction (prior to steady state): half of each day’s dose remains in the body and is added to the next days, increasing levels without increasing dose (start low, go slow)!

Initial dose should not be greater than 30-40 mg on day 1

Facts regarding methadone levels:

There is no correlation between trough or peak levels at doses above 100 mg/day. Peak levels should be no more than twice the trough.

What is the most effective indicator for how the patient is benefitting from methadone?

Signs and symptoms!

facts regarding methadone maintenance treatment:

Relieve withdrawal - adequacy is based on 3-8 hours

Reach tolerance and reduce cravings

Establish adequate dose

Maintenance = preservation of desired effects

Complete physical exam and labs within 14 days

How is it decided if a patient can have take-home methadone maintenance

Depends on longevity in program (2 days/week in 1st 90 days to 1 month after 2 years). Patient is capable of handling and taking unsupervised, has abstinence from unauthorized substances, regular attendance, absence of behavioral or criminal issues, stable home and social environments, and the medication can be safely stored