Definition and Classification Context
Opioids, also known as narcotic analgesics, constitute a class of centrally acting medications that bind to opioid receptors (mu, delta, kappa) in the central and peripheral nervous systems to modulate pain perception and response. These agents are potent analgesics used in the treatment of moderate to severe acute or chronic pain, as well as in anesthesia, cough suppression, and palliative care. The term "opioids" encompasses both natural alkaloids derived from the opium poppy (e.g., morphine, codeine), semi-synthetic derivatives (e.g., oxycodone, hydromorphone), and fully synthetic compounds (e.g., fentanyl, methadone).
Opioids vary widely in potency, pharmacokinetics, receptor binding affinity, and abuse potential, and many are listed as controlled substances under international and national laws due to risks of addiction, tolerance, respiratory depression, and overdose.
1. Mechanism of Action
Opioids exert their effect by binding to G-protein coupled opioid receptors:
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μ (mu) receptor: primary target for analgesia, euphoria, respiratory depression, physical dependence
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κ (kappa) receptor: spinal analgesia, dysphoria, diuresis
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δ (delta) receptor: modulates analgesia and emotion
Mechanistically:
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Opioid binding inhibits adenylate cyclase, reducing cAMP production
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Opens K⁺ channels, leading to hyperpolarization
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Inhibits Ca²⁺ influx, suppressing neurotransmitter release
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Result: dampening of pain signal transmission and altered pain perception
2. Classification of Opioids
a. By Source and Structure
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Natural opiates: Morphine, Codeine (from Papaver somniferum)
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Semi-synthetic: Oxycodone, Hydromorphone, Buprenorphine
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Synthetic: Fentanyl, Methadone, Tramadol, Meperidine
b. By Receptor Activity
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Full agonists: Morphine, Fentanyl, Methadone
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Partial agonists: Buprenorphine
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Mixed agonist-antagonists: Nalbuphine, Butorphanol
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Pure antagonists: Naloxone, Naltrexone (used to reverse effects)
c. By Potency
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Low potency: Codeine, Dihydrocodeine
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Moderate: Morphine, Hydrocodone
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High: Fentanyl, Hydromorphone, Sufentanil, Carfentanil (used in veterinary medicine)
3. Generic and Brand Names
| Generic Name | Brand Name(s) |
|---|---|
| Morphine | MS Contin, Kadian |
| Codeine | Tylenol with Codeine |
| Hydrocodone | Vicodin, Norco |
| Oxycodone | OxyContin, Percocet |
| Fentanyl | Duragesic, Actiq |
| Methadone | Dolophine, Methadose |
| Hydromorphone | Dilaudid |
| Meperidine | Demerol |
| Tramadol | Ultram |
| Buprenorphine | Subutex, Suboxone |
| Tapentadol | Nucynta |
| Nalbuphine | Nubain |
| Butorphanol | Stadol |
4. Therapeutic Uses
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Acute pain: trauma, surgery, myocardial infarction
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Chronic pain: cancer pain, end-of-life care, severe arthritis
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Obstetric pain: labor analgesia (e.g., meperidine)
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Cough suppression: codeine (off-label)
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Diarrhea control: loperamide (peripherally acting)
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Opioid dependence therapy: methadone, buprenorphine
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Anesthesia adjuncts: fentanyl, sufentanil
5. Dosage and Routes of Administration
| Route | Examples |
|---|---|
| Oral | Morphine, Codeine, Oxycodone, Methadone |
| IV/IM/Subcutaneous | Morphine, Fentanyl, Hydromorphone |
| Transdermal | Fentanyl patches (chronic pain) |
| Buccal/sublingual | Buprenorphine films, fentanyl lozenges |
| Epidural/spinal | Morphine, Fentanyl |
| Rectal | Morphine suppositories |
| Intranasal | Butorphanol, Naloxone |
6. Adverse Effects
| System Affected | Common Adverse Effects |
|---|---|
| CNS | Sedation, dizziness, confusion, euphoria, hallucinations |
| Respiratory | Respiratory depression (dose-limiting, life-threatening) |
| Gastrointestinal | Constipation (universal), nausea, vomiting |
| Cardiovascular | Hypotension, bradycardia, QT prolongation (e.g., methadone) |
| Dermatologic | Pruritus, flushing (histamine release) |
| Urogenital | Urinary retention, sexual dysfunction |
| Endocrine | Hypogonadism with long-term use |
| Addiction risk | Tolerance, dependence, misuse |
7. Contraindications
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Severe respiratory depression not monitored in controlled settings
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Acute or severe bronchial asthma
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Known hypersensitivity to opioids
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Paralytic ileus (especially with codeine, loperamide)
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Co-administration with MAOIs (e.g., with meperidine)
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Uncontrolled seizure disorders (esp. with tramadol)
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Head injury or increased intracranial pressure (risk of masked symptoms)
8. Precautions
