Narcotics

Question 1

What are the key definitions: Narcotic, Opioid, Opiate?,”Narcotic: Drug that produce

Answer 1

Narcotic: Drug that produces analgesia (pain relief) and narcosis (stupor/sleep). Can cause euphoria and addiction.
Opioid: Any compound with morphine-like activity that interacts with opioid receptors (includes natural, synthetic, semisynthetic, and endogenous peptides).
Opiate: Substance extracted from opium (exudate of Papaver somniferum). Examples: Morphine, Codeine.”

Question 2

What is the source and composition of opium?

Answer 2

Source: Dried exudate from unripe seed capsule of Papaver somniferum.
Composition:
• Phenanthrene derivatives: Morphine (10%), Codeine (0.5%), Thebaine (0.2%, non-analgesic)
• Benzoisoquinoline derivatives: Papaverine (1%, smooth muscle relaxant), Noscapine (6%, antitussive)

Question 3

How are opioids classified based on origin and receptor activity?

Answer 3

By Origin:
1. Natural opium alkaloids: Morphine, Codeine
2. Semisynthetic opiates: Heroin (Diacetylmorphine), Pholcodeine
3. Synthetic opioids: Pethidine, Fentanyl, Methadone, Tramadol
By Receptor Activity:
• Pure agonists: Morphine, Fentanyl (μ-receptor)
• Agonist-antagonists: Pentazocine (κ-agonist, weak μ-antagonist)
• Partial agonists: Buprenorphine (weak μ-agonist, κ-antagonist)
• Pure antagonists: Naloxone, Naltrexone

Question 4

What are the three main opioid receptor types and their effects?

Answer 4

1. μ (Mu) receptors:
   • Effects: Analgesia, euphoria, respiratory depression, constipation, nausea/vomiting, dependence
   • Location: CNS, GI tract
2. δ (Delta) receptors:
   • Effects: Analgesia, affective behavior, proconvulsant
   • Location: CNS, periphery
3. κ (Kappa) receptors:
   • Effects: Analgesia, dysphoria, psychotomimetic effects, sedation
   • Location: CNS, spinal cord
   Note: κ and δ activation do NOT cause significant respiratory depression or decreased GI motility.

Question 5

What is the mechanism of opioid action at the cellular level?

Answer 5

Opioids are GPCR agonists that:
1. Inhibit adenylyl cyclase (μ, δ) → ↓ cAMP
2. Stimulate K+ efflux (μ, δ) → hyperpolarization
3. Inhibit voltage-gated Ca2+ channels (κ) → ↓ neurotransmitter release
Overall: Decrease release of pain neurotransmitters (Substance P, glutamate, neurokinins) from primary afferent neurons in spinal cord and brain.

Question 6

Describe the endogenous opioid system.

Answer 6

Endogenous opioid peptides:
• β-Endorphins: Act on μ receptors (analgesia, euphoria)
• Enkephalins (Met-enkephalin, Leu-enkephalin): Act on μ and δ receptors
• Dynorphins: Act on κ receptors (analgesia, dysphoria)
• Endomorphins: Selective μ receptor agonists
• Nociceptin: Acts on NOP (ORL-1) receptor (modulates pain)
These are produced in brain, spinal cord, pituitary, and GI tract.

Question 7

What is the gate control theory of pain and opioid action?

Answer 7

Gate Control Theory: Pain transmission is modulated in substantia gelatinosa (SG) of spinal cord.
• Aβ fibers (touch) stimulate SG interneurons to release enkephalins → inhibit pain transmission
• Opioids mimic this by:
1. Inhibiting glutamate release from primary afferent fibers
2. Enhancing descending inhibitory pathways (from brainstem)
3. Disinhibiting pain-inhibitory neurons by blocking GABAergic interneurons

Question 8

What are the CNS effects of morphine?

Answer 8

1. Analgesia: Reduces both sensory and affective components of pain
2. Euphoria: Pleasant floating sensation (DA release in nucleus accumbens)
3. Sedation: Drowsiness, clouded mentation (little amnesia)
4. Respiratory Depression: ↓ responsiveness to CO2 (primary cause of death)
5. Cough Suppression: Especially with codeine
6. Miosis: Pinpoint pupils (Edinger-Westphal nucleus stimulation)
7. Nausea/Vomiting: CTZ stimulation
8. Truncal Rigidity: Interferes with ventilation
9. Temperature & Vasomotor Depression: Hypothermia, hypotension

Question 9

What are the peripheral effects of morphine?

