Physiology of Addiction Carl Christensen, MD PhD Dawn Farm Education Series October 25, 2007

History: Tommy Walker Tommy Walker has been sent to you for addiction evaluation. He began drinking when he was 13. His mother also admits to drinking during her pregnancy with him. When he was born, he was small, irritable and was “slow to grow”

Tommy Walker has been sent to you for addiction evaluation.

He began drinking when he was 13.

His mother also admits to drinking during her pregnancy with him.

When he was born, he was small, irritable and was “slow to grow”

Neuroplasticity/Neurotoxicity Neuro = brain Plasticity = change toxicity = damage Exposure to drugs and alcohol in the womb can cause permanent damage Most extreme example: Fetal Alcohol Syndrome (FAS)

Neuro = brain

Plasticity = change

toxicity = damage

Exposure to drugs and alcohol in the womb can cause permanent damage

Most extreme example: Fetal Alcohol Syndrome (FAS)

FAS

Fetal Alcohol Syndrome

Tommy Walker: Genetics? Tommy’s father was an alcoholic and was also addicted to heroin. His older brother died of a heroin overdose.

Tommy’s father was an alcoholic and was also addicted to heroin.

His older brother died of a heroin overdose.

Genetics? The biological children of alcoholics are more likely to become alcoholics. If they are raised by another family, they are STILL more likely to become alcoholics. Non-alcoholic offspring raised in alcoholic homes are NOT more likely to become alcoholics.

The biological children of alcoholics are more likely to become alcoholics.

If they are raised by another family, they are STILL more likely to become alcoholics.

Non-alcoholic offspring raised in alcoholic homes are NOT more likely to become alcoholics.

POSSIBLE FAMILIES OF RISK FACTORS Alcoholics metabolize alcohol BETTER (= tolerance) Alcoholics are impulsive Alcoholics are more likely to have personality disorders Stolen from Shuckitt et al…….

Alcoholics metabolize alcohol BETTER (= tolerance)

Alcoholics are impulsive

Alcoholics are more likely to have personality disorders

Stolen from Shuckitt et al…….

Tommy Walker: Tolerance He found that he could “drink anyone under the table” by the time he was 15. TOLERANCE: a predictor of later alcoholism. Future alcoholics are able to drink MORE than their peers. The one who “can’t handle their liquor” is LESS likely to become an alcoholic.

He found that he could “drink anyone under the table” by the time he was 15.

TOLERANCE: a predictor of later alcoholism.

Future alcoholics are able to drink MORE than their peers.

The one who “can’t handle their liquor” is LESS likely to become an alcoholic.

Tommy: Hedonic Tone? He describes feeling “uncomfortable in his own skin” unless he was drunk . Hedonic Tone: your “set point” for feeling pleasure/normal. Addicts feel better when given amphetamine, normal people feel worse . Addiction: seeking to regain hedonic tone? Salsitz, 2006 ASAM

He describes feeling “uncomfortable in his own skin” unless he was drunk .

Hedonic Tone: your “set point” for feeling pleasure/normal.

Addicts feel better when given amphetamine, normal people feel worse .

Addiction: seeking to regain hedonic tone?

Salsitz, 2006 ASAM

Polysubstance abuse He began smoking cigarettes when he was 14. At age 17 he began using marijuana, LSD and ecstasy. He later starts using cocaine. He finds that when he stops using one drugs, he simply switches to another.

He began smoking cigarettes when he was 14.

At age 17 he began using marijuana, LSD and ecstasy. He later starts using cocaine.

He finds that when he stops using one drugs, he simply switches to another.

“ Hi…I’m Joe. I’m cross addicted”

The Pleasure Center Nucleus Accumbens Responds to dopamine (DA) Responds to drugs Responds to food Responds to sex Sends signals to your frontal cortex THE PLEASURE CENTER IS ABNORMAL (DAMAGED) IN ADDICTION

Nucleus Accumbens

Responds to dopamine (DA)

Responds to drugs

Responds to food

Responds to sex

Sends signals to your frontal cortex

THE PLEASURE CENTER IS ABNORMAL (DAMAGED) IN ADDICTION

The Pleasure Center

Addicts have abnormal pleasure centers…. and abnormal responses to visual cues of their addictions…..