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Elderly patients: increased sensitivity to CNS and respiratory effects
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Hepatic/renal impairment: altered drug metabolism; dose adjustment required
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Pregnancy: potential for neonatal abstinence syndrome
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Breastfeeding: some opioids (e.g., codeine) pass into milk and may depress infant respiration
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Sleep apnea: increased risk of respiratory depression
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Polypharmacy: increased risk of serotonin syndrome, sedation, hypotension
9. Drug Interactions
| Drug or Class | Effect with Opioids |
|---|---|
| Benzodiazepines | Profound sedation, respiratory depression, death risk |
| Alcohol | Enhanced CNS depression |
| Antidepressants (SSRIs/SNRIs) | Risk of serotonin syndrome (especially with tramadol) |
| MAO inhibitors | Dangerous interactions with meperidine, tramadol |
| CYP3A4 inhibitors | ↑ Fentanyl, methadone, oxycodone levels |
| CYP2D6 inhibitors | ↓ Codeine efficacy (requires CYP2D6 activation) |
| Naloxone/naltrexone | Blocks opioid effects; used to reverse or prevent overdose |
| QT-prolonging drugs | Additive cardiac risks with methadone |
10. Tolerance, Dependence, and Withdrawal
Chronic opioid use results in:
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Tolerance: requiring higher doses for same effect
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Physical dependence: abrupt discontinuation leads to withdrawal
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Withdrawal symptoms: rhinorrhea, lacrimation, mydriasis, vomiting, diarrhea, tremors, anxiety, yawning, piloerection
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Managed via tapering, methadone, or buprenorphine treatment
Addiction (opioid use disorder) is a behavioral condition characterized by compulsive use despite harm, distinct from physiological dependence.
11. Overdose Management
Signs:
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Pinpoint pupils
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Respiratory depression
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Coma
Treatment:
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Naloxone (Narcan): opioid receptor antagonist; reverses overdose rapidly
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Available as intranasal spray, auto-injector, IV
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Multiple doses may be needed (e.g., with fentanyl analogs)
12. Regulatory Classification
Most opioids are classified as Controlled Substances:
| Schedule | Examples |
|---|---|
| C-II | Morphine, Fentanyl, Oxycodone, Hydromorphone |
| C-III | Buprenorphine, Codeine combinations (e.g., Tylenol 3) |
| C-IV | Tramadol, Butorphanol |
| C-V | Some low-dose codeine cough syrups (restricted use) |
13. Clinical Guidelines and Monitoring
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CDC, WHO, and national pain societies issue guidelines on:
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Initiating opioid therapy
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Monitoring for misuse
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Tapering protocols
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Urine drug testing and PDMP review
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Monitoring Parameters:
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Pain control and functional improvement
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Sedation score and respiratory rate
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Signs of misuse or diversion
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Constipation management
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ECG (for methadone, QT interval)
14. Opioid-Sparing and Adjunct Strategies
To reduce risks:
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Use lowest effective dose, shortest duration
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Combine with non-opioid analgesics: acetaminophen, NSAIDs
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Employ adjuvants: antidepressants, anticonvulsants (e.g., gabapentin)
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Regional blocks, physiotherapy, or cognitive behavioral therapy
15. Public Health and Abuse Crisis
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Synthetic opioids (e.g., illicit fentanyl) are driving opioid overdose deaths globally
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Emphasis on naloxone distribution, prescriber education, opioid stewardship programs
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Medication-Assisted Treatment (MAT) using methadone, buprenorphine, and naltrexone is central to opioid use disorder management
16. Opioid Rotation and Equianalgesic Dosing
When switching opioids:
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Consider equianalgesic dose tables
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Adjust for cross-tolerance (often reduce dose by 25–50%)
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Monitor closely for efficacy and adverse effects
Example equivalency (approximate):
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10 mg IV morphine = 30 mg oral morphine = 20 mg oral oxycodone = 100 mcg fentanyl patch/day
17. Special Populations
| Group | Key Considerations |
|---|---|
| Elderly | Start low, go slow; ↑ sensitivity to sedation |
| Children | Use weight-based dosing; avoid codeine (CYP2D6 variability) |
| Pregnant women | Avoid if possible; use methadone for addiction |
| Renal failure | Avoid morphine (active metabolites accumulate); use fentanyl or methadone with caution |
| Liver disease | Reduce dosing; monitor mental status (risk of hepatic encephalopathy) |
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