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OPIOIDS - Pharmacology
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Opioids
Transmitters: Endogenous opioid peptides
Enkephalins (m & d receptors)
Dynorphins (κ receptors)
Endorphins
Actions
Opioids stimulate axons of inhibitory interneurons
Peripheral inflammation: Sensitivity to opioids in spinal
cord is increased
Peripheral neuropathic pain: Sensitivity to opioids is
greatly reduced
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Pain Modulation: Central
mechanisms
 Gate control
Aβ axons stimulate inhibitory interneuron
Activity in central projection neuron is reduced
 Opiate-induced analgesia
μ Receptor :Agonists: Morphine; Antagonist: CTAP

Reduces acute pain & hyperalgesia in most models
δ Receptor :Agonist: SNC80 , Antagonist: Naltrindole

Reduces acute pain & hyperalgesia in inflam. pain models

May have fewer side effects (Constipation, respiratory
depression, physical dependence) than μ-agonists
κ Receptor : Agonist: U50,488

No effect on chronic muscle pain
Locations: PAGM, Ventral medulla, Dorsal horn
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BRAIN
PAG, RVM etc
Descending
pathways
Carbamazapine,
lignocaine
C-fibre
OPIOIDS
amytriptyline
Glutamate
SG
sP
Ca2+
VDCCs
Lamina V
Ketamine
Lamina I
GABAPENTIN
Dorsal Horn
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Weak opioids
Codeine
Weak m agonist, methbolize to morphine (30%)
Dose 30-60 mg oral q 4-6 hrs
Side effects : constipation/ itching/ nausea/
vomiting
Available as:
TWC(15)
TWC(30)
Codeine (15, 30 mg)
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Weak opioids (cont.)
Tramadol
Weak µ agonist
Amine uptake inhibiting action:NE and serotonin
Dose 50-100 mg oral q 6 hrs
Anticholinergic side effects: tachycardia,
nausea, vomiting,voiding difficulty, sweating
Available as IR, ER (Tramal) and combination
( Ultracet® (Tramadol& paracetamol)
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Strong Opioids
agonists: morphine, pethidine,fentanyl,
methadone
partial agonists :-buprenorphine,
pentazocine
agonist-antagonist :- nalbuphine
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Morphine
Pethidine
 Only parenteral route in TH
 Bioavailability: 30-60%,
to1st
 Faster onset, short duration (2-
due
part metabolism
3 hr)
 Immediate release: 3-4 hr
 No more effective than
 Extended release:12-24 h
morphine at treating biliary or
renal pain
 Metabolize to M6G
(agonist), M3G
 High addictive potential (rush
(neurotoxicity), may
and stimulant effect)
accumulate in renal failure  More CNS toxicity (i.e.
seizures, delirium due to norpethidine metabolite
 Should not be used any more
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MST, MS Contin (10, 30, 60 mg)
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Kapanol (20, 50, 100 mg)
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Immediate release opioid
 Oral morphine solution
Rama, Siriraj, Songkhla 2mg/ml
-stability, convenience, dosage
 Fentanyl lollipop
 Fentanyl buccal tablet
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Methadone
 Cheap and available for opioid maintenance
 Racemic of L and R –isoform, theoretically support NMDA




