Introduction to Pain & Analgesics
Pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage." Analgesics are drugs that relieve pain without causing loss of consciousness.
Nociceptive Pain
Caused by activation of peripheral nociceptors by noxious stimuli (mechanical, thermal, chemical). Examples: post-surgical pain, fractures, burns, osteoarthritis.
Neuropathic Pain
Arises from damage or disease of the somatosensory nervous system. Examples: diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, phantom limb pain.
Nociplastic Pain
Altered nociception despite no clear evidence of tissue/nerve damage. Central sensitization plays a key role. Examples: fibromyalgia, IBS, tension-type headache.
Classification of Analgesics
Non-Opioid Analgesics
1. NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
Non-selective COX inhibitors, COX-2 selective inhibitors, preferential COX-2 inhibitors
2. Paracetamol (Acetaminophen)
Centrally acting, analgesic-antipyretic, weak anti-inflammatory action
3. Nefopam
Non-opioid centrally acting analgesic; inhibits reuptake of 5-HT, NE, and DA
Opioid Analgesics
1. Strong Opioid Agonists
Morphine, Fentanyl, Methadone, Pethidine, Hydromorphone
2. Moderate Opioid Agonists
Codeine, Tramadol, Tapentadol, Dihydrocodeine
3. Partial Agonists & Mixed
Buprenorphine (partial μ-agonist), Pentazocine (κ-agonist/μ-antagonist), Nalbuphine
4. Opioid Antagonists
Naloxone (IV), Naltrexone (oral), Methylnaltrexone (peripheral)
Adjuvant Analgesics
Drugs whose primary indication is not pain relief but have analgesic properties in certain conditions:
WHO Analgesic Ladder
Originally developed for cancer pain (1986), now widely applied. A stepwise approach to pain management:
Non-Opioid ± Adjuvant
Paracetamol, NSAIDs (Ibuprofen, Diclofenac, Naproxen). Add adjuvants if neuropathic component present.
Weak Opioid + Non-Opioid ± Adjuvant
Tramadol, Codeine, or Tapentadol combined with Paracetamol/NSAIDs. Monitor for efficacy and side effects.
Strong Opioid + Non-Opioid ± Adjuvant
Morphine, Fentanyl, Oxycodone, Hydromorphone. Titrate to effect. Continue non-opioids for synergistic benefit.
🔑 Clinical Pearl: The WHO ladder is a guideline, not a rigid rule. For severe acute pain (e.g., renal colic, fractures), start at Step 3 directly. "By the clock, by the ladder, by the mouth" — give analgesics at regular intervals, follow the stepwise approach, and prefer oral route when possible.
NSAIDs — Mechanism of Action
NSAIDs inhibit cyclooxygenase (COX) enzymes, blocking the conversion of arachidonic acid to prostaglandins (PGs), thromboxane A₂ (TXA₂), and prostacyclin (PGI₂).
Arachidonic Acid Cascade
Membrane Phospholipids
Phospholipase A₂ (PLA₂) releases arachidonic acid (AA) from cell membrane. Corticosteroids block this step via lipocortin.
Arachidonic Acid → COX Pathway
AA is metabolized by COX-1 (constitutive) and COX-2 (inducible) to form PGG₂ → PGH₂. NSAIDs block here.
Prostaglandins, Thromboxane, Prostacyclin
PGH₂ is converted by tissue-specific synthases to: PGE₂ (pain, fever, inflammation, gastric protection), PGI₂ (vasodilation, platelet inhibition), TXA₂ (vasoconstriction, platelet aggregation), PGF₂α (uterine contraction), PGD₂ (sleep, allergy).
LOX Pathway (Not blocked by NSAIDs)
AA → 5-Lipoxygenase → Leukotrienes (LTB₄, LTC₄, LTD₄, LTE₄). Responsible for bronchoconstriction & chemotaxis. Blocked by Zileuton, Montelukast.
COX-1 (Constitutive)
- • Present in most tissues (housekeeping enzyme)
- • GI mucosal protection (PGE₂, PGI₂ → mucus, bicarbonate, blood flow)
- • Platelet aggregation (TXA₂ in platelets)
- • Renal blood flow (afferent arteriolar vasodilation)
- • Inhibition → GI ulcers, bleeding, renal impairment
COX-2 (Inducible)
- • Induced at sites of inflammation by cytokines (IL-1, TNF-α)
- • Produces inflammatory PGs (PGE₂ → pain, vasodilation, fever)
- • Also constitutive in: kidney, brain, endothelium, reproductive
- • Endothelial PGI₂ (anti-thrombotic) — produced via COX-2
- • Selective COX-2 inhibition → ↓PGI₂ but TXA₂ intact → CV risk
⚠️ Important: Selective COX-2 inhibitors (e.g., Rofecoxib/Vioxx) were withdrawn due to increased MI and stroke risk. The mechanism: COX-2 inhibition reduces endothelial PGI₂ (anti-thrombotic) while leaving platelet TXA₂ (pro-thrombotic, via COX-1) intact → prothrombotic imbalance.
