Opiods 2017 spring (1)

OPIOID
ANALGESICS

Pain
• Pain is the most common symptom for which patients see
a doctor.
• TYPES OF PAIN:
Now differentiated into two types of pain based on etiology
NOCICEPTIVE PAIN: Result of activation of sensory receptors
by mechanical, thermal, or chemical stimuli. Functional
,physiologic or normal pain.
NEUROPATHIC PAIN: Pain resulting from damage to
peripheral nervous or central nervous system tissue or from
altered processing of pain in the central nervous system.

Different types of drugs are used for treatment of pain. In
general, they include:
1. Drugs, relieving pain due to multiple causes:
(Analgesics (Painkillers)=Drugs that relieve pain
without loss of consciousness)
‣Narcotic/Opiod Analgesics (morphine, fentanyl, etc):
-------------------- act chiefly in the CNS.
‣Non-Narcotic Analgesics (paracetamol, metamizole):
--------------------- act chiefly peripherally.

2. Drugs relieving pain due to a single cause or
specific pain syndrome only.
They are not classified as analgesics:
• naratriptan (migraine)
• carbamazepine (neuralgias)
• glyceryl trinitrate (angina pectoris)
• adrenal steroids (inflammatory pain)
• butylscopolamine (spasm of visceral smooth muscles)
• baclofen (spasm of striated muscles)

3. Adjuvant drugs:
(anxiolytics, neuroleptics, antidepressants) may
modify the perception of pain and remove the
concomitants of pain such as anxiety, fear,
depression.
4. Anaesthetics (general and local)
are used during surgical operations, some diagnostic,
and other painful procedures.

• OPIOIDS are the most widely used and
effective analgesics for the treatment of
pain and related disorders.
• Opium: – white latex (exudate) obtained
by incision of seed pod of Papaver
somniferum
• Classification:
Opioid Analgesics
-Natural Opium Alkaloids: (morphine,
Codeine)
-Semi-synthetic (Diacetylmorphine
(Heroin)
-Synthetic (Pethidine, fentanyl)

Opioid Analgesics
Natural or synthetic compounds producing morphine
like actions.
Bind to specific opioid receptors.
Mimic the actions of endogenous opioids.
Relieve pain due to surgery or injury.
Their widespread use has led to abuse (euphoria).
Antagonists available.

Opioid Receptors
Effects
(mu)(for morphine)
(delta)
(kappa)
ORL1 (opioid receptor like-1)
Subtypes: μ1, μ2, κ1, κ2, κ3, δ1 and δ2
• All four receptors are G-protein coupled and activate
inhibitory G proteins.
• Located in peripheral nerve endings
• Opioids are – agonists, partial agonist or competitive
antagonists of these receptors
• Overall effect depends on nature of interaction and affinity to
these
• Morphine is agonist of all, but affinity is higher for mu

EFFECT OF DIFFERENT OPIOID
RECEPTOR STIMULATION

Endogenous opioid peptides
• They are dynorphins, enkephalins, endorphins,
endomorphins and nociceptin.
• There are endogenous analgesic substances with peptide
structure and morphine-like action.
• They are called endogenous peptides and were discovered
during the investigation of the mechanism of analgesic action
of morphine.
• They are neurohormones that act as neurotransmitters by
binding to one or more G protein-coupled opioid receptors
and thus relieving pain.
• Endogenous opioid peptides are found in the CNS and
peripheral tissues. They are termed “the brain’s own
morphine”.
• Released during stress and pain anticipation

Opioid receptor intracellular mechanism
• All opioid receptors are
coupled to inhibitory G-
proteins to inhibit adenylate
cyclase activity.
• Activates receptor-activated K +
currents which increase K + efflux
(cause hyperpolarization).
• Reduces voltage-gated Ca 2+
entry.
• Hyperpolarization of membrane
potential by K + currents and
inhibition of Ca 2+ influx prevents
neurotransmitter release and
pain transmission in varying
neuronal pathways.

