PHARMACOLOGY OF OPIOIDS

Maher Khdour, MSc. PhD

Clinical Pharmacy
 SOME DEFINITIONS
 “OPIOID”: drug with morphine-like effects

 The naturally occurring opioids in opium

are morphine and codeine.

 MORPHINE is the prototype opioid.

SOME DEFINITIONS
 “Narcotic”: (Gr. “to make numb”)
common synonym for opioids, but not
accurate

 Analgesia: specific reduction in pain

perception without affecting other
sensory modalities
 EXCERPTS FROM JAMA EDITORIAL, 1998
 “Undertreatment of pain is a persistent medical
problem. A leading indicator of inadequate pain
management is the poor control of cancer pain.
Cancer pain is feared by patients, their families
and the general public”

 “The optimal management of pain requires

aggressive use of controlled substances,
potentially raising fears of regulatory scrutiny or
the disapproval of professional colleagues.”
 Pain Transmission Gate Theory
 Describes how impulses from damaged
tissues are sensed in the brain
 Pain fibers enter the spinal cord at the
DORSAL HORN and travel up to the
brain.
 The DORSAL HORN is the location
of the “GATE
 Pain Transmission
 This gate regulates the flow of sensory
impulses to the brain.
 Closing the gate stops the impulses.
 If no impulses are transmitted to higher
centers in the brain, there is NO pain
perception.
Pain Transmission
Tissue injury causes the release of:
 Bradykinin.
 Histamine.
 Potassium.
 Prostaglandins.
 Serotonin.
These substances stimulate nerve endings,
starting the pain process.
 Pain Transmission
 Body has endogenous neurotransmitters
 Enkephalins
 Endorphins
 Produced by body to fight pain
 Bind to opioid receptors
 Inhibit transmission of pain by closing gate
 Nociceptive pain is pain detected in either the
body's soft tissues (such as muscles and skin)
or organs by specialized sensory nerves,
known as nociceptors.
 Nociceptors detect painful stimuli, sending
information to the spinal cord and brain for
interpretation and response
 Neuropathic pain is the result of an injury or
malfunction in the peripheral or central nervous
system
 (widespread nerve damage). Among the many
causes of peripheral neuropathy, diabetes is the
most common, but the condition can also be
caused by chronic alcohol use, exposure to other
toxins (including many chemotherapies), vitamin
deficiencies
 KEY CONCEPTS ON NEUROPATHIC
(NEUROGENIC) PAIN
 Neuropathic pain may develop after an injury to
nerve fibers, but somatic injury has healed.

 Injured nociceptive fibers are hyperexcitable and

discharge spontaneously.
 KEY CONCEPTS ON NEUROPATHIC
(NEUROGENIC) PAIN
 Pain is “burning”, “tingling”, “pins and needles”,
“electric”.

 Periodic lancinating stabs

 Allodynia: severe pain elicited by innocuous

stimuli, e.g., touch
 Opioid Analgesics:
Mechanism of Action
 Bind to receptors on inhibitory fibers,
stimulating them
 Prevent stimulation of the GATE
 Prevent pain impulse transmission
to the brain
Actions of Opioid Receptors
Response Mu Kappa
Analgesia  
Respiratory 
Depression
Sedation  
Euphoria 
Physical Dependence 
 GI motility  
 PHARMACOLOGICAL ACTIONS
OF OPIOID AGONISTS: CNS

 Analgesia: Reduction in pain perception w/o

affecting other sensory modalities
 Decreased pain perception

 Decreased emotional response

 Indicated for moderate to severe intensity pain

 Not very effective for neuropathic pain
OTHER CNS ACTIONS OF OPIOIDS
 Respiratory depression
 Suppression of cough
 Pupillary mioisis: pinpoint pupils
 Nausea and vomiting
 Euphoria or dysphoria [feeling unwell]
 Sedation and drowsiness
 Seizures
 ACTIONS OF OPIOID AGONISTS:
PERIPHERY
 GI tract: constipation