Chemical Classification of NSAIDs
Aspirin is unique — it irreversibly acetylates COX (Serine-530 in COX-1), unlike all other NSAIDs which are reversible inhibitors.
Dose-Dependent Effects of Aspirin:
Low dose (75–150 mg): Antiplatelet (irreversible TXA₂ inhibition in platelets which lack nucleus → cannot resynthesize COX) — used in IHD, stroke prophylaxis.
Analgesic/Antipyretic (300–600 mg): For headache, myalgia, fever.
Anti-inflammatory (3–6 g/day): For rheumatic fever, RA (rarely used now due to toxicity).
Toxic (>6 g/day): Salicylism — tinnitus, deafness, vertigo, nausea.
Ibuprofen: Safest NSAID for short-term use (lowest GI risk). Dose: 200–400 mg TDS. OTC analgesic.
Naproxen: Longest acting in this group (t½ ~14h, BD dosing). Best CV safety profile among NSAIDs. Preferred in patients with CV risk.
Diclofenac: Most widely prescribed NSAID globally. Preferential COX-2 inhibitor. Available oral, topical, IM, IV. Dose: 50 mg BD–TDS. Higher CV risk than naproxen/ibuprofen.
Indomethacin: Most potent anti-inflammatory NSAID. Used for acute gout, ankylosing spondylitis, patent ductus arteriosus closure in neonates. High GI and CNS toxicity.
Ketorolac: Most potent analgesic NSAID. IM/IV for post-operative pain. Use limited to ≤5 days due to GI bleed risk. Analgesic potency comparable to morphine for moderate pain.
Piroxicam: Very long t½ (~50h), once daily dosing. Higher GI risk. Used in OA, RA, ankylosing spondylitis.
Meloxicam: Preferential COX-2 inhibitor at low doses. Better GI profile than piroxicam. Dose: 7.5–15 mg OD.
Designed to inhibit COX-2 selectively → reduced GI toxicity while maintaining anti-inflammatory/analgesic efficacy.
Celecoxib: 375× selective for COX-2 over COX-1. Sulfonamide derivative (cross-allergy with sulfa drugs). Dose: 100–200 mg BD. FDA-approved for OA, RA, FAP.
Etoricoxib: Most selective COX-2 inhibitor (106× selectivity). Used in acute gout, OA, RA, ankylosing spondylitis, dental pain. Once daily dosing.
⚠️ CV Risk: Rofecoxib withdrawn (2004) — VIGOR & APPROVe trials showed 5× increased MI risk. All coxibs carry a CV warning. Contraindicated in established CVD, uncontrolled HTN, recent CABG.
Mefenamic Acid (Fenamates): Used for dysmenorrhea, mild-moderate pain. Can cause diarrhea. Dose: 500 mg TDS.
Nimesulide: Preferential COX-2 inhibitor. Banned in many countries due to hepatotoxicity. Still used in India (restricted to adults, ≤15 days).
Nabumetone: Prodrug (converted to active metabolite 6-MNA in liver). Non-acidic, lower direct GI irritation. Once daily dosing.
