• POMC
  • gene product- beta endorphin
  • mechanism- primarily endocrine (syn. and released from pituitary), small amount in brain
  • other hormones from POMC: ACTH, MSH, beta lipotropin
• enkephalin
  • gene product- pro enkephalin
  • mechanism: only active in brain
  • active peptides: met-enkephalin and Leu-enkephalin
• dynorphin
  • gene product- pro dynorphin
  • active peptides (multiple)- dynorphin A and B, neo-endorphins, Leu-enkephalin
  • only in brain (some peptides may enhance pain response)

• mu (major R for most drugs)
  • analgesia
  • resp. depression
  • euphoria
  • dependence
• kappa (few opioid drugs are kappa agonists)
  • analgesia
  • sedation
  • endocrine
  • dysphoria
  • psychotomimetic
• delta- possibly analgesia

• sigma
  • agitation
  • hallucinations
  • dysphoria
• DM- antitussive effects

1. inhibit cAMP
   • inhibit certain calcium channels
   • activation of K channels
2. neurons will
   • decrease spontaneous firing
   • decrease evoked firing
   • inhibited transmitter release

• analgesia (but NOT with neuropathic pain)
• antitussive
• antidiarrheal, but could lead to constipation
• reduce preload, afterload, and anxiety leading to relief of acute pulmonary edema, but can have respiratory depressive effects
• mood enhancement to contribute to pain relief, but leads to potential for abuse

• slow nociceptive pain
  • those mediated by paleospinothalamic tract (C fibers)
• fast and neuropathic pain
  • fast pain mediated by neospinothalamic tract (A delta fibers)

• peripheral ? on afferent pain nerves
• spinal: dorsal horn
• supraspinal- central gray, thalamus, limbic system, sensory cortex
  • inhibition of ascending pain pathways (paleospinothalamic tract)
  • activation of descending inh. pathways

• increase pain threshold (discriminative)
• increase pain tolerance (affective)- makes them unique
• selective for analgesia (aka it is selective for the sense of pain)

• unlike the opioid receptors, the DM receptor is NOT stereoselective
  • d isomer is antitussive, but no opioid effects
  • l isomer is antitussive and opioid effective in nature

1. opioids that dont reach the CNS stimulates mu opioid receptors on enteric nerves
   1. decrease propulsive movements while increasing the tone
   2. decrease secretions
2. results in delayed gastric emptying, increased transit time, increased water absorption

there will be no tolerance to this effect

• common
  • constipation
  • nausea, vomit
  • sedation
  • miosis
  • tolerance
  • itch
• less common
  • resp dep.
  • dysphoria
  • urinary retention
  • postural hypotension
  • truncal rigidity
  • physical dependence
  • addiction

1. decrease the response of medullary respiratory center to P_CO2
2. decrease in rate, depth of inspiration
3. leads to irregular rhythmm and increaases in P_CO2

CI: COPD, asthma

CI: sedative hypnotics, anti-psychotics (additive effect of respiratory depression)

Name the CNS effects of opioids

• analgesia
• resp. depression
• cough suppression
• mood effects
• sedation
• nausea and vomitting
• miosis
• truncal rigidity
• hyperthermia

• usually mild euphoria, decreased anxiety (helps with relief of pain)
• some patients may experience dysphoria

• not always desirable
• is additive with other sedative drugs
• can cause sleep disturbances: suppress REM sleep

• diminishes with time
• stimulates CTZ and vestibular component

• reduced thoracic compliance and ventilation
• problems with fentanyls used during surgery
  • more resp. depression

• morphine act on hypothalamus to cause hyperthermia

• anti-diarrheal
• CV effects (indirect)
• pruritis
• renal effects
• biliary tract contraction/spasm, leading to biliary colic (although treats bilariy colic)
• neuroendocrine effects
• increased intracranal P (secondary to increase P_CO2)
• labor and delivery- decrease uterine tone, cause neonatal intoxication
• altered immune function (secondary to alter stres hormones)

• in CV, it is not direct
  • it will cause release of histamine, leading to vasodilation, causing reflex tachycardia, could cause postural hypotension
    • CI: shock
  • benificial in pulmonary edema (decreased preload and afterload)
• pruritis due to histamine release

• increased ADH- difficulty voiding
• stimulate autonomic NS- increased urgency

• increased: GH, ADH, PRL
• decrease: FSH, LH, CRF, ACTH

• head injury (increase intracranial P caused by opioids)
• pregnancy (fetus become physically dep.)
• impaired pulm. function (asthma, COPD)
• impaired renal function (major excretion route, so half life prolonged)
• impaired hepatic function (inh. met leads to increase blood levels)
• Addisons, hypothyroidisn (reduce dose to to exaggerated response)
• substance abuse history (still need pain relief, but be careful and look for tolerance)

• MAOI's
• sedative hypnotics, antipsyc.
  • increase sedation, possibly increase resp. distress

• first pass elim, so oral doses must be higher than parenteral doses to obtain the same effect
• many routes available
  • oral
  • buccal
  • sublingual
  • transdermal (ex: fentanyl)
  • nasla
  • suppository
  • parenteral (in patient controlled administration)
    • intrathecal opioids for labor

