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 Functions Endogenous Opioid Peptide Affinity
Subtype
 (mu) Supraspinal and spinal analgesia; Endorphins > enkephalins > dynorphins
sedation; inhibition of respiration;
slowed gastrointestinal transit;
modulation of hormone and
neurotransmitter release
 (delta) Supraspinal and spinal analgesia; Enkephalins > endorphins and dynorphins
modulation of hormone and
neurotransmitter release
 (kappa) Supraspinal and spinal analgesia; Dynorphins > > endorphins and enkephalins
psychotomimetic effects; slowed
gastrointestinal transit
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 Approximately Oral:Parenteral Duration of Maximum
Effects1 Equivalent Dose Potency Ratio Analgesia Efficacy
(mg) (hours)
  
Morphine2 +++ + 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 Approximately Oral:Parenteral Duration of Maximum
Effects1 Equivalent Dose Potency Ratio Analgesia Efficacy
(mg) (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 (+, 60–1207 Oral only 4–5 Very low

very
weak)
Pentazocine ± + 30–507 Medium 3–4 Moderate

Nalbuphine –– ++ 10 Parenteral only 3–6 High

Buprenorphine ± –– –– 0.3 Low 4–8 High
Butorphanol ± +++ 2 Parenteral only 3–4 High
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 Neuroendocrine
Effects Pruritus
Cardiovascular System
Gastrointestinal Tract
Biliary Tract
Renal
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