Adverse Effects of NSAIDs
🔴 GI Toxicity (Most Common)
- • Dyspepsia, nausea, epigastric pain
- • Gastric/duodenal erosions and ulcers
- • Upper GI bleeding and perforation
- • Risk: elderly, H. pylori+, steroids, anticoagulants
- • Prevention: PPI co-prescription (Omeprazole), Misoprostol
🔵 Renal Effects
- • ↓ Renal blood flow (PGE₂/PGI₂ maintain afferent arteriolar dilation)
- • Na⁺/H₂O retention → edema, HTN worsening
- • Hyperkalemia (↓renin, ↓aldosterone)
- • Analgesic nephropathy (chronic abuse → papillary necrosis)
- • AKI (especially in dehydrated/CKD/elderly patients)
- • Interstitial nephritis (rare, idiosyncratic)
🟣 Cardiovascular Effects
- • All NSAIDs (except low-dose aspirin & naproxen) increase CV risk
- • COX-2 inhibitors: highest thrombotic risk (↓PGI₂, intact TXA₂)
- • Diclofenac: CV risk similar to coxibs
- • Naproxen: lowest CV risk among NSAIDs
- • HTN exacerbation, heart failure worsening
- • Contraindicated post-CABG (FDA black box)
🟡 Other Adverse Effects
- • Bleeding: ↓TXA₂ → ↓platelet aggregation (aspirin is irreversible)
- • Hepatic: Transaminase elevation (Diclofenac), hepatotoxicity (Nimesulide)
- • Hypersensitivity: Aspirin-exacerbated respiratory disease (AERD), urticaria, angioedema
- • CNS: Headache, dizziness (Indomethacin most common)
- • Pregnancy: Premature closure of ductus arteriosus (3rd trimester), oligohydramnios
- • Reye's Syndrome: Aspirin in children with viral illness → hepatic encephalopathy
🔑 NSAID "Triple Whammy": The combination of NSAID + ACE inhibitor/ARB + Diuretic dramatically increases AKI risk. All three decrease renal perfusion. Avoid this combination, especially in elderly and CKD patients.
Opioid Receptors & Mechanism
Opioids act on G-protein coupled receptors (Gi/Go) in the CNS and PNS, mimicking endogenous opioid peptides (endorphins, enkephalins, dynorphins).
| Receptor | Endogenous Ligand | Effects of Activation | Key Agonists |
|---|---|---|---|
| μ (Mu) — MOP | β-Endorphin, Endomorphins | Supraspinal analgesia, euphoria, respiratory depression, miosis, ↓GI motility, physical dependence, sedation | Morphine, Fentanyl, Methadone, Oxycodone |
| κ (Kappa) — KOP | Dynorphin | Spinal analgesia, sedation, dysphoria, diuresis, miosis. Less respiratory depression than μ. | Pentazocine, Nalbuphine, Butorphanol |
| δ (Delta) — DOP | Enkephalins (Met/Leu) | Spinal/supraspinal analgesia, mood modulation, possible seizure threshold lowering | Limited clinical use. Some contribution from morphine |
| NOP (Nociceptin) | Nociceptin/Orphanin FQ | Anxiety, modulation of μ-opioid function, complex pain modulation | Cebranopadol (novel, under investigation) |
Intracellular Signaling (Gi/Go Coupled)
↓ cAMP
Inhibition of adenylyl cyclase → ↓cAMP → ↓PKA activity → reduced neuronal excitability
↑ K⁺ Efflux
Opening GIRK channels → hyperpolarization of postsynaptic neuron → reduced pain signal transmission
↓ Ca²⁺ Influx
Closing VGCCs in presynaptic terminal → ↓neurotransmitter release (Substance P, glutamate)
Key Opioid Drugs
💊 Morphine — Gold Standard
Source: Papaver somniferum (opium poppy). Natural alkaloid (phenanthrene group).
Routes: Oral (significant first-pass; oral bioavailability ~25%), SC, IM, IV, epidural, intrathecal, rectal.
Metabolism: Hepatic glucuronidation → M3G (inactive, neuroexcitatory) + M6G (active, 40× more potent — accumulates in renal failure).
t½: 2–3 hours. Duration: 4–6h (immediate release). SR: 8–12h.
Pharmacological Effects:
- • Analgesia — both affective & sensory component
- • Euphoria (μ), Sedation
- • Respiratory depression — ↓response to CO₂ in brainstem. Dose-limiting toxicity.
- • Miosis (pinpoint pupils) — diagnostic. Edinger-Westphal nucleus (μ/κ).
- • Antitussive — suppresses cough center
- • Emesis → then anti-emesis (CTZ stimulation initially)
- • ↓GI motility → constipation (most persistent side effect, no tolerance)
- • Histamine release → pruritus, urticaria, bronchospasm, hypotension
- • Biliary spasm — constricts sphincter of Oddi
💊 Fentanyl & Congeners
Fentanyl: 80–100× more potent than morphine. Highly lipophilic → rapid onset (IV: 1–2 min). Short acting (30–60 min IV bolus). Used in anaesthesia, breakthrough cancer pain, transdermal patch (72h), lollipop, nasal spray.
Sufentanil: 500–1000× morphine. Used intra-operatively.
Alfentanil: Less potent but fastest onset. Ultra-short acting.
