3“Self-Directed Cessation” or “Natural Recovery” Factors Recognition of health/legal/family hazardsFinancial considerationsConflict with career goalsSocial mores and peer pressureReduced access/availability of drugsConflict with personal values“Maturation”
4INTERVENTION Professional Family Consequential No Further Problem Drug useSuccessfulContinuingProblemDrug UseContinuedProblemDrug UseUnsuccessful
5“Interventions” Professional Primary care physiciansMental health professionalsEAP’sClergyLaw enforcement personnelSchool counselors
6“Interventions” Family Any family member or friend
7“Intervention” Consequential AccidentArrestJob loss (last chance agreements)Relationship lossWork place drug testNegative drug experienceSanctions in schoolLoss of health
8Factors Affecting Treatment Consideration Recognition of drug use as a problemMedical/legal/financial problemsEmployer influence (EAP)Family influenceAwareness of treatmentPerception of treatment
9Factors Affecting Treatment Participation Access issues (time of day, transportation, child care, etc)Treatment environmentTreatment contextTreatment contentExternal pressureParticipant need/treatment service matchFamily participation
10Effective Treatment Strategies Accurate informationContingency management techniquesCognitive-Behavioral approachesFamily participationDrug and alcohol testingSelf-help supportAdequately trained staffMedication/Detoxification
11Role of Pharmacotherapy “Cure” of withdrawal or overdoseTo increase the holding power of outpatient treatment and thus reduce costsTo create a “window of opportunity” during which patients can receive psycho-social intervention to decrease the risk of relapseTo serve as a long-term maintenance agents for patients who can’t function without them, but can lead productive lives with them
12Types of Pharmacotherapy Anti-withdrawalAgonistsAntagonistsAnti-cravingTreatment of co-morbid disorders
13When Drugs Make You Feel Normal No Drugs = Danger Alcohol withdrawal – DT’s and seizuresGHB – “I go crazy when I stop”Sedatives – “crawling out of my skin”Heroin - kicking with medication or cold turkeyStimulants – sad and fatMarijuana – “wet dog shakes”Nicotine – irritable and fat
14GHB marketed to bodybuilders in 1980’s Purported effects of muscle mass increase and fat lossEuphoric and sexual effects led to more widespread use as a “party drug”No data at that time about addictiveness or lethality of GHBGHB abuse is widespread. It’s common in the club and gay scene. Dancers think it makes their performance more sexy. Bodybuilders are deeply involved in this problem, believing it is a great sleep aid that enhances growth hormone production, but it doesn’t work that simply. Anyone taking it daily is at risk of becoming addicted. Rapists are using it. People on drug testing are also using it as a substitute for alcohol or other drugs because it isn’t included in most drug test protocols, but that will be changing. Remember, those giving GHB to others, especially in rape situations, may be liable for their death or injury.
16Locus Coeruleus in Opiate Withdrawal located in the pontine tegmentumlargest group of NE-containing neuronsactivated by pain, blood loss and cardiovascular collapseLC hyperactivity - neural substrate for opiate withdrawalclonidine or lofexidine (alpha-2 agonist) and opiates inhibit the LC
17Opiate Detoxification Anesthesia-aided Rapid Opiate Detoxification (AROD) Shortens withdrawal to 4-6 hoursespecially useful for “detox phobic”controlled study of risk/benefit ratiowithdrawal symptoms can persist for significant period post detoxificationexpensivelarge increase in stress hormones
18Opiate Detoxification: Pros & Cons of Various Techniques Methadone taperPro:Simple to usefew side effectsCon:Requires special licenselongest withdrawalrebound symptoms associated with relapse
19Maintenance Opiate Agonist Reduce medical complications and deathSatisfy drug hunger, reduce craving, prevent withdrawalBlocks effects of abused opiatesReduce medical care burden and costsReduce crime rateReduce “hassle” of addict lifestyleSocial rehabilitation (e.g. tax eater to tax payer)
20Methadone Maintenance Best studied & most effective opiate treatment program so far, but also most controversialTreatment provided in licensed clinicsMethadone is an orally effective, 24-hour opioid drug used to maintain heroin or other opiate addictsPatients maintained usually several years, but many need maintenance for many years
21. . . As long as patient desires and benefits from continued treatment How Long Does OAT Last?Long Enough!!. . . As long as patient desires and benefits from continued treatment21Opioid Agonist Treatment of Addiction - Payte
22Maintenance Opiate Agonist Reduce medical complications and death fold reduction in death rateSatisfy drug hunger, reduce craving, prevent withdrawalBlocks effects of abused opiatesReduce medical care burden and costsReduce crime rateReduce “hassle” of addict lifestyleSocial rehabilitation (e.g. tax eater to tax payer)
23BuprenorphineDetoxification or MaintenanceTreatment – Physician Office BasedHigh affinity partial mu agonist & kappa antagonistReduced opioid agonist effects, with less respiratory depressionWithdrawal easier than from methadone or heroinCombo form (buprenorphine/naloxone) may further decrease diversion potential & will be main maintenance form
24Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone) 10090Full Agonist(Methadone)8070Intrinsic Activity60Partial Agonist50(Buprenorphine)40302010Antagonist (Naloxone)-10-9-8-7-6-5-4Log Dose of Opioid
25Naltrexone Opioid antagonist approved by FDA in 1984 Blocks opioids without agonist effectsNeed to be off opiates to beginCan be abruptly stopped without withdrawalNo tolerance to antagonist effect even after years“Ideal” drug but most addicts uninterested in using it
