Opioid analgesics

Abuse
 Terminology

• “opium” is a Greek word meaning “juice,” or

the exudate from the poppy
• “opiate” is a drug extracted from the exudate
of the poppy
• “opioid” is a natural or synthetic drug that
binds to opioid receptors producing agonist
effects
Heroin – Heroin is a derivative of morphine and is the
opioid most commonly abused by injection. The
chemical name for heroin is diacetylmorphine.

Endorphin – The term endorphin refers to a subclass of

opioids consisting of endogenous peptides (ie, peptides
produced by the human body) that cause pain relief,
including enkephalins, dynorphins, and beta-
endorphins.
 History of Opioids

• Opium is extracted from poppy seeds (Paper

somniforum)
• Used for thousands of years to produce:
– Euphoria
– Analgesia
– Sedation
– Relief from diarrhea
– Cough suppression
 What is an Opioid?

• Opioids are drugs derived from or related to the Opium

• Opium is derived from the juice of the opium poppy,
Papaver somniferum
• Opium contains over twenty distinct alkaloids (morphine
was the first alkaloid of opium to be isolated in 1806)
• By the late 19th century use of these “pure” opium
derivatives spread throughout the medical world, however,
the method by which these drugs works was unknown.
PREVALANCE
 CLASSIFICATION OF DRUGS
Natural drugs
• Morphine
• Codeine
Synthetic Drugs
• Fentanyl
• Meperidine
• Tramadol
• Methadone
 Pharmacological Effects

• Sedation and anxiolysis

– Drowsiness and lethargy
– Apathy
– Cognitive impairment
– Sense of tranquility
• Depression of respiration
– Main cause of death from opioid overdose
– Combination of opioids and alcohol is especially dangerous
• Cough suppression
– Opioids suppress the “cough center” in the brain

• Pupillary constriction
– pupillary constriction in the presence of analgesics is characteristic of
opioid use
 Pharmacological effects cont’d.
• Nausea and vomiting
– Stimulation of receptors in an area of the medulla called
the chemoreceptor trigger zone causes nausea and
vomiting
– Unpleasant side effect, but not life threatening
• Gastrointestinal symptoms
– Opioids relieve diarrhea as a result of their direct actions
on the intestines. Decrease GI motility and produce
constipation.
• Other effects
– Opioids can release histamines causing itching or more
severe allergic reactions including bronchoconstriction
– Opioids can affect white blood cell function and immune
function
 MECHANISM OF ADDICTION AND ABUSE
One of the brain circuits that is activated by opioids is the
mesolimbic (midbrain) reward system.

This system generates signals that result in the release of the

chemical dopamine (DA)

This release of DA into the NAc causes feelings of pleasure. Other

areas of the brain create a lasting record or memory that
associates these good feelings with the circumstances and
environment in which they occur.

These memories, called conditioned associations, often lead to the

craving for drugs when the abuser reen-counters those persons,
places, or things, and they drive abusers to seek out more drugs in
spite of many obstacles.
Three Opioid Receptors

• Mu

• Kappa

• Delta
 Delta Receptor

• It is unclear what delta’s responsible for.

• Delta agonists show poor analgesia and little
addictive potential
• May regulate mu receptor activity
 Mu-Receptor: Two Types

• Mu-1 • Mu-2
– Located outside spinal – Located throughout CNS
cord – Responsible for
– Responsible for central respiratory depression,
interpretation of pain spinal analgesia, physical
dependence, and
euphoria
 Kappa Receptor

• Only modest analgesia

• Little or no respiratory depression
• Little or no dependence
• Dysphoric ( feeling of depression and anxiety)
effects
All three opioid receptors are members of the G protein coupled
receptor family and inhibit adenylyl cyclase.

They are also associated with ion channels, increasing

postsynaptic K+ efflux (hyperpolarization) or reducing presynaptic
Ca2+ influx, thus impeding neuronal firing and transmitter release
MORPHINE
Opioids exert their major effects by interacting with opioid
receptors in the CNS and in other anatomic structures, such as the
gastrointestinal tract and the urinary bladder.

Opioids cause hyperpolarization of nerve cells, inhibition of nerve

firing, and presynaptic inhibition of transmitter release. Morphine
acts at mu receptors in Lamina I and II of the dorsal horn of the
spinal cord, and it decreases the release of substance P, which
modulates pain perception in the spinal cord. Morphine also
appears to inhibit the release of many excitatory transmitters from
nerve terminals carrying nociceptive (painful) stimuli
PHARMACOKINETICS
•Absorption of morphine from the gastrointestinal tract is slow and
erratic.

