School of Biomedical Sciences

MEDI7211: Pharmacology

Drugs of Dependence
http://learn.genetics.utah.edu/content/addiction/mouse/

Mary-Louise Roy Manchadi, PhD

School of Biomedical Sciences
G&G: Chapter 24
m.roymanchadi@uq.edu.au
 Objectives

• Brief coverage of dependence,

addiction and brain regions
involved in reward and euphoria.
• Dependence involves factors of
the drug, host, and environment,
as well as tolerance;
• Mechanisms of action of some of
the more abused drugs will be
discussed, including depressants
and stimulants.
• Possible mechanisms of
intervening with dependence,
including withdrawal, patient
support and rehabilitation
principles.
 Drug Dependence
and Australian
society

• “Drug dependence is one of the

biggest health challenges facing
the world today.
• Each year, many millions of
people die as a result of
dependence/addiction to
substances such as tobacco and
alcohol, as well as other
medicinal and recreational
medications.”

2021
https://www.aihw.gov.au/reports/alcohol/alcohol-tobacco-other-drugs-australia/contents/drug-types/tobacco#consumption
 Some important definitions and concepts
Some drugs may produce changes in the CNS which lead to abnormal states.

First is physical dependence, which occurs when pharmacological adaptation

leads to tolerance – thus more drug is needed to reach the same effect.

• If the drug is stopped, withdrawal symptoms may emerge; if there are

withdrawal symptoms, there is physical dependence.

• Second is psychological dependence which may also lead to emotional-

motivational withdrawal symptoms – many daily drug users show both
dependences.

• Third is addiction, which occurs in a small minority of people who initiate drug
use – addiction leads to compulsive and out-of-control drug use as a
component of physical dependence.

• In these lectures, we will consider drugs used recreationally and medicinally.

 Origins of substance dependence
• Many variables work simultaneously to influence the probability
and likelihood that a beginning user will develop
physical/psychological dependences and/or an addiction.

• Generally speaking, these variables can be organized into three

categories: agent (drug), host (user), environment

Reinforcement is the ability of drugs to produce effects in the user

which make reuse more likely and desirable.

The more reinforcing the drug is, the more likely the user will seek
re-use, possibly leading to abuse.

Reinforcement is due to effects within the CNS.

 Specialized brain circuits have
evolved to direct behaviour to enhance survival

• these circuits reward actions, such as the

intake of nutrients and procreation,
leading to the propagation of the species

• activation of brain “reward systems”

produces slight mood elevation to intense
pleasure and euphoria

• these psychological states normally help

to direct behaviour toward “natural”
rewards
As shared yesterday…
• Alcohol from fermentation, nicotine from tobacco, opium derivatives
- all activate the brain reward mechanism directly, as do many other
drugs.

Moderate use of these substances has gained widespread acceptance

over the centuries, although their use has been occasionally
prohibited or restricted.

Initial uses of these substances may be accompanied by mood

elevation and other affective changes that lead to their potential for
abuse.
 Animal Drug Models

Generally, animals are good

models of self-administration of
drugs with positive effects.
 Physical reward pathways in the rat and brain...

rodent human

• the ventral tegmental area (VTA), the nucleus accumbens, and the frontal cortex.
• Collateral communication also occurs to the amydala and hippocampus such that
affective and memory systems are impacted, and 5-HT, glutamate, NA, GABA and
endogenous opioids may play roles as well.
 (Russo and Nestler, Nature Reviews Neuroscience, 14. 609-625, 2013)

A simplified schematic of the major DA, Glu and GABAergic

connections to and from the VTA and NAc in the rodent brain.
(mPFC – medial prefrontal cortex, hipp = hippocampus, amy = amygdala, LDTg = lateral dorsal tegmentum,
LHb – lateral habenula, LH = lateral hypothalamus)
 In animals and humans...

...many abused
substances share one
common physiological
effect:

The red items increase

DA release in the nucleus
accumbens to varying
degrees, leading to the
dopamine theory of
addiction.
The dopamine D2 receptor
Transgenic mice without D2 receptors
do not demonstrate reward properties
of morphine administration;

Interestingly, these animals still went

through physical withdrawal syndrome.

This suggests that the D2 receptors are

involved in the reward dimension of
addiction, but not the withdrawal
aspects.

Dopamine is but one of many

neurotransmitter players in the circuitry
affected.
 How does the
brain cope
with change?
The CNS has plasticity in
that it can modify its
hardware to best
function in a changing
environment.

