This document discusses opioids and their classification, sources, chemistry, receptors, endogenous peptides, pharmacokinetics, mechanisms of action, effects, toxicity, dependence, and clinical use. It summarizes that opioids are derived from poppy plants and act primarily on mu opioid receptors to produce analgesia, euphoria and respiratory depression. Tolerance develops to their effects over time and physical dependence and withdrawal symptoms occur with discontinuation. The document outlines the different types of opioids and their properties in detail.

1. By
Bohlooli S. PhD
School of Medicine, Ardabil University of Medical Sciences

2. 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

4. 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%

5. Classification & Chemistry
 Opioid drugs include:
 Full agonists
 Morphine
 Partial agonists
 Codeine
 Antagonists
 Naloxone

6. Chemical structure

7. 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

8. Chemistry; Opioids with Mixed Receptor Actions
 Phenanthrenes
 Nalbuphine , Buprenorphine
 Morphinans
 Butorphanol
 Benzomorphans
 Pentazocine
 Miscellaneous
 Tramadol, Tapentadol

9. 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

10. 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)

11. Pharmacokinetics
Generic Name Receptor
Effects1
Approximately
Equivalent Dose
(mg)
Oral:Parenteral
Potency Ratio
Duration of
Analgesia
(hours)
Maximum
Efficacy
  
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

12. Pharmacokinetics
Generic Name Receptor
Effects1
Approximately
Equivalent Dose
(mg)
Oral:Parenteral
Potency Ratio
Duration of
Analgesia
(hours)
Maximum
Efficacy
  
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
Buprenorphine ± –– –– 0.3 Low 4–8 High
Butorphanol ± +++ 2 Parenteral only 3–4 High

13. Pharmacokinetics
 Absorption
 Distribution
 Metabolism
 Excretion

14. Absorption
 Well absorbed
 Variable first-pass metabolism
 Subcutaneous, intramuscular, and oral routes- other
routes:
 Nasal insufflation
 Oral mucosa via lozenges
 Transdermal patches

15. 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

17. Mechanism of Action

18. Receptor Types
 Based on pharmacologic criteria
  1,  2
 1, 2
  1,  2,  3
 Genetically one subtype from each of the ,  and 
receptor families

19. 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

20. 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

21. Receptor Distribution and
Neural Mechanisms of
Analgesia: Transmission

22. Receptor Distribution and
Neural Mechanisms of
Analgesia: Modulation

23. 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

24. Tolerance and Physical Dependence
 Tolerance
 Physical dependence
 Withdrawal or abstinence syndrome
 Mechanism
 receptor recycling
 receptor uncoupling

25. Organ System Effects of Morphine
 Central Nervous System
Effects
 Cardiovascular System
 Gastrointestinal Tract
 Biliary Tract
 Renal
 Uterus
 Neuroendocrine
 Pruritus

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. • Clinical Use of Opioid Analgesics
• Toxicity & Undesired Effects

33. 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

34. 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)

35. 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

36. Physical Dependence
 Signs and symptoms
 Rhinorrhea
 Lacrimation
 Yawning
 Chills
 Gooseflesh (piloerection)
 Hyperventilation
 Hyperthermia
 Mydriasis
 Muscular aches
 Vomiting
 Diarrhea
 Anxiety, and hostility

37. 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

38. 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

39. The Opioid Antagonists
 Naloxone,naltrexone, and nalmefene
 Methylnaltrexone bromide
 Alvimopan