86
WHY DO MY PATIENTS KEEP RELAPSING? The Neurobiology of Addiction Kevin Wandler, M.D., Dip ABAM, F.iaedp Chief Medical Officer Advanced Recovery Systems
WHY DO MY PATIENTS KEEP
RELAPSING?
The Neurobiology of Addiction
Kevin Wandler, M.D., Dip ABAM, F.iaedp
Chief Medical Officer
Advanced Recovery Systems
Goals and Objectives
After this presentation the attendee will:
Understand at least 3 neurotransmitters
in the brain and how they relate to
addiction, mood and anxiety.
Be able to describe the areas of the brain
involved in reward, happiness and
memory.
Describe medication interventions that can
contribute to alcohol and opioid use
disorder recovery and how they work.
New York Times September 2017
Drug overdoses killed ~64,000 people in the US last year.
2015 ~52,400 people died from drug overdoses
Drug-Overdose Deaths Involving
Opioids, by Type of Opioid, US
2000-2014
Age-Adjusted Rates of Death Related
to Prescription Opioids and Heroin
Drug Poisoning in US 2000-2014
Compton WM et al. N Engl J Med 2016, 374:154-163
Drug Overdose Deaths by Major
Drug Type, US 1999-2010
Dr William Oshler
Father of Modern Medicine??
1849-1919
“The good physician treats the disease, the great physician
treats the patient who has the disease“
“The first duties of the physician is to educate the masses not to
take medicine”
“If there are more than one treatment for an illness, then most
are insufficient”
YOUR BRAIN ON DRUGS--1980
YOUR BRAIN ON DRUGS 2017!!
The Neurobiology of
Addiction
ASAM Definition
Short Definition of Addiction:
ADDICTION is a primary, CHRONIC DISEASE of BRAIN
reward, motivation, memory and related circuitry.
Dysfunction in these circuits leads to characteristic
biological, psychological, social and spiritual
manifestations.
This is reflected in an individual pathologically pursuing
reward and/or relief by substance use and other
behaviors.
ASAM Definition
Short Definition of Addiction (cont.):
Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response.
Like other chronic diseases, addiction often involves cycles of relapse and remission.
WITHOUT TREATMENT or engagement in recovery activities, ADDICTION is progressive and CAN RESULT IN disability or premature DEATH.
DSM-V Definition: Substance Use Disorders
1. Using larger amounts or over a longer period of time than intended.
2. Persistent desire or unsuccessful efforts to cut down or control
3. Great deal of time spent in obtaining, using, and recovering from
4. Craving or a strong desire or urge to use
5. Recurrent use resulting in failure to fulfill major role obligations
6. Continued use despite persistent or recurrent social or interpersonal problems caused or exacerbated by use
7. Important social, occupational, or recreational activities are given up or reduced because of use
8. Recurrent use in physically hazardous situations
9. Continued use despite knowledge of having a persistent or recurrent physical or psychological problems that is caused or exacerbated by use.
10. Tolerance defined by need for increased amounts to achieve desired effect or markedly diminished effect with continued use of the same amount
11. Withdrawal either with withdrawal symptoms, or continued use to relieve or avoid withdrawal
DSM-V Definition: Substance
Use Disorder
Mild: Presence of 2-3 symptoms
Moderate: Presence of 4-5 symptoms
Severe: Presence of 6 or more symptoms
DSM-V Definition: Substance Use Disorders
If the narcotics are prescribed, example for chronic pain, then we do
not consider these two items even when present.
1. Tolerance defined by need for increased amounts to achieve
desired effect or markedly diminished effect with continued use
of the same amount
2. Withdrawal either with withdrawal symptoms, or continued use to
relieve or avoid withdrawal
Relapse does not deem treatment a failure!
Successful treatment for Diabetes, Hypertension and Addiction
requires continual evaluation and modification, reinstatement of
treatment (as appropriate) for the treatment plan.
JAMA, 284:1689-1695, 2000
QUESTION OF THE DAY:
We know that Addictions are chronic illnesses.
Why is Addiction treated differently than
hypertension, diabetes and asthma?