•Significant first-pass metabolism of morphine occurs in the liver;

therefore, intramuscular, subcutaneous, or IV injections produce
the most reliable responses.

•Morphine rapidly enters all body tissues, including the fetuses of

pregnant women, and should not be used for analgesia during
labor
•Morphine is the least lipophilic as compared with the more fat-
soluble opioids, such as fentanyl, methadone, and heroin, which
readily penetrate into the brain.
Morphine is conjugated in the liver to glucuronic acid. Morphine-6-
glucuronide is a very potent analgesic, whereas the conjugate at
position 3 is much less active.

The conjugates are excreted primarily in the urine, with small

quantities appearing in the bile. The duration of action of morphine
is 4 to 6 hours when administered systemically to individuals but
considerably longer when injected epidurally, because its low
lipophilicity prevents redistribution from the epidural space.
Tramadol
It is a centrally acting analgesic that binds to the µ-opioid receptor. In
addition, it weakly inhibits reuptake of norepinephrine and serotonin. It is
used to manage moderate to moderately severe pain.

Its respiratory-depressant activity is less than that of morphine. Naloxone can

only partially reverse the analgesia produced by tramadol or its active
metabolite. Concurrent use with carbamazepine results in increased
metabolism, presumably by induction of the cytochrome P450 2D6 system.

[Note: Quinidine, which inhibits this isozyme, increases levels of tramadol

when taken concurrently. Anaphylactoid reactions have been reported. Of
concern are the seizures that can occur, especially in patients taking selective
serotonin reuptake inhibitors, tricyclic antidepressants, or in overdose.
Tramadol should also be avoided in patients taking monoamine oxidase
inhibitors.
 TREATMENT OF OPIOID ADDICTION

Methadone is a long-acting opioid medication. Unlike morphine,

heroin, oxycodone, and other addictive opioids that remain in the
brain and body for only a short time, methadone has effects that
last for days. Methadone causes dependence, but—because of its
steadier influence on the mu opioid receptors—it produces minimal
tolerance.

Methadone treatment reduces relapse rates, facilitates behavioral

therapy, and enables patients to concentrate on life tasks such as
maintaining relationships and holding jobs.

Patients are generally started on a daily dose of 20 mg to 30 mg,

with increases of 5 mg to 10 mg until a dose of 60 mg to 100 mg per
day is achieved.
Buprenorphine
Buprenorphine’s action on the mu opioid receptors elicits two
different therapeutic responses within the brain cells, depending
on the dose.

At low doses buprenorphine has effects like methadone, but at

high doses it behaves like naltrexone, blocking the receptors so
strongly that it can precipitate withdrawal in highly dependent
patients (that is, those maintained on more than 40 mg
methadone daily).
 Naltrexone
Opioid Antagonist
• PHARMACOKINETICS
*latency to onset (oral tablet 15-30 min.)
*duration of action 24-72 hours
*peak effect (6-12 hours)

• EFFECTS
• *Reverses the psychotomimetic effects of opiate
• agonists.
• * Reverses hypotension and cardiovascular instability
• secondary to endogeneous endorphins (potent
vasodilators)
• *inhibits Mu, Delta, and Kappa receptors.
 Naloxone
Opioid Antagonist
It blocks μ receptors at much lower doses than those needed
to block κ or δ receptors.

Naloxone is the drug of choice for morphine poisoning (0.4–

0.8 mg i.v. every 2–3 min: max 10 mg)

It is also used to treat overdose with other opioids and agonist

(except buprenorphine)
 Withdrawl Reactions
Acute Action
• Analgesia
• Respiratory Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood pressure
• Constipation
• Pupillary constriction
• Hypothermia
• Drying of secretions
• Reduced sex drive
• Flushed and warm skin
Withdrawl Sign
• Pain and irritability
• Hyperventilation
• Dysphoria and depression
• Restlessness and insomnia
• Fearfulness and hostility
• Increased blood pressure
• Diarrhea
• Pupillary dilation
• Hyperthermia
• Lacrimation, runny nose
• Spontaneous ejaculation
• Chilliness and “gooseflesh”