Narcotics or Opioids

Abuse
 The origin of Abused Opioids

 Opium is the dried juice from the unripe seed

capsules of the opium poppy (the plant of joy).
 Morphine (10%) and codeine were isolated from
opium.
Endogenous Opioids

All opioids act by binding to opioid receptors in the

CNS to produce effects that mimic the action of
endogenous peptide neurotransmitters
 Endorphins,
 Enkephalins,
 Dynorphins.
Narcotic?

 Narcotic refers to a drug that induces drowsiness

or stupor (marked impairment but no loss of
consciousness) with analgesia.
 Classification of Narcotic Analgesics

1. Natural opium alkaloids:

Morphine, Codeine

2. Semisynthetic Opioid agonists:

Heroin, Hydrocodone, Oxycodone

3. Synthetic Opioid agonists:

Methadone, Tramadol, Diphenoxylate (Lomotil)

Mixed agonist–antagonist and
Partial Agonists

 Buprenorphine
 Pentazocine
Antagonists

 Naloxone (Narcan)

 Nalmefene (Revex)

 Naltrexone (Revia)
 The most popular abused opioids.

 Heroin, methadone, morphine, hydromorphone,

meperidine, oxycodone, and oxycodone sustained-
release.
 Heroin

 Heroin is Diacetyl morphine (Pro-drug)

Morphine Heroin
 The 2 acetyl groups increase lipid solubility, passes BBB
and → “Hero” due to its rapid onset.

 Heroin is 2-3 times more potent than morphine

 converted to morphine, but Shorter duration.

 Street names: black tar Smack, "H," Horse, Hero,

brown sugar, dope and junk.

 The most addictive drugs “Schedule I”

Controlled substance schedules
Schedule Criteria Examples

No medical use; high

I Heroin, LSD, mescaline, PCP, MDA
addiction potential

Medical use; high Secobarbital, strong opioids, Amphetamines,

II
addiction potential cocaine, methylphenidate

Medical use; moderate

Moderate opioid agonists, Anabolic steroids,
III abuse potential
Phenobarbital, dronabinol, ketamine

Benzodiazepines, Tramadol, chloral hydrate,

Medical use; low abuse mild stimulants (e.g, phentermine,
IV
potential sibutramine), most hypnotics (e.g, zaleplon,
zolpidem), weak opioids
 Routes of Administration

Injecting (rush)
- IV or IM Heroin doesn't
dissolve easily, so users
have to dissolve it in a
spoon with water before
they can inject it.
-Transmission of HIV and
other diseases that can
occur from sharing
needles or other
injection equipment
Snorting/sniff
Smoking Snorters can sniff the
'chasing the dragon'. powder up their nose,
heating up the powder like cocaine users do.
on some foil, and then
inhaling the fumes
through a small tube.
 Opioids Mechanism of action
- The opioid receptors (μ,k,δ,σ) exist in the
CNS & peripherally on organs (GIT,……)
Opioid receptors
- G-protein coupled receptors
Mu Kappa Delta
- Endorphins & Enkephalins (endogenously (m) () ()
produced morphine-like peptides) act on
opioid receptors & give the same actions as
that of opioids.
- Analgesia, euphoriant, respiratory
depressant, and physical dependence
properties of morphine result principally
from actions at μ receptors*****
Opioid receptors
G-protein coupled receptors →  cAMP
 Ca2+ influx (presynaptic) OR
 K+ efflux (postsynaptic)

Hyperpolarization
 Reward Pathway

Pleasure
center
 Heroin Binds to opioid
receptors that inhibit the
inhibitory GABAergic
neurons that project to
dopaminergic neurons
in the VTA

Cannabinoids - (Cocaine)

- -
 Therapeutic Uses of opioids

1. Analgesia: (cancer pain)

2. Treatment of diarrhea: (Lomotil: Diphenoxylate +Atropine)

3. Relief of cough (antitussive):

Codeine and dextromethorphan are used (less addictive) .

4. Treatment of pulmonary edema

associated with Left Ventricular heart failure. It reduces anxiety

and reduced cardiac preload and afterload via VD action.

5. Anesthesia: (especially in CVS surgery)

 Adverse effects of Morphine

1. Severe respiratory depression → death (Most

common cause of Death)
2. Vomiting, constipation, delay labor, itching around
nose & urticaria
3. Histamine-enhanced hypotension, Bronchospasm….
4.  intracranial pressure, particularly in head injury
5. Urinary retention in patients with BPH.
 Tolerance & Dependence to
Morphine

 Physical dependence → Withdrawal symptoms

exaggerated rebound: rhinorrhea, lacrimation, yawning,
chills, hyperventilation, hyperthermia, mydriasis, muscular
aches, vomiting, diarrhea, anxiety, and hostility.

