Opioids and NSAIDs

Opioid Analgesic Drugs (Opiates)

  • Definition: The term OPIATE refers to compounds derived from the opium poppy.

  • Morphine Composition: Found in opium at a concentration of approximately 10%.

  • Codeine: Present naturally but in smaller amounts compared to morphine and can be synthesized from morphine.

Structure of Key Opioids

  • Morphine:

    • Structure: HO-

    • Chemical representation:

    morphine structure

  • Codeine:

    • Structure: H\N-CH3

    • Chemical representation:

    codeine structure
Endogenous Opioid Peptides

  • Function: Opioid drugs mimic endogenous opioids found in the body, which consist of peptides acting at various opioid receptors.

  • Morphine-like Effects: Naturally occurring peptide effects similar to those produced by morphine.

  • Opioid Receptors: Bind to distinct opioid receptors in the body.

Types of Endogenous Opioids

  1. Endorphins

    • Definition: Endogenous polypeptides with a high affinity for mu (μ) receptors.

    • Production: Synthesized in the pituitary gland and hypothalamus during exercise, excitement, and pain.

  2. Enkephalins

    • Definition: Endogenous ligands with high selectivity for delta (δ) opioid receptors, also binding to mu receptors.

    • Forms: Met-enkephalin and Leu-enkephalin are two known forms.

  3. Dynorphins

    • Definition: Have a high selectivity for kappa (κ) opioid receptors and include dynorphin A and B.

    • Presence: Increased levels detected in the dorsal horn following tissue injury and inflammation.

Receptor Selectivity Table for Opioids

| Receptor |

μ (Mu) |

δ (Delta) |

κ (Kappa) |
| :-------------- | :-------------- | :-------------- | :-------------- |
| Endorphins | +++ | + | - |
| Enkephalins | ++ | +++ | + |
| Dynorphins | + | + | +++ |
| Morphine | +++ | ++ | ++ |
| Fentanyl | +++ | + | + |
| Buprenorphine | Partial Agonist | Antagonist | Antagonist |
| Naloxone | Antagonist | Antagonist | Antagonist |

Opioid Receptors

Types of Opioid Receptors

  • μ (Mu) Receptor: Key target for pain relief and associated euphoria.

  • δ (Delta) Receptor: Modulates analgesia and emotional responses.

  • κ (Kappa) Receptor: Associated with sedation and dysphoria.

Mechanisms of Opioid Action

  1. Binding Mechanism: Opioids bind to opioid receptors on neurons, which are G-protein coupled.

  2. Channel Regulation:

    • Ca²⁺ Channels: Closure of voltage-gated Ca²⁺ channels reduces transmitter release.

    • K⁺ Channels: Opening of K⁺ channels hyperpolarizes neurons, reducing action potential firing.

  3. Effect on Action Potentials:

    • Neurons in absence of opioids are primed to fire an action potential, while presence of opioids leads to reduced likelihood of firing.

Nociceptive Pathway Targeting by Opioids

  • Areas of Action:

    • Possible direct actions on peripheral tissues.

    • Inhibition at spinal cord and brain areas (ventral caudal thalamus, midbrain, medulla) affecting pain signal transmission.

Relative Potencies of Opioid Drugs

  • Potency Table:

    Drug

    Relative Potency (vs. Morphine = 1)

    Morphine

    1

    Codeine

    0.1

    Fentanyl

    100

    Sufentanil

    1000

    Hydromorphone

    5-7

    Oxycodone

    1.5-2

    Methadone

    1-3 (acute); variable (chronic)

    Buprenorphine

    25-100 (partial agonist)

    Levorphanol

    4

    • Routes of Administration:

      • Oral mucosa (lozenges), sublingual sprays, transdermal patches, nasal insufflation.

      • These methods bypass portal circulation, avoiding first-pass metabolism.

    Strong Opioid Agonists

    1. Morphine:

      • Effects: Elevates pain threshold without loss of consciousness (μ, κ receptors).

      • Euphoria at μ receptors but may cause dysphoria at κ receptors.

    2. Methadone:

      • Long-acting, primarily oral; treatment for opioid addiction.

    3. Fentanyl:

      • Synthetic with higher lipophilicity than morphine; 100 times more potent.

      • Short duration (30-40 min) due to rapid CNS penetration.

    Weak Opioid Agonists

    1. Codeine:

      • Low efficacy; about 10% metabolized to morphine; used for mild to moderate pain and as an antitussive.

    2. Tramadol:

      • Analogue of codeine, weak μ receptor agonist, also inhibits reuptake of norepinephrine (NA) and serotonin (5-HT).

      • Associated risks include respiratory depression, seizures, and serotonin syndrome.

    Opioid Antagonists

    • Naloxone: Rapidly reverses opioid action and is essential in overdose cases. Short t1/2t_{1/2} (1-2 hours).

    • Naltrexone: Longer acting than naloxone and used for treating withdrawal rather than overdose.

    Opioid Partial Agonists

    • Buprenorphine:

      • Acts as a mixed agonist-antagonist, showing full antagonism when combined with full agonists.

      • Used for moderate pain in opioid non-tolerant individuals and helpful in addiction treatments.

    Additional Opioid Drugs

    • Levorphanol (stronger than morphine, used pre-operatively), Sufentanil (1000X more potent than morphine, used post-operatively), Hydromorphone (semi-synthetic), Oxycodone (semi-synthetic).

    Opioid Drug Tolerance

    • Overview: Tolerance develops with repeated use of opioid drugs but varies by effect type:

      • Fast Tolerance: Euphoria from morphine.

      • Slow (or no) Tolerance: Efficacy regarding constipation and respiratory effects.

    Inflammatory Pain Treatment Agents

    • Overview:

      • Inflammatory mediators (e.g., histamine, NGF) activate nociceptors post-tissue injury.

      • Treatments include steroidal and non-steroidal agents.

      • Steroidal Drugs: Bind cytosolic glucocorticoid receptors, translocate to the nucleus, and modulate gene expression affecting inflammation.

      • NSAIDs: Inhibit COX enzymes, reducing prostaglandin production.

    Mediators of Inflammation in Nociceptive Pathway

    1. Substance P and CGRP: Excite nociceptors, elicit pain, cause vasodilation.

    2. Histamine: Released by mast cells, excites nociceptors.

    3. Nerve Growth Factor (NGF): Binds to nociceptors, activating pain signaling.

    4. Other Mediators: Include serotonin, acetylcholine, low pH, and ATP, all contributing to nociceptor excitation.

    Corticosteroids - Mechanism of Action

    • Key Actions: Bind to the cytosolic glucocorticoid receptor, influencing transcription of genes coding for cytokines involved in inflammation, ultimately decreasing inflammation through various pathways.

    Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

    • Mechanism: Block formation of prostaglandins, which are crucial for nociceptor activation.

    • Examples: Aspirin, ibuprofen inhibit COX enzymes.

    Side Effects of NSAIDs

    • Risks: Can lead to gastric ulcers or increased risk of bleeding; some NSAIDs also increase gastric acid secretion.

    Paracetamol (Acetaminophen) Summary

    • Function: Analgesic and antipyretic effects but lacks significant anti-inflammatory properties.

    • Comparison: Similar to aspirin in analgesic and antipyretic activity but not effective for inflammatory condition management.

    Neuropathic Pain and Treatment Agents

    • Definition: Arises from actual nerve damage, often described as burning or numb sensations.

    • Treatment Options: Anticonvulsants (e.g., carbamazepine, lamotrigine), antidepressants (e.g., amitriptyline, venlafaxine) each targeting neuronal excitability and pain signaling pathways.