Chapter 44:  Opioids

Opioids

•  Nomenclature:
  • "Narcotic" -- imprecise term suggesting "narcosis": indicated of a somnolent state
  • "Opioid analgesic" -- more appropriate: suggesting analgesia (pain absence)
    • without resulting in loss of consciousness/sleep
• Opioids: Definition---
  • all natural/semisynthetic opium alkaloid derivatives
  • synthetic agents
  • other drugs whose opioid-like effects are blocked by naloxone (Narcan) -nonselective opioid receptor antagonist
•   Source:
  • Opium -- from the opium poppy
    • Constituents:
      • morphine
      • codeine
      • thebaine-- nonanalgesic
      • papaverine-- nonanalgesic, vasodilator
• Classification/Chemistry:
  • Opioid Classification:
    • full agonists (high efficacy, strong agonists)
    • partial agonists
      1. may cause agonist effects; may displace full agonists thereby reducing their effects.
      2. a partial agonist may act either as an agonist or antagonist
    • antagonists: multiple opioid receptor subtypes allow agonists/antagonist combination effects -- e.g.:
      • opioid -- agonist at one opioid receptor subtype; partial agonist or antagonist at another subtype -- "agonist-antagonists" or "mixed agonist-antagonists"
    • Examples:
      • naloxone (Narcan): pure antagonist: no effects normally associated with agonist binding
      • morphine: full agonist at mu receptor
      • codeine: partial or "weak" agonist -- < maximal effect with complete receptor saturation
      • nalbuphine (Nubain)  : agonist that one opioid receptor; antagonist at another
• Chemical substitutions:
  • Partial agonist/antagonist characteristics: replacement of methyl moiety on the nitrogen atom with larger substituents:
    • Allyl substitution-- nalorphine and naloxone
  • Substitutions at the C₃ and C₆ morphine hydroxyl groups (see below)
    • Pharmacokinetic properties altered
    • Methyl substitution at C₃  reduces first-pass hepatic metabolism by glucuronide conjugation: -- as a consequence codeine and oxycodone have a higher oral: parenteral potency

Morphine

Codeine and Oxycodone (methylated at C₃)

• Acetylation of both morphine hydroxyls = heroin {more rapid access across the blood-brain barrier compared morphine}; in the brain heroin:
  • rapidly hydrolyzed to monoacetylmorphine and morphine

• Endogenous Opioid Peptides:
  • Morphine (and related agents) cause analgesia by acting the brain regions containing peptides which have opioid-like properties
  • Endogenous substances = endogenous opioid peptides
  • Previous used term "endorphin" now refers to ß-endorphins and related peptides derived from the precursor: prepro-opiomelanocortin
  • Most widely distributed opioid analgesic peptides:
    • pentapeptides
      1. methionine-enkephalin (met-enkephalin)
      2.  leucine-enkephalin (leu-enkephalin)
  • Three major precursor proteins:
    • prepro-opiomelanocortin (POMC) {contains}:
      • met-enkephalin sequence
      • ß-endorphin sequence
      • some nonopioid peptides:
        1. ACTH
        2. ß-lipotropin
        3. melanocyte-stimulating hormone
    • preproenkephalin (proenkephalin A ) {contains}:
      • six copies of met-enkephalin
      • one copy of leu-enkephalin
    • preprodynorphin (proenkephalin B) {contains-- active peptides containing the leu-enkephalin sequence}:
      • dynorphin A
      • dynorphin B
      • a and ß neoendorphin
  • Endogenous opioid precursors: localized at pain modulation brain regions
    • May be released during: stress (pain; pain anticipation)
    • Precursor molecules also found:
      • adrenal medulla
      • neural plexuses of the gut