Tommy’s story cont’d…. He comes to see you , his doctor, now because he has found that he cannot stop drinking and using drugs. His wife has left him several times, but when he quits, he finds he cannot stay sober. She is getting a divorce. He has tried “controlled drinking” several times, but finds that he drinks more than he plans to. Whenever he starts drinking, he finds that he starts using cocaine again He constantly thinks about drinking and using drugs. Diagnosis???

He comes to see you , his doctor, now because he has found that he cannot stop drinking and using drugs.

His wife has left him several times, but when he quits, he finds he cannot stay sober. She is getting a divorce.

He has tried “controlled drinking” several times, but finds that he drinks more than he plans to.

Whenever he starts drinking, he finds that he starts using cocaine again

He constantly thinks about drinking and using drugs.

Diagnosis???

Substance Dependence - DSM IV Maladaptive pattern with three or more: Tolerance Withdrawal Using more and/or using for longer times A desire or repeated attempts to cut down Lots of time using or recovering Reduced activities: social, work, recreation Recurrent use despite physical and psychological problems

Maladaptive pattern with three or more:

Tolerance

Withdrawal

Using more and/or using for longer times

A desire or repeated attempts to cut down

Lots of time using or recovering

Reduced activities: social, work, recreation

Recurrent use despite physical and psychological problems

Addiction/chemical dependence: A chronic progressive disease characterized by the following physical and psychological symptoms (the four (five) C’s): Craving Compulsion Loss of Control Continued use despite consequences, and Chronic use

A chronic progressive disease characterized by the following physical and psychological symptoms (the four (five) C’s):

Craving

Compulsion

Loss of Control

Continued use despite consequences, and

Chronic use

Addiction? He comes to see you now because he has found that he cannot not drinking and using drugs. His wife has left him several times, but when he quits, he finds he cannot stay sober. She is getting a divorce. He has tried “controlled drinking” several times, but finds that he drinks more than he plans to. Whenever he starts drinking, he finds that he starts using cocaine again He constantly thinks about drinking and using drugs. Diagnosis: Chemical Dependence = ADDICTION

He comes to see you now because he has found that he cannot not drinking and using drugs.

His wife has left him several times, but when he quits, he finds he cannot stay sober. She is getting a divorce.

He has tried “controlled drinking” several times, but finds that he drinks more than he plans to.

Whenever he starts drinking, he finds that he starts using cocaine again

He constantly thinks about drinking and using drugs.

Diagnosis: Chemical Dependence = ADDICTION

Tommy… Tommy is seen for his yearly checkup. His BP is 160/100, his face is puffy. He had an episode of severe right sided pain last month after a “weekend at Bernie’s” and he thought he looked yellow for the rest of the week, had a fever and was throwing up. His cholesterol tests come back abnormal.

Tommy is seen for his yearly checkup.

His BP is 160/100, his face is puffy.

He had an episode of severe right sided pain last month after a “weekend at Bernie’s” and he thought he looked yellow for the rest of the week, had a fever and was throwing up.

His cholesterol tests come back abnormal.

Consequences: Medical Hypertension: the most common cause of “essential” (unexplained) hypertension is alcohol. Diabetes: damage to the pancreas (temporary or permanent) Cholesterol: LDL (bad cholesterol) goes up, triglycerides (fat) goes up.

Hypertension: the most common cause of “essential” (unexplained) hypertension is alcohol.

Diabetes: damage to the pancreas (temporary or permanent)

Cholesterol: LDL (bad cholesterol) goes up, triglycerides (fat) goes up.

Consequences? The Liver Fatty liver : from drinking; body uses alcohol rather than fat. Fat accumulates. Alcoholic Hepatitis : inflammation of the liver; fever, jaundice, pain, nausea and vomiting. Viral Hepatitis : usually hepatitis C, from sharing needles, straws (cocaine), sex. Cirrhosis : more to be revealed

Fatty liver : from drinking; body uses alcohol rather than fat. Fat accumulates.

Alcoholic Hepatitis : inflammation of the liver; fever, jaundice, pain, nausea and vomiting.

Viral Hepatitis : usually hepatitis C, from sharing needles, straws (cocaine), sex.

Cirrhosis : more to be revealed

The (keen) Alcoholic Mind When you see him today, he denies that he has a problem, but says that he needs to "take a break". His wife left him, he says, because of his mother in law. On the way out the door, he says: “I’m worried about you Dr. Are you getting any exercise?”

