Analgesics are drugs that relieve pain without causing loss of consciousness. They are classified into three major categories: non-opioid analgesics (NSAIDs, acetaminophen), opioid analgesics, and adjuvant analgesics (drugs developed for other indications that have analgesic properties in specific pain conditions).

Pills and capsules for pain relief — Analgesics are medications that relieve pain — ranging from NSAIDs and acetaminophen to opioids and adjuvant agents. Source: Unsplash.

Non-Opioid Analgesics

Acetaminophen (Paracetamol)

Acetaminophen is the most widely used analgesic and antipyretic. Its mechanism is not fully understood but involves inhibition of cyclooxygenase (COX) in the central nervous system, with minimal peripheral COX inhibition (and therefore no anti-inflammatory effect). Acetaminophen is effective for mild to moderate pain, especially osteoarthritis, headache, and musculoskeletal pain. The typical dose is 325-1,000 mg every 4-6 hours (maximum 3,000-4,000 mg/day). At therapeutic doses, it has minimal GI and renal side effects. The major concern is hepatotoxicity at supratherapeutic doses. Chronic use of over 3,000 mg/day or acute ingestion of over 7.5-10 g can cause severe hepatic necrosis. N-acetylcysteine (NAC) is the antidote — most effective within 8 hours of ingestion.

Non-Steroidal Anti-Inflammatory Drugs

NSAIDs inhibit cyclooxygenase enzymes (COX-1 and COX-2), reducing prostaglandin synthesis. Prostaglandins mediate inflammation, pain, and fever, but also protect gastric mucosa (COX-1), regulate renal blood flow, and support platelet function (COX-1 - thromboxane A2). NSAIDs are effective for mild to moderate pain with an inflammatory component: arthritis, dental pain, dysmenorrhea, musculoskeletal injuries. They have a ceiling effect for analgesia (increasing dose beyond a certain point does not increase pain relief but does increase side effects). Common NSAIDs include ibuprofen (200-800 mg every 6-8 hours, max 3,200 mg/day), naproxen (220-500 mg every 12 hours, max 1,500 mg/day), diclofenac, indomethacin, meloxicam, ketorolac (injectable, short-term for moderate-severe pain — max 5 days), and celecoxib (COX-2 selective — reduces GI risk but not renal or cardiovascular risk).

⚠ Caution

NSAIDs carry significant risks that limit their use in certain populations. Gastrointestinal effects include dyspepsia, ulcers, and GI bleeding (2-4% annual risk of symptomatic ulcer in chronic users; COX-2 selective NSAIDs like celecoxib reduce GI risk by 50-60% but do not eliminate it). Cardiovascular effects include increased risk of MI and stroke (especially with COX-2 selective NSAIDs and at high doses — all NSAIDs except low-dose aspirin carry some CV risk). Renal effects include reduced renal blood flow leading to acute kidney injury (especially in patients with CKD, heart failure, cirrhosis, or volume depletion), fluid retention, and worsening hypertension. Patients with significant CKD (GFR under 30 mL/min), active GI bleeding, or recent cardiovascular events should avoid NSAIDs. The lowest effective dose for the shortest duration should be used. In older adults, NSAIDs are best avoided due to increased GI, renal, and CV risk.

Opioid Analgesics

Opioids are the most potent analgesics available, effective for moderate to severe acute pain, cancer pain, and selected chronic pain conditions. They act on mu-opioid receptors (MOR) in the central and peripheral nervous system, inhibiting pain transmission.

Classification

Natural and semi-synthetic opioids include morphine (the standard for comparison — the “gold standard” opioid), codeine (prodrug converted to morphine by CYP2D6), oxycodone, hydromorphone (Dilaudid — 5-7 times more potent than morphine), hydrocodone, and buprenorphine (partial mu agonist — ceiling effect for respiratory depression). Synthetic opioids include fentanyl (50-100 times more potent than morphine), methadone (unique: NMDA antagonist and mu agonist — used for both pain and opioid use disorder), tramadol (weak mu agonist + serotonin/norepinephrine reuptake inhibition), and tapentadol (mu agonist + norepinephrine reuptake inhibition with less serotonin activity than tramadol).