Circuits Involved In Drug Abuse and Addiction
All of these brain regions must be considered in developing strategies to effectively treat addiction
Inhibitory/ Control
PFC – prefrontal
cortex
ACG – anterior
cingulate gyrus;
Motivation/ Drive
OFC – orbitofrontal
cortex
SCC – subcallosal
cortex
Reward/ Saliency
NAc – nucleus
accumbens
VP – ventral pallidum;
Memory/ Learning
Hipp – hippocampus;
Amyg – amygdala
substantia nigra
locus coeruleus
Normal Pleasure Response
nucleus accumbens
VTR
Pleasure/Motivation Response
Increased Dopamine Release
YUM!!
substantia nigra
locus ceruleus
Brain Reward Pathway
Psychoactive Addictive
Drugs Act on this Pathway
Brain Reward Pathway
substantia nigra
locus ceruleus
Wow!!!
Dopamine surge!!!
Drug
Brain Reward Pathway
substantia nigra
locus ceruleus
Wow!!!
Dopamine surge!!!
Drug
Dopamine, Serotonin, Norepinephrine…
Reward Pathway
The “Wow!!!” is
a big reason
people take
drugs but other
things also
happen…
Drugs act on the
Brain Reward
Pathway
Reward Pathway
Emotional & behavioral
learning
Control of body movement
Early learning and
memory processing
Attention states and
automatic function
Areas
Continued Drug Use – Spine
Development
substantia nigra
locus ceruleus
Wow!!!
Structural changes
Drug
Continued Drug Use
substantia nigra
locus ceruleus
Wow!!!
A “molecular switch” is thrown in the brain
• Sensitization, Craving and Relapse
• Loss of control over drug use
• Compulsive drug seeking behavior
Natural Rewards and
Dopamine Levels
Adapted from: DiChiara et at, Neuroscience, 1999
Adapted from Fiorino and Phillips, J Neuroscience, 1997
Effects of Drugs on Dopamine
Levels
Adapted from: DiChiara and Imperato, Proceedings of the National Academy of
Sciences USA, 1988, courtesy of NoraD Volkow, MD
Effects of Amphetamines on
Dopamine Levels
Adapted from: DiChiara and Imperato, Proceedings of the National
Academy of Sciences USA, 1988, courtesy of NoraD Volkow, MD
Dopamine vs. Serotonin
Pleasure(WOW!!!) vs. Happiness(YUM!)
Dopamine produces a feeling of pleasure
Serotonin produces a feeling of well
being
Difference between pleasure and
happiness (short lived vs big picture)
Happiness--Developing skills, interest,
relationships, meaning (“getting a life”)
Pleasure
“I feel good”
Bored
Anhedonia
Interested
“I feel negative”
NORMAL RANGE
Dysphoria Euphoria
Pleasure Scale
Neocortex (modern man)
1. Reasoning and learning
2. Consciousness
3. Motor and sensory
4. Memory
5. Language
6. Abstract thought
7. Flexible and plastic
8. Able to execute both yes and no
9. Both on and off
Limbic and Reptilian (beast)
1. Survival
2. Emotions
3. Autonomic functions
4. Reward and appetite
5. Reliable and rigid
6. Only able to execute yes
7. Always on
NEOCORTEX
LIMBIC SYSTEM
REPTILIAN COMPLEX
Hijacked Brain!!
Circuits Involved In Drug Abuse and Addiction
All of these brain regions must be considered in developing strategies to effectively treat addiction
Inhibitory/ Control
PFC – prefrontal
cortex
ACG – anterior
cingulate gyrus;
Motivation/ Drive
OFC – orbitofrontal
cortex
SCC – subcallosal
cortex
Reward/ Saliency
NAc – nucleus
accumbens
VP – ventral pallidum;
Memory/ Learning
Hipp – hippocampus;
Amyg – amygdala
Inside the brain:
Brian cells called neurons send chemical messages
Neurotransmitter -chemical messenger which are electrical signals.
Synapse - Space between neurons where neurotransmitters travel
Millions of electrical signals cause brain waves (measured by EEG)
Do all drugs of abuse work the
same? No / Yes / Maybe?