This change in receptor

numbers is profoundly
sensitive to the presence
of CNS drug, depending
upon the concentration
used and time period of
treatment.
 What affects a drug’s abuse liability?
Rapidity of onset: when coca leaves are chewed,
cocaine is absorbed slowly, and this results in low
cocaine levels within the blood and CNS.

Crack cocaine is alkaloid cocaine which can be

readily vaporised by heating, which when inhaled,
produce blood levels comparable to iv administration
of drug.

Availability

Cost

Purity/potency

Mode of Administration chewing (absorption through

mucus membranes), GI tract, intranasal,
subcutaneous, IV, inhalation

Economic and pharmacological factors prevail…

 What about variables about the host (user)?
Effects of all drugs vary from person to
person.

Gene polymorphisms encoding the

enzymes involved in absorption,
metabolism, and excretion, as well as
the receptor mediated drug effects
(subunits, dimerisation) may combine to
determine the overall degree of
reinforcement or euphoria experienced.

Psychiatric disorders are also host

variables of significance. People with
depression, anxiety, insomnia,
schizophrenia, ADD, ADHD, etc. may
turn to drugs to give relief – self-
medication, if you will.

Innate tolerance may also be a factor.

Tolerance Tolerance to some drug effects
develops much more rapidly
than to other effects of the same
drug, e.g. tolerance to opioid
euphoria occurs quickly, so more
drug is taken for the “high”.

Tolerance to constipation effects,

however, is much slower, as is
that of decreased respiration,
meaning that fatal overdose is
indeed possible.

Tolerance is the most common Cross-tolerance: repeated use

response to repetitive use of one drug not only results in
of the same drug, defined as the
tolerance for its own effects, but
reduced response to a drug with
also the effects of other drug
repeated use. As the dose of the
drug increases, the curve shifts to classes which function in the
the right, with less effect. same general way.
 And environmental influence?

Often underestimated, the environment plays a major role in determining

drug taking, use, and relapse likelihood.

Associating drug use with a certain place or group of people, sounds and
smells can initiate the euphoria of expectation, and such conditioning
responses need to be minimised should an addict seek to stop the habit.

Environmental changes are key for rehabilitation success.

Combining drug, host, and environment = risk of addition….

Comparing the relative risk of addiction (dependence rates), it is interesting

to consider that tobacco is most likely to drive addiction, and yet is legal.

Alcohol is not as likely to provoke addiction, perhaps as it is not as

“reinforcing” as other drugs, such as tobacco.
 • “Narcotics” refers to the pain-relieving and sleep-
inducing properties of these addictive alkaloids,
including morphine and codeine.
Opioids • Morphine is synthetically acetylated to produce heroin.
• Heroin is injected and once it crosses the blood-brain
barrier more quickly than morphine.
• Codeine is metabolised by CYP2D6 to morphine, which
is further degraded. There are genetic variations in rate
of codeine metabolism.
Prescription opioids or heroin?
An estimated 4 – 6% who misuse
prescription opioids switch to heroin and
about 80 percent of people who used heroin
first misused prescription opioids.
More recent data suggest that heroin is Prince
frequently the first opioid people use. In a
study of those entering treatment for opioid
use disorder, approximately one-third
reported heroin as the first opioid they used
regularly to get high. (NIDA 5/2020)

• There is no legal supply of heroin for

clinical use; purity has improved Cory Monteith
dramatically on the illicit market; this
increase in purity has led to increased
physical dependence amongst addicts, Peaches Geldof
with users experiencing withdrawal when
their schedule of use is interrupted.
 MOA of opioid at µ and D2 receptors in reward pathway

Opioids modify the action of DA in the nucleus accumbens and the VTA. The binding of
morphine to the µ opioid receptors inhibits the release of GABA from the nerve terminal,
reducing the inhibitory effect of GABA on DA neurons, as presynaptic µ receptors reduce Ca2+
entry.
The increased activation of DA neurones and the release of DA into the synaptic gap results in
sustained activation of the post-synaptic membrane. Effects wear off after 3-5 hours
depending upon concentration, and experienced users may inject 2-4 times per day.
Thus, the user is oscillating between being “high” and feeling ill with onset of withdrawal.
 Should you be
opioid dependent...

• Tolerance occurs involving a

decrease in adenylyl cyclase
activity, with a progressive
uncoupling of receptor with
second messenger systems as
well (desensitization).

• Tolerance to the euphoric effects

occurs before tolerance to
respiratory depression.

