Date post: | 07-May-2015 |
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OPIOID ANALGESICS
Dennis Paul, Ph.D.
MEB 7154
Opioid Receptor Subtypes
• Mu receptors:– Mu1 and Mu2 receptors
• Kappa receptors:– Kappa1, and Kappa3 receptors
• Delta receptors:– Delta1 and Delta2 receptors
Endogenous Opioids
• Pro-opiomelanocortin peptides: -endorphin
• Pro-enkephalin peptides:
– met-enkephalin and leu-enkephalin
• Prodynorphin peptides:– Dyn-A, Dyn-B and -neo-endorphin
• Endomorphins:
– Endomorphin-1 and Endomorphin-2
Opioid receptors, endogenous ligands and function:
Mu receptorsMu1: B-endorphin, endomorphin
enkephalinMu2: B-endorphin, endomorphin
Kappa receptorsKappa1: dynorphinsKappa2 & 3: dynorphins, unknown
Delta receptorsDelta1: enkephalins, dynorphinsDelta2: enkephalins
Cloned Opioid Receptors
• MOR, DOR, KOR
• 7-transmembrane domains
• G-protein linked (Gi or Go) to adenylyl cyclase or potassium channels
In vivo assays:
1. Analgesic properties
2. Reinforcing properties
3. Stimulus properties
Analgesic Assays
• Thermal stimuli
• Tactile stimuli
• Inflammation
• Neuropathy
Reinforcing Properties
• Self-administration
• Conditioned Place Preference
Stimulus Properties
• Discrimination tasks
• Addiction Research Center Inventory
II Opioid AgonistsA. Opium alkaloids and
derivativesB. Synthetic compounds
III. Antagonists
IV. Mixed agonist-antagonists
V. Partial agonists
Desirable properties of morphine as an analgesic
• Effective over a wide range of doses
• Effect on mood
• Sedation
Undesirable properties of morphine as an analgesic
• Sedation*• Mental Clouding• Dysphoria• Constipation*• Dizziness• Nausea and vomiting• Respiratory
depression*• Cough reflex
depression* (medulla)
• Circulatory depression• Pinpoint pupils• Pruritis and rash• Biliary tract spasms• Ureter and vesical
spasms• Urinary retention• Behavioral dependence• Physical dependence• Tolerance
Tolerance
• Associative or behavioral tolerance
• Nonassociative or pharmacologic tolerance
• Cross-tolerance
• Intrinsic efficacy may affect development of tolerance and cross-tolerance
Multiple sites of action
• Dorsal horn of the spinal cord
• Activate descending inhibitory system
• Peripheral receptors
Multiple sites of action
• Dorsal horn of the spinal cord
• Activate descending inhibitory system
• Peripheral receptors
Metabolism of morphine
• Morphine-3ß-glucuronide (inactive)
• Morphine-6ß-glucuronide (active)
• Accumulate in patients with renal damage
Heroin
• Crosses blood-brain barrier more rapidly than morphine
• 2-4 X greater potency than morphine
• Converted to morphine
Hydromorphone(Dilaudid)
• About 8-10X potency of morphine
• Slightly shorter duration than morphine
• available as suppository
Oxymorphone(Numorphan)
• Same as hydromorphone
Codeine
• About 1/10th the potency of morphine
• lower efficacy than morphine• about 10% converted to morphine
by CYP450 2D6• 10% of patients do not possess this
enzyme
Oxycodone
• About 10X potency of codeine
• Also metabolized by CYP450-2D6
• Controlled release formulation (OxyContin)
Hydrocodone and Dihydrocodeine
• Same as oxycodone
Mixtures containing Codeine
• Acetaminophen or NSAIDs
• Logic: Additive or synergistic analgesia without concomitant increase in adverse effects.
Mixtures containing Codeine
0
10
20
30
40
50
60
70
80
90
0 1 2 3 4 5
TIME (hrs)
Per
cen
t A
nal
ges
ia
APAP
Codeine
A + C
Synthetic compounds
• Meperidine• Fentanyl, Sufentanyl, Alfentanyl
Remifentanyl• Methadone• L-α-acetyl-methadol: LAAM• Propoxyphene
Meperidine
• About 1/8th potency of morphine• shorter duration• fewer smooth muscle spasms than
morphine• No meiosis• biotransformed to a toxic metabolite that
builds up and can cause seizures.• Synergistic with gila monster venom
Fentanyl
• 80 - 100 x potency of morphine
• fast onset, short duration
• used i.v. for anesthesia
• available as patch
• available as oral slow release device.
Fentanyl derivatives
• Alfentanyl
• Sufentanyl
• Remifentanyl
Methadone
• Potency similar to morphine for i.v. administration, but 4 x more potent orally
• long plasma half-life
• used in treatment of narcotic dependence
• Duration of action increases with repeated use
LAAM
• Extremely long plasma half-life (>72 hr)
• Suppresses opiate withdrawal for 4-5 days
Propoxyphene
• Potency compared to codeine
• Potency compared to placebo
• Produces cardiotoxicity and pulmonary edema
• Active metabolite produces convulsions
Opioid Antagonists
• Naloxone
• Naltrexone
• Nalmefene
Signs of Overdose
• Stuporous or in coma
• Respiratory rate extremely low
• pinpoint pupils
• low body temperature
• flacid skeletal muscles, jaw relaxed
Naloxone
• Short half-life
• not effective orally
Naltrexone
• Long half-life
• effective orally or injected
• available in oral form only
• used for treatment of dependence
Nalmefene
• Intermediate duration (4-6 hr)
• orally active
• no hepatotoxicity with long term use
Mixed agonist-antagonists
• Nalorphine and cyclazocine
• Pentazocine: Talwin NX
• Butorphanol
• Nalbuphine
Nalorphine and Cyclazocine
• Kappa3 receptor agonists
• Mu receptor antagonists
• produce psychotomimetic effects
• produce dysphoria
Pentazocine
• Kappa and delta agonist
• ‘Ts and blues’
• Talwin NX
Butorphanol
• Kappa receptor agonist
• Mu receptor antagonist
• Available as nasal spray
• 5 X more potent in women than men
Nalbuphine
• Kappa receptor agonist
• Mu receptor antagonist
• Little dysphoria compared to nalorphine
• Less abuse potential than morphine
Partial agonist: Buprenorphine
• Partial agonist at mu receptors
• Partial agonist at kappa3 receptors
• Antagonist at kappa1 receptors
• Lower efficacy analgesic than morphine
Tramadol
• Opioid receptor agonist (mu and delta)
• NE and 5-HT reuptake blocker (antidepressant)
• α-2 adrenoceptor agonist• These actions are synergistic for
analgesia
Dependence and Withdrawal
• Dependence varies from mild craving to compulsion to take the drug
• Degree depends upon dose and frequency
• Withdrawal signs opposite in direction to the drug effects.
• Will last about 72 hrs for morphine or heroin
• Not life threatening
Other factors that influence the effectiveness of opioid
treatment
• Progression of tissue-damaging disease
• Sensitization of CNS neurons
• Collateral transmission
Salvinorin A
• Active ingredient in Salvia Divinorum
• Very selective kappa opioid agonist
• Hallucinogen