Answer 9

Cardiovascular:
• Bradycardia (except Pethidine → tachycardia)
• Hypotension (vasodilation, histamine release, vasomotor depression)
• ↑ Cerebral blood flow/ICP (due to ↑ PCO2)
Gastrointestinal:
• Constipation (↑ tone, ↓ motility, ↑ water absorption)
• ↓ Gastric acid secretion
• Biliary colic (sphincter of Oddi constriction)
Renal:
• ↓ Renal plasma flow, ↑ Na+ reabsorption
• Urinary retention (↑ sphincter tone)
Uterus: Prolongs labor (↓ uterine tone)
Endocrine: ↑ ADH, prolactin, GH; ↓ LH
Other: Pruritus (histamine), immunosuppression

Question 10

What are the pharmacokinetics of morphine?

Answer 10

Absorption:
• PO: Peak 30-60 min, Duration 3-4h
• IV: Peak 5-15 min, Duration 1-2h
• SC/IM: Peak 30-60 min, variable
Metabolism: Conjugated in liver (glucuronidation)
Excretion: 90-95% renal (active metabolites)
Half-life: 2-3h (steady state in 24h)
Special Populations: Adjust dose in renal/hepatic impairment, dehydration

Question 11

What are the clinical uses of opioid analgesics?

Answer 11

1. Analgesia: Moderate to severe pain (acute, chronic, cancer)
2. Cough: Codeine as antitussive
3. Diarrhea: Loperamide, Diphenoxylate (peripheral action)
4. Acute Pulmonary Edema: Morphine (reduces anxiety, preload)
5. Balanced Anesthesia: Component of anesthetic regimen
6. Preanesthetic Medication: Reduces anxiety, analgesic
7. Opioid Dependence Treatment: Methadone, Buprenorphine

Question 12

Describe acute morphine poisoning.

Answer 12

Symptoms: Stupor → coma, shallow breathing, cyanosis, pinpoint pupils, hypotension, convulsions
Lethal Dose: ~250 mg (death from respiratory failure)
Treatment:
1. Airway/Respiratory Support: Positive pressure ventilation
2. Antidote: NALOXONE IV (repeated as needed)
3. Supportive: IV fluids, gastric lavage with KMnO4
4. Monitoring: Vital signs, respiratory status

Question 13

What is opioid tolerance and dependence?

Answer 13

Tolerance: Reduced response with repeated use → need higher doses
Dependence: Physical adaptation → withdrawal syndrome if stopped
Mechanism of Tolerance:
• Morphine fails to induce μ-receptor endocytosis/resensitization
• NMDA receptor activation plays role (ketamine blocks tolerance)
• Methadone DOES induce endocytosis → used in treatment
Withdrawal Symptoms: Agitation, hyperalgesia, hypertension, diarrhea, mydriasis, anxiety, dysphoria (highly aversive)

Question 14

Compare Pethidine (Meperidine) with Morphine.

Answer 14

Pethidine vs Morphine:
• Potency: 1/10th of morphine
• CV Effects: Tachycardia (antimuscarinic), less histamine release
• Smooth Muscle: Less spasmodic action
• Uses: Labor pain (less neonatal depression), preanesthetic, analgesia
• Disadvantages: Short duration, toxic metabolite (normeperidine → seizures)
• Note: Related to atropine chemically, but acts on opioid receptors

Question 15

Describe Fentanyl and its derivatives.

Answer 15

Fentanyl:
• Potency: 80-100x morphine
• Onset/Duration: Peak 5 min IV, short (30-40 min) due to redistribution
• Advantages: Minimal CV effects, little histamine release
• Forms: IV, transdermal (chronic pain), lozenge, patch
• Derivatives: Alfentanil (ultra-short), Sufentanil (5-10x fentanyl), Remifentanil (ultra-short, ester metabolism)
• Uses: Anesthesia, cancer pain, procedural sedation

Question 16

What is Methadone and its role in opioid dependence?

Answer 16

Methadone:
• Long-acting synthetic opioid (t½ 24-36h)
• Mechanism: μ-agonist, NMDA antagonist, serotonin reuptake inhibitor
• Advantages: Less euphoria (‘no kick’), slow onset, prevents withdrawal
• Use in Dependence: Maintenance therapy (1 mg ≈ 4 mg morphine)
• Other Uses: Chronic pain, opioid-resistant pain
• Caution: QTc prolongation, respiratory depression (delayed onset)

Question 17

Describe Tramadol’s unique mechanism.