• Purity ranges from 25%-90%

pure. Users can never be sure
which concentration they are
receiving, and overdose can
occur very easily.
 Cocaine
• Cocaine is powerfully addictive, isolated Injecting or smoking cocaine delivers
from coca plant leaves. the drug rapidly into the bloodstream
and brain, producing a quicker, stronger,
• It causes talkativeness, physical energy and
but shorter lasing high than snorting
short-term euphoria, with potentially (high lasts 5-10 min).
dangerous increases in heart rate and blood
pressure. The high from snorting cocaine is not as
• Cocaine can be snorted in powder form and strong, but may last 15-30 min.
absorbed across the nasal mucosa (septum
issues and runny nose); or dissolved in water With repeated use, tolerance develops,
and many users are frustrated that they
and injected into the bloodstream. cannot achieve the same level of high
• Crack cocaine is processed to crystalline that they experienced initially.
form, and this can be smoked. Heating it
produces vapours which are breathed in, and Increasing dosage significantly does risk
adverse physiological and psychological
absorption occurs through the lung mucosa.
effects.
 Cocaine’s mechanism of action

• Cocaine binds to DA re-uptake transporters (DAT) on the pre-synaptic

membranes of DA neurones, inhibiting the clearance of DA from the
synaptic cleft and its degradation by MAO in the nerve terminal.
• DA remains in the synaptic cleft and is free to bind to its receptors on the
post-synaptic membrane, producing feelings of euphoria and the ‘high’
associated with cocaine use in the nucleus accumbens.
Heroin/morphine + cocaine = speed-ball
Because heroin and cocaine work via different
mechanisms on DA neurons of the reward
pathway, they can be combined to produce even
more intense dopamine activation. The IV
combination of heroin/morphine and cocaine is
known by users as a "speed-ball” and is
extremely dangerous. Users show very rapid
psychological and physiological deterioration,
and there is a very high fatality rate. Phillip Seymour Hoffman

Cocaine (20 mg/kg, i.p.) elevates DA in nucleus

accumbens by ~ 380% above baseline in mice,
while heroin elevates DA by ~ 70%.
Coadministration of these two drugs, however,
produces a synergistic DA elevation of 1000%.

Eur J Pharmacol 1999

Sep 3;380(1):1-4
Amphetamine and methamphetamine
Amphetamine use results in a variety of
effects, including euphoria, insomnia,
psychomotor stimulation, anxiety, loss of
appetite, decreased fatigue, increased
concentration, respiratory stimulation.

It also produces sympathomimetic effects:

mydriasis, tachycardia, and hypertension.

The euphoria is largely due to DA effects,

whereas the jittery and anxious feelings are
largely due to the NA effects.

Medical uses may include for ADHD,

narcolepsy, and obesity.

dopamine Crystal meth (ice) is preferred by abusers as it

has fewer NA effects.
How is methamphetamine used? Effects?
• Swallowed, snorted, smoked or injected. Ice
is usually smoked or injected.

• Short term effects: increased energy,

attention, alertness, talkativeness, decreased
appetite, increased heart rate, breathing and
body temperature, nausea, vomiting, anxiety
and paranoia -“psychosis”. High doses may
lead to aggressiveness and violent behaviour.

• Long term effects: agitation or aggression,

depression and anxiety, poor concentration
and memory, weight loss, chest pains.

Heavy users may also experience blurred vision,

tremors, irregular breathing, loss of coordination
or collapse.
Amphetamine MOA?
• Amphetamine (Amph) is a substrate of
the DAT, and competitively inhibits DA
transport.

• Once in the neuron, Amph interferes

with the vesicular monoamine transporter
(VMAT) and impedes the filling of synaptic
vesicles and cytoplasmic DA concentration
increases.

• This leads to a reversal of DAT

direction, strongly increasing non-
vesicular release of DA, further increasing
extracellular DA concentrations.
 Nicotine
and tobacco

• Tobacco growing and

“consumption” was
initially done in the
Americas and Australia,
then taken back to
Europe in the 16th
century.
• Present day, total global
consumption slowly
decreasing in some “1.1 billion smokers in the world (18%
countries offset by the of the population, excess of ~6 trillion
growing demand in cigarettes sold each year, which is more
than 900 per every man, woman and
others.
child. In 2010, 12 million cigarettes per
minute were smoked around the world.”
-Rang and Dale
Nicotine
• Nicotine provides the reinforcement for cigarette smoking, which
has been identified as the number one cause of preventable
death and disease in the Australia (total costs $31.5B)
• This makes nicotine, perhaps, the most dangerous dependence-
producing drug in current society.