27Ideal ‘Anti-Cocaine’ Medication In active users it will induce abstinence (or significantly decrease cocaine use)It will decrease withdrawal dysphoria in binge usersIn abstinent patients it will attenuate the reactivity to drug-related cuesIn abstinent patients who lapse it will block the progression to the full relapseSafe in combination with cocaine, low abuse potential, no dysphoric effectsNow I would like to move on to pharmacotherapy and start with the description of an ideal Anti-Cocaine medication. In active users, such a medication will induce abstinence or significantly decrease cocaine use with improvement in other areas of functioning.It will decrease withdrawal dysphoria in binge users.In abstinent patients it will attenuate the reactivity to drug-related cues. In abstinent patients who lapse it will block the progression to the full relapse.An “ideal medication” should be safe in combination with cocaine, have a low abuse potential, and have no dysphoric effects and and possibly have mild positive subjective effects that will foster compliance.It is unknown if a single medication will be able to “fulfill” this role, more likely several therapeutics will be used to treat various components of cocaine dependence syndrome.
28Treatment of Stimulant Addiction: Current Status There are several effective psychotherapies for stimulant dependence but no effective medicationMedication development was predominantly centered on dopamine receptor and models of drug reinforcementMedication that may prevent relapse in abstinent patients may be a more viable optionStimulant Addiction is a behavioral disorder and behavioral interventions must play a major role in any treatment paradigmI am going to start with a summary slide which is also an outline for my talk. The main message I have for you today is that we have several effective psychotherapies for cocaine dependence but no effective medication.A great effort has been put to develop medications that affect dopaminergic neurotransmission by either substituting for or blocking effects of cocaine. This receptor-centered approach was based on the effective treatments for heroin and nicotine dependence and used animal models of cocaine self-administration for testing new medications. Unfortunately, this approach has not been successful. Despite many positive findings in animal models, dopaminergic medications tested so far do not help our patients.Perhaps we have to look beyond dopamine and beyond cocaine reinforcement.Cocaine dependence is different from heroin or nicotine dependence. It is not difficult to stop using cocaine for a few days or even a week. The problem is that most individuals eventually return to drug use. Therefore relapse to cocaine use following periods of abstinence may be more central from treatment perspective than simply the euphoric and reinforcing effects of cocaine. Understanding the neural mechanisms and factors that contribute to relapse should guide the development of new medications.But even if we had medication, we cannot forget that Cocaine Addiction is primarily a behavioral disorder, and therefore behavioral interventions must play a major role in any treatment paradigm.
29Determinants of Stimulant Use Euphoria and reinforcementEffect of CuesExteroceptive (environmental)Interoceptive (stress, emotions, drug euphoria)Availability of alternative reinforcersPresence of psychopathologyWithdrawal dysphoriaSeveral factors can change cocaine-taking behavior in humans and understanding them can help us in the development of new treatments.People report taking cocaine for its euphorigenic effects. Euphoria is dependent on the route of administration and the dose. The slower the entry of cocaine to the brain and lower the dose the less reinforcing it s effects. There is a little interest in abusing topical cocaine and low purity samples are not popular. These observations lead to thought that if one can develop medication attenuating the euphoric effects of cocaine, cocaine will become less reinforcing, and patients will eventually stop taking it.However, this turned out to be not that simple.The other major determinants of cocaine use are cues previously associated with exposure to drugs. These are exteroceptive, environmental cues like people, places, and things as well as internal, subjective states like the experience of stress, negative affect, and drug euphoria. Drug euphoria is particularly central to relapse. Small dose of cocaine will invariably increase urge for more cocaine with eventual loss of control. Which is why drug dealers give the first dose for free.Cues are believed to have major impact on the relapse to cocaine taking in abstinent individuals. Medication that will attenuate the effects of cues in combination with therapy that helps to extinguish the effects of cues can be useful in maintaining abstinence, perhaps more useful than medication that block effects of cocaine.Availability of alternative reinforcers is another important determinant of cocaine use. Animal studies reliably show that the presence of alternative reinforcers (like sweetened water) can significantly impair cocaine self-administration. Similarly in humans, presence of reinforces like a decent job or a happy marriage can diminish cocaine taking. This observations were central to the development of a Contingency Management Therapy - a behavioral intervention that promotes alternative reinforcers.Presence of psychiatric pathology, like depression or hypomania is a well known determinant of cocaine use. Luckily, we have effective treatments for those comorbid conditions.Withdrawal is traditionally a factor that greatly determines taking of heroin or sedatives. It appears to be less significant for cocaine and some even question its presence. Treating withdrawal is however an important stage of treatment as it engages patients in the process and facilitates transition to long-term therapy.
