Pain Pharmacology

• Poppy – Papaver somniferum


  Source of opioids
• Heroin (diamorphine)


  Synthesized opioid
• Opioid

  All compounds that work at opioid receptors
• Opiate

  Naturally occurring alkaloids: morphine, codeine, thebaine, and papaverine
• Narcotic

  Causes sleep
• Opioid receptors


  • Mu (μ)
  • Kappa (κ)
  • Delta (δ)
• Endogenous Opioid Peptide Affinity

  • Mu - Endorphins > enkephalins > dynorphins
  • Delta - Enkephalins > endorphins and dynorphins
  • Kappa - Dynorphins > > endorphins and enkephalins
• Mu, Delta, Kappa Receptors:

  Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed gastrointestinal transit; modulation of hormone and neurotransmitter release, psychomimetic
• Absorption

  Well absorbed orally, also subligual, buccal, rectal, nasal and transdermal
• First pass effect

  Especially morphine
• Distribution

  Concentrate in highly perfused organs
• Metabolism

  Converted to polar metabolites (glucuronides)
• Metabolites


  Accumulate in reduced renal function, increasing ADRs
• Examples of opioids

  • Codeine (morphine)
  • Oxycodone (oxymorphone)
  • Hydrocodone (hydromorphone)
• Phenylpiperidines


  Oxidative to inactive metabolites, except meperidine -> normeperidine is active, accumulates with poor renal function -> seizures & other ADRs
• Excretion

  Polar metabolites eliminated in urine, small amount in bile
• Unchanged drug in urine

  Small amounts, metabolites can accumulate
• Opioids' actions on neurons

  • They close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce transmitter release
  • They open K+ channels and hyperpolarize and thus inhibit postsynaptic neurons
• How do opioids produce analgesia?


  They have two well-established direct Gi/0 protein-coupled actions on neurons
• Central nervous system effects

  • Analgesia – sensory and emotional component
  • Euphoria (dysphoria)
  • Sedation – drowsiness, clouding of mentation
  • Respiratory depression – dose related (cause of fatal overdoses)
  • Truncal rigidity – contributes
  • Used palliatively to reduce dyspnea
  • Miosis
  • Cough suppression
  • Nausea and vomiting - brainstem chemoreceptor trigger zone
  • Temperature
  • Sleep architecture - sleep-disordered breathing and central sleep apnea
• Peripheral effects

  • Cardiovascular system – little to
  • Gastrointestinal tract - opioid-induced constipation (tolerance doesn't develop)
  • Reduced peristaltic activity throughout
  • Biliary tract
  • Renal function - depressed
  • Uterus – prolonged labor
  • Endocrine – chronic -> low testosterone
  • Pruritus – common with morphine (histamine release), other mechanisms exist
  • Immune system
• Therapeutic effects

  • Analgesia - Moderate-Severe Pain
  • Dyspnea relief (Acute Pulmonary Edema)
  • Cough
  • Diarrhea
  • Anesthesia - sedative, anxiolytic, and analgesic properties
  • Shivering
• Adverse effects

  • Side-effects – extension of pharmacology
  • Toxicity (Overdose) – reduced consciousness/unarousable (to painful stimuli), respiratory arrest, meiosis
  • Hypersensitivity (hives, maculopapular rash, erythema multiforme, pustular rash, severe hypotension, bronchospasm, and angioedema)
  • Pseudo allergy (histamine release from mast cells): (flushing, itching, sneezing, hives, sweating, exacerbation of asthma, and low blood pressure)
• Opioid analgesics

  • Morphine
  • Hydromorphone
  • Oxymorphone
  • Levorphanol
  • Codeine
  • Butorphanol
  • Hydrocodone
  • Oxycodone
  • Nalbuphine
  • Buprenorphine
  • Meperidine
  • Fentanyl
  • Sufentanil
  • Alfentanil
  • Remifentanil
  • Pentazocine
  • Diphenoxylate
  • Loperamide
  • Methadone
  • Tramadol
  • Tapentadol
• Tolerance

  With repeated doses, diminished effects. Increased dose needed to achieve previous analgesic effects
• Cross-tolerance

  Incomplete, especially with pure agonists, tolerance exists with introduction of a different opioid
• Dependance

  Withdrawal (abstinence syndrome): Caused by reducing or stopping opioids
• Addiction

  Primary, chronic disease of brain reward, motivation, memory, and related circuitry
• Opioid antagonists

  MOA: With high-affinity for μ opioid receptors, compete and bind to opioid receptors; reducing/reversing effects of exogenous opioids
• Naloxone

  • Onset – 1-3 minutes (IV), 2-5 min (sub-Q, IM, nasal)
  • Duration – 1-2 hrs (but dissociates from receptors, additional doses may be needed)
• Drugs of opioid overdose

  Naloxone, nalmefene
• Drugs for opioid-induced constipation

  Methylnaltrexone, naldemedine, naloxegol
• Opioids

  A group of drugs that act on the central nervous system to produce morphine-like effects such as pain relief and euphoria
• Transmission of pain

  1. Pain begins at nociceptors

  2. Transmitted to second-order neurons in dorsal horn of spinal cord

  3. Carried through spinothalamic tract to thalamus

  4. Perceived in somatosensory cortex
• Pain signal

  • Takes the form of a series of action potentials that fire repeatedly depending on the intensity of pain
  • Transmitter chemicals released include glutamate, substance P, and CGRP
• Glutamate

  An important neurotransmitter for pain that can activate NMDA and AMPA receptors
• Substance P

  Binds to neurokinin-1 (NK-1) receptors, leading to intracellular signaling and activation of NMDA receptors
• CGRP

  Binds to receptors on second order neurons, leading to changes in receptor expression and function, and central sensitization
• Endogenous opioids

  Enkephalins, dynorphins, and endorphins released by the body to cope with pain
• Opioid receptors

  μ (mu), δ (delta) and κ (kappa) receptors, present in high concentrations in the dorsal horn of the spinal cord