When you see him today, he denies that he has a problem, but says that he needs to "take a break". His wife left him, he says, because of his mother in law.

On the way out the door, he says: “I’m worried about you Dr. Are you getting any exercise?”

The (keen) Alcoholic Mind As you discuss his situation, you are amazed by his ability to: Minimalize -Rationalize Deny -Deflect Project He appears to have no insight about his worsening drinking problem.

As you discuss his situation, you are amazed by his ability to:

Minimalize -Rationalize

Deny -Deflect

Project

He appears to have no insight about his worsening drinking problem.

Cognition and Addiction Recovering addicts make bad decisions Ex: 3 weeks into recovery, a man decides to make a trip to…… Amsterdam? Q: what does an alcoholic bring on a 2 nd date? A: a U haul.

Recovering addicts make bad decisions

Ex: 3 weeks into recovery, a man decides to make a trip to……

Amsterdam?

Q: what does an alcoholic bring on a 2 nd date?

A: a U haul.

“Biopsychosocial (?)”

Treatment of Addiction I A “biopsychosocial” disease: The body/brain The person (mind, soul) The environment You are not just removing a drug, you are treating a chronic, progressive, relapsing disease Treatment for chronic diseases must be chronic: diabetes, hypertension, obesity: “quick fixes lead to quick problems”

A “biopsychosocial” disease:

The body/brain

The person (mind, soul)

The environment

You are not just removing a drug, you are treating a chronic, progressive, relapsing disease

Treatment for chronic diseases must be chronic: diabetes, hypertension, obesity: “quick fixes lead to quick problems”

Treatment of Addiction II Abstinence : removes the drug, doesn’t treat the disease (Hogback Hilton) Pharmacology : see later Cognitive Behavioral Therapy : thoughts  emotions  behavior (relaspe) Motivational Enhancement Therapy : variation of Motivational Interviewing (MI): enhance’s the patient’s motivation to change

Abstinence : removes the drug, doesn’t treat the disease (Hogback Hilton)

Pharmacology : see later

Cognitive Behavioral Therapy : thoughts  emotions  behavior (relaspe)

Motivational Enhancement Therapy : variation of Motivational Interviewing (MI): enhance’s the patient’s motivation to change

Alcoholics Anonymous: Cult, Threat or Menace?

CBT vs. AA Therapist: Sponsor:

Therapist:

Sponsor:

CBT vs. AA Therapist: “you need closure with your family” Sponsor: “you need to closure mouth and go to meetings”

Therapist:

“you need closure with your family”

Sponsor:

“you need to closure mouth and go to meetings”

Tommy Cont’d Tommy completes his IOP. He declines attendance at AA, says that it is a “cult”. He feels he has everything under control. His wife, now attending Alanon, declines to return. He is lost to follow up.

Tommy completes his IOP.

He declines attendance at AA, says that it is a “cult”.

He feels he has everything under control.

His wife, now attending Alanon, declines to return.

He is lost to follow up.

Tommy Cont’d He returns to see you 2 years later and has relapsed. He reveals that he has had continual craving for drugs and found that when he started using them again he could not quit. He says he had use just to feel "normal".

He returns to see you 2 years later and has relapsed.

He reveals that he has had continual craving for drugs and found that when he started using them again he could not quit.

He says he had use just to feel "normal".

Tommy Cont’d He has been drinking heavily. He was admitted to detox but had to be sent to the hospital for DTs.

He has been drinking heavily.

He was admitted to detox but had to be sent to the hospital for DTs.

Drug Withdrawal I Withdrawal : what happens when the drug is removed Typically the opposite effect for which the drug is taken A physiologic response that depends on where the drug acts Not a cause/result of addiction

Withdrawal : what happens when the drug is removed

Typically the opposite effect for which the drug is taken

A physiologic response that depends on where the drug acts

Not a cause/result of addiction

Drug Withdrawal: types of withdrawal Sedative withdrawal Brain has been tranquilized, now goes into “overdrive” May result in seizures Stimulant withdrawal Brain has been in overdrive, now goes to “sleep” Not physically dangerous Patient will complain of dysphoria/craving when awake

Sedative withdrawal

Brain has been tranquilized, now goes into “overdrive”