34Antabuse (disulfiram) Helpful in maintaining abstinenceInhibits aldehyde dehydrogenaseLeads to the accumulation of acetaldehyde if alcohol is consumedAcetaldehyde is toxic and produces nausea and hypotensionDaily dose 250 mg, or 3-4 day interval dosing
35Disulfiram Use for cocaine and methamphetamine dependence Inhibits Dopamine beta Hydroxylase (catalyzing the synthesis of NE from DA)Indirectly increases the ratio of DA to NEIncreasing the dopamine availability , enhances the aversive effects of stimulants.
36Adjunctive medication for alcohol craving - naltrexone Opiate antagonistProposed mechanism of actionDosing and side effectsClinical efficacy
37TopiramateInhibition of mesocortical dopamine release via facilitation of GABA activityInhibition of glutamate functionHypothesis:Decreases mesocorticolimbic dopamine activity after alcohol intakeAntagonize chronic changes induced by alcohol in the glutamate system
38Abstinence-initiation trial N=150 Oral Topiramate for Treatment of Alcohol Dependence Bankole Johnson et al (2003)Abstinence-initiation trial N=150N=150 Double-blind randomized control trial 12 weekTopiramate (up to 300 mg per day)Outcomes2.9 fewer drinks per day3.1 fewer drinks per drinking day27.6% fewer drinking days26.2% more abstinent daysReduced craving
39Acamprosate Amino acid derivative - acetyl-homotaurine similar to homocysteic acid (NMDA receptor)mimics GABA (GABAA receptor)interacts with calcium channel proteinsReduces alcohol craving (conditioned withdrawal)Reduces severity and frequency of relaspeSuppress physical signs of withdrawal in animal models(J Littleton Addiction 1995)
40Acamprosate Amino acid derivative - acetyl-homotaurine similar to homocysteic acid (NMDA receptor)mimics GABA (GABAA receptor)interacts with calcium channel proteinsReduces alcohol craving (conditioned withdrawal)Reduces severity and frequency of relaspeSuppress physical signs of withdrawal in animal models(J Littleton Addiction 1995)
41CAMPRAL NORMAL EQUILIBRIUM-Glutamate and GABA balanced This figure represents the brain (triangle) in a regular state of equilibrium with regard to excitation and inhibition processes.Excitation InhibitionAlcoholACUTE ALCOHOL INTAKE-Increased levels of GABAAcute alcohol intake disrupts the equilibrium by exaggerating the inhibitoryprocessesExcitation InhibitionNeuro-Adaptation AlcoholCHRONIC ALCOHOL CONSUMPTION-Increased levels of glutamateChronic alcohol consumption induces neuroadaptation (increase in glutamate) to counteract the inhibitory action of alcohol.Excitation Inhibition
42CAMPRAL ACUTE WITHDRAWAL AND POST-ACUTE WITHDRAWAL-Increased glutamate Acute Withdrawal of alcohol triggers a hyperexcitatory state because of the excess of glutamate present dur to the neuroadaptation. This results in withdrawal symptoms.Post-Acute Withdrawal stage follow. Environmental of learned cues associated with alcohol intake may trigger a hyperexcitatory state similar to acute withdrawal in abstinent patients. This precipitates mini-withdrawal symptoms in the post-acute stage-eg, anxiety tremors, sweating-that may contribute to relapse.Environmental/Learned Cues No AlcoholExcitation InhibitionEnvironmental/Learned Cues CAMPRALCAMPRAL-Modulation of glutamate restores balanceCAMPRAL interacts with the glutamate neurotransmitter system to block the response to environmental and learned cues. CAMPRAL is though to restore the normal balance.The mechanism of action of CAMPRAL is believed to address the biochemical aspect of alcohol dependence, complementing psychosocial therapy that targets the emotional and behavioral components of the disease.Excitation Inhibition