 Skin: urticaria from histamine release

 Urinary tract: urinary urgency and

retention
 Opioid Effects: Degree of Tolerance
Developed
High Intermediate Limited/None
analgesia bradycardia miosis
euphoria,
constipation
dysphoria
mental clouding convulsions
sedation antagonist actions
respiratory
depression
antidiuresis
nausea/vomiting
cough suppression
Opioid Analgesics: Therapeutic Uses
 Main use: to alleviate moderate to
severe pain from surgery, injury or
disease

 Opioids are also used for:

 Cough center suppression

 Treatment of diarrhea
 Opioid Analgesics
Three classifications based on their actions:
 Agonist

Strong agonists
 Morphine sulfate

 Meperidine HCl (Demerol)

 Methadone HCl (Dolophine)

 Fentanyl, Sufentanil

Moderate agonists
 Codeine sulfate
 Opioid Analgesics
 Mixed agonist-antagonist
 Buprenorphine

 Pentazocine

 Antagonists
 Naloxone

 Naltrexone
 Opioid Analgesics
Combinations
Codeine/acetaminophen
Codeine/aspirin
Propoxyphene/aspirin !!!!!???
Codone/acetaminophen
Oxycodone/aspirin
Antitussives
Codeine
Dextromethorphan
Morphine
Opioid Analgesics: Strong Agonists
• Morphine
• Hydromorphone (Dilaudid)
• Oxymorphone (Numorphan)
• Heroin -- not available in United States

management of severe pain

Morphine
• Analgesia
- Raise pain threshold at spinal cord
- Altering the brain’s perception of pain
- Aware of pain but not unpleasant
• Euphoria
- Powerful sense of contentment and well being
• Respiratory Depression:
- cause of death in overdose
Morphine
Depression of Cough reflex
• Cough suppression does not correlate with

analgesic effect (different receptors)

Miosis:
• pinpoint pupils, characteristic of morphine use

• Little tolerance to this effect

• Important diagnostically, most other causes of

coma and respiratory depression produce

dilation of pupils
Morphine
Emesis:
• causes vomiting, not unpleasant

GI Tract:
• stimulate constipation, little tolerance

develops
Histamine Release:
• can cause bronchoconstriction, do not give to

asthmatics
Hormonal action:
 antidiuretic hormone, urinary retension
Morphine PK
 Administration:
 IV, IM, or SubQ.
 Not given orally, poor absorption, high 1 st pass.
 Distribution.
 Enters all tissues.
 Do not use for labor.
 Infants of addicted mothers are addicted.
 Small percentage crosses BBB.
 Least lipophilic of common opioids.
 Metabolism: glucuronidation then urine
 Meperidine: (Demerol)
• Synthetic opioid, used for any type of acute severe
pain
• Significant anticholinergic (antimuscarinic) effects:
se peripheral vascular resistance and  peripheral
blood flow, heart rate, pupils dilate (unlike
morphine)
• Contraindicated in the presence of underlying
tachycardia
• Dilates cerebral vessels and CSF pressure
• Risk of seizures: due to accumulation of CNS active
metabolite, normeperidine
Meperidine Pharmacokinetics
 available orally
 Most often administered IM

 2-4 hour Duration

 N-demethylation and excrete in Urine

 Preferred analgesia during labor

Adverse Events:
 Mostly anti-cholinergic; severe hypotension

possible
 Causes dependence, addiction, & cross tolerance
 Methadone:
Pharmacodynamics
• similar to morphine, longer acting, less euphoria
• reliable following oral administration
• compared to morphine, methadone tolerance and
physical dependence develops more slowly
• following abrupt methadone discontinuation--
withdrawal symptoms less severe than with
morphine
• Useful drug for detoxification in maintenance of
chronic, heroin addict
Fentanyl Group
 Fentanyl (Sublimaze®)
 Sufentanil (Sufenta®)
 Alfentanil (Alfenta®),
 Remifentanil (Ultiva®)
 differences: biodisposition, potency