May result in seizures

Stimulant withdrawal

Brain has been in overdrive, now goes to “sleep”

Not physically dangerous

Patient will complain of dysphoria/craving when awake

Sedative Withdrawal I Alcohol, Benzos and Barbituates Bind to the GABA receptor: Causes sedation Inhibits the NMDA receptor: Prevents excitation Now stop the sedative and……

Alcohol, Benzos and Barbituates

Bind to the GABA receptor:

Causes sedation

Inhibits the NMDA receptor:

Prevents excitation

Now stop the sedative and……

Sedative Withdrawal II Brain becomes over-excited, “disinhibited” “ Angry Grey Planet” Stimulates the autonomic nervous system

Brain becomes over-excited, “disinhibited”

“ Angry Grey Planet”

Stimulates the autonomic nervous system

Drug Withdrawal: Gardner 2006

Alcohol Withdrawal: Stage I A “bad hangover”: increased pulse, blood pressure, stimulation, “everything hurts” Treatment: eye of the dog SEIZURES MAY OCCUR DURING THIS TIME SEIZURES ARE MORE LIKELY ONCE YOU HAVE HAD ONE (“kindling”) ANYONE WITH A HISTORY OF ALCOHOL WITHDRAWAL SEIZURES SHOULD BE MEDICALLY DETOXED (benzos, phenobarb)

A “bad hangover”: increased pulse, blood pressure, stimulation, “everything hurts”

Treatment: eye of the dog

SEIZURES MAY OCCUR DURING THIS TIME

SEIZURES ARE MORE LIKELY ONCE YOU HAVE HAD ONE (“kindling”)

ANYONE WITH A HISTORY OF ALCOHOL WITHDRAWAL SEIZURES SHOULD BE MEDICALLY DETOXED (benzos, phenobarb)

Alcohol Withdrawal: Stage II Alcoholic Hallucinosis The “string sign” Should be admitted to hospital Visual hallucinations are often friendly (“pink elephant”)

Alcoholic Hallucinosis

The “string sign”

Should be admitted to hospital

Visual hallucinations are often friendly (“pink elephant”)

Alcohol Withdrawal: Stage III Delerium Tremens Brain is in overdrive Agitation, audio and visual hallucinations; delirium (acute confusion) Mortality used to be up to 35%!! MUST be admitted and heavily sedated “ Helicopter sign”

Delerium Tremens

Brain is in overdrive

Agitation, audio and visual hallucinations; delirium (acute confusion)

Mortality used to be up to 35%!!

MUST be admitted and heavily sedated

“ Helicopter sign”

Alcohol Withdrawal: Stage IV Prolonged withdrawal Anxiety, insomnia, headache “Restless, irritable and discontent” Post Acute Withdrawal Syndrome: PAWS Recommended treatment: AA/meds Most COMMON treatment: alcohol

Prolonged withdrawal

Anxiety, insomnia, headache

“Restless, irritable and discontent”

Post Acute Withdrawal Syndrome: PAWS

Recommended treatment: AA/meds

Most COMMON treatment: alcohol

Pharmacotherapy? His new addiction doctor, Dr. Uptha Creek, has put him on disulfiram (Antabuse), naltrexone (Rivea ® ), acamprosate (Campral ® ), lorazepam (Ativan ® ), fluoxetine (Prozac ® ), and zolpidem (Ambien ® ). No spiritual treatment is recommended. He wants to sell his house* to pay for a Prometa treatment. * already gone!

His new addiction doctor, Dr. Uptha Creek, has put him on disulfiram (Antabuse), naltrexone (Rivea ® ), acamprosate (Campral ® ), lorazepam (Ativan ® ), fluoxetine (Prozac ® ), and zolpidem (Ambien ® ).

No spiritual treatment is recommended.

He wants to sell his house* to pay for a Prometa treatment.

* already gone!

