Non-opioid analgesics

Non-opioid analgesics include nonsteroidal anti-inflammatory drugs (NSAIDs), selective COX-2 inhibitors, and acetaminophen. NSAIDs inhibit cyclooxygenases (COX-1 and COX-2), thereby disrupting the production of prostaglandin, an important mediator of pain and inflammation. Consequently, NSAIDs possess antipyretic, analgesic, and anti-inflammatory effects, and are particularly effective in the management of musculoskeletal pain (e.g., rheumatic disorders, inflammatory joint pain). Side effects include gastrointestinal ulcers and bleeding, increased risk of heart attacks, and renal function impairment. The severity of these side effects is often underestimated because most non-opioid analgesics are easily available OTC. Selective COX-2 inhibitors have similar effects to NSAIDs, but show a lower risk for gastrointestinal side effects. Acetaminophen possesses antipyretic and analgesic effects and is the most commonly used over-the-counter (OTC) oral analgesic drug. It is generally well tolerated, but overdose can result in significant hepatotoxicity with the risk of acute liver failure.

Agents

• Ibuprofen
• Diclofenac
• Indomethacin
• Naproxen
• Piroxicam
• Meloxicam
• Ketorolac
• Sulindac
• Aspirin

Mechanism of action

• Reversible inhibition of the enzymes COX-1 and COX-2 → decreased prostaglandin synthesis
• Aspirin is the exception, because it leads to irreversible COX-1 and COX-2 inhibition. (See aspirin for more information.)

Effects

• Analgesic
• Antipyretic
• Anti-inflammatory (antirheumatic)
• Minor antiplatelet function (with the exception of aspirin)

Side effects

• Gastric and duodenal ulcers with the risk of gastrointestinal bleeding and perforation (inhibition of COX disrupts the production of protective gastric mucosal prostaglandins)
  • Risk increases with duration and dose of treatment ^[2][3]
  • Prophylaxis:
    • Administration of proton pump inhibitors (in case long-term intake is needed) ^[4]
    • See “Prevention of NSAID-induced GI toxicity” for details.
• Increased risk of heart attack and stroke (with the exception of aspirin and naproxen) ^[5]
• Renal function impairment: Prostaglandins normally maintain renal blood flow by inducing vasodilation of the afferent arterioles. NSAIDS inhibit prostaglandin production, which leads to harmful hypoperfusion of the kidneys and reduced GFR. ; ^[6]
  • Electrolyte and fluid abnormalities (edema, hyperkalemia, hyponatremia)
  • Worsening of hypertension
  • In rare cases, acute renal failure
  • Analgesic nephropathy: prolonged NSAID use results in tubulointerstitial nephritis and papillary necrosis (↑ crea/BUN ratio, slight ↑ K⁺) ^[7]
• Aplastic anemia ^[8]
• Pseudoallergic reactions ^[9]
  • Urticaria and angioedema
  • Asthma
  • Aspirin-exacerbated respiratory disease (AERD)
• For side effects of aspirin, see aspirin.

The risk of an ulcer is 10–15 times higher if NSAIDS and glucocorticoids are administered simultaneously!

Indications

• Acute and chronic pain (particularly musculoskeletal)
  • Rheumatoid arthritis
  • Inflammatory arthritis
  • Kawasaki disease
  • Acute gout attack
  • Post-operative pain
  • Dysmenorrhoea
  • Headache, migraine
• Fever
• Indomethacin: closure of a patent ductus arteriosus
• See aspirin for specific indications of aspirin.

Contraindications

• Gastroduodenal ulcers
• Acute hemorrhage (especially aspirin)
• Renal failure
• Recent myocardial infarction, unstable angina, heart failure
• Surgery: discontinue NSAIDs 1–3 days prior to surgery
• Avoid NSAIDs during pregnancy!

NSAIDs are contraindicated in the second and third trimester as they may cause premature closure of the ductus arteriosus. Furthermore, they can inhibit uterine contractility.