Pure Opioid Agonists
Pure opioids agonists are subdivided into:
Strong agonists e.g. morphine
Moderate to strong agonists e.g. codeine
A- Natural Derivatives:
Morphine and related opioids produce their major
effects on the CNS and the GIT.
•Morphine:
It is the prototype of strong opioid analgesics and
has multiple pharmacologic effects. With prolonged
use, it produces tolerance and physical
dependence.

• Morphine mechanism of action:
• mimic the action of endogenous opioid peptides on
µ receptors.
• Morphine acts on 1
- receptors (analgesia, euphoria)
and 2
-receptors (respiratory depression and reduced gut
motility).
• It causes analgesia without loss of consciousness,
because it increases the pain threshold at the spinal cord
level and alters the perception of pain by the brain.
• The ability of morphine to cause mental clouding,
sedation, euphoria and anxiety reduction can contribute to
relief of pain.

Actions (CNS effects)
• Analgesia
– No loss of consciousness
– Raises the pain threshold
– Alter brain perception of pain
• Euphoria
– Stimulation of VTA
• Sedation
– Little or no amnesia
– More in elderly
– Deep sleep when combined with other CNS
depressants
• Respiration
– Respiratory depression
– Reduces sensitivity to CO 2
– Cause of acute death in opioid overdose

Actions (Cont.)
• Depression of cough reflex
– Antitussive
– Not related to analgesia
– May lead to accumulation of secretions and
airway obstruction
• Miosis
– Pinpoint pupil
• Emesis
– CTZ

• GIT
Actions (Cont) peripheral
– Relieves diarrhea
– Decreasing the propulsive motility of intestines
• Allowing absorption of water to fecal matter
– Increases the tone of anal sphincter
• Cardiovascular
– In large doses
• Hypotension (histamine release)

Actions (Cont)
• Histamine release
– Avoid in asthmatics
• Hormonal actions
– Inhibits
• GnRH, CRH
• LH
• ACTH
• Testosterone
• Cortisol
– Increases
• Prolactin
• GH
• ADH (urine retention that may require catheter)

1. Chronic pain:
Therapeutic indications:
• Chronic pain arising from terminal illness can
be relieved by opioid drugs.
2. Acute pain: postoperative pain, diagnostic
procedures, orthopedic manipulations and
myocardial infarction.
3. Preanaesthetic medication

Therapeutic Uses
Analgesia
Diarrhea
Cough
relief (no
longer
used)
Acute
Pulmonary
edema

Morphine undesired side effects
Respiratory depression:
• most serious adverse effect
• by activation of mu receptors but κ receptors also
contribute.
• is increased with drugs with CNS-depressant actions (alcohol,
barbiturates, benzodiazepines).
• With prolonged use, tolerance develops to respiratory
depression, whether in addicts or during long-term clinical use
in malignant patients.
• Morphine causes depression of respiration by reducing
sensitivity of the respiratory center to the rise in blood
CO 2
.
• Morphine is dangerous when the respiratory drive is impaired
by diseases as in COPD or asthma (causes bronchospasm and
aggravates attacks as it can cause histamine release from mast
cells).

• Constipation: morphine reduces the propulsive peristaltic
movement and inhibits secretion of fluids into the intestinal
lumen (sometimes used in management of diarrhea).
• Biliary colic: has a spasmogenic effect on the biliary tract.
• Miosis: stimulation of the 3 rd cranial nerve (pin-point pupil).
• Urinary retention: * increases tone in the sphincter of the
bladder, *suppresses awareness by bladder stimuli and
• stimulates the release of anti-diuretic hormone (ADH).
• Emesis: stimulates CTZ in medulla.
• Orthostatic hypotension: dilates peripheral arterioles and
veins (histamine release) and blunt baroreceptors reflex
(centrally).
• Allergic reactions: caused by histamine liberation from
mast cells.