• most have similar DOA (3-4 hrs)
  • meperidine less
  • methadone more
• duration increases with slow release oral preps (morphine, oxymorphone, oxycodone)
• transdermal preps also longer acting
• drugs with fast CNS penetration have enhanced abuse potential (ex: heroin and morphine)

• morphine: liver oxidation and glucuronidation
• metabolism
  • morphine 6 glucuronide can act at opioid receptors
  • morphine 3 glucuronide is neuroexcitatory (not opioid)
    • these two cant contribute to effects because they cant cross BBB (polar)
    • but if OD, or renal insuff., cause adverse effects unexpectedly
  • oxidative met. by CYP3A4 yields some toxic, nonopioid metabolites
  • codeine is demethylated to morphine, and polymorphisms in CYP2D6 can cause variable response to codeine
• renal excretion

• can occur with continuous use
  • usually not during early dosing
  • can become extreme when doses are pushed up and used longer
• no effect on saftey (TI unchanged)
• all affects exhibit tolerance together (except miosis and constipation)
• cross tolerance seen to other opioids
  • when substituting new one, start with 3/4 equivalent dose, then build up

• you will see abstinence syndrome when drug removed or precipitated with antagonist
• some likely to occur and readily managed
• intensity and time course of syndrome depends on a function of dose and kinetics of the drug
• dependence measured based on withdrawal symptoms
• cross dependence seen with other opioids

• altered behavior
• uncommon with normal clinical use

• all full agonists (high efficacy) can achieve the same maximal effect if dose adjusted for binding affinity and route of administration

• high efficacy analgesics (strong agonists)
• low medium efficacy oral analgesics (mild to moderate agonists)
• opioids with mixed receptor actions (agonist- antagonists)
• antagonists
• nonanalgesic opioids
• miscellaneous

• first line
  • morphine (prototype)
  • methadone
  • fentanyl
• second line
  • meperidine
  • heroin

• prodrug converted to morphine
• rapid penetration of BBB so associated with high abuse potential

• available in several slow release oral forms

• similar to morphine, more potent and soluble
• can be used in highly tolerant patients

• very short acting
• use- anesthesia
• sever other fentanyls that differ in potency and kinetics
• novel forms: transdermal patch

• indications
  • treat heroin addicts
  • good analgesic
• longer acting, good oral-parenteral ration
• non opioid effects that add to analgesic effect
  • NMDA
  • MAO reuptake

• same
  • analgesia
  • resp. dep.
  • likelihood of dep.

• nausea, vomiting
• dizziness
• antimuscarinic activity
• toxicity

• constipation
• urinary retention
• delay of labor
• biliary spasm
• cough suppression
• miosis
• duration
• potency

1. metabolized to normeperidine
2. causes CNS stimulation and convulsions

• This happens w/chronic dosing (esp. oral) and kidney impairment
• CI: MAOI (fatal interaction)
• use only for short term tx

• all available ONLY inoral preps
• usually given with NSAID to have two separate mechanims to control pain
  • but caution: acetomeniphin (liver toxicity)

• PK- partially converted to morphine by oxidative metabolism (some dont do this aka codeine resistance)
• relatively low efficacy
• indications- good antitussive (useful at lower doses)
  • but at higher doses, analgesic
• adverse effects- pruritis (sign. histamine release)

• highest efficacy of the low-medium efficacy opioids
  • metabolized to oxymorphone
• PK- available in slow release tablets
• adverse effects- abuse (crush pills will disable slow release mechanism, causing higher effective dose)

• first line
  • codeine
  • oxycodone
• second line
  • hydrocondone
  • dihydrocodeine
• propoxyphene

• low efficacy
• toxicity due to metabolite norpropoxyphene
  • cardiotoxicity- arrhythmias
  • CNS toxicity- like normeperidine

• mechanism of action
  • agonist on kappa R's
    • source of analgesic effects
    • unique adverse effects: dysphoria, hallucinations
  • antagonists of mu R's
    • antagonist effects of most opioid analgesics
• benefits
  • lower dependence
  • OD toxicity uncommon
• drawbacks
  • dose related psychotomimetic and other adverse effects
  • ceiling analgesia
  • can percipitate withdrawl in pateints on full agonists

• pentazocine- available in combination with acetomeniphin (dont use parenteral)

• dextromethophan: antitussive that active at DM receptors, but inactive at opioid R's
• loperamide: antidiarrheals with little BBB penetration
  • active ingredient: imodium AD
  • possible utility in treating neuropathic pain

• naloxone
  • PK
    • parenteral only
    • rapid acting with short DOA
  • competitve antagonist at ALL opioid receptors

• assess type of pain
  • acute vs. chronic
  • nociceptive vs. neuropathic
• assess pain intensity
  • pain subjective
  • continual re-evalulation needed to assess response to drug and disease progress
  • different drug efficacies useful for different pain intensities
• remember equi analgesia
• match drug duration to pain duration
• easier to maintain pain free than remove exisiting pain
• PRN inappropriate
• tolerance may develop when pushing dose
• never withhold or underdose opioids for fear of addiction

• mild pain: ASA/acetominophen/NSAIDS
• moderate pain: above drugs combined with oral opioid (low to medium efficacy)
• severe pain: high efficacy opioids, parenteral or oral, alone or with adjuncts

• it causes the cycle of pain