Each substance mimics a particular
neurotransmitter
Each of these trigger a cascade/ series of
chemical events that results in activation of
the VTA and NAc
Most likely, if the event did not end up in the
VTA/NAc, it wouldn’t be addicting
Receptors/ Neurotransmitters: Excitatory vs. Inhibitory
Excitatory: Tends to increase action
potential firing.
Inhibitory: Tends to decrease or block
action potentials.
Receptors are classified as excitatory or
inhibitory. Some neurotransmitters can be
classified this way, but many are both.© 2013, CC-BY, by Zak Fallows, 2013-11-23
Agonist vs. Antagonist
Agonist: Binds to a receptor and sends
the “normal” signal (either excitatory or
inhibitory).
Antagonist: Binds to a receptor and does
not send a signal. Antagonists block
receptors and prevent agonist binding.© 2013, CC-BY, by Zak Fallows, 2013-11-23
One Synapse
Presynaptic
cell
Postsynaptic
cell
© 2013, CC-BY, by Zak Fallows, 2013-11-23
One Synapse
Postsynaptic
cell
Action potential
© 2013, CC-BY, by Zak Fallows, 2013-11-23
One Synapse
Receptor
binding
Action potential
© 2013, CC-BY, by Zak Fallows, 2013-11-23
Neurotransmitter Agonist (drug) Antagonist (drug)
Agonist vs. Antagonist
© 2013, CC-BY, by Zak Fallows, 2013-11-23
2 × 2 Table QuizExcitatory
receptor:
Inhibitory
receptor:
Agonist:More Signal
+ + + +
Less Signal
- - - -
Antagonist:Less Signal
- - - -
More Signal
+ + + +
© 2013, CC-BY, by Zak Fallows, 2013-11-23
Excitatory
receptor:
Inhibitory
receptor:
Agonist:
Drugs here may be
stimulants, promoting
wakefulness,
alertness, and fast
thinking, but also
seizures.
Drugs here may be
sedatives,
promoting relaxation
and sleep.
Antagonist: May be sedatives. May be stimulants.
© 2013, CC-BY, by Zak Fallows, 2013-11-23
Excitatory
receptor:
Inhibitory
receptor:
Agonist:
Stimulants of this type:
Nicotine
Psychedelics (LSD,
psilocybin mushrooms,
mescaline)
Sedatives of this type:
Ethanol (alcohol)
Barbiturates
Benzodiazepines
(Valium, Klonopin,
Xanax, Ativan)
Antagonist:
Sedatives of this type:
Diphenydramine (Benadryl)
Antipsychotics (Haldol,
Thorazine, Seroquel)
Caffeine
© 2013, CC-BY, by Zak Fallows, 2013-11-23
Neuro- Normal Functions
Transmitters
Dopamine (pleasure, learning)
Serotonin (emotional stability)
Norepinephrine
(behavioral & physical activity)
Glutamate
GABA
Pleasure (hunger/thirst/sexual), attention, organization of thought, muscle control and motor function
Regulates mood, emotions, thought processes, sleep, and appetite
Energy, motivation, attention span, alertness, pleasure, assertiveness, confidence, heart rate, blood pressure, etc.
Excitatory
Inhibitory
How Drugs of Abuse Effect Dopamine
Inhibit Reuptake of Dopamine (stimulate release of
Dopamine as well to a lesser extent)
Cocaine
Stimulate Dopamine transporter (release of Dopamine)
Amphetamine, Methamphetamine
Modulate firing of Dopamine releasing cells by actions
on GABA and Glutamate
Nicotine, alcohol, opiates, cannabis
Cocaine, Amphetamine, Methamphetamine
When COCAINE
is present:
COCAINE blocks the reuptake of dopamine (And to a lesser extent releases DA)
Synapse is flooded with dopamine, causing feeling of euphoria
When AMPHETAMINES ARE present: AMPHETAMINES release
dopamine
Synapse is flooded with dopamine, causing feeling of euphoria
Stimulants:
Cocaine & Amphetamines
Cocaine (blocks DA reuptake)
Licit use: schedule II (topical anesthetic)
Illicit use:
Salt (cocaine-HCL): powder
Water-soluble
Incinerates when heated
Snorted or injected
Base (freebase or “crack”)
Water-insoluble
Vaporizes when heated
Able to be inhaled (smoked)
Amphetamines (enhance DA release)
Licit use: schedule II (ADHD, narcolepsy, weight loss)
Amphetamine
Dextroamphetamine
Methamphetamine
Methylphenidate
Dexmethylphenidate
Illicit use:
Abuse of above
Methamphetamine epidemic
Easy manufacture
Nucleus
accumbens
(NAc)
AmphetaminesOpiatesTHCPCPKetamineNicotine
Alcohol benzodiazepines barbiturates
Dopamine Pathways
VTA
Stimulants- Withdrawal
Dopamine Hypothesis
Stimulants cause increased release and/or
delayed reuptake of DA
Chronic use downregulation of DA receptors
An example of downregulation is the cellular decrease in the
number of receptors to a drug, such as a neurotransmitter,
which reduces the cell's sensitivity to the molecule.
