Drug Dependence/Withdrawal Reactions and Analgesics

Addiction

primary chronic neurobiological disease (genetic, psychosocial and environmental factors)

What are the behaviors that are signs of addiction?

Impaired control over drug use. compulsive use, despite harm, hallmark is drug craving

Tolerance

resistance or decreased responsiveness to expected actions of a drug, higher or more frequent dosing becomes necessary to achieve initial effects of drug

Tolerance does NOT imply:

addiction

what is the clinical definition of 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

Physical dependence

a state of neuroadaptation manifested by a drug-class specific withdrawal syndrome (following cessation of taking the drug)

What causes clinical definable withdrawal syndrome?

abrupt cessation of dosing, rapid dose reduction, decreasing bioavailability, use of an antagonist

Physical dependence is an expected occurrence in all individuals in the presence:

of continuous use of many CNS-active drugs, like opioids, for days or weeks

What is the key element in psychological dependence?

emotional need; drug/substance abuse for pleasurable mental effects, addiction, craving, drug seeking behavior, and relapse

What is withdrawal?

physical and emotional signs and symptoms precipitated by abrupt cessation or rapid decrease in dosage of a psychoactive substance

What are the signs of withdrawal?

usually opposite of the intoxication effects of the drug (usually occurs in two phases, acute withdrawal and protracted)

Acute withdrawal begins within:

hours of drug cessation and gradually resolves

Protracted withdrawal

symptoms that persist, evolve, or appear past the expected timeframe for acute withdrawal

What is the brain’s involvement in dependence?

psychoactive drugs such as opiates stimulate the mesolimbic dopamine system with repeated exposure causes drug target receptors to become less sensitive to stimulation

What are the goals of therapy with drug dependence?

relief of subjective symptoms, prevention/treatment of more serious complications, treatment of pre-existing or concurrent psychiatric illness, and preparation for long-term rehabilitation

Drug dependence can cause changes in:

the brain, peripheral nervous system, behavior that are not appreciable by histopathy or standard clinical observations

How long does it take to become addicted to morphine?

30 days at doses over 1200 mg/day

When will the symptoms of withdrawal start with morphine?

onset will begin about 6-12 hours after last dose, peak in 35-72 hours, and subside 5-10 days

What are the symptoms of initial withdrawal of opioids?

diaphoresis, mydriasis, nausea, anxiety, watery nasal/ocular discharge, muscle cramps

What are symptoms of later withdrawal in opioids?

low back pain, abdominal cramps, vomiting, diarrhea, elevated vital signs, and strong cravings

What are some ways to treat symptoms of withdrawal on opioids?

Promethazine, haloperidol, and then after discharge can use methadone and clonidine

What are some drugs used to help with opioid addiction?

buprenorphine, buprenorphine and naloxone, and naltrexone

buprenorphine

partial agonist at mu opioid receptor, and antagonist at kappa opioid receptor

Buprenorphine/Naloxone

naloxone added to prevent IV abuse

Naltrexone

pure opioid antagonist, IM injection every 4 weeks

Benzodiazepines drug dependence onset:

long-acting benzos have a lag time of 3-7 days before peak onset effect in 5-8 days (gradual decrease in 10-16 days)

drug dependence short-acting benzos

withdrawal symptoms within 24 hours

what is clinical presentation benzos?

hyperexcitable state will be associated perceptual and sensory symptoms; minor symptoms include anxiety, insomnia, blurred vision, nausea, palpitations, headache and tremor; major symptoms include seizures confusion, depersonalization

What are some treatments for benzodiazepine withdrawal?

reinstitute benzodiazepine therapy until symptoms resolve, with short-acting benzos taper dose over 5-7 days, long-acting maintain dose for 5 days then taper

What are some drugs to avoid while on benzos?

phenothiazines, and tricyclic antidepressants

Acetaminophen actions:

analgesic (60%) and antipyretic

What is teh intermediate metabolite of acetaminophen?

NAPQI (n-acetyl-p-benzoquinoneimine)

What is the main enzyme for breaking down acetaminophen?

cytochrome P450

If there is an increase in NAPQI and a decrease of glutathione it causes:

liver tissue damage

How does acetaminophen poisoning work?

In acetaminophen poisoning, there is an increase of NAPQI which depletes glutathione (binds with NAPQI and forms cysteine and mercapturic acid conjugates that will be excreted)

Phase I of acetaminophen overdose

0\.5-24 hours - nausea, vomiting, diaphoresis, malaise

Phase II of acetaminophen poisoning

24-48 hours - symptoms seem to resolve

Phase III of acetaminophen poisoning

72-96 hours - hepatic necrosis, coagulation defects, jaundice, renal failure, death

Phase IV of acetaminophen poisoning

When treated after 4-14 days there is recovery, and resolution of the hepatic dysfunction

Laboratory analysis for acetaminophen poisoning include:

acetaminophen blood level, glucose, coagulation values, liver and renal function tests

What are some treatments done to help with acetaminophen poisoning?

gastric decontamination (emesis, gastric lavage, activated charcoal, and cathartic) and using N-acetylcysteine (antidote)

When do you discontinue N-acetylcysteine?

patient remains asymptomatic and APA blood level falls to less than 10 mcg/ml in 24 hours and there is no significant increase in liver enzymes in 30-36 hours

If acetaminophen poisoning is bad enough the patient may have to:

receive a liver transplant

Salicylates actions:

analgesic, antipyretic, and anti-inflammatory

What is the mechanism of toxicity of salicylates?

First stage is respiratory alkalosis (CNS stimulation, then hyperventilation = less plasma CO2)

What is the second stage of toxicity of salicylates?

metabolic acidosis, which includes uncoupling of oxidative-phosphorylation, renal compensation by excreting more bicarbonate and retaining more hydrogen

What are the early symptoms of salicylate toxicity?

GI disturbances, CNS stimulation and respiratory stimulation

What are the late symptoms of salicylate toxicity?

CNS depression, respiratory depression, and death due to cardiovascular collapse

What are some labs done to test salicylate poisoning?

salicylate level (can only test after 6 hours of ingestion), blood gases and pH, blood glucose, electrolytes, coagulation tests, urine pH, and renal function

What are some treatments for salicylate poisoning?

Good supportive care, checking ABC’s, and gastric decontamination if caught early enough

If a patient has metabolic acidosis, you give them:

bicarbonate