Pharmacokinetics

• Absorption:
  • opioid analgesics: generally well absorbed destined cutaneous/intramuscular/mucosal surfaces
  • fentanyl transdermal: important Route of Administration
  • Gastrointestinal absorption:
    • some opioids-- subject to first-pass effects:
    • codeine; oxycodone -- high oral: parenteral potency (protected from conjugation by substitution on C₃ aromatic hydroxyl)
• Distribution:
  • various extent of plasma protein binding
  • highest concentrations in tissues: function of perfusion
  • skeletal muscle: largest reservoir
  • for highly lipophilic opioids(e.g. fentanyl): concentration in adipose tissue
  • Blood Brain Barrier:
    • amphoteric agents (possessing both an acidic and basic group, e.g. morphine {phenolic hydroxyl at C₃}: greatest difficulty for brain entry)
    • other substitutions that C₃ improve blood-brain barrier penetration: e.g., heroin, codeine
    •  neonatal considerations: neonates lack the blood-brain barrier:
      1. placental opioid transfer (uses in obstetric analgesia) can result in depressed respiration in the newborn.
• Metabolism:
  • Conversion to polar metabolites; renal excretion
  • Opioids with hydroxyl groups: likely conjugated with glucuronic acid
    • Examples: morphine , levorphanol (Levo-dromoran) 
    • morphine-6-glucuronide: analgesic potency (perhaps > parent compound morphine)
    • in patients with compromised renal function:accumulation metabolites -- prolonged analgesia
  • Esters: hydrolyzed by tissue esterases:
    • Examples: heroin, remifentanil (short duration of action)
  • N-demethylation: minor pathway
    • accumulation of demethylated meperidine (Demerol)  metabolite, normeperidine:
      • patients with decreased renal function or on high dosages: CNS excitatory effects:
        •  seizures (more likely in children)
  • Oxidative metabolism (hepatic) primary route of phenylpiperidine opioid metabolism:
    • fentanyl (Sublimaze)
    • alfentanil (Alfenta)
    • sufentanil (Sufenta)
• Excretion:
  • polar metabolites -- renal; small amounts excreted unchanged
  • glucuronide conjugates -- bile (enterohepatic circulation minor)

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Pharmacodynamics

• Mechanism of Action:
  • analgesia: specific receptor binding -- localization:
    • spinal cord
    • brain
• Receptor Types:
  • Mu (m)
  • Delta (d)
  • Kappa (k)
  • General Opioid Receptor Characteristics:
    • G protein coupled receptor family
    • Significant amino acid sequence homology
    • Each-receptor: subtypes
      • Mu₁, Mu₂
      • Delta₁, Delta₂
      • Kappa₁, Kappa₂
  • Receptor types and physiological effects:
    • Mu (m) :Analgesia, euphoria, respiratory depression, physiological dependence
    • Most opioid analgesics: act at the mu receptor
    • Delta (d) and Kappa (k): Spinal analgesia
  • Drugs/endogenous opioids: Receptor- type affinity
    • morphine -- (m)
    • pentazocine -- (k) some (m)
    • endogenous opioid peptides:
      • leu-enkephalin --(d)
      • dynorphin --(k)

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• Cellular Action:
  • Opioids:G protein linked-- affecting
    • ion channel state
    • intracellular Ca²⁺ levels
    • protein phosphorylations states
  • Two well-defined opioid actions:
    1. reduce neurotransmitter release; by closing a voltage-gated Ca²⁺ channel on presynaptic neuronal terminals Or
    2. inhibit postsynaptic neurons (hyperpolarization) by increasing and K⁺ channel conductance

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Spinal Cord Sites of Opioid Action

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• Spinal cord presynaptic sites:
  • reduced transmitter released-- affects acetylcholine, norepinephrine, glutamate, serotonin, substance P

•  Serotonin, bradykinin, histamine, prostaglandins, substance P (sP) , and various ions (ie, H+ or K+)--the biochemical mediators released as a result of tissue injury--have been implicated in nociceptive activation and sensitization (hyperalgesia).
•  Hyperalgesia results in enhancement of spontaneous pain via a reduction in pain threshold and a lengthening in duration of nociceptor response to stimuli.
•  PGE₁, PGE₂, and PGF_2a, are the most potent prostaglandins to produce these sensitization effects.
•  Substance P, synthesized by cells of the spinal ganglia, has been identified at the peripheral terminal of unmyelinated primary afferent fibers.
  •  This putative neurotransmitter may play a role in the propagation of visceral nociceptive pain from the gastrointestinal (GI) tract, ureters, and urinary bladder.
•  In addition, to sP, other potential nociceptive transmitters include glutamate, aspartate, somatostatin, cholecystokinin, and vasoactive intestinal polypeptide.

courtesy of Roxane Pain Institute used with permission

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• Opioid Receptor Distribution
  • spinal cord: dorsal horn
  • primary afferents to pain transmission neurons
    • Opioid agonists:
      • inhibit excitatory transmitters release from these primary afferents
      • inhibit dorsal horn pain transmission neurons
      • Clinical application: directed demonstration of opioid agonists allow regional analgesia which minimizes CNS side effects

• Systemic Opioid Administration:
  • Action in both supraspinal and spinal sites
  • Important opioid binding sites in descending pathways
    • rostral ventral medulla
    • locus ceruleus
    • midbrain periaqueductal gray
  • Administration of exogenous opioids promotes release of endogenous opioids

• Tolerance/Physical Dependence
  • Repeated opioid administration:
    • gradual loss of effect, e.g. tolerance
  • Physical Dependence = physiological withdrawal symptoms (abstinence syndrome) if an antagonist is administered or the agonist is stopped.
  • Tolerance is not developed equally to all opioid effects.

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