Opioids II
psychological dependence to opioids
(aka positive reinforcement) • Powerful reinforcer • Intense craving "rush" • Opioids support self-administration and conditioned place preference in rodents • Increases release of DA in NA
2 types of tolerance to opioids
1. cellular/pharmacodynamic 2. contextual/situational
what causes the lethal effect contributing to opioid overdose ?
Suppression of Medullary Centers of Respiration that control... • Intercostal muscles • Diaphragm
how does body show cellular (pharmacodynamic) tolerance to opioids?
o 1. Decrease in opioid receptors (cell protects itself by downregulation) o 2. Increase in Adenylyl Cyclase
Suboxone (composition, route of administration)
o Buprenorphine absorbed sublingually, but Naloxone can't be o Get effect of buprenorphine without naloxone blocking its effect o No effect if drug is extracted and injected because Naloxone will block the effect of buprenorphine -> theory was to discourage abuse by injection
contextual/situational tolerance
o Context in which drug is taken o Tolerance develops if heroin injections are given in same room as practice injections -> less deaths
Methadone (how does it bind receptor? route of administration? strength of effects? how does it effect heroin and morphine's effects? how does it affect overdose risk? how does it affect withdrawal symptoms?)
o Full agonist o Administered orally o Milder opioid effects o Reduces effect of heroin and morphine (competes for receptors) o Reduces risk of overdose o Reduces intensity of withdrawal symptoms (occupies receptors to prevent hypersensitization)
Naltrexone (how does it bind receptor? how does it effect opioid's effects? how does it affect withdrawal? what's its purpose?)
o Full antagonist o Blocks opioid effects o Precipitates withdrawal o Blocks life-threatening effects o Long-acting naloxone
Clonidine (how does it bind receptor? which receptor? purpose? how does it effect withdrawal?)
o Noradrenergic alpha2 autoreceptor agonist o Reduces release of vesicular norepinephrine o Suppresses physical withdrawal symptoms during week of withdrawal o Reduces withdrawal effects of opioids o Binding -> reduces [cAMP] -> closes Ca2+ channels -> reduces NE release
Buprenorphine (Buprenex) (how does it bind receptor? route of administration? strength of effects? how does it effect heroin and morphine's effects? how does it affect overdose risk? how does it affect withdrawal symptoms?)
o Partial agonist o Administered sublingually or buccally o Milder opioid effects o Reduces effect of heroin and morphine o Reduces risk of overdose o Reduces intensity of withdrawal symptoms • Less effect than full agonists on Mu activation
how do opioids increase the release of DA in nucleus accumbens?
o Via effects of Mesolimbic DA pathway o *Opioid neurons inhibit GABA neurons in VTA -> disinhibits DA neurons in VTA -> increases DA release in NA Opioids release endogenous enkephalins and exogenous morphine onto Mu receptors of GABA neurons Presynaptic and postsynaptic inhibition
How do Cyclic AMP Levels Adapt to Chronic Exposure to Morphine? (begin morphine, tolerance, dependence, removal of morphine)
• 1. Acute: opioid causes cell to decrease [cAMP] • 2. Over time, cell develops tolerance and returns to baseline [cAMP] • 3. Back to baseline, but now dependent on drug • 4. Take drug away, cell keeps fighting back and produces a large amount of [cAMP] • 5. Large amount of [cAMP] produces withdrawal symptoms until back to normal baseline • Cell learned to fight back too hard, forgot to stop fighting back when drug was gone
3 Waves in opioid overdose deaths
• 1999: prescription drugs • 2010: heroin • 2013: synthetic opioids
Steps to help someone who has overdosed
• ALIVE: • Arouse: try to wake them up • Look: for signs of overdose • Inhale: rescue breathing • Vapor: naloxone • Evaluate: check for breathing, give another dose of naloxone after 5 minutes
5 therapeutic uses of opioids
• Analgesia • Cough suppression • Anesthesia (fentanyl) • Substance abuse treatment • Reduce intestinal motility (anti-diarrrheal)
comparison of opioid toxicity (heroin, fentanyl, buprenorphine, carfentanil, oxycodone, morphine) (3 factors it depends on)
• Carfentanil > Fentanyl > Heroin > Morphine > Oxycodone > Buprenorphine • Based on likelihood of overdose / toxicity • Depends on receptor affinity, intrinsic efficacy, administration route • Carfentanil = 10,000x morphine's receptor affinity • Fentanyl = 100x morphine's receptor affinity • Buprenorphine has only partial intrinsic efficacy
Signs of Opioid Overdose
• Dizziness and confusion • Tiny pupils • Gurgling, snoring, or choking sounds • Blue lips or nails • Can't be woken up • Slow or no breathing • Cold and clammy skin • No movement
how does route of administration affect development of opioid dependence?
