By
Bohlooli S. PhD
School of Medicine, Ardabil University of Medical Sciences
Introduction
 Opium poppy is the source of crude opium
 Sertürner in 1803 isolated morphine
 Naming it after Morpheus, the Greek god of
dreams
 Opioid analgesics is a widely used term for:
 Natural, semi-synthetic, synthetic
 Endogenous peptides
Source
 Opium, the source of morphine, is obtained from the
poppy, Papaver somniferum and P album
 Opium contains many alkaloids, the principle one being
morphine, which is present in a concentration of about
10%
Classification & Chemistry
 Opioid drugs include:
 Full agonists

Morphine
 Partial agonists

Codeine
 Antagonists

Naloxone
Chemical structure
Chemistry
 Phenanthrenes
 Morphine, hydromorphone, and oxymorphone
 Codeine,oxycodone, dihydrocodeine, and hydrocodone
 Phenylheptylamines
 Methadone
 Propoxyphene
 Phenylpiperidines
 Fentanyl, sufentanil, alfentanil, and remifentanil
 Diphenoxylate and its metabolite, difenoxin
 Loperamide
 Morphinans
Chemistry; Opioids with Mixed Receptor Actions
 Phenanthrenes
 Nalbuphine , Buprenorphine
 Morphinans
 Butorphanol
 Benzomorphans
 Pentazocine
 Miscellaneous
 Tramadol, Tapentadol
Opioid Receptor Subtypes, Their Functions, and Their
Endogenous Peptide Affinities
Receptor
Subtype
Functions
Endogenous Opioid Peptide Affinity
 (mu)
Supraspinal and spinal analgesia;
sedation; inhibition of respiration;
slowed gastrointestinal transit;
modulation of hormone and
neurotransmitter release
Endorphins > enkephalins > dynorphins
 (delta)
Supraspinal and spinal analgesia;
modulation of hormone and
neurotransmitter release
Enkephalins > endorphins and dynorphins
 (kappa)
Supraspinal and spinal analgesia;
psychotomimetic effects; slowed
gastrointestinal transit
Dynorphins > > endorphins and enkephalins
Endogenous Opioid Peptides
 Endorphins
 Drived from: prepro-opiomelanocortin
 Enkephalins
 met-enkephalin
 leu-enkephalin
 Drived from: preproenkephalin
 Dynorphins
 Drived from: preprodynorphin
 Endomorphins
 Nociceptin / Orphanin FQ
 Orphanin opioid-receptor-like subtype 1 (ORL1)
Pharmacokinetics
Generic Name
Receptor
Effects1

Morphine2
Approximately
Equivalent Dose
(mg)
Oral:Parenteral
Potency Ratio
Duration of Maximum
Analgesia
Efficacy
(hours)
 
+++
+ 10
Low
4–5
High
Hydromorphone +++
1.5
Low
4–5
High
Oxymorphone
+++
1.5
Low
3–4
High
Methadone
+++
10
High
4–6
High
Meperidine
+++
60–100
Medium
2–4
High
Fentanyl
+++
0.1
Low
1–1.5
High
Sufentanil
+++ + + 0.02
Parenteral only
1–1.5
High
Alfentanil
+++
Titrated
Parenteral only
0.25–0.75
High
Remifentanil
+++
Titrated3
Parenteral only
0.054
High
Pharmacokinetics
Generic Name Receptor
Effects1


Approximately
Oral:Parenteral
Equivalent Dose Potency Ratio
(mg)
Duration of Maximum
Analgesia
Efficacy
(hours)

Levorphanol
+++
2–3
High
4–5
High
Codeine
±
30–60
High
3–4
Low
Hydrocodone5 ±
5–10
Medium
4–6
Moderate
Oxycodone2,6 ±
4.57
Medium
3–4
Moderate
Propoxyphene (+,
very
weak)
60–1207
Oral only
4–5
Very low
Pentazocine
±
+
30–507
Medium
3–4
Moderate
Nalbuphine
––
++
10
Parenteral only
3–6
High
0.3
Low
4–8
High
Parenteral only
3–4
High
Buprenorphine ±
Butorphanol
±
–– ––
+++ 2
Pharmacokinetics
 Absorption
 Distribution
 Metabolism
 Excretion
Absorption
 Well absorbed
 Variable first-pass metabolism
 Subcutaneous, intramuscular, and oral routes- other
routes:
 Nasal insufflation
 Oral mucosa via lozenges
 Transdermal patches
Metabolism
 Converted to polar metabolites
 Morphine
 morphine-3-glucuronide ::neuroexcitatory
 morphine-6-glucuronide ::potency four to six times
 Accumulation can produce unexpected results
 Hydromorphone like morphine
 H3G has CNS excitatory properties
 Esters (eg, heroin, remifentanil) are rapidly hydrolyzed
 Hepatic oxidative metabolism for phenylpiperidine opioids
meperidine, fentanyl, alfentanil, sufentanil
 Normeperidine cause seizures in renal failure

 Polymorphism of CYP2D6

Codeine :: no significant analgesic effect or an exaggerated response
Mechanism of Action
Receptor Types
 Based on pharmacologic criteria
  1,  2
 1, 2
  1,  2,  3
 Genetically one subtype from each of the ,  and 
receptor families
Cellular Actions
 Closing voltage-gated Ca2+ channels on presynaptic
nerve terminals
 Inhibit release of