➢ Psychologic Dependence → compulsive use (Addiction)

Administration of an opioid at this time ↓abstinence signs &
symptoms immediately
 Opioid Intoxication

 https://www.youtube.com/watch?v=KxGL2bZyDbk
 https://www.youtube.com/watch?v=Edi3ta0lkAA
 https://www.youtube.com/watch?v=Jis6NlZMV2c
 https://www.youtube.com/watch?v=JviPUbYPlSc
 https://www.youtube.com/watch?v=rJvCo9p5XfY
 Management Opioid
Intoxication
1. Emergency: support Vital data (resp. & CVS)

2. Non-specific therapy:

Prevent Further absorption by vomiting (syrup of

ipecac& G lavage) and cathartics

3. Specific Therapy: (Opioid antagonists)

Naloxone [Narcan]

nalmefene [Revex]
 Naloxone

 short t1/2 (60 -90 min.)

 Initial IV naloxone (0.4mg vial) dosing is approximately 0.8 mg per

70 kg of body weight.

 Signs of improvement—increase in respiratory rate and pupillary

dilation—should occur promptly.

 If there is no response to the initial dosage, naloxone may be

repeated after intervals of a few minutes
In April 2014, FDA approved naloxone pen (Evzio)
Auto-injector (it needs training& has single dose
In 2015, FDA approved Narcan nasal
spray (easy, safe, no contaminated
needles and has Multi-dosing)
 Nalmefene

 a longer duration (t1/2= 10 hours),

 single dose can reversal overdose.

 Initial dose = 0.5 to 1.0 mg.

 Too much naloxone or nalmefene may → opioid
withdrawal symptoms& agitation.
 Advantage of naloxone is that its withdrawal effects—if
they occur—are of relatively shorter than nalmefene-
withdrawal can last for hours
 Opioid Dependence or
Addiction → Withdrawal S

Withdrawal symptoms start 6 -10 hrs after last dose. Peak effects at 36–48 hrs,
Then, gradually subside. By 5 -7 days, most of the effects have disappeared, but
some may persist for months. Craving for it may persist
 Management of Opioid
Withdrawal (Detoxification)
I. symptomatic treatments………

II. α2 Agonists (sympatholytics)

 to ↓ hyperactivity in the locus ceruleus (sympathetic
overactivity). Clonidine and Lofexidine (less hypotension)
 Management of Opioid
Withdrawal (Detoxification)
III. Opioid Agents
 Methadone (full agonist)
 Buprenorphine (partial agonist)
 Methadone

-It is synthetic, oral, equi-analgesic to morphine

-Methadone less euphoria and has longer duration.

The mechanism of action:

mu-opioid receptors agonist .

 Methadone

 effective in suppressing opioid withdrawal S &S

 initial dose: 10 - 20 mg orally. If withdrawal S persist,

repeat the dose after 2 hours.

 Not > 40 mg of methadone during the first 24 hours.

 After 48 hours of dose stabilization, methadone dose can
be gradually reduced (Inpatient: 10% /day or
Outpatient:10 % /week).
 Outcomes from methadone withdrawal are poor & Relapse is common.
 Methadone
Adverse effects: (like morphine)
 Physical dependence like morphine, but has less neurotoxicity
than morphine due to the lack of active metabolites.
 Methadone can prolong QT interval and cause torsades de
pointes, by interacting with K-channels→ drug interactions
 Buprenorphine

Mechanism of action:
-Buprenorphine is a partial mu-opioid (μ ) receptor agonist
Indications:
1-It is a safe and effective for the treatment of opioid withdrawal
2-It is approved for the treatment of pain.
Dosing
➢ initial dose is 0.3 - 0.6 mg IM, 2-3 times per day for 1 to 2 days
➢ Then dose reductions of 25 to 33 % each day over 3 to 5 days.
 Buprenorphine has shorter and less severe
withdrawal symptoms than methadone.

Buprenorphine has
long duration of
action (tight binding
to the μ receptor),
and patients tolerate
a 3- 5 day withdrawal
Routes & Formulations of
Buprenorphine

1. Sublingually,
2. Parenterally,
3. Transdermally
 Routes & Formulations of
Buprenorphine
Sublingual tablets

1. Sublingually,
Buprenorphine (Subutex).
Buprenorphine/Naloxone (Suboxone) ???.

Sublingual tablets

Sublingual strips or Film

 Routes & Formulations of
Buprenorphine

2.Parenterally,
 Routes & Formulations of
Buprenorphine

3. Transdermally
 Maintenance Medications for
Opioid Dependence

Naltrexone (available since 1984), the most

commonly used till Now.
 Naltrexone
It is opioid (mu-receptor) antagonists ????

-Orally

-Depot naltrexone (Vivitrol) one injection per month.

-Naltrexone implants

-A period of 30 to 60 days of naltrexone immediately after

detoxification reduces the probability of relapse to opioid use.
Naltrexone implants
 Indications of Naltrexone

1. Alcohol dependence (reduce

craving and intensity and
frequency of alcohol binges) and

2. Opioid dependence (for those

who wish to remain abstinent from
all opioids →↓ relapse).
Side effects of Naltrexone

1. GIT upset: abdominal pain, nausea, vomiting

2. headache
3. dizziness
4. hepatocellular injury So,
 Contraindicated in acute hepatitis or liver failure.
(check liver function before, q1 month for 3
months, then q 3 months). ALT, AST and bilirubin
 Caution about ibuprofen and other NSAIDs