Pharmacology of Opioid Analgesics

Introduction

Opioid analgesics comprise a diverse class of drugs used primarily for pain management. Derived from natural sources such as the opium poppy or synthesized in laboratories, these agents have been used for centuries for their potent analgesic and sedative properties. Opioids remain the most effective agents for controlling intense and certain chronic pain syndromes, but their therapeutic efficacy is balanced by the significant risk of adverse effects and misuse.​

Classification of Opioid Analgesics

Opioids can be classified in several ways—by source (natural, semi-synthetic, synthetic), efficacy (strong, moderate, weak agonists; antagonists; mixed-activity), and receptor affinity.

I. By Origin

II. By Receptor Activity

*Buprenorphine: Partial μ agonist, κ antagonist.

III. By Clinical Use/Efficacy

Mechanism of Action

Opioid analgesics exert their effects by binding to and activating specific opioid receptors—mu (μ), delta (δ), and kappa (κ)—primarily in the central and peripheral nervous systems:

• Mu (μ) receptors: Analgesia, respiratory depression, euphoria, miosis, reduced GI motility, physical dependence.
• Delta (δ) receptors: Modulate analgesia and emotional responses.
• Kappa (κ) receptors: Spinal analgesia, miosis, sedation, dysphoria.

Mechanistic Summary Table

*References: Goodman & Gilman, Katzung, Rang & Dale.​

Cellular Actions

• Inhibition of adenylyl cyclase, reduced cAMP
• Opening of K+ channels (hyperpolarization, reduced neuronal excitability)
• Closing Ca2+ channels (reduced neurotransmitter release)
• Inhibition of pain pathways at spinal and supraspinal levels; augmentation of descending inhibitory pathways

Pharmacokinetics (ADME)

Special Pharmacokinetic Considerations

• First-pass effect: Many opioids (e.g., morphine) are extensively metabolized on first pass through the liver.
• Renal failure: Metabolites (e.g., M6G) may accumulate, increasing risk of toxicity.
• Interindividual variation: CYP2D6 polymorphisms alter codeine, tramadol response.

Pharmacological Effects

Central Nervous System

• Analgesia: Most significant effect; opioids relieve most types and intensities of pain, especially nociceptive pain.
• Euphoria and Dysphoria: Euphoria due to μ-receptor stimulation; dysphoria more with κ-agonists.
• Sedation: Dose-dependent, especially with strong and mixed agonists.
• Respiratory Depression: Dose-limiting and potentially fatal.
• Cough Suppression: Central suppression of the medullary cough center (codeine).
• Miosis: Parasympathetic stimulation of oculomotor nerve (diagnostic for overdose).
• Truncal Rigidity: High IV doses (especially fentanyl); may impair ventilation.

Peripheral Effects

• Gastrointestinal: Reduced peristalsis, increased tone—marked constipation, which is persistent with chronic use.
• Biliary: Spasm of sphincter of Oddi—may exacerbate biliary colic.
• Urinary: Urinary retention (increased sphincter tone).
• Cardiovascular: Minimal unless hypoxic; histamine-mediated hypotension with some agents.
• Endocrine: Inhibit release of gonadotropin, CRH, increase prolactin.
• Immune: Immunosuppression with chronic use (mechanism under investigation).

Therapeutic Uses

1. Pain management: Most effective for moderate-to-severe acute and chronic pain (including post-surgical, cancer, myocardial infarction, trauma, palliative/hospice care).
2. Cough suppression: Codeine, dextromethorphan.
3. Diarrhea: Loperamide, diphenoxylate.
4. Pre-anesthetic medication/adjuncts to anesthesia: Fentanyl, morphine.
5. Opioid dependence treatment: Methadone, buprenorphine/naloxone (Suboxone).
6. Acute pulmonary edema: Morphine (reduces preload/afterload, relieves dyspnea; use now controversial).
7. Opioid antagonist therapy: Naloxone/naltrexone for overdose or prevention of relapse.

Adverse Effects

Opioid Tolerance, Dependence, and Withdrawal

• Tolerance: To euphoria, analgesia, respiratory depression—not to miosis/constipation.
• Physical dependence: Withdrawal syndrome with abrupt discontinuation—rhinorrhea, lacrimation, yawning, anxiety, irritability, chills, muscle aches, vomiting, diarrhea.
• Addiction: Compulsive drug-seeking and use.

Contraindications & Precautions

• Severe respiratory depression, acute asthma
• Head trauma, increased intracranial pressure
• Paralytic ileus
• Severe hepatic/renal dysfunction
• Concurrent MAOI use (risk of serotonin syndrome, especially with meperidine, tramadol)
• Known hypersensitivity
• Pregnancy (risk of neonatal abstinence syndrome)
• Elderly, debilitated, and those with compromised pulmonary function—sedative effects heightened
• Caution: concomitant CNS depressants, alcohol

Drug Interactions

Special Populations

• Pediatrics: Opioid dosing must be cautious; respiratory depression risk higher.
• Elderly: Heightened sensitivity, longer duration of action.
• Renal/Hepatic impairment: Dosage adjustment, close monitoring needed.
• Pregnancy/Lactation: Dependence and withdrawal risk in neonate.
• Genetic polymorphisms: CYP2D6 affects response to codeine/tramadol.

Opioid Antagonists

• Naloxone: Competitive antagonist at all opioid receptors; IV use rapidly reverses toxicity, short duration (1–2h).
• Naltrexone: Oral; used in maintenance therapy for opioid/alcohol dependence.
• Nalmefene: Similar to naloxone, longer duration.
• Methylnaltrexone/Alvimopan: Peripherally acting antagonists for opioid-induced constipation.

Clinical Tables

Table 1: Comparative Potency and Use

Table 2: Key Features of Selected Opioids

Recent Advances and Controversies

• Opioid stewardship: Clinical guidelines recommend careful patient selection, assessment of risk, and limits on initiation dose and quantity.
• Hyperalgesia paradox: Chronic opioid use can lead to paradoxical increased pain sensitivity.
• Genetic screening: Personalized medicine (e.g., CYP2D6 genotyping for codeine).
• Opioid crisis: Epidemic of prescription opioid misuse, resulting in widespread harm. Non-opioid and multimodal approaches are preferred wherever possible.

Summary Points

• Opioid analgesics are the gold standard for severe pain but must be used judiciously.
• They act primarily through μ (and to lesser extents, δ, κ) opioid receptors in the CNS and periphery.
• Clinical differences among opioids reflect variations in pharmacokinetics, receptor selectivity, and metabolic pathways.
• Adverse effects are significant and can be life-threatening—most notably, respiratory depression and addiction.
• Opioid antagonists (e.g., naloxone) are lifesaving in overdose scenarios.
• Multimodal pain management strategies and opioid-sparing approaches are increasingly recommended.

References

1. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition
2. Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 15th Edition
3. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G. Rang & Dale’s Pharmacology, 9th Edition
4. Pasternak GW. Opiate Pharmacology and Relief of Pain. PubMed Central. 2014.​
5. Inturrisi CE. Clinical Pharmacology of Opioids for Pain. Weill Cornell Med.​
6. Opioid Therapy in Acute and Chronic Pain. American College of Clinical Pharmacology.​
7. StatPearls Publishing: Physiology, Opioid Receptor (NCBI).​
8. Sage Journals: Basic Opioid Pharmacology — An Update.​
9. The Oxford Catalogue of Opioids, 2021.​
10. ScienceDirect. Trends in the Pharmacology of Opioids: Implications for Pain Management.