231206 regan addiction-substance use disorders.pdf

Addiction-Substance Use Disorders PCOL825A, Fall 2023 know conditionalVS unconditional Stimuli ssociative learning claptive Gold Guns Girls 4:54 live Rock the Garden 2013 M etric Vs maladaptive learning Gold Guns Girls official M V 4:23 M etric 1 1 questions Substance Use Disorder: Backgr...

Addiction-Substance Use Disorders PCOL825A, Fall 2023 know conditionalVS unconditional Stimuli ssociative learning claptive Gold Guns Girls 4:54 live Rock the Garden 2013 M etric Vs maladaptive learning Gold Guns Girls official M V 4:23 M etric 1 1 questions Substance Use Disorder: Background ruing memory ! Substance use disorders affect ~20 million Americans (2006); not including the misuse of prescription drugs and alcohol/tobacco ! Substance use disorders are complex and in the most basic definition involves the use of a substance in a manner that was not intended • this use could be once, occasional or chronic • what about “off label drug use”??? • it does not necessarily imply the presence of tolerance, physical dependence, psychological dependence or addiction and compulsive use 2 2 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 1 Addiction-Substance Use Disorders PCOL825A, Fall 2023 Substance Use Disorders have Significant Mortality ! Deaths in 2021 from methamphetamine = 33,000 ! Deaths in 2021 from opiates = 71,000 ! Deaths in 2021 from guns = 49,000 (~60% from suicide) 3 3 Substance Use Disorders often Involve Multiple Prescription Drugs ! Heath Ledger ! Michael Jackson ! Whitney Houston • Oxycodone • Propofol • Cocaine • Hydrocodone • Lidocaine • Ethanol • Diazepam • Midazolam • Alprazolam • Alprazolam • Clonazepam • Clonazepam • Temazepam • Diazepam • Diphenhydramine • Doxylamine • Lorazepam • Cyclobenzaprine • Temazepam • Fentanyl • Tizanidine • Hydrocodone • Trazadone • Phencyclidine • Methamphetamine/NMDA • Ibuprofen/acetaminophen 4 4 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 2 Addiction-Substance Use Disorders PCOL825A, Fall 2023 Substance Use Disorders Can be Hard to Define ! Substance misuse as strictly defined (using drugs in a manner that was not intended) is not necessarily harmful • for example, occasional use of Viagra in the absence of erectile dysfunction • compare with smoking, which traditionally was not viewed as a “disorder” ! Substance use disorders do not discriminate on the basis of sex, age, religion, race/ethnicity, family income or profession • substance use disorders by pharmacists is similar to the general public (10-15%) 5 5 Substance Use Disorder: DMS-5 ! The following list of criteria are used to characterize Substance Use Disorders: 2-3 = mild; 4-5 = moderate; 6-7 = severe • Taking the substance in larger amounts or for longer than intended* • Wanting to cut down/quit but unable to do so (psychological dependence) • Spending an inordinate amount of time obtaining the substance* • Craving and/or very strong desire to use the substance (psychological dependence) • Repeatedly unable to carry out obligations (work, school, home) due to use* • Recurrent use in physically hazardous situations (driving, using guns, etc) * • Persistent use in spite of recurrent problems that are known to arise from use (physical/psychological harm; legal issues) * • The development of tolerance; e.g. the diminished “effect” that occurs with repeated use or the need for increased amounts to achieve the same “effect” • The development of physical dependence; e.g. withdrawal symptoms following cessation of use *maladaptive behavior that overrides rational executive decision making 6 6 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 3 Addiction-Substance Use Disorders PCOL825A, Fall 2023 Substance Use Disorder: The Physical vs Psychological ! Note that the characterization of a substance use disorder DOES NOT require the development of tolerance and/or physical dependence ! Nor does it require the psychological aspects of “drug craving” or the inability to quit, which essentially represent a loss of voluntary control and are generally regarded as the sine non qua of “addiction” ! However, it is these psychological aspects of substance use disorders, rather than the physical aspects, that makes their treatment, and the treatment of other addictive behaviors (gambling, sex, eating, etc), so difficult and subject to relapse and failure ! The psychological aspects of addictive behaviors represent a form of maladaptive “learned behavior” whose physiological basis is in the “dopamine reward pathway” 7 7 The Dopamine (DA) Reward Pathway ! The mesolimbic DA pathway is the primary DA reward pathway • its origin is in the ventral tegmental area (VTA) of the midbrain and it projects to the nucleus accumbens (ventral striatum) • activation of this pathway regulates “incentive