Anesthesia Pharmacology Chapter 28:  Pain Management 

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

• 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)

Pharmacodynamics

• Mechanism of Action:

  • analgesia: specific receptor binding -- localization:

    • spinal cord

    • brain

• Receptor Types:

  • Mu (μ)

  • Delta (δ)

  • Kappa (κ)

  • General Opioid Receptor Characteristics:

    • G protein coupled receptor family

    • Significant amino acid sequence homology

    • Each-receptor: subtypes

      • μ₁, μ₂

      • δ₁, δ₂

      • κ₁, κ₂

  • 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 -- (μ)

    • pentazocine -- (κ) some (μ)

    • endogenous opioid peptides:

      • leu-enkephalin --(δ)

      • dynorphin --(κ)

• 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

• 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

• 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.