Drugs for Pain and Inflammation Disease

• Nociception


  Ability to detect painful stimuli by specialized neurons
• Dorsal root ganglia (DRG), trigeminal ganglia


  • Connected to skin and soft tissues
• Nociceptive pain


  Mild to moderate arthritic pain, treated with non-opioid analgesics (NSAIDs)
• Neuropathic pain


  Can be treated with opioids often at higher doses, but responds best with anticonvulsants, TCAs, or SNRIs
• Chronic or severe Malignant / non-malignant pain


  Treated with opioids
• Pain


  Serves as a protective function by signaling the presence of noxious, tissue-damaging conditions
• Nociceptors


  Receptors for pain; free nerve endings found in every tissue of the body except the brain; intense thermal, mechanical, or chemical stimuli can activate nociceptors
• Prostaglandins (PG), kinins and K+ ions


  Released during tissue irritation or injury, stimulate nociceptors
• Opioids


  Natural, semi-synthetic or synthetic compounds with morphine-like effects
• Mechanism of action of opioids

  Bind to specific opioid receptors in the CNS to produce effects that mimic the action of endogenous peptide neurotransmitters (i.e., endorphins, enkephalins, and dynorphins)
• Primary function/use of opioids

  Relieve intense pain (pain that results from surgery, injury, or chronic disease)
• Source of opioids

  Papaver somniferum and P. album (poppy) → incision of poppy seed pod exudates a white substance that turns into a brown gum that is crude opium (contains many alkaloids, the principal one is Morphine which is about 10%)
• Major opioid receptors


  • Mu (μ)
  • Kappa (κ)
  • Delta (δ)
• Mu (μ) receptor


  Mediates analgesic properties of opioids, modulates responses to thermal, mechanical, and chemical nociception, located at supraspinal level
• Kappa (κ) receptor


  Found in the dorsal horn, contribute to analgesia by modulating the response to chemical and thermal nociception
• Delta (δ) receptor


  Interacts with enkephalins in the periphery, involved in mechanical inflammation and inflammatory pain
• Endogenous opioid receptors


  Painful stimuli can evoke release of endogenous opioid peptides under the stress associated with pain or the anticipation of pain, and they diminish the perception of pain
• Endogenous opioid peptides and their receptor affinities

  • Endorphins > Enkephalins > Dynorphins (μ receptor)
  • Enkephalins > Endorphins and Dynorphins (δ receptor)
  • Dynorphins >> Endorphins and Enkephalins (κ receptor)
• Functions of endogenous opioid peptides

  • Endorphins: it can reduce stress, and improve well-being
  • Enkephalins: involve BP regulations, memory processes, and possesses neuroprotection
  • Dynorphins: associated with addiction, mood regulation
• Pharmacokinetic properties of opioids

  • Well-absorbed when given SQ, IM or oral route; first pass effect is evident hence oral dose may need to be higher than parenteral dose to elicit therapeutic effect; Codeine and Oxycodone are effective orally due to reduced first pass metabolism
  • Localize in highest concentrations in highly perfused tissues such as brain, lungs, kidneys and spleen
  • Converted in large part to polar metabolites (mostly glucuronides); Codeine, Oxycodone, and Hydrocodone are metabolized by CYP2D6 to produce more potent metabolites; Morphine is metabolized to morphine-6-glucuronide (very potent analgesic) and morphine-3-glucuronide (does not have analgesic activity)
  • Polar metabolites are excreted mainly in the urine; glucuronide conjugates are found in the bile
• Morphine


  Major analgesic drug contained in crude opium; prototype strong μ receptor agonist
• Mechanism of action of morphine

  Morphine and other opioids exert their major effects by interacting stereospecifically with opioid receptors on the membranes of certain cells in the CNS and other anatomical structures (GI tract and urinary bladder); Morphine acts at κ receptors in lamina I and II of dorsal horn of spinal cord, decreases release of substance P which modulates pain perception in spinal cord and inhibit the release of excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli
• Opioid agonist actions


  • Analgesia
  • Euphoria
  • Respiratory depression
  • Depression of cough reflex
  • Emesis
  • Miosis
  • Cardiovascular effects
  • Histamine release
  • Hormonal actions
  • Effects on labor
• Analgesia


  Morphine and other opioids produce analgesia (relief of pain without loss of consciousness) and relieve pain both by raising pain threshold in spinal cord level and altering brain's perception of pain
• Euphoria


  Morphine produces powerful sense of contentment and well-being, caused by disinhibition of dopamine-containing neurons of the ventral tegmental area
• Respiratory depression


  Morphine causes respiratory depression by reduction of sensitivity of respiratory center neurons to CO2, most common cause of death in acute opioid overdoses
• Cough reflex


  Morphine and Codeine have antitussive properties
• Emesis


  Morphine directly stimulates chemoreceptor trigger zone in the area postrema that causes vomiting
• Miosis


  Pinpoint pupil characteristic of Morphine is through stimulation of μ and κ receptors and there is little tolerance to this effect
• Cardiovascular effects


  Morphine has no major effects on the blood pressure or HR at lower dosages; at large doses, hypotension and bradycardia may occur; Morphine is contraindicated in individuals with head trauma or severe brain injury due to ability to increase cerebrospinal fluid pressure
• Histamine release


  Morphine releases histamine from mast cells causing urticaria, sweating, and vasodilation; Morphine can cause bronchoconstriction hence should be used with caution in patients with asthma
• Hormonal actions


  Morphine increases growth hormone release and enhances prolactin secretion; increases antidiuretic hormone leading to urinary retention
• Effects on labor


  Morphine may prolong 2nd stage labor by decreasing duration and frequency of uterine contractions
• Adverse effects of opioids


  Severe respiratory depression, elevation of intracranial pressure particularly in head injury, used with caution in patients with asthma, liver disease or renal dysfunction
• Tolerance and physical dependence


  Repeated use leads to tolerance to respiratory depressant, analgesic, euphoric and sedative effects; physical and psychological dependence develops
• Drug interactions


  Depressant actions of Morphine are enhanced by Phenothiazines, MAOIs, and TCAs
• Codeine


  Naturally occurring opioid that is a weak analgesic compared to Morphine, used for mild to moderate pain, analgesic action derived from its conversion to Morphine by CYP450 2D6 enzyme system, exhibits good antitussive activity at doses that do not cause analgesia
• Hydromorphone and Hydrocodone

  orally active, semi-synthetic analogs of morphine and codeine, respectively
• Fentanyl


  Synthetic opioid chemically related to Meperidine, 100-fold the analgesic property of Morphine, used for anesthesia, administered IV, epidurally, or intrathecally, highly lipophilic with rapid onset and short duration of action, used with local anesthetic for epidural anesthesia and for breakthrough pain in cancer patients tolerant to opioids
• Meperidine


  100-fold the analgesic property of Morphine and is used for anesthesia