salience” which is related to “wanting” or desire and underlies the motivation to obtain a reward; it is also involved in the acquisition of learned behaviors, a form of associative learning (classical conditioning or “instrumental” or Pavlovian learning) it was once thought to mediate subjective aspects of pleasure (the “hedonia” or “liking” of a reward) but is probably more important in learning and encoding memories about a reward • Prefrontal cortex 8 8 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 4 Addiction-Substance Use Disorders PCOL825A, Fall 2023 The Dopamine (DA) Reward Pathway ! Two other pathways that originate in the VTA are also generally considered to be part of the DA Reward Pathway • • The first is the mesocortical DA pathway that goes from the VTA to the prefrontal cortex and is involved with cognitive control, motivation and emotional response The second is a DA pathway that goes from the VTA to the amygdala and hippocampus and is involved with processing of memory, decision-making, and emotional responses Prefrontal cortex Amygdala 9 9 Glutamate Pathways are also Involved in Reward ! Glutamate is the major excitatory neurotransmitter in the brain, which acts on the NMDA (N-methyl-D-aspartic acid), the AMPA (amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and the kainate receptor subtypes • The initial activation of the DA reward pathway from the VTA to the nucleus accumbens (NAc), • Results in the activation of a glutamate (Glu) pathway from the NAc to the prefrontal cortex and back again. • Activation of these Glu pathways leads to neuroadaptation related to the environmental contextual cues associated with the drug “reward” green = DA pathways black = Glu pathways 10 10 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 5 Addiction-Substance Use Disorders PCOL825A, Fall 2023 The Activation of Dopamine and Glutamate Pathways is Central to the “Neuroadaptation” that takes Place During Learning: be it Beneficial or Harmful ENVIRONMENTAL CONTEXT “NATURAL” REWARD (sex, food, shelter) “UNNATURAL” REWARD (drugs-substance abuse) ACTIVATION OF DOPAMINE/GLUTAMATE REWARD PATHWAYS NEUROADAPTATION-PLASTICITY-LEARNING ACQUISITION OF ADAPTIVE BEHAVIORS ACQUISITION OF MALADAPTIVE BEHAVIORS (beneficial to survival) (responsible for addiction: potentially harmful) 11 11 Addiction is a Form of Maladaptive Learned Behavior ! Conditioned stimuli are sensory stimuli that are present during highly rewarding activities (eg, sex, eating/drinking, gambling, etc) • • examples of conditioned stimuli could include the smell of perfume and the vision of high heels and fishnet stocking immediately before, during or after sex or could include the smell of french fries and the vision of the “Golden Arches” immediately before, during or after eating 12 12 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 6 Addiction-Substance Use Disorders PCOL825A, Fall 2023 Addiction is a Form of Maladaptive Learned Behavior ! Unconditioned stimuli represent the rewarding activities themselves (sex, eating/drinking, gambling, etc), which can become associated with the conditioned stimuli (the smell of perfume, the vision of high heels and fishnet stockings, the smell of french fries, the vision of Golden Arches, etc) ! This represents a form of learning in which subsequent exposure to the conditioned stimuli can create the expectation of the reward but not the reward itself • for example, exposure to perfume, high heels and fishnet stockings may create the expectation of sex • while exposure to the Golden Arches and French fries may create the expectation of eating 13 13 Addiction is a Form of Maladaptive Learned Behavior ! It is the expectation of the reward that gives rise to “wanting” and the motivation to obtain the reward (incentive salience), which is distinct from the “liking” or pleasure of the reward (hedonia) ! A person’s motivation to obtain the reward is strongly coupled to one’s expectation of success, which can give rise to excitement and pleasure that is independent of the pleasure of the reward itself ! Thus, addiction involves the acquisition of maladaptive learned behaviors in which environmental or contextual clues (conditioned stimuli) can become associated with the positive reward activities (unconditioned stimuli) An example: A street in New York City vs a club in Las Vegas 14 14 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 7 Addiction-Substance Use Disorders PCOL825A, Fall 2023 Activation of the DA/Glu Reward Pathway Facilitates the Acquisition of Learned Behaviors ! Virtually all addictive drugs (or activities) either directly or indirectly activate the DA/Glu reward pathways ! Stronger activation of the DA reward pathways increases the addiction potential of drugs by increasing the likelihood that “maladaptive learning” will take place ! Thus, previously innocuous cues (people, places, equipment) may become associated with drug use ! Re-exposure to these cues can then initiate drug ideation, including: • • the desire to get high; or have sex, gamble, eat, or whatever… and obsessive thoughts (craving) related to the drug or activity 15 15 Other Factors Can Influence the Potential for Addiction and the Risk of Relapse ! There is strong evidence that genetic factors can influence the potential for addiction and risk of relapse ! Emotional stress increases the release of endogenous corticosteroids, which can increase the risk of drug relapse ! The potential of a drug to cause physical dependence can reinforce addictive drug use; e.g. by the desire of the individual to avoid aversive drug-withdrawal symptoms • however, physical dependence should not be confused with addiction • if addiction were only related to physical dependence, the treatment of addiction would be relatively easy ! Clearly exposure to the contextual cues related to the development of addiction will increase the risk of relapse 16 16 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 8 Addiction-Substance Use Disorders PCOL825A, Fall 2023 A Variety of Classifications are Used to Group Drugs that are Involved with Use Disorders ! General pharmacological effect stimulant vs depressant vs hallucinogenic, etc ! Drug class opiate vs cannabinoid, etc ! Physical/chemical class inhalant vs solvents, etc ! Context or situation of use club drugs, performance-enhancing, etc 17 17 (pharmacological effect) AP* 5 5 4 1 (pharmacological effect) AP* 3 3 3 *AP, relative addiction potential, 5 = most addicting 1 = least. 18 18 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 9 Addiction-Substance Use Disorders PCOL825A, Fall 2023 (drug class) AP 4 3 (drug class) AP 2 (pharmacological effect) AP 1 0 *AP, relative addiction potential, 5 = most addicting 1 = least. 19 19 (physical/chemical property) (context of use) 20 20 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 10 Addiction-Substance Use Disorders PCOL825A, Fall 2023 (context of use) (context of use) 21 21 General Considerations for the Treatment of Substance Use Disorders ! Difficult with high rates of relapse, upwards of 80% ! No good pharmacological treatment ! Generally managed by the type of drug use disorder • therapeutic agents to minimize withdrawal symptoms (e.g. clonidine for opiate dependence) • drug substitution (e.g. methadone, nicotine) ! Psychological counseling/behavior modification is essential for success • support groups (e.g., Alcoholics Anonymous) 22 22 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 11 Addiction-Substance Use Disorders PCOL825A, Fall 2023 Drugs for Alcohol Use Disorder • Disulfiram (Antabuse®) – Inhibits acetaldehyde dehydrogenase – Use of alcohol will cause accumulation of acetaldehyde resulting in hangover-like symptoms – Generally poor compliance • Acamprosate (Campral®) – Structural analogue of GABA, exact mechanism unclear – No established efficacy • Naltrexone (Revia) – Opiate receptor antagonist – Adjunct to pyscho-social therapy 23 23 Drugs for Nicotine Use Disorder • Nicotine Replacement Therapy (NRT) – Replace tobacco smoking with nicotine containing gums, transdermal patches, lozenges, nasal sprays, etc. – Alleviates craving, substitution of one addiction for another? – Best used with a comprehensive treatment program • Bupropion (Zyban®) – NDRI class anti-depressant that is has some nicotinic cholinergic receptor antagonist activity – May reduce severity of craving/withdrawal – Modest efficacy as monotherapy 24 24 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 12 Addiction-Substance Use Disorders PCOL825A, Fall 2023 Drugs for Nicotine Use Disorder ! Varenicline (Chantex®) – Selective partial agonist of the a4b2 nicotinic cholinergic receptor – May reduce severity of craving/withdrawal – Side effects include nausea, headache, disturbed sleep – Concerns about neuro-psychiatric side effects • Increased hostility • Aggression • Suicidial ideation 25 25 Drugs for Opiate Use Disorder ! Methadone (Dolophine® and many others) – Long-acting mu-opioid receptor agonist – Maintenance therapy/long term detox – Deaths from methadone overdose are increasing ! Buprenorphine (Subutex®) – Mixed partial agonist (mu); antagonist (kappa) – Maintenance therapy/long term detox ! Naltrexone (Revia®, Vivitrol®) – Opiate receptor antagonist – Used in “rapid detox” (8-hr) • done under general anesthesia/heavy sedation • promoted as a “one-step” cure • expensive and high rate of relapse Rapid Detox Clinic 26 26 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 13 Addiction-Substance Use Disorders PCOL825A, Fall 2023 27 27 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 14