• In low doses, nicotine has stimulatory effects, while in high doses,

it is reported by users to be “relaxing”.
• Cardiovascular vessels are seen to constrict initially, followed by
dilation, with decrease in bp.
• Antidiuretic actions as well as a decrease in GI motility.
• Steady use of nicotine leads to tolerance of nausea and anxiety
initially experienced with use.
 Nicotine activates nAChRs

• Systemically, nicotine temporarily stimulates

all sympathetic and parasympathetic ganglia,
skeletal muscle and CNS followed by
depression.
• These receptors are located pre- and post-
synaptically, and activation leads to
enhanced NT release and increased
excitation.
• Nicotine also causes receptor
desensitization, with reduced effects
resulting from the same dose.
• Long-term use, interestingly, up-regulation
of nicotine receptor numbers occurs as well.
• Increased DA in nucleus accumbens results.
 Nicotine’s Tolerance and Dependence
• Tolerance to CNS effects is much less
than that observed for peripheral
effects, remembering that receptor
numbers increase but so does
desensitization.

• Environmental cues are particularly

important in smoking (animal studies
as well!), and for this reason,
nicotine patches seem not be to as
addiction forming.
• Trained monkeys will continue to
smoke post-reward if nicotine is
present but will cease if nicotine is
not.
 Ethanol use and abuse

Australia’s average rate of

alcohol consumption is at its
lowest since 1961-62.
• This equates to 9.4 litres
for every person per year
aged 15 years +.
• ~224 stubbies of beer
(which is down from over
500 per year in the 1970s)

On molar basis, ethanol

consumption exceeds all
other drugs. Associated costs
to society = $15.3B for
healthcare, road accidents,
crime, pain and suffering.
https://www.youtube.com/watch?v=pSm7BcQHWXk
 Pharmacokinetics of ethanol 50% of Asian population
expresses ALDH-2, which is
• rapidly absorbed in GI tract inactive – and such
• first-pass metabolism in most cases, although individuals experience
saturation of enzymes occurs quickly “disulfiram effects”
• can lead to quick distribution of ethanol into blood when consuming.
stream if taken on an empty stomach.
Ethanol can also undergo
oxidation by cytochrome
P450 enzymes, with
Easily saturable CYP2E1 being the key,
which is induced by long-
term alcohol use,
contributing to tolerance.

90% metabolised, 10% in urine

and air, hence can be used for
alcohol testing.
 Metabolism of methanol

Brenner, 2010

Methylated spirit is ethanol purposefully contaminated with methanol to prevent

(or at least discourage) consumption. Methanol, or methyl alcohol, is highly
toxic. Mouth “pipetting” fuel or organic solvent? Methanol is converted to
formate, which damages the optic nerve, resulting in visual impairment or
blindness.

Treatment for methanol poisoning? Give ethanol! This will saturate the alcohol
dehydrogenase enzyme and slow the formation of formate. Ethanol has a
greater affinity for the enzyme than methanol does.

Alternatively, give patient fomepizole, which inhibits alcohol dehydrogenase –

combined with haemodialysis to remove methanol.
Ethanol effects on the CNS
In total – general depressant.

Ethanol: -enhances GABAA-

mediated inhibition by positive
allosteric interaction
-inhibition of function of NMDA
glutamate receptors thus also
depressant
-inhibition of opening of voltage-
dependent Ca2+ channels reducing
excitation

• associated with disinhibition of the reward pathways of the brain, with an

increase in DA in nucleus accumbens, euphoria and reduction of behavioural
inhibitions.
• inhibits the release of antidiuretic hormone (ADH) from pituitary gland,
therefore diuretic.
• wide variety of individual host (user) affects based on genetics and exposure.
Benzodiazepines and addiction: mechanism of
“disinhibition”
GABAergic neurons in VTA
express the a1 subunit,
whereas DA neurons
in the VTA express the a3
subunit.

(a) Binding of BNZ to a1 in the

complex leads to reduction of
activity of these GABAergic
cells, which regulates the
release of GABA and thus DA.

(b) With BNZs, increased

GABA impact on a1 subunits
occurs, with reduced GABA
released. This results in an
increase in dopamine release
Nature Reviews Drug Discovery 10, 685-697 (September 2011) in the nucleus accumbens (3).
 Cannabis
• Isolated from the hemp plant,
originally from Himalayas and Kashmir
• Marijuana = dried leaves and flowers
• Hashish = extracted resin from stems

• Each contain cannabinoids, of which

DTHC (delta-9-tetrahydrocannabinol)
is the most abundant and active.

