Opioids: Mechanism of Action

• Opioids are a class of drugs that include opium derivatives and synthetic substitutes with opium-like activity
• Opioids produce analgesia, euphoria, and other effects by interacting with specific receptors in the central and peripheral nervous systems

Mechanism of Action

• Opioids primarily act by binding to opioid receptors, which are G protein-coupled receptors (GPCRs)
• The main opioid receptors are mu (μ), delta (δ), and kappa (κ) receptors
• Activation of opioid receptors leads to:
  • Inhibition of adenylyl cyclase, reducing intracellular cAMP levels
  • Activation of potassium channels, causing hyperpolarization
  • Inhibition of calcium channels, reducing neurotransmitter release
• These actions result in decreased neuronal excitability and reduced transmission of pain signals
• Opioids affect both ascending (sensory) and descending (modulatory) pain pathways in the central nervous system
• Mu (μ) receptors:
  • High affinity for morphine and related opioids
  • Mediate analgesia, euphoria, respiratory depression, sedation, and physical dependence
  • Distributed in the brain (e.g., thalamus, periaqueductal gray) and spinal cord
• Delta (δ) receptors:
  • Contribute to analgesia, particularly in inflammatory and neuropathic pain
  • May modulate the effects of mu receptors
  • Found in the brain and peripheral tissues
• Kappa (κ) receptors:
  • Mediate analgesia (primarily spinal), dysphoria, and sedation
  • Have limited effects on respiratory function compared to mu receptors
  • Located in the brain (e.g., hypothalamus, pituitary) and spinal cord
• Opioids can also act at the spinal level to inhibit the release of pain neurotransmitters, such as substance P and glutamate
• Endogenous opioid peptides (endorphins, enkephalins, dynorphins) also bind to opioid receptors and modulate pain

Side Effects

• Common side effects of opioids include:
  • Respiratory depression: Mu receptor activation in the brainstem reduces the sensitivity to carbon dioxide, leading to decreased respiratory rate and depth
  • Constipation: Opioids reduce gastrointestinal motility and increase fluid absorption, leading to hard stools and infrequent bowel movements
  • Nausea and vomiting: Stimulation of the chemoreceptor trigger zone (CTZ) in the medulla can induce nausea and vomiting
  • Sedation: Opioids depress the central nervous system, causing drowsiness and cognitive impairment
  • Itching and urticaria: Opioid-induced histamine release can cause itching and skin reactions
  • Miosis (pinpoint pupils): Mu and kappa receptor activation causes pupillary constriction
  • Urinary retention: Opioids can increase bladder sphincter tone and decrease the sensation of bladder fullness
  • Hypotension: Opioids can cause vasodilation and decreased blood pressure
• Less common but serious side effects:
  • Adrenal insufficiency: Long-term opioid use can suppress the hypothalamic-pituitary-adrenal (HPA) axis
  • Immunosuppression: Opioids can impair immune cell function
  • Endocrine effects: Opioids can suppress gonadotropin-releasing hormone (GnRH) and lead to decreased libido, infertility, and menstrual irregularities
  • Neurotoxicity: High doses of some opioids can cause seizures and other neurological effects
• Opioid-induced hyperalgesia can occur with chronic use, leading to increased sensitivity to pain
• Tolerance and dependence can develop with prolonged opioid use

Clinical Uses

• Analgesia:
  • Management of acute pain (e.g., post-operative, trauma)
  • Treatment of chronic pain (e.g., cancer pain, neuropathic pain)
  • Often used in combination with non-opioid analgesics (e.g., NSAIDs, acetaminophen) to enhance pain relief and reduce opioid dosage
• Cough suppression:
  • Codeine and dextromethorphan are used as antitussives to reduce coughing
• Treatment of diarrhea:
  • Loperamide and diphenoxylate are used to reduce bowel motility and control diarrhea
• Anesthesia:
  • Fentanyl and related opioids are used as adjuncts to general anesthesia for pain control and sedation
• Management of opioid dependence:
  • Methadone and buprenorphine are used as maintenance therapies to reduce cravings and withdrawal symptoms
• Pulmonary edema:
  • Morphine and other opioids are used to reduce anxiety and shortness of breath associated with pulmonary edema

Tolerance and Dependence

• Tolerance:
  • Reduced response to a drug after repeated administration
  • Requires higher doses to achieve the same effect
  • Mechanisms involve receptor desensitization, downregulation, and changes in intracellular signaling pathways
  • Cross-tolerance can occur between different opioids
• Dependence:
  • Physiological adaptation to chronic drug exposure
  • Withdrawal symptoms occur upon abrupt discontinuation or dose reduction
  • Physical dependence is characterized by somatic symptoms (e.g., muscle aches, sweating, diarrhea, goosebumps)
  • Psychological dependence involves cravings, anxiety, and dysphoria
• Opioid withdrawal syndrome:
  • Onset and duration vary depending on the specific opioid and duration of use
  • Symptoms include anxiety, insomnia, sweating, muscle aches, abdominal cramping, diarrhea, vomiting, and hypertension
  • Severity can range from mild to life-threatening
• Risk factors for opioid dependence include:
  • History of substance abuse
  • Mental health disorders
  • Chronic pain
  • High doses and long duration of opioid use
• Strategies to minimize tolerance and dependence:
  • Use the lowest effective dose for the shortest duration
  • Consider non-opioid analgesics and alternative therapies
  • Rotate opioids to reduce tolerance
  • Taper opioids gradually when discontinuing treatment
• Opioid overdose:
  • Can cause severe respiratory depression, coma, and death
  • Naloxone is an opioid antagonist that can rapidly reverse the effects of an opioid overdose
  • Naloxone is available as an injection or nasal spray
  • Public health campaigns promote the use of naloxone to prevent opioid overdose deaths

Opioid Receptor Types

• Mu (μ) receptors:
  • μ1: Analgesia (supraspinal), euphoria, physical dependence
  • μ2: Analgesia (spinal), respiratory depression, constipation
  • μ3: Immunosuppression
• Delta (δ) receptors:
  • δ1 and δ2 subtypes
  • Analgesia, antidepressant effects
  • Modulation of mu receptor activity
• Kappa (κ) receptors:
  • κ1: Analgesia (spinal), dysphoria, diuresis
  • κ2: Psychomimetic effects
  • κ3: Analgesia (peripheral)
• Opioid receptors are widely distributed throughout the central and peripheral nervous systems
• Receptor distribution varies between individuals and may be influenced by genetics, age, and disease state
• Endogenous opioid peptides have varying affinities for different opioid receptors
• Opioid receptor subtypes continue to be a focus of research for developing more selective analgesics with fewer side effects