• Morphine Contraindications:
1. Children, elderly
2. Prostate hypertrophy
3. Biliary colic
4. Head injury
5. Reduced blood volume
6. Hepatic insufficiency
7. Convulsant states
8. Pregnancy (birth defects)
9. during labor (suppresses uterine contraction
and causes respiratory depression in neonates).

Acute toxicity:
Morphine Toxicity
‣Symptoms: profound coma, depressed
respiration, cyanosis, low blood pressure, pin
point pupils, decreased urine formation, low
body temperature and flaccid muscles.
‣Treatment:
• Ventilation
• Naloxone (morphine antagonist) will reverse
toxic signs
• Naltrexone has a longer duration of action

Chronic toxicity
• Tolerance is a diminished responsiveness to
the drug’s action
• Tolerance can be demonstrated by a
decreased effect from a constant dose of drug
or by an increase in the minimum drug dose
required to produce a given level of effect

Tolerance is not shown equally on all effects.
Tolerance extends to:
analgesia
euphoria
To much lesser extent on:
respiratory depression
constipation
pupil constriction

Takes two forms :
DEPENDENCE
physical
psychological
• Physiological dependence occurs when the
drug is necessary for normal physiological
functioning – this is demonstrated by the
withdrawal reactions
• Withdrawal reactions are usually the opposite
of the physiological effects produced by the
drug

Withdrawal 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
Withdrawal 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”

Psychological dependence
Problems are:
- Desire for the drug
- Want to experience the “rush” – positive
- Don’t want the withdrawal – negative
- Some opioids, e.g. codeine & pentazocine, are
much less likely to cause dependence

Why does dependence occur?
• It could be explained by suppression of release of
endogenous enkephalins and endorphins. It has been also
suggested that chronic exposure to opioids leads to
adaptive changes in the endogenous opioid system, with
changes in the receptor number, sensitivity and cellular
response.
• withdrawal of opiates is unpleasant but rarely
dangerous.
• To minimize symptoms of abstinence syndrome,
opioids should be withdrawn gradually and
substituted by a less potent drug as methadone,
then gradually withdrawing methadone.

Drug interactions:
• CNS depressants (intensify respiratory
depression)
• Anti-cholinergics (exacerbate constipation and
urinary retention)
• Agonist-antagonist opioids or opioid antagonists
(precipitate abstinence syndrome)
• Antihypertensive drugs (exacerbate hypotension)

Moderate agonists
Codeine
– Much less potent analgesic
– It is orally administered and acts by binding to
the -receptors
– More antitussive
– Lower potential for abuse
– Less euphoria
– In combination with acetaminophen or aspirin
in cough preparations
– Replaced by dextromethorphan, synthetic
cough suppressant, no analgesia and low
potential for abuse

B- Semi-Synthetic Derivatives:
1-Heroin
(diacetylmorphine)
Similar action to morphine
More active than morphine
More lipid soluble – crosses BBB faster to give
greater rush
Shorter duration of action than morphine

2-Apomorphine:
• It is a derivative of morphine, however its
pharmacologic effects results from activation
of dopamine receptors in CTZ.
• It is used to induce emesis in cases of toxicity.

C- Synthetic Derivatives:
Pethidine
• (Meperidine – USAN; Lydol ® – Sopharma)
Almost identical to morphine
Tends to cause restlessness rather than sedation
Antimuscarinic effects: dry mouth
blurred vision
Less antitussive
Shorter duration of action (4-6 h) –
preferred in labour

• It has less analgesic action than morphine and
has a shorter duration of action (dosing must
be repeated at short intervals).
• However, repeated administration (> 48 h)
results in accumulation of normeperidine, a
toxic metabolite that can cause dysphoria,
irritability, tremors and seizures.
• Tolerance and addiction is less severe than
morphine, therefore, it can be used as
analgesic in labor (does not depress
respiration in new-born) and as a preanesthetic
medication.