• Can be inhaled in cigarette smoke or

taken orally. Smoking delivers 50% of
THC to CNS within seconds, while oral
route achieves 25-30%, due to
metabolism in liver. Onset is delayed
(0.5–2 hr), but duration is prolonged
due to slow absorption from GI tract.

• Being very lipophillic, it can be stored

in body fat, and excretion can take
days; with detection in urine.
 Distribution of DTHC in the body
Once absorbed,
distribution is dependent
upon blood flow.

Being lipophillic, DTHC

accumulates in fatty
tissues, reaching peak
concentrations in 4-5
days. They are then
slowly released back into
other body compartments,
including the brain.

It can take up to 30 days

to clear a single dose.
Thus, repeated doses can
cause significant
accumulation.
ASHTON C H BJP 2001;178:101-106
©2001 by The Royal College of Psychiatrists
Pharmacological effects:

CNS: psychomimetic and depressant

• Relaxation, peace, euphoria

• Uncontrolled laughing
• Greater intensity of senses (taste,
sound, sight)
• Impairment of memory
• Increased appetite
• Analgesia, antiemetic actions
• Slight bronchodilation, but more
tar than tobacco
• High doses cause anxiety,
paranoia, hallucinations
Cannabinoid receptors CB1 receptors: abundant in
hippocampus (memory),
cerebellum (loss of motor
coordination),
hypothalamus (appetite
stimulation), mesolimbic
DA pathway. Positioned
pre-synaptically, activation
inhibits NT release. Very
few receptors in brain
stem, thus lack of
cardiovascular and
respiratory inhibition for
most.

CB2 receptors: exist in

immune tissues and may
mediate cytokine release
and modulate pain.
 Medicinal uses of THC?
Cannabis Tolerance and
Drug Dependence

• Relatively minor, even in

heavy users • Used for treatment of nausea and
• Withdrawal syndrome is also vomiting after chemotherapy
generally weak, with treatment;
restlessness, confusion, • Stimulation of appetite and
sweating, tremor, sleep prevention of weight loss in AIDS
disturbances, and mild patients.
irritability.
• Analgesia
• Long term effects with
chronic use: decreased • Glaucoma
testosterone and sperm • Treatment resistant epilepsy
count, impaired memory, • Legal use has significantly
apathy.
advanced in US and Australia.
 What is an overdose?
• “overdose”: an excessive and dangerous dose of a drug, can mild, moderate,
severe or lethal.

• Most people who overdose are under the influence of more than one drug – on
average 2.7 drugs are identified in fatal overdose cases.
• When overdose is lethal, it is common that no single drug is usually present at a
lethal dose. Rather it is the synergistic effects of combining the drugs that is
lethal.

• The majority of overdoses involve legal drugs.

• e.g., a combination of opiates (heroin or prescription painkillers) and alcohol

can be especially dangerous. Both suppress breathing, but by different
mechanisms.
Death by respiratory
failure
• Prescription opioids are
the cause for more deaths
by overdose than any
other single drug.

• Like opioids, alcohol

overdose can suppress
breathing by either
decreasing the excitatory
effect of glutamate, such
that high doses can result
in passing out and reduced
breathing;
• and/or an unconscious
individual may inhale their
own vomit, which further
reduces breathing.
 Death by stimulants
• Cause of death is
predominantly due to the
indirect increases of
noradrenaline. There are
no clear antagonists to
addresses overdose.

Brain damage:
Microischemia caused by
drugs such as cocaine.

Hyperthermia: differs by drug

(up to 38.3C)
Some stimulants primarily impact
on the temperature of the brain
(amphetamines), whereas others
are more systemic (cocaine).
Being in a warm club or
environment can make this even
more dangerous.
 What is done in overdose?

First priority is support of

cardiovascular and
pulmonary functions.

If dependence is an issue or
suspected, management of
the withdrawal symptoms is
next that may occur as the drug
is eliminated from the body
without being replaced.
 Withdrawal timelines
A
B
C

Brody’s Human Physiology, 2005

A) Withdrawal from long-acting drugs: delayed onset over days or weeks as

half-life impacts on this.
B) Withdrawal from short-acting drugs: more intense but of shorter duration.
C) Precipitated withdrawal: occurs if an antagonist is given to displace the
drug from its receptors, causing more rapid and severe effects, i.e. giving
naltrexone to heroin addicts.
Spontaneous withdrawal: occurs upon cessation of drug taking.
What are symptoms of withdrawal?