Remifentanil: Metabolized by plasma esterases (context-insensitive t½ ~3–4 min). Ideal for infusion in surgery. No accumulation.
Tramadol
Weak μ-agonist + NE/5-HT reuptake inhibitor (dual mechanism). 1/10th potency of morphine. Lower respiratory depression & constipation. Lowers seizure threshold. Serotonin syndrome risk with SSRIs/MAOIs. O-desmethyltramadol (M1) via CYP2D6 is active.
Methadone
Long t½ (15–60h). μ-agonist + NMDA antagonist + NE/5-HT reuptake inhibitor. Used in: cancer pain, opioid substitution therapy (prevents withdrawal). QT prolongation risk. No active metabolites.
Buprenorphine
Partial μ-agonist / κ-antagonist. Ceiling effect on respiratory depression (safety advantage). Sublingual, transdermal, IV. Very high receptor affinity (difficult to displace). Used in moderate-severe pain & opioid dependence (with naloxone as Suboxone).
Codeine
Weak opioid. Prodrug — converted to morphine by CYP2D6 (5–10% of dose). Poor metabolizers: no effect. Ultra-rapid metabolizers: toxicity/death (especially children). Used for mild-moderate pain, cough suppression. Now largely replaced by Tramadol.
⚠️ Opioid Toxicity Triad: Miosis (pinpoint pupils) + Respiratory depression + Coma/Reduced consciousness. Treatment: Naloxone IV 0.4–2 mg, repeat every 2–3 min (t½ shorter than most opioids → monitor for renarcotization). Supportive: airway management, ventilation.
Tolerance, Dependence & Withdrawal
Tolerance
Develops to: analgesia, euphoria, sedation, respiratory depression, emesis.
Does NOT develop to: Miosis, constipation (clinically important — laxatives always needed).
Mechanisms: receptor desensitization, β-arrestin recruitment, receptor internalization/downregulation.
Physical Dependence
Withdrawal syndrome on abrupt cessation: lacrimation, rhinorrhea, yawning, piloerection, mydriasis, diarrhea, abdominal cramps, muscle aches, insomnia, agitation.
Onset: 6–12h for short-acting (morphine), 24–48h for long-acting (methadone).
Management of Dependence
- • Methadone substitution — oral, once daily, supervised
- • Buprenorphine ± Naloxone — sublingual (Suboxone)
- • Clonidine — α₂-agonist for autonomic symptoms
- • Naltrexone — relapse prevention (oral or depot)
Paracetamol (Acetaminophen)
Most widely used OTC analgesic-antipyretic globally. NOT classified as an NSAID — negligible peripheral anti-inflammatory action.
Mechanism (Multiple Proposed):
- • Central COX inhibition (COX-3 hypothesis — inhibits PG synthesis in hypothalamus)
- • Activation of descending serotonergic inhibitory pathways
- • Endocannabinoid system modulation (AM404 metabolite acts on CB₁ and TRPV1)
- • Peroxidase-dependent mechanism — ineffective in inflammatory sites with high peroxide
Pharmacokinetics:
Well absorbed orally. t½: 2–3h. Hepatic metabolism: 90% glucuronidation/sulfation (safe), 5% CYP2E1 → NAPQI (toxic) → normally conjugated by glutathione.
⚠️ Paracetamol Hepatotoxicity
Toxic dose: >150 mg/kg or >7.5 g in adults. Leading cause of acute liver failure in developed countries.
Mechanism: Glutathione depletion → unopposed NAPQI accumulates → centrilobular hepatic necrosis.
Stages of toxicity:
- Stage 1 (0–24h): Nausea, vomiting, malaise (may be asymptomatic)
- Stage 2 (24–72h): RUQ pain, ↑transaminases, ↑PT/INR
- Stage 3 (72–96h): Peak hepatotoxicity — jaundice, coagulopathy, hepatic encephalopathy, renal failure, death possible
- Stage 4 (4–14 days): Recovery phase (if survived)
Antidote: N-Acetylcysteine (NAC) — replenishes glutathione. Most effective within 8h. Use Rumack-Matthew nomogram to guide treatment.
Adjuvant Analgesics
Antidepressants
TCAs (Amitriptyline): First-line for neuropathic pain. Blocks NE & 5-HT reuptake + Na⁺ channel blockade. Effective in diabetic neuropathy, PHN, fibromyalgia. Dose much lower than for depression (10–75 mg HS).