References:^[2][10][11]

Agent

• Celecoxib ^[12]

Mechanism of action

• Reversible selective inhibition of COX-2 with almost no inhibition of COX-1
• COX-2 is found in:
  • Cells that mediate inflammation and pain (e.g., macrophages, leukocytes)
  • Vascular endothelial cells (i.e., cells that control vasodilation)

Effects

• Analgesic and anti-inflammatory
• Advantages in comparison to nonselective NSAIDs
  • No antiplatelet effect: platelets only possess COX-1 and are therefore not targeted by selective COX-2 inhibitors. This means that the activity of thromboxane A₂ (TXA₂) is not interrupted (TXA₂ normally promotes platelet aggregation).
  • Gastric mucosal cells express mostly COX-1, which is involved in maintaining a healthy gastric mucosa, so there are minimal gastrointestinal side effects and a lower risk of gastric ulcers.

Side effects

• Increased risk of thrombosis, MI, and/or stroke
• Sulfa drug allergic reaction
• Renal side effects in at-risk patients
  • Deterioration of chronic renal failure
  • Worsening of hypertension

Indications

• Rheumatoid arthritis, osteoarthritis, acute pain, nonrheumatoid joint pain
• Especially as an alternative to nonselective NSAIDs for patients with a history of peptic ulcer disease and platelet disorders (e.g., Glanzmann thrombasthenia)

Contraindications

• Severe heart failure, recent myocardial infarction, gastrointestinal bleeding
• Sulfa drug allergy

“seleCOXib:” celecoxib is a selective COX-2 inhibitor.

References:^[12][13]

Agent

• Acetaminophen

Mechanism of action

• Reversibly inhibits cyclooxygenase, mainly in the CNS
• Inactivated peripherally

Effects

• Antipyretic
• Analgesic
• No anti-inflammatory effect

Side effects

• Minimal gastric side effects
• Hepatotoxicity due to acetaminophen overdose (drug-induced hepatitis)
  • Minimum toxic dose: 7.5 g/day in adults
  • Leading cause of acute hepatic failure in the US
  • Pathophysiology
    • Exhaustion of hepatic metabolic pathways causes increased formation of a toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine (NAPQI).
      • Glutathione initially inactivates NAPQI, but its reserves are eventually depleted, leading to NAPQI build-up.
      • NAPQI → irreversible oxidative hepatocyte injury → liver cell necrosis
  • Clinical features
    • Nonspecific symptoms (nausea, vomiting, pallor lethargy) or asymptomatic in the first 24 hours after ingestion
    • Progressive liver impairment (RUQ pain; , liver enlargement and tenderness, abnormal liver function tests)
    • If acute liver failure does not develop, patients typically begin to recover within 2 weeks after ingestion.
    • Acute kidney failure occurs in approx. 50% of patients with acute hepatic failure.
  • Management
    • Activated charcoal; administered < 4 hours after ingestion
    • Measure acetaminophen (APAP) levels 4 hours after ingestion (or immediately, if ingestion occurred > 4 hours prior to presentation)
    • Antidote: PO or IV N-acetylcysteine (NAC)
      • Administered 4–24 hours after ingestion
      • NAC replenishes glutathione stores in the liver
      • Indications
        • Serum acetaminophen level above the treatment line when measured 4 hours after ingestion
        • Single ingestion of acetaminophen > 150 mg/kg (7.5 g irrespective of patient weight) if the acetaminophen level cannot be assessed within 8 hours of ingestion
        • History of acetaminophen ingestion with signs of liver injury
        • High serum acetaminophen level (> 10 mcg/mL) with an unknown time of ingestion
    • Treatment of liver failure
    • Liver transplant in severe cases

Indications

• Fever and pain
  • Good tolerability
  • Preferred analgesic/antipyretic drug during pregnancy
  • Preferred over aspirin in pediatric viral infections because it has a lower risk of causing Reye syndrome

Contraindications

• Severe liver impairment

Maximum daily dose of acetaminophen: 4 g (adults).
References:^[13]