Symptoms of withdrawal are generally the opposite of the effects of the drugs. This
“rebound effect” in terms of symptoms is due to the re-sensitisation and re-regulation
of receptors of CNS and PNS.

Bear in mind that dependence on combinations of drugs is very likely, so

management of CV aspects is crucial, perhaps requiring constant monitoring.
 Detoxification and Rehabilitation
• Detoxification: drug is cleared from the system
and support measures are implemented, is
overseen by a physician and nursing team.
This can be physically dangerous.

• Generally speaking, this may require up to 30

days in hospital or care unit, depending upon
the half life of the drug(s) of dependence.

• In parallel, counseling and therapy processes

are started. Through group sessions, users
hear and share stories about reasons for drug
addiction, how to avoid triggers, and how to
successfully live a drug-free life.
• For many, detox and rehab are crucial, as
patients are learning how to live without the
drug(s) for the first time in perhaps a very long
time.
 So where do we start with effective treatment of
dependence or addiction?
• Goal is to stop using, avoid relapse and • Medications are a key point in
recover. treatment, when combined with
Key steps have been identified: counseling.
• Addiction is a complex but treatable • An individual’s treatment must be
disease, and no single treatment will assessed continually to make
work for everyone. adjustments as needed.
• Treatment needs to be readily • Many drug-addicted individuals have
available, and needs to attend to other mental disorders.
multiple needs, not just drug abuse. • Medically assisted detoxification is
• Remaining in treatment for an only the first stage of treatment and
effective time is crucial. does virtually nothing to prevent
• Counselling – alone or in groups – and relapse.
other behavioural strategies are • Treatment programs should assess for
commonly used. presence of HIV/AIDS, Hepatitis B and
C, TB, and other infectious diseases to
help patients’ overall health and to
reduce such diseases spreading.
 This work is best done out of the “normal”
environment of the user…

…thus the use of drug rehab centres or wards

in hospitals.
• These serve many purposes, including:
– Medical support through withdrawal
processes
– No contact with drug suppliers or fellow
users (environment)
– Counseling or behavioural therapy
implemented
– Refocusing on something to fill time
and reorient outward focus and role in
society.
– Education of patient and family/friends.
What strategies can be used in treatment?
• Substitution therapy can be used to “maintain” the individual, preventing
them from going into withdrawal and reducing the need/drive to retake
(methadone or buprenorphine for opioid users). This can be followed by
weaning off of the element of substitution. Alone, this is usually
insufficient to prevent relapse.
• Facilitating drug withdrawal (detox) by either substituting a drug in the
same class which has less severe withdrawal or by use of symptomatic
relief.
• Blocking the effects of an abused drug by prior administration of a long-
acting antagonist so that if relapse occurs, the euphoria experience does
not occur. (naltrexone)
• Blocking the effects of an abused drug by immunisation to produce
circulating antibodies. Very slow progress here…
• Making the drug experience unpleasant (disulfiram) – aversion therapy.
• Reducing the craving for a drug – very slow progress here.
 Opioid
Withdrawal
and Treatment

• Recall that tolerance develops early to the euphoric effects of opioids,

along with tolerance to respiration depression, analgesic effects, and
sedative effects.
• Overdose is likely to occur when expected purity of drug is exceeded, if a
stronger opioid is used, or if combined with another depressant (alcohol).
• Treatment addresses the physical dependence aspects and requires
detox in supervised facility.

Withdrawal symptoms are not life-threatening, but very unpleasant,

beginning 6-12 hours after use of short-acting opioid or 72 hours after a long-
acting medication.
How can pharmacology assist?
Buprenorphine, a partial agonist at the µ-opioid receptor either alone or in
combination with naloxone.

Methadone has been used for more than 30 years to treat opioid addiction and can
be used to assist in heroin withdrawal treatment. Opioids may have half-lives of 4-6
hours, whereas methadone’s half life is 24-100+ hours.

The most successful treatment for heroin addiction is stablising the user on
methadone at a concentration sufficient to prevent withdrawal for 24 hours, and then
reducing the concentration gradually.
 Benzodiazepine
Withdrawal
Patients who have used high dose
BNZs for long-term treatment will need
to gradually reduce doses used over
months. Withdrawal symptoms, if they
occur, will be mild.