Glutamate, acetylcholine, norepinephrine, serotonin, and
substance P
 Hyperpolarizing and thus inhibiting postsynaptic
neurons by opening K+ channels
Relation of Physiologic Effects to
Receptor Type
 Opioid analgesics act primarily at the  -opioid
receptor
 Analgesia, euphoria, respiratory depression, and
physical dependence
 Butorphanol and nalbuphine
 Preference for  opioid receptors
 Greater analgesia in women
Receptor Distribution and
Neural Mechanisms of
Analgesia: Transmission
Receptor Distribution and
Neural Mechanisms of
Analgesia: Modulation
Ion Channels & Novel Analgesic Targets:
chronic Pain
 Capsaicin receptor, TRPV1 and TRPA1
 P2X : purines receptor
 Tetrodotoxin-resistant voltage-gated sodium channel (Nav1.8)-PN3/SNS
channel
 Lidocaine and mexiletine
 Ziconotide, a blocker of voltage-gated N-type calcium channels
 Related to marine snail toxin -conotoxin
 Gabapentin/Pregabalin : analogs of GABA
 Ketamine: NMDA antagonists
 Nicotine
  9-tetrahydrocannabinol
Tolerance and Physical Dependence
 Tolerance
 Physical dependence
 Withdrawal or abstinence syndrome
 Mechanism
 receptor recycling
 receptor uncoupling
Organ System Effects of Morphine
 Uterus
 Central Nervous System




Effects
Cardiovascular System
Gastrointestinal Tract
Biliary Tract
Renal
 Neuroendocrine
 Pruritus
Central Nervous System Effects
Degrees of Tolerance that May Develop to Some of the Effects of the Opioids.
High
Moderate
Minimal or None
Analgesia
Bradycardia
Miosis
Euphoria, dysphoria
Constipation
Mental clouding
Convulsions
Sedation
Respiratory depression
Antidiuresis
Nausea and vomiting
Cough suppression
Central Nervous System Effects
 Analgesia
 Sensory
 Affective (emotional)
 Nonsteroidal anti-inflammatory analgesic drugs

Has no effect on emotional part
 Euphoria
 Pleasant floating sensation
 Lessened anxiety and distress
 Dysphoria may occure
 Sedation




are common effects
no amnesia
Sleep is in the elderly
Occurs more frequently phenanthrene derivatives
Central Nervous System Effects
 Respiratory Depression
 Significant respiratory depression
 Sepressed response to a carbon dioxide challenge
 Influenced significantly by the degree of sensory input
 Most difficult clinical challenges
 Cough Suppression
 Codeine
 May allow accumulation of secretions
 Miosis
 Mediated by parasympathetic pathways
 Truncal Rigidity
 Intensification of tone in the large trunk muscles
 Nausea and Vomiting
 Activate the brainstem chemoreceptor trigger zone
 Temperature
 -opioid receptor agonists  hyperthermia
  -opioid receptor agonists  hypothermia
Cardiovascular System
 Bradycardia
 Meperidine antimuscarinic action  tachycardia
 Hypotension may occur
 Peripheral arterial and venous dilation


Release of histamine
Central depression of vasomotor-stabilizing mechanisms
 Caution in patients with decreased blood volume
Gastrointestinal Tract
 Constipation
 the stomach
 Motility decrease
 Tone increase
 Gastric secretion of hydrochloric acid is decreased
 Biliary Tract
 Contract biliary smooth muscle

biliary colic
 Sphincter of Oddi may constrict
Other Peripheral Effects
 Renal
 Antidiuretic effect
 Enhanced renal tubular sodium reabsorption
 Increased ureteral and bladder tone
 Uterus
 May prolong labor
 Neuroendocrine
 stimulate the release of ADH, prolactin, and
somatotropin
 inhibit the release of luteinizing hormone
• Clinical Use of Opioid Analgesics
• Toxicity & Undesired Effects
Alternative Routes of Administration
 Rectal suppositories
 morphine and hydromorphone
 Transdermal patch
 Fentanyl
 Intranasal
 Butorphanol
 Buccal transmucosal
 Fentanyl citrate lozenge
 Patient-controlled analgesia (PCA)
 infusion device
Toxicity & Undesired Effects
 Behavioral restlessness, tremulousness, hyperactivity







(in dysphoric reactions)
Respiratory depression
Nausea and vomiting
Increased intracranial pressure
Postural hypotension accentuated by hypovolemia
Constipation
Urinary retention
Itching around nose, urticaria (more frequent with
parenteral and spinal administration)
Tolerance and Dependence
 Does not become clinically manifest until after 2–3
weeks
 Tolerance to methadone develops more slowly
 Cross-tolerance is an extremely important
 But often be partial or incomplete
 Opioid rotation
 Recoupling opioid receptor  ketamine
Physical Dependence
 Signs and symptoms
 Rhinorrhea
 Lacrimation
 Yawning
 Chills
 Gooseflesh (piloerection)
 Hyperventilation
 Hyperthermia
 Mydriasis
 Muscular aches
 Vomiting
 Diarrhea
 Anxiety, and hostility
Physical Dependence
 time of onset, intensity, and duration of abstinence
syndrome depend on
 biologic half-life
 morphine or heroin, usually start within 6–10 hours
 methadone required several days
Psychologic Dependence
 Euphoria, indifference to stimuli, and sedation
 Abdominal effects that have been likened to an intense
sexual orgasm
 Reinforced by the development of physical dependence
The Opioid Antagonists
 Naloxone,naltrexone, and nalmefene
 Methylnaltrexone bromide
 Alvimopan