Alcohol Metabolism and Disulfiram Ethanol------  Acetaldehyde-----------  C02 (1) (2) 1: alcohol dehydrogenase : M>W; younger>older; protective metabolizes 1 drink/hour 2: aldehyde dehydrogenase: Detoxifies acetaldehyde Inhibited by Disulfiram (Antabuse)

Ethanol------  Acetaldehyde-----------  C02

(1) (2)

1: alcohol dehydrogenase :

M>W; younger>older; protective

metabolizes 1 drink/hour

2: aldehyde dehydrogenase:

Detoxifies acetaldehyde

Inhibited by Disulfiram (Antabuse)

Naltrexone Blocks the opiate ( µ) receptor Prevents you from using opiates Also blocks your endogenous (own) opiates: endorphins Opiate receptors may be partly responsible for alcohol craving Has been shown to reduce drinking ONCE YOU HAVE ALEADY STOPPED Available as an injection (Vivitrol®)

Blocks the opiate ( µ) receptor

Prevents you from using opiates

Also blocks your endogenous (own) opiates: endorphins

Opiate receptors may be partly responsible for alcohol craving

Has been shown to reduce drinking ONCE YOU HAVE ALEADY STOPPED

Available as an injection (Vivitrol®)

The Reward Pathway: Gardner 2006

Acamprosate (Campral ®) Thought that it worked through GABA (where alcohol works) Not known how it works May decrease “number of drinking days” May reduce craving Often being used by patients being admitted to detox units.

Thought that it worked through GABA (where alcohol works)

Not known how it works

May decrease “number of drinking days”

May reduce craving

Often being used by patients being admitted to detox units.

Benzodiazepines Ativan (lorazepam) Valium (diazepam) Xanax (alprazolam) Klonopin (clonazepam) Restoril (temazepam) Analogues: Ambien (Zolpidem) Lunesta Produce amnesia!

Ativan (lorazepam)

Valium (diazepam)

Xanax (alprazolam)

Klonopin (clonazepam)

Restoril (temazepam)

Analogues:

Ambien (Zolpidem)

Lunesta

Produce amnesia!

Benzodiazepines Work through the same receptor as alcohol (GABA) Prevent alcohol withdrawal The original pharmacotherapy for alcoholism – Valium Often results in “cross addiction” Dangerous combination in relapse

Work through the same receptor as alcohol (GABA)

Prevent alcohol withdrawal

The original pharmacotherapy for alcoholism – Valium

Often results in “cross addiction”

Dangerous combination in relapse

Antidepressants: SSRIs 85% of patients admitted to rehab will have a diagnosis of clinical depression Only 15% will have that diagnosis on discharge Patients are often prescribed SSRIs while using

85% of patients admitted to rehab will have a diagnosis of clinical depression

Only 15% will have that diagnosis on discharge

Patients are often prescribed SSRIs while using

Suboxone ® (buprenorphine) Binds to the opiate receptor ( µ) Reduces craving and withdrawal Safer than methadone Doesn’t require a methadone clinic (DEA) Primarily for withdrawal/detox; cravings DOESN’T treat the disease of addiction

Binds to the opiate receptor ( µ)

Reduces craving and withdrawal

Safer than methadone

Doesn’t require a methadone clinic (DEA)

Primarily for withdrawal/detox; cravings

DOESN’T treat the disease of addiction

Prometa ®?? Combination of three drugs: Flumazenil: a benzodiazepine antagonist: Gabapentin (Neurontin ®) : an antiepileptic drug: Hydroxizine (Atarax ®): Cost: $15,000+ Controlled studies now in progress

Combination of three drugs:

Flumazenil: a benzodiazepine antagonist:

Gabapentin (Neurontin ®) : an antiepileptic drug:

Hydroxizine (Atarax ®):

Cost: $15,000+

Controlled studies now in progress

He is now smoking crack, drinking 1 pint to 1/5 per day, using marijuana daily, abusing his Ativan, and has lost his job. He continues to take Vicodin with his Suboxone. However, he says that he is "doing okay" and feels that he is "on the right track". He declines your recommendation for residential therapy.

He is now smoking crack, drinking 1 pint to 1/5 per day, using marijuana daily, abusing his Ativan, and has lost his job. He continues to take Vicodin with his Suboxone.

However, he says that he is "doing okay" and feels that he is "on the right track".

He declines your recommendation for residential therapy.

Consequences: brain You are asked to see him in the hospital several years later. He says he knows you, but cannot remember your name. You ask him who the president is, he replies “Who cares? They’re all crooks”. He walks with a shuffling broad-based gait and has to hold his hand on the wall to keep his balance.

You are asked to see him in the hospital several years later.

He says he knows you, but cannot remember your name.