In the case of BNZ and opioid

dependence, reduction of BNZ
gradually while maintaining the opioid
component with low dose methadone
is possible. Alternatively, a long acting
BNZ can be substituted.

If low dose BNZs have been used for

long-term treatment, no adverse
effects are usually seen.

If anxiety returns, non-BNZ drugs can

be prescribed instead.
Blood levels of nicotine via
various delivery systems
Shaded areas indicate nicotine
delivery.

Note how most methods increase

nicotine concentrations to between
10-15 ng/ml, with mixed timelines
for decay from this “hit”.

“Combining the nicotine patch with a self-

administered form of nicotine replacement
therapy (gum or nicotine nasal spray) is
more efficacious than a single form of
therapy. Patients should be encouraged to
use combined treatments if unable to quit
using a single form of first-line
pharmacotherapy.”
US Department of Health and Human
Services
Only 25-35% of users who wish to quit
without assistance will succeed
long-term (1 year).

Nicotine Replacement Strategies

As cigarettes give boluses of

nicotine with a half life of 2 hours,
using the patch or chewing gum
stabilises the nicotine levels within
the blood, and allows the user to
begin the dissociation of smoking
and the physical aspects of the
habit.

The adverse effects on the lungs

are absent using many NRSs, and as
discussed previously, some nicotine
users have only used these
treatments.
 Bupropion is an antidepressant
that inhibits neuronal reuptake
Bupropion as a treatment of dopamine and
strategy noradrenaline, and is also a
noncompetitive nicotine
antagonist at nAChR.

It is effective as a nicotine-
replacement drug, as it has
fewer side effects than using
nicotine itself.

In randomised controlled trials,

bupropion combined with
behavioural therapy and
However, a a serious adverse effect in regular follow-up has been
1:1000 patients - bupropion lowers the shown to be at least as
seizure threshold within the CNS, effective as nicotine
especially in patients taking other replacement therapy (NRT) for
medications which act similarly. smoking cessation—and it may
reduce relapse rates.
Varenicline (Chantix)
• a partial agonist that is
selective for alpha-4, beta-2
(a4b2) nicotinic acetylcholine
receptors (nAChRs). Its action
is thought to result from
competition with nicotine for
binding sites.

Being a partial agonist, its

activity is significantly lower
than that of nicotine.

Varenicline helps smokers quit by

(A) Nicotine from cigarettes stimulates the
preventing withdrawal symptoms production of high levels of dopamine in terminal
while moderate levels of synapse in the nucleus accumbens. (B) No
nicotine present, which induces a state of nicotine
dopamine are maintained in the withdrawal. (C) Varenicline blocks the nicotine-
brain. receptor sites and partially agonizes the
receptors, stimulating moderate levels of
dopamine in the terminal synapse in the nucleus
accumbens.
Alcohol The level of physical dependence is
reflected by the severity of the
Withdrawal Syndrome withdrawal symptoms experienced
by the user.

The symptoms and severity are

determined by the amount and
duration of alcohol consumption,
leading to possible sleep disruption,
ANS activation, tremors, and in
severe cases, seizures and cardiac
arrest.

Two or more days after

withdrawal, individuals may
experience “delirium tremens”,
with hallucinations, delirium,
fever and tachycardia.

Hydration, electrolytes, vitamins

(high dose thiamine) should be
strongly encouraged.
• Sometimes, sedating medication might be used, such as benzodiazepines, but
care needs to be taken due to possible cross-tolerance effects following long-term
alcohol use.
• Ideally, a short-acting benzodiazepine is used according to the stage and severity
of the withdrawal.
• Anticonvulsants, such as carbamazepine, may also assist. If there is a history of
medical problems, seizures, or use of other drugs, hospitalization is required.
Pharmacology of treating alcohol dependence:
disulfiram

Disulfiram has been utilised to help cease alcohol consumption by users, but its
side effects (flushing, tachycardia, hyperventiliation and stress) challenges with
patient compliance has made it a third choice by many.

Abstinence is reinforced to avoid the resulting adverse reaction.

Pharmacology of treating alcohol dependence:
naltrexone
Naltrexone, the opioid receptor antagonist, may
block the reinforcing properties of alcohol, so
that the “high” experienced is not possible,
which may reduce the urge to drink.

As naltrexone reverses opioid effects, it can only

be used when full detox has been completed
and the individual is clear of alcohol and all
opioid based drugs and medications. If opioids
are involved, naltrexone would cause
precipitated withdrawal which could be
dangerous.