Answer 17

Tramadol:
• Dual Mechanism:
1. Weak μ-opioid receptor agonist
2. Inhibits NE and 5-HT reuptake (enhances descending inhibition)
• Advantages: Less respiratory depression, constipation, abuse potential
• Uses: Moderate pain (equal to morphine), labor pain, postoperative
• Disadvantages: Lower efficacy in severe pain, seizure risk (lower threshold)
• Note: Rapid psychomotor recovery

Question 18

What are agonist-antagonist opioids?

Answer 18

Examples: Pentazocine, Butorphanol, Nalbuphine
Mechanism: κ-receptor agonists + weak μ-receptor antagonists
Effects:
• Analgesia (κ-activation)
• Less respiratory depression (vs pure μ-agonists)
• Dysphoria/Psychotomimetic effects (κ-activation)
• Can precipitate withdrawal in opioid-dependent patients
Uses: Moderate-severe pain, preoperative, anesthesia adjunct

Question 19

Describe Buprenorphine.

Answer 19

Buprenorphine:
• Partial μ-agonist + κ-antagonist
• Potency: 25-50x morphine
• Administration: Sublingual, transdermal, IV
• Advantages: Ceiling effect for respiratory depression, long duration, less abuse potential
• Disadvantages: Difficult to reverse (naloxone less effective), postural hypotension
• Uses: Opioid dependence treatment, chronic pain
• Avoid in labor: Respiratory depression not fully reversible

Question 20

What are pure opioid antagonists?

Answer 20

Examples: Naloxone, Naltrexone, Nalmefene
Mechanism: Competitive antagonists at μ, δ, κ receptors
Naloxone:
• IV onset: 1-2 min, Duration: 30-90 min (shorter than opioids)
• Uses: Opioid overdose, diagnostic test for addiction, neonatal respiratory depression reversal
• Caution: Can precipitate acute withdrawal
Naltrexone:
• Long-acting (oral), used in alcohol/opioid dependence prevention
Nalmefene: Longer duration than naloxone

Question 21

What are peripherally acting opioids?

Answer 21

Peripheral μ-agonists (don’t cross BBB):
• Loperamide, Diphenoxylate: Antidiarrheal (increase tone, decrease motility)
Peripheral μ-antagonists:
• Alvimopan, Methylnaltrexone: Treat opioid-induced constipation without reversing analgesia or causing withdrawal
• Uses: Postoperative ileus, chronic opioid-induced constipation
Mechanism: Block peripheral opioid receptors in GI tract only

Question 22

What are the special considerations for opioid use in specific populations?

Answer 22

Renal Impairment: ↓ Dose (active metabolites accumulate)
Hepatic Impairment: ↓ Dose (metabolism impaired)
Elderly: ↑ Sensitivity, ↓ dose, monitor for sedation/falls
Pregnancy: Avoid (neonatal withdrawal, respiratory depression). Pethidine preferred in labor.
Asthma/COPD: Caution (respiratory depression, histamine release)
Head Injury: Avoid (↑ ICP, miosis masks neurological signs)
Addiction History: Use with caution, consider abuse-deterrent formulations

Question 23

Compare Codeine with Morphine.

Answer 23

Codeine:
• Naturally occurring in opium (0.5%)
• Prodrug: Converted to morphine by CYP2D6 (10% of dose)
• Potency: 1/10th of morphine (analgesic), good antitussive
• Uses: Mild-moderate pain, cough suppression
• Disadvantages: Genetic variability (poor metabolizers get no effect, ultrarapid metabolizers get toxicity), constipation
• Formulations: Often combined with acetaminophen/NSAIDs

Question 24

What is Heroin and why is it more addictive?

Answer 24

Heroin (Diacetylmorphine):
• Semisynthetic derivative of morphine
• Higher lipid solubility → faster BBB penetration → rapid onset of euphoria (‘rush’)
• Converted to 6-acetylmorphine and morphine in brain
• Greater abuse potential due to rapid CNS entry and intense euphoria
• No medical use in most countries (Schedule I)
• Associated with higher overdose risk (potency variability)

Question 25

Describe the NMDA receptor's role in opioid tolerance.

