MANAGEMENT OF PAIN
What is pain?
How can pain be treated?
Cycle-oxygenase inhibitors
Opioids
“OPIOID ANALGESICS
Narcotics”
“Analgesia” = “without pain sensation”
Opioids:
- reduce pain sensation
- reduce concern about pain
OPIUM: exudate of seed capsules of
Papaver somniferum 10% morphine
OPIUM TINCTURE: laudanum, 10% opium,
1% morphine
PAREGORIC: camphorated opium tincture,
0.04% morphine
Opium poppies in Columbia
The milky fluid that oozes from the
seed pod of the poppy is opium
Various poppy products
HISTORY OF OPIOIDS
4000 B.C.
2000 B.C.
15th Cent.
A.D.
18th Cent.
1803
1800’s
1900’s
Sumerian pictographs of opium poppy
Use of opium by Greeks
Laudanum used in Europe
Opium smoking popular in Orient
Serturner isolated morphine
Opium wars in China
Civil war in U.S.A.
Heroin
Methadone
Meperidine Endorphins
Naloxone
OPIATES
Morphine
Heroin
Codeine
OPIOID DRUGS
Prototype = MORPHINE
MORPHINE BASE
MORPHINE
CNS actions
Cardiovascular actions
Gastrointestinal actions
MORPHINE
CNS ACTIONS
A. Mechanism: Acts at brain and spinal opioid receptors
(especially mu receptors)
B. Effects
1. Analgesia-selective
2. Euphoria
3. Drowsiness (coma in overdose)
4. Pituitary: increase PRL and ADH, can decrease ACTH
5. Pupils: miosis
6. Respiratory depression
7. Depression of cough center
8. Stimulation of CTZ, depression of VC
9. Depression on multineuronal reflexes
10. Generalized stimulation (rare)
11. Central cardiovascular, GI actions
MORPHINE
CARDIOVASCULAR ACTIONS
A.
Orthostatic hypotension
1.
Peripheral vasodilation (?histamine
release, inhibition of NE release?)
2.
Sympathetic inhibition (CNS)
B.
Cerebral vasodilation (hypercapnia)
MORPHINE
GASTROINTESTINAL ACTIONS
A. Increased incidence and amplitude of
circular muscle contraction
B. Decreased gastric emptying
C. Decreased transit, constipation
D. Spasm of biliary tract, sphincter of Oddi
OPIOID DRUGS
SITES OF ACTION
OPIOID DRUGS
Actions
OPIOID DRUGS
DISPOSITION OF OPIATES
ABSORPTION
DISTRIBUTION
BIOTRANSFORMATION
EXCRETION
Fig. 1. Effect of route of administration on plasma-free morphine levels.
Means  S.E. are shown.
HAZARDS
Respiratory depression
GI: nausea, vomiting, constipation
Orthostatic hypotension
Perceptual disturbance
Dependence
HEROIN
(Diacetylmorphine)
1.
2.
3.
4.
Analgesic
Penetrates into brain well, potent
Hydrolyzed to monoacetylmorphine
and to morphine
Other pharmacology like morphine
Heroin is manufactured in remote
“laboratories” using rudimentary equipment
Heroin removed from latex balloons prior to
being packaged for street sales.
Heroin repackaged for sale on the
streets of the United States
CODEINE
(Methylmorphine)
1.
2.
3.
4.
5.
6.
Analgesic
Effective orally
Antitussive
Low dependence liability
Often stimulatory in overdose
Some O-demethylated in vivo
MEPERIDINE
Shorter duration of action than morphine
Not an effective antitussive
MEPERIDINE
1.
2.
CNS effects
a. analgesia
b. euphoria
c. respiratory depression
d. convulsions (normeperidine)
e. pupil response variable
Smooth muscle
a. spasmogenic but not constipating
METHADONE
1.
CNS effects
a. analgesia
b. respiratory
c. antitussive
2.
Other actions
a. similar to morphine
METHADONE
Disposition
Well absorbed, orally active
Metabolized in liver
Long duration of action
DEXTROMETHORPHAN
Antitussive
Not addicting
Not analgesic
OPIOID ANTAGONISTS
Prototype:
NALOXONE
Naloxone:
“pure antagonist”
no agonist actions
Naloxone:
short duration of action
OPIOID ANTAGONISTS
(Naloxone, naltrexone)
$ Competitive antagonists at opioid receptors
$ Rapid reversal of opioid agonist effects
- analgesia
- respiratory depression
- miosis
$ Do NOT directly antagonize barbiturates, alcohol,
benzodiazepines
MIXED AGONIST-ANTAGONIST
Nalorphine (Nalline)
Pentazocine (Talwin)
Nalbuphine (Nubain)
Butorphanol (Stadol)
Buprenorphine (Temgesic)
Cyclazocine
MIXED OPIOID AGONISTS-ANTAGONISTS
1. NALORPHINE: not used as agonist, replaced by
naloxone as antagonist (can induce respiratory
depression).
2. PENTAZOCINE
Used clinically as agonist
Analgesic
Euphoria or dysphoria
Mild respiratory depression
Moderate abuse potential
3. BUTORPHANIL
About like pentazocine
OPIOID TOLERANCE
Cellular tolerance
Cross-tolerance with other opioids
No cross-tolerance to other drug classes
OPIOID DEPENDENCE
Users seek euphoria, freedom from anxiety,
pleasure
Dependence
primary psychological
physical
secondary psychological
OPIOID DEPENDENCE
Withdrawal syndrome
abstinent
precipitated with antagonist
HEROIN/MORPHINE WITHDRAWAL
Early abstinence
8 hr
lacrimation, rhinorrhea, yawning, sweating
12 hr
“yen” (restless sleep), miserable, dilated
pupils, anorexia, gooseflesh, restlessness,
irritability, tremor
48 hr
symptoms peak, severe sneezing, yawning,
diarrhea, nausea, vomiting, waves of
gooseflesh, alternate chills and sweating,
weakness, depression, cramps, bone pain,
muscle spasm, tachycardia, hypertension,
sexual orgasm, dehydration
7 days
acute phase ended
Protracted abstinence
Weeks, months
OVERDOSE
Triad
Coma
Respiratory depression
Pinpoint pupils
Management
Support of vital functions
Antidotal therapy
Narcotic antagonist