Opioid Receptors and Pain Management

Opioid Receptors and Analgesics

• Analgesics are categorized by their therapeutic use into classes
• Opioids (narcotic analgesics) are major for acute and moderate-severe chronic pain relief
• NSAIDs and acetaminophen are commonly used for mild to moderate pain and fever reduction.
• Triptans (antimigraine medications) target migraine and cluster headaches.
• Analgesic adjuvants include tricyclic antidepressants (amitriptyline), anticonvulsants (gabapentin, pregabalin), and topical analgesics (lidocaine patches) for neuropathic pain.

Origin of Pain

• Pain is classified into physiological (nociceptive), inflammatory, and neuropathic types.
• Physiological pain results from injury to body organs or tissues.
• Inflammatory pain arises from infection or inflammation following tissue damage.
• Neuropathic pain is a chronic pain from nervous system injury.

WHO 3-Step Analgesic Ladder

• A step-wise approach to pain management
• Step 1: Non-opioid analgesics (acetaminophen or NSAIDs) with or without adjuvants.
• Step 2: Less potent opioids (hydrocodone, codeine, tramadol) with or without non-opioid analgesics and adjuvants.
• Step 3: Potent opioids (morphine, oxycodone) with or without non-opioid analgesics and adjuvants.

Opioid Receptors

• Opioid receptors are distributed throughout the brain, spinal cord, and peripheral tissues.
• These receptors (μ, δ, κ) often overlap.
• All opioid receptors are G-protein-coupled.
• Receptor activation inhibits adenylate cyclase, decreasing cyclic AMP (cAMP).
• This inhibits voltage-gated calcium channels, decreasing firing and release of pain neurotransmitters (e.g., glutamate, substance P).

The μ-Receptor

• Primarily located in the brainstem and medial thalamus.
• Endogenous peptides include endomorphin-1, endomorphin-2, and β-endorphin.
• Exogenous agonists include drug classes: 4,5-epoxymorphinan, morphinan, benzomorphan, 4-phenyl/4-anilido piperidines, and diphenylheptanes.
• Agonists produce analgesia, respiratory depression, decreased gastrointestinal motility, euphoria, and hormone release. Addictive effects are also linked to these receptors.
• Most clinically used opioid drugs act on the µ-opioid receptor.

The δ-Receptor

• Targeting these receptors is thought to lead to new treatments for schizophrenia, bipolar disorder, and depression.
• In humans, proconvulsive activity is reported,potentially limiting use.

The κ-Receptor

• Primarily found in the limbic, brainstem, and spinal cord.
• In clinical trials, most к-agonists produce dysphoria. This limits psychological addiction but is acceptable for patients.
• Some available compounds with к-agonist activity include pentazocine, nalbuphine.
• Clinical trials in humans show spiradoline (к-agonist), did not produce analgesia, but also did not produce dysphoria, diuresis, or sedation

SAR of Morphine

• Morphine is the prototype ligand for the µ-opioid receptor.
• It has 5 chiral centers and potentially 16 optical isomers.
• The naturally occurring and active form is the levorotatory enantiomorph.
• The X-ray structure is described as a "T" shape with defined rings formation.

SAR of Meperidine

• Meperidine has low potency at the μ-receptor vs. morphine (0.2% compared to morphine) but higher brain penetration (10% potency compared to morphine).
• Meperidine is a μ receptor agonist.
• Dose equivalence with morphine is described.
• Metabolism to normeperidine is described.
• The 4-ethyl ester is optimal length for analgesic potency.
• Structural changes that increase potency include the introduction of m-hydroxyl on the phenyl ring, replacing the methyl at N with a phenylethyl or p-aminophenyl group.
• Replacing the N-methyl with N-allyl/N-cyclopropylmethyl does not result in an antagonist.
• Analgesia duration may be shorter than the half-life, requiring frequent dosing to reduce pain.
• Normeperidine can cause CNS excitation, including tremors, twitches, and multifocal myoclonus, followed by grand mal seizures.
• Risk factors for normeperidine toxicity include high doses, long duration of treatment, renal dysfunction, or CYP inducers

SAR of Methadone

• Methadone (Dolophine) is a synthetic opioid for analgesia and opioid addiction treatment and maintenance.
• It is a racemic mixture, with R-enantiomer having about 7-50 times higher opioid activity than the S-enantiomer.
• Methadone is a μ-receptor agonist.
• The major metabolic pathway involves N-demethylation to EDDP, an inactive product.
• Adverse effects include standard opioid effects (pupil constriction, respiratory depression, physical dependence, extreme somnolence, coma, cardiac arrest, death), as well as QT interval prolongation and torsades de pointes.

Benzomorphans

• Structural simplification of morphine (removing the C ring of the morphinan structure) yields benzomorphans, also called benzazocines.
• Active benzomorphans have similar bridgehead carbons to morphine (carbons 9, 13 and 14 of morphine).
• Pentazocine is the only clinically used benzomorphan, and is prepared as the 2(R), 6(R), 11(R) enantiomer.

Pentazocine

• Pentazocine is a mixed agonist/antagonist opioid receptor. It is a partial agonist at the µ-receptor and a weak antagonist at the μ receptor.
• Pentazocine is also an agonist at the κ-receptor .
• This specific activity impacts higher rates of dysphoria in patients compared with morphine.
• It is available as a 50-mg tablet that also includes a low dose (0.5 mg) of naloxone (antagonist).