Can be administered as an implant for 6 months

treatment, which may allow for consolidation of
recovery; and if needed, further implants can be
used. On average, drug relapses occur within
two years of sobriety, after which they
dramatically drop.
 Naltrexone and alcohol use
• A µ-opioid receptor antagonist with a
longer duration of action than naloxone,
naltrexone can be used in initially
interventions.
• Naltrexone blocks the activation of DA
reward centres in the brain by blocking
opioid receptor activity.
• Naltrexone reduces the urge to drink in
someone abstaining, but it is not a cure
and does not prevent relapse in all users.
• Combining naltrexone with psychosocial
support, such as cognitive behavioural
therapy is crucial for success.
• The exact MOA in this case is not clear,
but the euphoria and pleasurable
sensations of alcohol use are suppressed.
Pharmacology of
treating alcohol
dependence:
acamprosate

Acamprosate is a GABA analogue has multiple sites of action, including

weak antagonism on NMDA glutamate receptors and agonism of GABAA
receptors.

This can help maintain abstinence and can be maintained if relapse occurs –
usually used for 1 year.

Its use is thought to decrease drinking frequency and reduce relapse in

abstinent drinkers. Disulfiram can be used with acamprosate as well.
 No clear strategy
for psychostimulant
withdrawal

Cocaine?
Amphetamine?

• Generally three phases has been identified in the withdrawal process:

“Crash”: acute dysphoria, irritability and anxiety, increased desire to sleep,
increased appetite, etc.
“Withdrawal”: increased craving to use, poor concentration, some irritability
and lethargy.
“Extinction”: intermittent craving to use in response to external cues.
• Disturbances in heart function may result, accompanied by chest pain,
headaches, and heart attacks.
• Provision of psychosocial support in a safe non-threatening environment
• Provision of symptomatic relief medication when indicated on an individual
basis.
What does supportive care look like?

Current Psychiatry 2014 September 13(9) 36-42,44

 Relapse: Aspects of Psychological Dependence
• During periods of drug withdrawal, individuals experience irritability, stress,
anxiety, low mood and blunted responses to experiences that would normally be
pleasurable. These aversive behavioural changes can be long-lasting and contribute
to the drive to retake the drug to escape from what is a negative emotional state
(negative affect).

• The memory of previous drug-induced experiences can be very intense and long
lasting, giving rise to craving; it may drive an individual to take the drug again –
referred to as relapse – even after a prolonged period of abstinence.

• Craving may be triggered by stress or by cues, such as experiencing the

environment that a person associates with previously taking the drug or the sight
of drug administration paraphernalia e.g. a crack pipe or syringe. This suggests that
associative learning may be an important factor in psychological dependence.
 UN Office on Drugs and Crime: Global support
• Psychological and social interventions have demonstrated to be
effective in rehabilitation and relapse prevention, both in out-patient
and residential settings.
• Psychotherapies such as cognitive behavioural therapy, motivational
interviewing and contingency management, have shown promising
results.
• Social support interventions like employment programmes, vocational
training and legal advice and support have been demonstrated to be
effective in facilitating social inclusion.
• Self-help support groups complement formal treatment options and
can support standardized psychosocial interventions
• Socio-cultural relevance. Evidence-based treatment methodologies
and strategies need to be adapted to the diverse regional, national and
local circumstances, taking into account both cultural and economic
factors.

https://www.unodc.org/docs/treatment/Principles_of_Drug_Dependence_Treatment_and_Care.pdf
 Long-term treatment of drug dependence
Once rehab has been
successfully completed,
the behavioural therapy
that should follow is
just as important as the
pharmacology.

There is no “cure”, and

this is usually a life-long
process. One is
effectively in remission,
and relapse is an ever-
present possibility.
 Summary of
speaking points
• Brief coverage of dependence,
addiction and brain regions
involved in reward and euphoria.
• Dependence involves factors of
the drug, host, and environment,
as well as tolerance;
• Mechanisms of action of some of
the more abused drugs will be
discussed, including depressants
and stimulants.
• Possible mechanisms of
intervening with dependence,
including withdrawal, patient
support and rehabilitation
principles.
 Conclusion

• Our understanding of drug dependence has advanced significantly;

• Pharmacologically, we can look at mechanisms of the brain which are altered by
drug use, and assist by either replacement therapy, the easing of withdrawal
symptoms and support mechanisms so that the patient goes into remission.
• Psychological steps/programs can support addicts so that relapse risks are
reduced.