and mu-receptor mechanism
Variable half life, extended with long term use
Use as third line, for switching in refractory case
Start at lower dose, then slowly titrate
Study recommends to switch from morphine to methadone in
3-day (one third reduction and substitution with equianalgesic
dose (4 to 1- 6 to 1 ratio), followed by a one week titration
Fredheim OM, Eur J Pain. 2007 ;11:599-604.
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Narcotic Type 2
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Transdermal narcotics
Fentanyl TTS ( Durogesic®/ D-Trans® )
•12, 25, 50, 100 µgm/patch
•onset : 6-12 hrs, change patch q 3 days
•Should not use for acute pain due to delay onset
•Indications
Terminal cancer pts. who are not able to eat
Cancer of the head and neck region
Pts. who develop severe side effects of oral
narcotics
Pts. who consume very high dose oral narcotics
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Opioid Therapy and Chemical
Dependency
• Risk of addiction: Evolving view
Acute pain: Very unlikely
Cancer pain: Very unlikely
Chronic noncancer pain:
Surveys of patients without abuse or psychopathology
show rare addiction
Surveys that include patients with abuse or
psychopathology show mixed results
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Opioid Therapy: Drug
Selection
• Immediate-release preparations
Used mainly
For acute pain
For dose finding during initial treatment of
chronic pain
For “rescue” dosing
 Can be used for long-term management in
select patients
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Opioid Therapy: Drug
Selection
 Immediate-release preparations
Combination products
Acetaminophen, aspirin, or ibuprofen combined with
codeine, hydrocodone, dihydrocodeine
Single-entity drugs, eg, morphine
Tramadol
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Opioid Therapy: Drug
Selection
 Extended-release preparations

Preferred because of improved treatment
adherence and the likelihood of reduced risk in
those with addictive disease
 Morphine, oxycodone, fentanyl,
hydromorphone, codeine, tramadol,
buprenorphine

Adjust dose q 2–3 d
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Opioid Therapy: Drug
Selection
 Role of methadone
Another useful long-acting drug
Unique pharmacology when commercially available
as the racemic mixture
Potency greater than expected based on single-dose
studies
When used for pain: multiple daily doses, steadystate in 1 to several weeks
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Opioid Selection:
Poor Choices for Chronic Pain
 Meperidine
Poor absorption and toxic metabolite
 Propoxyphene
Poor efficacy and toxic metabolite
 Mixed agonist-antagonists (pentazocine,
butorphanol, nalbuphine, dezocine)
Compete with agonists  withdrawal
Analgesic ceiling effect
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Opioid Therapy: Routes of
Administration
 Oral and transdermal—preferred
 Oral transmucosal—available for fentanyl
and used for breakthrough pain
 Rectal route—limited use
 Parenteral—SQ and IV preferred and feasible
for long-term therapy
 Intraspinal—intrathecal generally preferred for
long-term use
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Opioid Therapy: Guidelines
 Consider use of a long-acting drug and a
“rescue” drug—usually 5%–15% of the total
daily dose
 Baseline dose increases: 25%–100% or
equal to “rescue” dose use
 Increase “rescue” dose as baseline dose
increases
 Treat side effects
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Opioid Therapy: Side Effects
 Common
Constipation
Somnolence, mental clouding
 Less common
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Nausea
Myoclonus
Itch
Urinary retention
– Sweating
– Amenorrhea
– Sexual dysfunction
– Headache
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Opioid Responsiveness
• Opioid dose titration over time is critical to
successful opioid therapy
• Goal: Increase dose until pain relief is adequate
or intolerable and unmanageable side effects
occur
• No maximal or “correct” dose
• Responsiveness of an individual patient to a
specific drug cannot be determined unless dose
was increased to treatment-limiting toxicity
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Poor Opioid Responsiveness
 If dose escalation  adverse effects
Better side-effect management
 Pharmacologic strategy to lower opioid
requirement

 Spinal
route of administration
 Add nonopioid or adjuvant analgesic
“Opioid rotation”
 Nonpharmacologic strategy to lower opioid
requirement
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
Opioid Rotation
 Based on large intraindividual variation in
response to different opioids
 Reduce equianalgesic dose by 25%–50%
with provisos:
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Reduce less if pain severe
Reduce more if medically frail
Reduce less if same drug by different route
Reduce fentanyl less
Reduce methadone more: 75%–90%
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Equianalgesic Table
PO/PR (mg) Analgesic SC/IV/IM (mg)
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Morphine
10
4–8 Hydromorphone
1.5
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Oxycodone
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Methadone
10
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Acknowledgement
 Assoc. Professor Chutamanee Suttisisang
 Assoc. Professor Pongparadee Chaudakestrin
 Assist. Professor Penkae Ketuman
 Professor Anthony Dickenson
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