Relative depletion of dopamine is thought to be
the etiology of stimulant withdrawal.
Result is profound depression (NO PLEASURE)!!
Cocaine
Alcohol
Reward Circuits
DA
DA
DA
DA DA
DA
Drug Abuser
DA
DA
DA
DA DADA
DA
Reward Circuits
DADA DADA
DA
Non-Drug Abuser
Heroin
Meth
Dopamine D2 Receptors are Lower in Addiction
control addicted
Adapted from Volkow et al., Neurobiology of Learning andMemory 78:610-624, 2002.
Down regulation!!
Stimulants
Treatment of Withdrawal
Supportive- rest, eat, sleep in safe environment
Medications:
Anxiety: rapid acting, intermediate to long-half life benzodiazepines (lorazepam, diazepam)
Depression: may persist long enough to warrant treatment with SSRI
Psychosis/mania: may require treatment
Cocaine-induced psychosis usually self-limited
Methamphetamine psychosis can be longer lasting and require medication (think atipsychotics)
Long-term Damage?
Long-term drug use results in loss of dopamine receptors
Users report constant depression, sadness, feelings of hopelessness
Need more and more of the drug just to feel normal
Potential for “high” is gone
Meth Brain Damage
DopAmine (DA)
The Salience Neurotransmitter
Rewards eating, sex
Increases alertness, happiness, motivation
Opioids
Relieve pain, anxiety
Induce sleep
Important for pleasure
Slow the digestive tract
Opioids
Illicit Agonists
Heroin
Opium
Mixed Agonist/Antagonists
Buprenorphine (Buprenex, Suboxone)
Pentazocine (Talwin)
Butorphanol (Stadol)
Nalbuphine (Nubain)
Antagonists
Naloxone (mostly IV)
Naltrexone (mostly PO)
Licit Agonists
Morphine (MS Contin, Kadian, Avinza, Oramorph, MSIR)
Codeine (Tylenol #2,3,4)
Fentanyl (Duragesic)
Hydromorphone (Dilaudid)
Hydrocodone (Lor-, Vico-)
Levorphanol (Levo-Dromoran)
Meperidine (Demerol)
Oxycodone (OxyContin, Roxi-, Perco-)
Oxymorphone
Methadone (Dolophine)
Propoxyphene (Darv-)
GABA
GABA is the primary inhibitory neurotransmitter
GABA stands for Gamma-AminoButyric Acid
Sleep, muscle relaxation, anxiety relief, memory impairment
GABA Agonists: Sedatives
GABA agonists are almost always sedatives. Here are some famous GABA agonists:
Ethanol (alcohol) – Note that ethanol has other mechanisms, it does not act solely through GABA.
Barbiturates – Examples include phenobarbital (Luminal®) and pentobarbital (Nembutal®).
Benzodiazepines – Examples include diazepam (Valium®), clonazepam (Klonopin®), alprazolam (Xanax®), and lorazepam (Ativan®).
Serotonin (5-HT)
The Satiety Neurotransmitter
5-HT stands for 5-HydroxyTryptamine
Feelings of fullness, contentment
Relieves depression
Serotonin AgonistsSelective Agents
Buspirone is a partial 5-HT1A agonist used
clinically for the treatment of anxiety and
depression.