Equianalgesic Dosing

Opioid conversion is approximate and requires individual titration due to incomplete cross-tolerance. Morphine 30 mg oral = morphine 10 mg IV = oxycodone 20 mg oral = hydromorphone 7.5 mg oral = hydromorphone 1.5 mg IV = fentanyl 100 mcg IV = methadone variable (complex pharmacokinetics, requires expert consultation). When rotating opioids, the calculated equianalgesic dose should be reduced by 25-50% due to incomplete cross-tolerance. Fentanyl is approximately 100 times more potent than morphine. Dilaudid (hydromorphone) is approximately 5 times more potent than morphine.

Side Effects

Opioid side effects include constipation (30-50% — does not improve with time; requires bowel regimen with stimulant laxative + stool softener, and consideration of peripherally acting mu-opioid antagonists like naloxegol, methylnaltrexone, or lubiprostone). Nausea and vomiting (20-30% — typically improves within 3-7 days; treat with antiemetics — ondansetron, promethazine, or dopamine antagonists). Sedation (common initially — improves within 3-7 days; if persistent or severe, consider dose reduction or adding a stimulant like modafinil or methylphenidate). Pruritus (2-10% — histamine release, especially with morphine; antihistamines may help; consider opioid rotation to a non-histamine-releasing opioid like fentanyl or hydromorphone). Respiratory depression (overdose — CNS more concerning). Tolerance develops to respiratory depression and analgesia at different rates (tolerance to respiratory depression may develop faster with stable doses; rapid dose escalation carries greater risk).

⚠ Clinical Correlation

Opioid-induced constipation (OIC) is the most common and persistent opioid side effect — it affects 50-80% of chronic opioid users and does not improve with time (opioids delay GI transit through mu receptors in the enteric nervous system). All patients on opioids should receive a bowel regimen. First-line: stimulant laxative (senna, bisacodyl) + stool softener (docusate) combined. If inadequate: add osmotic laxative (polyethylene glycol, lactulose, milk of magnesia). For OIC refractory to laxatives: peripherally acting mu-opioid receptor antagonists (PAMORAs) — naloxegol (Movantik) 12.5-25 mg daily, naldemedine (Symproic) 0.2 mg daily, or methylnaltrexone (Relistor) subcutaneous or oral. These drugs do not cross the blood-brain barrier, so they block peripheral opioid effects (constipation) without affecting central analgesia. Lubiprostone (Amitiza) is a chloride channel activator that increases intestinal fluid secretion, approved for OIC.

Opioid Overdose

Opioid overdose causes the triad: pinpoint pupils, respiratory depression, and unconsciousness. Treatment is naloxone (Narcan) — 0.4-2 mg IV/IM/IN, repeat every 2-3 minutes as needed. Naloxone duration (30-90 minutes) is shorter than most opioids, so repeated doses are often needed. All patients on chronic opioid therapy should have naloxone available.

WHO Analgesic Ladder

The WHO analgesic ladder guides pain management. Step 1: mild pain — non-opioid analgesic (NSAID or acetaminophen) with or without adjuvant. Step 2: moderate pain — weak opioid (codeine, tramadol) plus non-opioid with or without adjuvant. Step 3: severe pain — strong opioid (morphine, oxycodone, hydromorphone, fentanyl) plus non-opioid with or without adjuvant. Adjuvant analgesics can be added at any step for specific pain types: neuropathic pain (gabapentin, pregabalin, tricyclic antidepressants, duloxetine, lidocaine patch), bone pain (NSAIDs, bisphosphonates, radiation), and visceral pain (anticholinergics, clonidine).

Summary

Non-opioid analgesics include acetaminophen (effective, hepatotoxic in excess) and NSAIDs (effective anti-inflammatory, but GI, renal, and cardiovascular risks limit use). Opioids are potent analgesics used for moderate to severe pain, with side effects including constipation (require bowel regimen), nausea, sedation, and respiratory depression (overdose). The WHO analgesic ladder guides stepwise treatment. Adjuvant analgesics target specific pain mechanisms. Opioid rotation accounts for incomplete cross-tolerance. Naloxone should be available for all patients on chronic opioid therapy.