Drugs used in treatment of addiction

What is Addiction? It is well known that the initial decision to use drugs is voluntary Addiction is a chronic, relapsing brain disease characterized by:  compulsive behavior of a person  continue taking drugs despite their many adverse health and negative consequences  craving

Reward pathway Regions of the brain

The Reward Pathway and Addiction Major structures of the reward pathway 1.Ventral tegmental area (VTA) 2.Nucleus accumbens 3.Prefrontal cortex VTA is connected to both the nucleus accumbens and the prefrontal cortex. Neurons of the VTA contain the neurotransmitter dopamine Rewarding stimulus  activation of reward pathway  release of dopamine from VTA neurons into nucleus accumbens and the prefrontal cortex

Rats self-administer heroin Activation of the reward pathway by an electrical stimulus

Dopamine Spells reward Release Activate Recycle

Addiction A state in which an organism engaged in a compulsive behavior  Even when faced with negative consequences  Behavior is reinforcing (pleasurable or rewarding)  Loss of control in limiting intake

Globus pallidus via increasing dopamine neurotransmission

Tolerance A state when organism no longer respond to normal dose of a drug. Higher dose is required to achieve desirable effect. Tolerance develops at the level of the cellular targets ( receptor desensitization ). The development of tolerance is not addiction Detected within hours of morphine administration Sensitivity returned to normal within about 3 days of removing the drug Extends to most of the pharmacological effects of morphine, but with different degree

The development of tolerance to the analgesic effects of morphine involves different areas of the brain and separate from those in the reward pathway. The two areas involved here, the thalamus, and the spinal cord (green dots). Both of these areas are important in sending pain messages and are responsible for the analgesic effects of morphine. The parts of the reward pathway involved in heroin or morphine addiction are shown for comparison. Tolerance to analgesic effect of morphine thalamus spinal cord

Dependence Organism functions normally ONLY in the presence of the drug Two components involved 1.Physical dependence 2.Psychological dependence

Physical dependence Characterized by physical disturbance (withdrawal symptoms) when drug removed. Resembling severe influenza Extreme restlessness and distress Neurons adapt to the repeated drug exposure and only function normally in the presence of the drug. Can be mild (e.g., for caffeine) or even life threatening (e.g., for alcohol) In the case of heroin, withdrawal can be very serious and the abuser will use the drug again to avoid the withdrawal syndrome. Lasting for a few days Precipitated by removal or antagonizing drug (e.g. μ-receptor antagonists, naloxone) Rapidly abolished by re-administration of drug

Psychological dependence Associated with craving Lasting for months or years Rarely occurs in patients being given opioids as analgesics

Drugs of addiction Stimulants - stimulate the central nervous system - amphetamines, cocaine, nicotine Depressant s - depress the CNS - alcohol, barbiturates, benzodiazepines Analgesics- powerful painkillers - from opium poppy, morphine, heroin Hallucinogens- dramatically alter perception - LSD, cannabis, Marijuana

 No single treatment is appropriate for all individuals  Pharmacological (medications)  Psychological  Behavioral Therapies  Medical and Social Services  Family Services of Addiction

Social interventions – Adjusting environmental triggers – Improving occupational, legal, financial situation – Attention to social circle, including self-help meetings Psychological interventions – Psychotherapy for depression, anxiety, etc. (individual, group, family therapies) – Skills training to prevent relapse, education about addiction, relaxation training, self-care, contingency management Biological interventions – Medications – Drug testing – Alternative therapies (e.g., acupuncture, exercise, massage, etc.)

Aim of Pharmacological Treatment Treatment of withdrawal (“detox”): medications used to alleviate withdrawal symptoms Treatment of psychiatric symptoms Reduction of cravings Substitution therapy Relapse prevention

Medications for Drug Addiction. Medications are an important element of treatment for many patients, especially when combined with counseling and other behavioral therapies. Alcohol: Naltrexone, Disulfiram, Acamprosate Opiates:Naltrexone, Methadone, Clonidine Nicotine: Nicotine replacement (gum, patches, spray), Bupropion Stimulants: [None to date]

Treatment of Chronic Alcoholism Hospitalization, psychotherapy and nutritional therapy may be needed.  Drug therapy includes: Benzodiazepines e.g. Diazepam (Valium), Lorazepam (Ativan), others are used to prevent alcohol withdrawal symptoms. They are preferred over barbiturates because of their wide margin of safety. The dose must be tapered slowly over 1-7 days to prevent withdrawal symptoms, seizures, and delirium

Alcohol Relapse Prevention Disulfiram (Antabuse) The drug given by itself to nondrinkers has little effects however, it causes extreme discomfort to patients who drink alcohol (Flushing, throbbing headache, nausea, vomiting, sweating, hypotension and confusion). Disulfiram acts by inhibiting aldehyde dehydrogenase thus, alcohol is metabolized as usual but acetaldehyde accumulates. Acetaldehyde will form the toxic intermediates; methanol and formaldehyde.

Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence (blocking the drugs’ euphoric effects) by adjusting natural endorphin levels in the brain Acamprosate (Campral) reduces alcohol relapse rates by treating post-acute withdrawal syndrome from alcohol : stabilize the chemical balance in the brain by modulating glutamatergic N- methyl-D-aspartate receptors and gamma aminobutyric acid(GABAA) receptors

Treatment of opioid addiction Hospitalization

Opioid Withdrawal Clonidine cocktail – Clonidine (stimulating α2-receptors in the brain), anti- inflammatory drugs, medications for nausea, diarrhea, cramping, etc. – Most common approach Substitution and taper – Can use any opioid; tramadol (Ultram) is commonly used; can also use methadone, buprenorphine, etc. Ultra-rapid detox – Opioid blocker (e.g., naltrexone or naloxone) administered under general anesthesia – Expensive and now a discredited approach

Opioid Relapse Prevention Naltrexone – Opioid blocker – Compliance is often the issue Methadone – Full opioid agonist – “Gold standard” for past 50 years – Only administered for addiction at federally licensed opioid treatment programs (“OTP’s”) Buprenorphine (Suboxone, Subutex) – “Next generation” methadone

Methadone Pharmacologically similar to morphine It has less sedative action Its duration of action is considerably longer (plasma half-life >24 hours) The physical withdrawal syndrome and psychological dependence are less than with morphine Widely used to treat morphine and diamorphine addiction In the presence of methadone, an injection of morphine does not cause the normal euphoria

Buprenorphine (Subutex, Suboxone) Advantages – Partial opioid agonist  has properties of both a blocker and activator – Reduces cravings – Less abusable than methadone – Less dangerous in overdose than methadone – Legally possible to prescribe in standard outpatient clinic  easier to access than methadone clinics

Opioid Antagonists Naloxone The first pure opioid antagonist, with affinity for all three opioid receptors It blocks the actions of endogenous opioid peptides as well as those of morphine-like drugs Given on its own, naloxone produces very little effect in normal subjects It produces a rapid reversal of the effects of morphine and other opioids Disadvantages Its effect lasts only 2-4 hours (shorter than that of most morphine-like drugs)

Opioid Antagonists Naltrexone very similar to naloxone but with the advantage of a much longer duration of action (half-life about 10 hours).

Tobacco Nicotine Replacement Therapy Bupropion (Wellbutrin, Zyban) Varenicline (Chantix)

Nicotine Replacement Therapy Many forms – Patch – Gum – Lozenge – Inhaler Usually not prescribed long enough; pts may need to be on NRT for months, years, or even lifetime (benefits outweigh costs)

Bupropion “Zyban” is specifically approved by FDA for smoking cessation, but not different from generic bupropion or “Wellbutrin” approved for depression Unclear mechanism, but reduces reward from smoking cigarettes and reduces craving

Varenicline “Chantix” MOA ; Partially activates same receptors that nicotine does Analogous to Buprenorphine (Suboxone) for opioid addiction Start taking it 1 week before quit date Very expensive Some reports of adverse psychiatric effects

Treatment of Stimulant Dependence There are no proven medications for the treatment of stimulant addiction Symptomatic treatment Behavioral therapies effective for treating stimulant addiction Slowly decrease dose Medications to treat withdrawal symptoms – Anxiety – Depression * NIDA

Medications for Stimulant Dependence Medications used to treat stimulant-induced psychiatric symptoms: – Antidepressants – Antipsychotics – Anti-anxiety agents – Medications to treat agitation, violence ER and outpatient settings Medications to treat co-occurring psychiatric disorders

Medications for Stimulant Dependence Disulfiram (Antabuse) – Has been shown to reduce cravings for cocaine, possibly by increasing dopamine levels Bupropion (Wellbutrin) – Chemical structure is closely related to that of amphetamine; reported to reduce cravings for amphetamines Tricyclic antidepressants - TCAs have been shown to reduce cocaine relapse rates in patients with major depression