o Fentanyl: 80 times the analgesic potency of

morphine: used in anesthesis
o Rapid onset (5 minute), short duration (45 minutes)
o Available as Transdermal Patches
 Fentanyl Group
 Sufentanil (Sufenta®): 5-7 times more potent
than fentanyl
 Alfentanil (Alfenta®)
 less potent than Fentanyl more rapid acting

 shorter duration of action

Mild/Moderate Agonists
o Codeine, Oxycodone, or Hydrocodone
 Less efficacious than morphine or have
limiting adverse effects
 Formulations: combination with aspirin or
acetaminophen
 THE MODERATE/INTERMEDIATE
OPIOIDS ( for mild-moderate pain)
 Codeine, hydrocodone and oxycodone

 These agents are commonly used in

combinations with aspirin or acetaminophen
 (Tylenol with codeine)
 (Percocet: oxycodone plus acetaminophen)
 (Percodan: oxycodone plus aspirin)
 (Hydrocodone plus acetaminophen)

 FDA Warning: May be habit forming

Opioids Equivalence to oral
morphine 30 mg:

Morphine 30 mg

Codeine 200 mg

Oxycodone 20 mg

Hydromorphone 6 mg

Meperidine 300 mg
 Mixed Agonist-antagonists
 Nalbuphine
 Kappa (k) agonist; Mu (m) antagonist
 parenteral administration
 possibly less respiratory depression than
with morphine
 when respiratory depression occurs: may
be more difficult to reverse with naloxone
Buprenorphine
 long acting, potent
 partial Mu (m) agonist
 slowed association for receptor =
relative naloxone-reversal resistant
Management of Diarrhea
• Diphenoxylate; (Lomotil®)
 Used in combination with atropine
 Limited abuse potential
• Loperamide (Imodium®)
 Management of diarrhea
 Limited abuse potential
Antitussives
Most commonly used opioid antitussives
are:
o Dextromethorphan
 essentially free of analgesic/addictive
properties
 less constipation compared to codeine
o Codeine
 IMPORTANT DRUG INTERACTIONS
WITH OPIOIDS
 CNS depression can be enhanced by other CNS-
depressant drugs.

 Meperidine (Demerol) is contraindicated with

MAO inhibitor antidepressants.
Opioid Antagonists: Naloxone
Naltrexone,

Naloxone:
 Injectable: short duration of action
(1-2 hours)
 Metabolism: glucuronide-conjugation
 Poor Efficacy after Oral administration
 Naltrexone
 Oral route of administration: well
absorbed
 Rapid first pass metabolism
 Half-life: 10 hours
 single, oral dose of 100 mg:  blocked
injected heroin effects for 48 hours
 Clinical Use of pure antagonist
o Naloxone
- management of acute opioid overdosage

 note short duration of action (coma relapse

possible within 1-2 hours; repetitive dosing

may be needed)
o Naltrexone

o suggested for drug "maintenance" for addicts in

treatment
o may be useful in management of alcoholism;
purported to reduce alcohol craving; 
Antagonists Pharmacodynamics
 No effect in the absence of agonist
 IV administration: rapid opioid effect reversal
(1-3 minutes)
 In a patient with acute opioid overdosage,
pure opioid antagonists will normalize:
o Respiration
o level of consciousness
o pupil size
o gastrointestinal motility
 Opioid Antagonists
• In an opioid-dependent patient, taking
opioids, pure opioid antagonists will
 precipitate an immediate withdrawal
(abstinence syndrome)
• No tolerance develops to opioid
antagonists
 Actions at Opioid Receptors
Drugs Mu Kappa
Pure Agonists Agonist Agonist
-morphine, codeine, meperidine (Demerol®),
fentanyl (Sublimaze®), remifentanil (Ultiva®),
propoxyphene (Darvon®), hydrocodone (Vicodin®),
oxycodone (Percocet®)
Agonist-Antagonist Antagonist Agonist
-nalbuphine (Nubaine®), butorphanol (Stadol®)
Pure Antagonist Antagonist Antagonist
-naloxone (Narcan®)
 OTHER OPIOIDS
 Tramadol (Tramadex®, Tramal®)
 Mu () weak agonist
 NE reuptak inhibitor and serotonin release
 Habit forming (high incidence reported in
Palestine)
Incidence of addiction from
long term Rx w/opioids
 4 out of 11,882 cancer patients