SNRIs (Duloxetine, Venlafaxine): FDA-approved for DPNP, fibromyalgia, chronic MSK pain. Better tolerability than TCAs.
Anticonvulsants
Gabapentin/Pregabalin: Bind α₂δ subunit of VGCCs → ↓Ca²⁺ influx → ↓excitatory neurotransmitter release. First-line for neuropathic pain, PHN, fibromyalgia. Pregabalin also anxiolytic.
Carbamazepine: DOC for trigeminal neuralgia (Na⁺ channel blocker). Monitor for blood dyscrasias, SJS/TEN (HLA-B*1502 screening in Asians).
NMDA Antagonists
Ketamine: Sub-anesthetic doses for refractory pain, central sensitization, opioid-resistant pain. Useful in complex regional pain syndrome, cancer pain. Intranasal esketamine approved for treatment-resistant depression.
Topical Agents
Capsaicin: TRPV1 agonist → initial nociceptor activation (burning) → defunctionalization (depletion of Substance P). 8% patch for PHN.
Lidocaine 5% patch: Na⁺ channel blocker for localized neuropathic pain.
Clinical Applications & Guidelines
🦴 Osteoarthritis
First-line: Paracetamol (up to 4 g/day in healthy adults) + non-pharmacological measures (exercise, weight loss). Second-line: Topical NSAIDs (Diclofenac gel) → Oral NSAIDs (lowest effective dose, shortest duration) + PPI. Third-line: Intra-articular corticosteroids, Duloxetine (for knee OA with central sensitization). Avoid: Opioids long-term.
🔥 Rheumatoid Arthritis
NSAIDs for symptomatic relief (do NOT modify disease). DMARDs are cornerstone (Methotrexate first-line). NSAIDs bridge therapy while DMARDs take effect. Naproxen or Celecoxib commonly used. Always co-prescribe PPI if risk factors present.
⚡ Acute Gout
First-line: NSAIDs (Indomethacin 50 mg TDS, Naproxen 500 mg BD, or Etoricoxib 120 mg OD) — start within 24h, continue 1–2 weeks. Alternative: Colchicine (0.5 mg BD–TDS) — narrow therapeutic index. If NSAIDs/Colchicine CI: Systemic or intra-articular corticosteroids. Avoid: Aspirin (alters uric acid excretion at low doses).
💢 Migraine
Acute mild: Aspirin 900 mg + Metoclopramide 10 mg, or Ibuprofen 400 mg, Naproxen 500 mg. Moderate-severe: Triptans (Sumatriptan 50–100 mg). Refractory: Ketorolac 30 mg IM/IV in ED. Prophylaxis: Propranolol, Valproate, Topiramate, Amitriptyline, CGRP monoclonal antibodies (Erenumab).
🩺 Post-Operative Pain
Multimodal analgesia approach: Paracetamol (scheduled, IV/oral) + NSAID (Ketorolac 15–30 mg IV q6h for ≤5 days, or Ibuprofen) + Regional anaesthesia (nerve blocks, epidural). Opioids for breakthrough/rescue only — PCA (patient-controlled analgesia) with Morphine or Fentanyl. Goal: opioid-sparing to reduce ileus, PONV, respiratory depression.
🩸 Dysmenorrhea
Primary dysmenorrhea: NSAIDs are DOC (Mefenamic acid 500 mg TDS, Ibuprofen 400 mg TDS, Naproxen 500 mg BD). Start at onset of menses or 1–2 days before. Mechanism: ↓endometrial PGF₂α & PGE₂. If NSAID-refractory: Combined OCP, Levonorgestrel IUS.
🧠 Neuropathic Pain
First-line: Amitriptyline/Duloxetine OR Gabapentin/Pregabalin. Second-line: Combination of first-line agents from different classes. Third-line: Tramadol, Tapentadol. Topical: Capsaicin 8% patch, Lidocaine 5% patch for localized pain. NSAIDs are generally INEFFECTIVE in pure neuropathic pain.
🎗️ Cancer Pain
Follow WHO ladder. Oral Morphine is the gold standard for moderate-severe cancer pain. Titration: Start IR Morphine 5–10 mg q4h, increase by 30–50% if inadequate. Convert to SR when stable. Breakthrough: 1/6th of 24h total opioid dose as IR. Fentanyl patch when stable opioid requirements + swallowing difficulty. Always prescribe laxatives prophylactically with opioids. Rotate opioids for tolerance/side effects.