• Fastest speed of onset and shortest duration of action = highest addictiveness • Oral = low addiction < Intranasal < Intravenous • LAAM < Methadone < Morphine < snorted Heroin < IV heroin
overdose deaths in 2016 vs 2017 vs 2018 (which 3 drugs)
• Fentanyl, Carfentanil, and heroin cause fatal drug overdoses • Increased in 2017, but steady in 2018
Acute effects of Heroin (IV) vs Methadone (PO)
• Heroin: high intensity quickly, then cleared • Methadone: lower intensity prolonged
Withdrawal Intensity and Duration of Heroin (IV) vs Methadone (PO)
• Heroin: high intensity quickly, then nothing • Methadone: lower intensity prolonged
withdrawal opioid effects
• Hyperthermia • Increased Blood Pressure • Piloerection • Chills • Mydrasis (Dilation) • Eye and Nasal Secretions • Diarrhea • Yawning, Panting • Coughing, Sneezing • Spontaneous Orgasms • Agitation, Restlessness • Pain • Dysphoria, Depression
acute opioid effects
• Hypothermia • Decreased Blood Pressure • Peripheral Vasodilation • Skin Flushing • Miosis (pupil constriction) • Drying of Secretions • Constipation • Respiratory Suppression • Antitussion (cough suppression) • Decreased Libido • Relaxation • Analgesia • Euphoria
Trends: Deaths by Drugs, Cars, Homicides (1980 vs now)
• In 1980: auto accidents > homicides > drug overdoses • Now: Drug overdoses > auto accidents > homicides • Drug overdose rate went up, other 2 went down • Just as prevalent in rural areas as urban areas
drug therapies for opioid dependence
• Methadone • Buprenorphine (Buprenex) • Naltrexone • Suboxone • Clonidine • Mixed Preparations (combinations of medications)
Why would oral methadone or sublingual buprenorphine reduce the risk of a future heroin overdose in a dependent opioid user?
• Occupies receptors -> competition -> heroin can't exert full effects • User develops tolerance because receptors are constantly stimulated
% change in D2/D3 receptors in human NA from opioid (morphine) administration
• Only minor downregulation of DA receptors by Morphine in humans • Convincing that opioids involve DA in rats though through CPP and self-administration
postsynaptic inhibition
• Opioid released onto Postsynaptic receptors -> K+ channels open, K+ efflux -> hyperpolarization -> IPSP
presynaptic inhibition
• Opioid released onto Presynaptic receptors -> Ca2+ channels close -> reduce NT release • Axoaxonic inhibition
Comparison of Lethal Doses between fentanyl, heroin, and carfentanil
• Potency: Carfentanil > Fentanyl > Heroin • Heroin requires the largest dose to be lethal
Physical Dependence to Opioids
• Withdrawal syndrome • Withdrawal effects = opposite of acute effects • Rarely life-threatening • 1-2 weeks in duration • (remember psychostimulants have very low physical dependence/withdrawal but strong reinforcing effects; but opioids have both)