Fentanyl
>80 times more potent than morphine in analgesia
Actions similar to morphine
Main use is in anaesthesia, used in conjunction with
droperidol, a neuroleptic, producing
neuroleptanalgesia
Durogesic ® (Fentanyl):
TTS/72 h

Neuroleptanalgesia
• combining a major neuroleptic tranquilizer
/antipsychotic (typically the potent D2 receptor
antagonist droperidol) and the potent opioid
analgesic fentanyl to produce a detached, painfree
state.
• Anxiety, motor activity, and sensitivity to painful
stimuli are reduced; the person is quiet and
indifferent to surroundings and is able to
respond to commands.

Methadone
Similar actions to morphine
Longer duration of action
(t 1/2 37 h)
Less problems with withdrawal
Can be used to wean heroin and morphine addicts
off the drug

Dextropropoxyphene
• (t 1/2
5 h) is structurally similar to methadone and
differs in that it is less analgesic and less
dependence producing. Its weak μ/κ/δ-agonist
• Analgesics usefulness approximates to that of
codeine, but its duration of action is longer.

Tramadol
• Tramadol provides moderate pain relief. Because of its
dual actions as a µ-agonist and monoamine transport
inhibitor, it produces less respiratory depression for a
given analgesic effect.
• It is a weak agonist at µ-receptors. Its major metabolites
are more potent agonists at µ-receptors.
• It inhibits monoamine transporters (NA and 5-HT)
which is thought to produce analgesia synergistically with
µ-agonism.
•

• It is used for post-operative pain and for
moderate chronic pain.
• It is less likely than morphine to cause
constipation, depress respiration or cause
dependence.

Other opioid agonists
Diphenoxylate (available only with atropine
in Lomotil ® ).
– lacks usual opiate effects except for very strong
inhibition of gastric motility, so very useful for
diarrhea; acute (as in food poisoning) or chronic
(as in ulcerative colitis)
– High doses may produce more typical opioid
effects;
Loperamide (Imodium ® ) is similar to
diphenoxylate but has poor GI absorption and
poor BBB crossing. Both these properties are
suitable for its anti-diarrheal effect.

Mixed Agonist-Antagonist
• Stimulate one receptor but block another
• In naive patients, they display agonistic activity
• In opioid-dependent patients, they are blockers
and can cause withdrawal
Pentazocine
– Agonist at κ “may be reason for dysphoria”
– Weak antagonist at µδ
– Relieve moderate pain at the spinal cord level
– Less euphoria
– High doses
• Respiratory depression
• Increase blood pressure
• Decrease GI activity

OPIOID COMPETITIVE ANTAGONISTS
• Naloxone (μ, κ and δ-antagonist)
• Naltrexone (μ, κ and δ-antagonist)
• Nalorphine (Allylnormorphine) – μ-antagonist/κagonist)

Naloxone
– Competitive blocker at µ,δ,κ, with a 10 fold affinity
to µ.
– treat opioid toxicity and in reversal of
postoperative opioid effects.
– Reverse coma and respiratory depression.
– Rapidly displaces all opioid bound molecules.
– Naloxone reverses respiratory depression>
analgesia.
– Short t 1/2 (relapse is possible).
– Precipitates withdrawal in dependent patients.
Naltrexone
– Longer t 1/2
– Chronic alcoholism treatment
– Hepatotoxic
– Can be used orally

• By the blockade of opioid receptors, it reversibly
blocks or attenuates the effects of opioids.
• Its mechanism of action in alcohol dependence is not
fully understood, but as an opioid receptor antagonist
is likely to be due to the modulation of the
dopaminergic mesolimbic pathway "pleasure
center” which is hypothesized to be a major center of
the reward associated with addiction that all major
drugs of abuse are believed to activate.
• Mechanism of action may be antagonism to
endogenous opiates such as tetrahydropapaveroline,
whose production is augmented in the presence of
alcohol.