Non-opioid analgesics

As part of “multimodal analgesia” and “opioid sparing” regime to control pain.

Drugs to consider:

Paracetamol
NSAID’s
Anti-convulsants ]
o Carbamazepine ]
o Gabapentinoids ] See neuro-pharmacology notes
Anti-depressants ]
o TCA’s ]
α2-agonists eg clonidine ] See anti-hypertensives notes
Local anaesthetics ] See LA notes
Ketamine ] See IV agent notes
N2O/Xenon/MTF ] See inhalational agent notes
? Cannabinoids ] Very topical

COX isoenzymes 1, 2 (and 3)

COX-1 – constitutional (house-keeping) enzyme, generating all prostanoids involved in normal

physiology eg haemostasis, gastric mucosal protection
COX-2 – has low baseline expression but inducible during physiological stress
COX-3 – splice variant of COX-1 ?? exact mechanism in humans
Paracetamol
Para-aminophenol derivative
Analgesic and antipyretic effect without anti-inflammatory action – direct effect on hypothalamus and
inhibition of endogenous pyrogens.
? COX3 inhibitor; it may also act on serotonergic and endogenous cannabinoid pathways

Absorption
Typical PO/PR dosing adults 2 – 4g/day, children 10-15 mg/kg q6-8hr
IV dose 10-15 mg/kg
Rapidly absorbed orally (OBA 70-90%) – peak concentration at 1 hour.
PR bioavailability about 80% and slower absorption

Distribution
Vd 1 L/kg
PPB = 5%

Metabolism
Normally 90% hepatically metabolised to sulfate and glucuronide conjugates by CYP450
Enzyme induction occurs with ethanol – increases toxic free radical metabolites

Excretion
Conjugated metabolites excreted renally; small amount excreted unchanged
T ½ 2 hours

Side effects
Generally very safe
 Low adverse reactions and hypersensitivity
 No GI / haem issues cf NSAIDs
 Safe in pregnancy / lactation / children
 Low drug interactions (low PPB)

Toxicity (see poisoning notes)

 Occurs when “normal” pathway above saturated eg high dose
 Metabolised to N-acetyl-p-benzoquinone imine (NAPQI); depending on available glutathione:
o Glutathione adequate ⇒ paracetamol-mercapturic acid derivative (non-toxic)
o Glutathione low ⇒ formation protein derivatives, lipid perioxidation, oxidative stress
causing liver cell death
 N-acetylcysteine is a synthetic analogue of glutathione
 Non-steroidal anti-inflammatory drugs (NSAIDs)
Indications: Analgesic, antipyretic; prevention of ductus arteriosis closure (indomethacin)

Classifications
 Nonspecific cox inhibitors (1&2)
 Salicylates eg aspirin (irreversible)
 Fenamates (eg diclofenac, ketorolac)
 Acetic acid derivatives (eg indomethacin)
 Proprionic acids eg ibuprofen, naproxen
 Enolic acid derivatives (oxicams) eg tenoxicam, meloxicam (preference for COX-2)
 Pyrazolones eg phenylbutazone
 Specific cox-2 inhibitors eg celecoxib & parecoxib

MoA
Inhibition of COX isoenzymes – decreased peripheral production of PG’s – decreased sensitisation of
nociceptors by mechanical or pain mediators eg bradykinin (esp ↓ PGE2)
Particularly useful for pain with inflammatory component
Probably also acts at CNS – dorsal horn COX inhibition
Antipyrexial action due to decreased PG synthesis in hypothalamus

Absorption
Rapidly absorbed orally with peak concentration in 2 hours
PR route is possible and not affected by changes in gastric emptying
IV forms available (eg ketorolac, ibuprofen, diclofenac, tenoxicam); we have IV parecoxib (prodrug;
valdecoxib produced)

Distribution
Generally are weak acids with pKa typically < 5, therefore mostly ionised at physiological pH
Highly PPB 90-99% primarily to albumin (except aspirin 50-80%)

Metabolism
Hepatic biotransformation by CYP450 – oxidation or glucuronides

Excretion
Renally – metabolites and small amounts of unchanged drug (<10%)
Some also undergo bile excretion
T1/2 variable depending on drug; ibuprofen = 6, naproxen = 14, diclofenac 1-2, ketorolac 4-6,
celecoxib 6-12 hours; parecoxib 20 min (valdecoxib 8-11 hours)

Side effects
Common: rash, GI upset.
Allergy/hypersensitivity: mostly due to COX1 inhibition. Asthmatic/bronchoconstriction (likely due
to ↓ PGE2). Urticaria / angioedema due to histamine release. Aseptic meningitis possible.
CVS: Increase in CV thrombotic events (MI, stroke) – likely due to imbalance of TXA2/PGI2 (↑/↓).
Rofecoxib and valdecoxib most implicated (now discontinued). Short term use probably OK – benefit
vs risk. Long term use associated with hypertension.
GI: Erosion and ulceration of gastric mucosa with long term use. PPI often used to cover. Careful in
the elderly. Hepatotoxicity possible.
Renal: Occurs with all COX inhibition. Decrease renal function with hypertension/oedema/AKI
possible. Increased risk with pre-existing CKD and hypovolaemia.
Haem: Inhibition of platelet aggregation (COX-1; COX-2 not found in platelets); possibility of
increased bleeding.
Bone: impaired fusion on animal models (controversial)

Drug interactions
PPB related issues rarely significant clinically.
Renal: other nephrotoxics eg diuretics, aminoglycosides, contrast
Haem: other antiplatelet and anti-coagulants
Something on Pregabalin

Gabapentinoid similar to… gabapentin

o Better tolerated, less toxicity due to specific receptor interaction cf early anti-convulsants
Indications: neuropathic pain in adults, partial seizures
Capsules: 25/50/75/100/150/200/225/300 mg (Medsafe)

MoA
GABA analogue
Binds to α2-δ subunit of pre-synaptic voltage gated Ca channels in CNS
Reduces release of glutamate, noradrenaline, substance P ? Also activates noradrenergic pathways

PG vs GP
• More predictable PK
• More potent
• Steeper dose-response curve
• Faster clinical onset
• Able to up titrate rapidly

Both safe in overdose – large margin of safety – pregabalin up to 15g, gabapentin up to 8g/kg
Equivalency: PG : GP - 450mg : 3600mg, or about 1:6

Side effects
• Dizziness and somnolence
• Dry mouth
• Weight gain
• Blurred vision
• Peripheral oedema
• Suicidal behaviour