Answer 25

NMDA Receptor Hypothesis: • Chronic opioid use → upregulation of NMDA receptors in pain pathways • NMDA activation → central sensitization and tolerance • Evidence: NMDA antagonists (ketamine, dextromethorphan) can: 1. Prevent tolerance development 2. Reverse established tolerance 3. Enhance opioid analgesia • Clinical application: Low-dose ketamine adjunct in chronic pain/opioid-tolerant patients

Question 26

What is opioid-induced hyperalgesia (OIH)?

Answer 26

Definition: Increased sensitivity to pain due to chronic opioid use Mechanism: • NMDA receptor activation • Descending facilitation from rostral ventromedial medulla • Neuroplastic changes in spinal cord Clinical Features: Paradoxical increase in pain despite dose escalation Management: Opioid rotation, dose reduction, NMDA antagonists (ketamine), adjuvant analgesics

Question 27

What are the guidelines for opioid prescribing in chronic non-cancer pain?

Answer 27

Principles: 1. Start low, go slow 2. Use immediate-release initially 3. Regular assessment of pain/function 4. Monitor for misuse/addiction (urine drug screens, prescription monitoring) 5. Have exit strategy/taper plan 6. Avoid benzodiazepine combinations (respiratory depression) 7. Consider non-opioid alternatives first 8. Educate about risks/benefits

Question 28

Describe the clinical scenario: Postoperative pain management.

Answer 28

Scenario: 50-year-old after abdominal surgery with moderate-severe pain. Options: 1. IV Morphine PCA: Basal + demand dosing, monitor respiration 2. Scheduled oral opioids: Oxycodone/acetaminophen q4-6h 3. Multimodal: Opioid + NSAID + local anesthetic 4. Avoid: Meperidine (neurotoxic metabolite), excessive sedation Monitoring: Pain scores, respiratory rate, sedation level, bowel function Transition to oral: When tolerating oral intake, pain controlled

Question 29

Describe the clinical scenario: Opioid overdose in emergency department.

Answer 29

Scenario: Unresponsive patient with pinpoint pupils, respiratory depression, needle marks. Immediate Actions: 1. ABCs: Airway, Breathing (assist ventilation), Circulation 2. Naloxone: 0.4-2 mg IV/IM/IN (repeat q2-3min until breathing adequate) 3. Supportive: IV fluids, monitor vitals 4. Investigate: Toxicology screen, check for co-ingestants 5. Observation: Re-dosing may be needed (naloxone shorter than opioids) 6. Consider: Intubation if refractory Disposition: Admit if significant ingestion, psychiatric evaluation

Question 30

Describe the clinical scenario: Cancer pain management.

Answer 30

Scenario: Patient with metastatic bone pain requiring chronic opioids. Approach: 1. By the Clock: Scheduled long-acting (morphine SR, fentanyl patch) 2. For Breakthrough: Short-acting opioid (morphine IR) PRN 3. Adjuvants: NSAIDs (bone pain), anticonvulsants (neuropathic), bisphosphonates 4. Route: Oral preferred, consider transdermal/SC if swallowing issues 5. Monitor: Pain control, side effects (constipation → laxatives), signs of misuse 6. Rotation: Switch opioids if inadequate response or intolerance Goal: Balance analgesia with quality of life

Question 31

Describe the clinical scenario: Opioid withdrawal management.

Answer 31

Scenario: Heroin-dependent patient presents with agitation, diarrhea, hypertension. Symptoms: Autonomic hyperactivity (tachycardia, hypertension, dilated pupils), GI distress, anxiety, craving Management: 1. Supportive: Hydration, electrolyte replacement 2. Pharmacologic: • Methadone: Long-acting, tapered • Buprenorphine: Partial agonist, sublingual • Clonidine: α2-agonist for autonomic symptoms • Benzodiazepines: Anxiety, insomnia (short-term) 3. Non-pharmacologic: Counseling, support groups Timeline: Peak 48-72h, resolves over 5-10 days

Question 32

What are the opioid equianalgesic dosing conversions?

Answer 32

Approximate Equianalgesic Doses (oral, compared to morphine 30 mg oral): • Codeine: 200 mg • Hydrocodone: 30 mg • Oxycodone: 20 mg • Hydromorphone: 7.5 mg • Methadone: Complex (dose-dependent, requires careful titration) • Fentanyl: Transdermal 25 mcg/h ≈ morphine 90 mg/day oral Note: Cross-tolerance incomplete → reduce calculated dose by 25-50% when switching opioids

Question 33

What are the monitoring parameters for opioid therapy?

