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