You ask him who the president is, he replies “Who cares? They’re all crooks”.

He walks with a shuffling broad-based gait and has to hold his hand on the wall to keep his balance.

Wernike-Korsakoff Syndrome Immediately after stopping drinking: Wernike’s encephalopathy (brain disease) Caused by thiamine (B1) deficiency Eye muscles are paralyzed Ataxia (can’t walk straight) Encephalopathy: confusion, agitation, restlessness

Immediately after stopping drinking: Wernike’s encephalopathy (brain disease)

Caused by thiamine (B1) deficiency

Eye muscles are paralyzed

Ataxia (can’t walk straight)

Encephalopathy: confusion, agitation, restlessness

Korsakoff’s psychosis Confabulation : make things up Retrograde amnesia : can’t remember what happened in the past Antegrade amnesia : can’t remember info you are given (remember these 3 objects…) Polyneuropathy : periperhal nerve damage

Confabulation : make things up

Retrograde amnesia : can’t remember what happened in the past

Antegrade amnesia : can’t remember info you are given (remember these 3 objects…)

Polyneuropathy : periperhal nerve damage

Consequences: liver You see him one more time, several years later. He has been readmitted for vomiting blood, jaundice, and encephalopathy. He is given multiple transfusions. He has esophageal varices from his cirrhosis. He is jaundiced. He says that he is asking his sister to pay for a liver transplant. When he are speaking to him, his hands will occasionally flap.

You see him one more time, several years later. He has been readmitted for vomiting blood, jaundice, and encephalopathy.

He is given multiple transfusions. He has esophageal varices from his cirrhosis.

He is jaundiced. He says that he is asking his sister to pay for a liver transplant.

When he are speaking to him, his hands will occasionally flap.

Alcoholic Cirrhosis Hardening of the liver (scar tissue) Causes blood to back up in the veins feeding the liver: Esophageal varices: vomit blood Hemorrhoids: rectal bleeding Can’t metabolize toxins: encephalopathy Can’t make proteins: bleeding (coagulopathy) Can’t hold fluids: ascites

Hardening of the liver (scar tissue)

Causes blood to back up in the veins feeding the liver:

Esophageal varices: vomit blood

Hemorrhoids: rectal bleeding

Can’t metabolize toxins: encephalopathy

Can’t make proteins:

bleeding (coagulopathy)

Can’t hold fluids: ascites

Cirrhosis

Ascites/Jaundice

“ Caput Medusae”

Esophageal Varices

He dies several weeks later of liver failure . “Jails, institutions, and death” Narcotics Anonymous

He dies several weeks later of liver failure .

“Jails, institutions, and death”

Narcotics Anonymous

The Brain and Addiction Dopamine is the chemical involved in reward The more dopamine receptors you have, the more “normal” you (may) feel Addicts have lower levels of dopamine receptors Must increase their levels of dopamine to feel “normal”?

Dopamine is the chemical involved in reward

The more dopamine receptors you have, the more “normal” you (may) feel

Addicts have lower levels of dopamine receptors

Must increase their levels of dopamine to feel “normal”?

The Reward Pathway: Gardner 2006

Withdrawal Pathways: Gardner 2006

RELAPSE Drug triggered: “I thought I could have just one drink” Stress triggered: “I’m going through too much right now” Cue triggered: “Wet faces and wet places”

Drug triggered: “I thought I could have just one drink”

Stress triggered: “I’m going through too much right now”

Cue triggered: “Wet faces and wet places”

Drug Triggered Relapse: Gardner 2006

Stress Triggered Relapse: Gardner 2006

Cue Triggered Relapse: Gardner 2006

Brain Scans

Effect of Alcohol on Brain Function

Ventricles Non-alcoholic Alcoholic

Volume Recovery During Treatment 2 Years Later

Stimulants & Blood Flow Healthy Control Cocaine-dependent Gottschalk, 2001, Am J Psychiatry High blood flow Low blood flow

Blood Flow Recovery Non users Cocaine users, 10 days sober Cocaine Users, 100 days sober High blood flow Low blood flow

Who in the room has the lowest hedonic tone??????

Salsitz 2006: Hedonic Tone

Volkow, Am J Psychiatry 2001; 158:377-382

Abnormal response to Ritalin is due to abnormal brain chemistry

Obese subjects have decreased DA