Answer 33

1. Efficacy: Pain scores (0-10), functional improvement 2. Adverse Effects: • Sedation/respiratory depression (especially first 24-72h) • Constipation (prophylactic laxatives) • Nausea/vomiting (antiemetics PRN) • Pruritus (antihistamines, low-dose naloxone infusion) 3. Misuse/Addiction: • Urine drug screens • Prescription monitoring program checks • Pill counts • Aberrant behaviors

Question 34

What are the contraindications and precautions for opioids?

Answer 34

Absolute Contraindications: • Significant respiratory depression • Acute asthma/COPD exacerbation • Paralytic ileus • Known hypersensitivity Relative Contraindications/Precautions: • Increased ICP/head injury • Severe hepatic/renal impairment • Pregnancy/labor (except pethidine) • Elderly/debilitated • Concurrent CNS depressants (benzodiazepines, alcohol) • History of substance abuse • Monoamine oxidase inhibitor use (meperidine risk)

Question 35

What are the strategies to minimize opioid side effects?

Answer 35

Constipation: Prophylactic stimulant laxative + stool softener Nausea/Vomiting: Antiemetic (metoclopramide, ondansetron) first 3-5 days Sedation: Start low dose, avoid other CNS depressants, consider caffeine Pruritus: Antihistamines, low-dose naloxone infusion, opioid rotation Respiratory Depression: Titrate slowly, use monitoring, have naloxone available Tolerance: Use adjuvant analgesics, consider drug holidays if possible

Question 36

What is the role of opioid receptors in the GI tract?

Answer 36

Location: Enteric nervous system, smooth muscle Effects of μ-agonists: • Increased tone (segmental contractions) • Decreased propulsive peristalsis • Increased sphincter tone (Oddi, anal) • Reduced secretions Result: Delayed transit, increased water absorption → constipation Clinical Applications: • Antidiarrheals: Loperamide, diphenoxylate • Adverse Effect: Opioid-induced constipation (treat with peripherally restricted antagonists)

Question 37

How do opioids affect the respiratory system?

Answer 37

Mechanism: Direct depression of brainstem respiratory centers (medulla) Effects: 1. ↓ Responsiveness to CO2 (flattened CO2 response curve) 2. ↓ Respiratory rate (primary effect) 3. May cause irregular/periodic breathing 4. Suppress cough reflex Risk Factors: Elderly, obesity, sleep apnea, concomitant CNS depressants Treatment: Naloxone, respiratory support Note: Tolerance develops to euphoria/analgesia but NOT to respiratory depression at equivalent doses

Question 38

What is the role of opioids in palliative care?

Answer 38

Principles: 1. Freedom from pain is a basic human right 2. Use WHO analgesic ladder: Non-opioid → weak opioid → strong opioid 3. Scheduled dosing with PRN for breakthrough 4. Individualize route/formulation 5. Manage side effects proactively 6. Address psychosocial/spiritual aspects Common Opioids: Morphine (gold standard), fentanyl (renal impairment), methadone (complex pain) Goal: Quality of life, dignity in dying

Question 39

What are the newer opioid formulations and abuse-deterrent technologies?

Answer 39

Abuse-Deterrent Formulations (ADF): 1. Physical barriers: Hard to crush/dissolve 2. Agonist-antagonist combinations: Naloxone with oxycodone (released if crushed) 3. Aversion: Irritants if snorted/injected 4. Prodrugs: Require GI metabolism 5. Delivery systems: Implants, depot injections Examples: OxyContin ADF, Embeda (morphine+naltrexone) Limitations: Not abuse-proof, can still be abused orally

Question 40

What are the ethical considerations in opioid prescribing?

Answer 40

1. Balance: Relief of suffering vs risk of harm/addiction 2. Autonomy: Patient's right to pain relief 3. Justice: Equitable access to pain management 4. Non-maleficence: Do no harm (overdose, addiction) 5. Veracity: Honest discussion of risks/benefits 6. Stigma: Avoiding discrimination against pain patients 7. Legal: Adherence to prescribing regulations while providing care Dilemma: Undertreatment of pain vs contributing to opioid epidemic