The “triptans” for the treatment of acute
migraine headaches. Imitrex®, Maxalt®,
Zomig®.
Trazodone is used generally as a sleeping
agent.
Non-selective agonists
Ergotamine—used for migraine attacks.
LSD
NorepinEphrine (NE)
The Fight-or-Flight Neurotransmitter
Also called noradrenaline
Excitement, fear, alertness
As a hormone, it increases heart rate, blood pressure, and blood sugar
AcetylCholine (ACh)
Nicotine is an agonist of the nicotinic cholinergic
receptor
Curare blocks this receptor (Used in anesthesia
and is quickly reversible)
Chantix ® is a partial agonist of this ACh receptor
Bupropion (Wellburtrin® and Zyban® are nicotinic
cholinergic receptor and increases release of
Dopamine
Incentive Salience—
Wants/ Cravings
Incentive salience is a type of motivation
created in the brain because it has developed an
association between a certain stimuli and reward.
“I want and I want it now!!”
In the case of addiction this stimuli will be
whatever drug the individual is using.
Incentive salience is a far greater incentive
than merely liking something.
Incentive Salience –
Wants/ Cravings
Previously neutral stimuli are assigned incentive salience.
Smelling cigarette smoke can trigger a craving for nicotine
Drug paraphernalia now trigger drug craving.
Driving in or near a neighborhood where drugs were purchased triggers craving
Thus, if a person's addiction subsides and the individual subsequently encounters one of these secondary reinforcers, a craving for that drug may reappear.
Drive
OFCSaliency
NAc
MemoryAmygdala
Control
CG
Non-Addicted Brain
AddictedBrain
STOP
GODrive
Memory
Saliency
Control
Drive
Memory
Saliency
Adapted from: Volkow et al.,
J Clin Invest 111(10):1444-1451, 2003.
Medications for Relapse Prevention
Interfere with conditioned memories (craving)Counteract stress responses that lead to relapse
Strengthen reinforcing effects of non-drug reinforcers
Strengthen inhibitory control
Strengthen prefrontal-striatal communication
Addicted Brain
Drive
Control
Saliency
Memory
GOSTOPSaliency Drive
Control
Memory
Non-Addicted Brain
Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.
Many of my patients just want a pill…..
Sorry,
there
are no
magic
pills.
Medications for Recovery from
Substances
Alcohol: (Data Conflicting on efficacy for AUD)
Naltrexone(ReVia)/ Depot Naltrexone (Vivitrol)
Acamprosate (Campral)
Disulfiram (Antabuse)
Naltrexone (ReVia)
Opiates: (Does patient need/ want to be off opiates?)
Naltrexone(ReVia)/ Depot Naltrexone (Vivitrol)
Buprenorphine/ Subutex (Depot Buprenorphine 2018)
Buprenorphine + Naloxone/ Suboxone
Methadone
Nicotine: (Great evidence of helping!!)
Varenicline(Chantix)
Buproprion (Wellbutrin/ Zyban
Nicotine-gum, patch, lozenge, inhaler
Opioid Full vs. Partial Agonist Levels
Sublocade® Buprenorphine
Like Probuphine® Subdermal Implant, for individuals who
have achieved and sustained a low to moderate dose of
buprenorphine—ie not more than 8 mg of buprenorphine
daily.
Once a month injection of Buprenorphine
300mg month one
300mg month two
Then 100mg monthly
ResourcesAdvanced Recovery Systems:
www.advancedrecoverysystems.com
National Institute on Drug Abuse (NIDA):
https://www.drugabuse.gov/
Substance Abuse and Mental Health Services Administration (SAMHSA)https://www.samhsa.gov/
American Society of Addiction Medicine (ASAM)
https://www.asam.org
Resources
✓ Advanced Recovery Systems:
✓ www.advancedrecoverysystems.com
✓ Academy of Eating Disorders: www.aedweb.org
✓ Binge Eating Disorders Association: www.bedaonline.com
✓ International Association of Eating Disorder Professionals: www.iaedp.com
✓ National Eating Disorders Association: www.nationaleatingdisorders.org