🔑 NSAID Prescribing Principles: 1) Use lowest effective dose for shortest duration. 2) Assess CV, GI, and renal risk before prescribing. 3) Co-prescribe PPI in high-risk patients. 4) Avoid in 3rd trimester pregnancy. 5) Monitor renal function and BP. 6) Beware drug interactions (anticoagulants, ACEi/ARBs, diuretics, lithium, methotrexate).
NSAID Comparison Table
| Drug | COX Selectivity | t½ (h) | GI Risk | CV Risk | Key Feature |
|---|---|---|---|---|---|
| Aspirin | Non-selective (irreversible) | 0.25 (dose-dep) | High | Low (protective) | Only NSAID with antiplatelet effect at low dose |
| Ibuprofen | Non-selective | 2 | Low | Moderate | Safest NSAID for short-term use. OTC. |
| Naproxen | Non-selective | 14 | Moderate | Lowest | Best CV safety. Long acting. BD dosing. |
| Diclofenac | Preferential COX-2 | 1.5 | Moderate | High | Most prescribed NSAID. CV risk ≈ coxibs. |
| Indomethacin | Non-selective | 4.5 | High | Moderate | Most potent anti-inflammatory. PDA closure. |
| Ketorolac | Non-selective | 5 | High | Moderate | Most potent analgesic NSAID. ≤5 days only. |
| Piroxicam | Non-selective | 50 | High | Moderate | Longest t½. Once daily. High GI risk. |
| Celecoxib | Selective COX-2 | 11 | Low | High | Sulfonamide allergy risk. 375× COX-2 selective. |
| Etoricoxib | Selective COX-2 | 22 | Low | High | Most selective. Once daily. Good for gout. |
| Paracetamol | Central COX (minimal peripheral) | 2–3 | Nil | Nil | No anti-inflammatory. Hepatotoxicity in OD. |
Opioid Comparison Table
| Drug | Relative Potency (to Morphine) | Receptor Activity | Duration | Key Clinical Use |
|---|---|---|---|---|
| Morphine | 1× (standard) | Full μ-agonist | 4–6h (IR) | Gold standard. Cancer pain. Acute severe pain. |
| Fentanyl | 80–100× | Full μ-agonist | 0.5–1h (IV); 72h (patch) | Anesthesia. Transdermal for chronic cancer pain. |
| Oxycodone | 1.5× | Full μ-agonist (+ κ) | 4–6h (IR); 12h (SR) | Moderate-severe pain. Common in acute settings. |
| Hydromorphone | 5–7× | Full μ-agonist | 4–5h | Alternative in morphine intolerance/renal failure. |
| Methadone | Variable (3–10×) | μ-agonist + NMDA antagonist | 15–60h (long t½) | Cancer pain. Opioid substitution therapy. |
| Codeine | 0.1× (weak) | Prodrug → Morphine (CYP2D6) | 4–6h | Mild pain. Antitussive. Genetic variability. |
| Tramadol | 0.1× (weak) | Weak μ + NE/5-HT reuptake | 4–6h | Moderate pain. Dual mechanism. Seizure risk. |
| Buprenorphine | 25–40× | Partial μ / κ-antagonist | 6–8h (SL); 7 days (patch) | Moderate-severe pain. Opioid dependence. |
| Pentazocine | 0.3× | κ-agonist / μ-antagonist | 3–4h | Moderate pain. Dysphoria. Can precipitate withdrawal. |
| Naloxone | Antagonist | μ, κ, δ antagonist | 30–90 min | Opioid overdose reversal. IV/IM/IN. |
Key Contraindications & Interactions
NSAID Contraindications
- • Active PUD or GI bleeding
- • Severe renal impairment (eGFR <30)
- • Severe heart failure (NYHA III–IV)
- • Third trimester pregnancy
- • Post-CABG surgery (FDA black box)
- • History of aspirin-induced asthma (AERD)
- • Concurrent anticoagulant therapy (relative)
Critical Drug Interactions
- • NSAIDs + Warfarin: ↑bleeding risk (platelet + GI effect)
- • NSAIDs + ACEi/ARB + Diuretic: "Triple whammy" → AKI
- • NSAIDs + Methotrexate: ↓MTX clearance → toxicity
- • NSAIDs + Lithium: ↓Li clearance → toxicity
- • Ibuprofen + Aspirin: Competitive antagonism at COX-1 (take aspirin 30 min before)
- • Tramadol + SSRIs/MAOIs: Serotonin syndrome
- • Opioids + Benzodiazepines: Synergistic respiratory depression