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.Sumerian pictographs of opium poppy 2000 B.C.Use of opium by Greeks 15th Cent.Laudanum used in Europe A.D. 18th Cent.Opium smoking popular in Orient 1803Serturner isolated morphine 1800’sOpium wars in China Civil war in U.S.A. 1900’sHeroin Methadone Meperidine EndorphinsNaloxone

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.Analgesic 2.Penetrates into brain well, potent 3.Hydrolyzed to monoacetylmorphine and to morphine 4.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.Analgesic 2.Effective orally 3.Antitussive 4.Low dependence liability 5.Often stimulatory in overdose 6.Some O-demethylated in vivo

MEPERIDINE Shorter duration of action than morphine Not an effective antitussive

MEPERIDINE 1.CNS effects a.analgesia b.euphoria c.respiratory depression d.convulsions (normeperidine) e.pupil response variable 2.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 hrlacrimation, rhinorrhea, yawning, sweating 12 hr“yen” (restless sleep), miserable, dilated pupils, anorexia, gooseflesh, restlessness, irritability, tremor 48 hrsymptoms 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 daysacute phase ended Protracted abstinence Weeks, months

OVERDOSE Triad Coma Respiratory depression Pinpoint pupils Management Support of vital functions Antidotal therapy Narcotic antagonist