 0 out of 10,000 burn patients

 3 out of 2369 headache patients

 0 out of 36 back pain patients

THE BOTTOM LINE
 Opioids have the potential for abuse,
but the actual incidence of abuse
among pain patients is very low.
 “Addiction rarely occurs among those who
use pain relievers as prescribed; the risk of
addiction exists when these meds are used
in ways other than prescribed.”
NIDA Position Statement 2001
 THE STRONG OPIOIDS
(for moderate to severe pain)
 Short duration of action:
 morphine: ~ 4-6 hr

 meperidine (Demerol®) : ~ 2-3 hr

 In anesthesia:
 fentanyl (Innovar®) and related

 Long duration of action:

 methadone (Dolophine®): ~ 10-15 hr
 Opioids and Cancer Pain
 pain is common, chronic pain is a major problem
 Opioids widely used for acute post-op pain control
and management of cancer pain
 33% cancer patients in active therapy suffer pain
 >70% patients with advanced cancer suffer pain
 >80% cancer pain patients express major fear as
dying in pain
 cancer pain management is inadequate
 Pain, Pain States and Pain
Management
 Inflammatory - NSAIDs, steroids
 Post-surgical - opioids, NSAIDs
 Neuropathic - anticonvulsants
 Cancer - opioids plus adjuvants
 Headache - 5-HT agonists 1d
 Opioid Analgesics: Implications
 Before beginning therapy, perform a
thorough history regarding allergies, use
of other medications,health history, and
medical history.
 Obtain baseline vital signs.
 Assess for potential contraindications and
drug interactions.
 Opioid Analgesics: Implications
 Perform a thorough pain assessment,
including nature and type of pain,
precipitating and relieving factors,
remedies, and other pain treatments.
 Opioid Analgesics: Implications
 Be sure to medicate patients before the
pain becomes severe as to provide
adequate analgesia and pain control.

 Pain management includes pharmacologic

and nonpharmacologic approaches. Be
sure to include other interventions as
indicated.
Opioid Analgesics: Implications
 Oral forms should be taken with food to
minimize gastric upset.
 Ensure safety measures, such as
keeping side rails up, to prevent injury.
 Withhold dose if there is a decline in the
patient’s condition or if VS are abnormal
—especially if respiratory rate is below
12 breaths/minute.
 Opioid Analgesics: Implications
 Follow proper administration guidelines for
IM injections, including site rotation.
 Follow proper guidelines for IV
administration, including dilution, rate of
administration, and so forth.

CHECK DOSAGES CAREFULLY

 Opioid Analgesics: Implications
 Constipation is a common side effect and
may be prevented with adequate fluid and
fiber intake.
 Instruct patients to follow directions for
administration carefully, and to keep a
record of their pain experience and
response to treatments.
 Patients should be instructed to change
positions slowly to prevent possible
orthostatic hypotension.
 Opioid Analgesics: Implications
 Patients should not take other medications
or OTC preparations without checking
with their physician.
 Instruct patients to notify physician for
signs of allergic reaction or adverse
effects.
 Opioid Analgesics: Implications
Monitor for side effects:
 Respiratory depression may be manifested
by respiratory rate of less than 12/min,
dyspnea, diminished breath sounds, or
shallow breathing.
 Opioid Analgesics: Implications
Monitor for therapeutic effects:
 Decreased complaints of pain
 Increased periods of comfort
 With improved activities of daily living, appetite,
and sense of well-being