2007A03 Discuss factors contributing to inter-individual variability in the therapeutic response to
opioid analgesic medications.

Problems

·  Variation in threshold opioid concentration for analgesia, for resp depression

·  Variation in individual perceptions and responses to pain (psychosocial factors)

·  Relatively narrow therapeutic index (e.g. fentanyl 2-5ng/mL)

Implication

·  Risk of underdose -> pain

·  Risk of overdose -> sedation, respiratory depression, airway obstruction, death

Oral

·  Neonate vomiting/reflux -> unreliable absorption (e.g. morphine)

·  Labour -> ↓gastric emptying -> ↓absorption rate

IM / SC / transdermal

·  ↓mAP, ↓temp -> vasoconstriction -> ↓skin and muscle blood flow -> ↓absorption rate

o Risk of dose stacking -> toxicity

·  Pregnancy, neonate -> ↑muscle and skin blood flow -> ↑absorption rate

Epidural

·  Scarring -> ↑thickness -> ↓rate of onset and intensity e.g. fentanyl

Cardiac output

·  ↑CO -> ↑Rate of distribution -> ↑rate of offset of drugs with high V_DSS (e.g. fentanyl)

Blood

·  ↓Blood volume -> ↓V_DC most opioids -> ↑acute toxicity

·  ↑pH -> ↑unionised % basic opioids -> ↑toxicity (e.g. morphine normally 23%)

·  ↓α₁ acid glycoprotein -> ↑% free basic drug -> toxicity if high %bound and low HER (e.g. methadone)

·  ↓Albumin -> same (binds opioids with lower affinity but high amount)

Tissue

·  ↑Fat mass -> ↑accumulation of lipophilic drugs (e.g. fentanyl) -> ↑duration of effect after long infusion

·  ↑Muscle mass -> ↑esterase activity -> ↓remifentanil duration

Brain

·  Blood brain barrier deficiency -> ↑penetration/toxicity if

o Highly ionized (e.g. morphine 77%)

o Hydrophilic (e.g. morphine-3-G (neurotoxicity), morphine-6-G (resp depression)

(immature in neonates, defective in elderly)

2D6 polymorphism

·  Ultra-rapid: 10% Arabs, North Africans

o ↑Effect if activated (e.g. codeine, tramadol) -> toxicity

o ↓Effect if inactivated

·  Intermediate or poor: 30% Hong Kong Chinese)

o ↓Effect if activated (e.g. codeine, tramadol) -> minimal analgesic effect

o ↑Effect if inactivated

↓Phase 1& 2 activity (if liver failure)

·  ↓Clearance if metabolism-limited (e.g. methadone)

↓Hepatic blood flow

(if cirrhosis, shock)

·  ↓Clearance if flow-limited (e.g. morphine)

Renal failure

·  ↓Excretion of small and/or hydrophilic drugs and metabolites -> toxicity

o e.g. M3G (seizures, cognitive dysfunction)

o e.g. M6G (analgesia, resp depression))

Liver failure

·  ↓Bile secretion -> ↓excretion of large and/or lipid-soluble drugs and metabolites

Receptors

·  Polymorphism -> ↑↓affinity for drug -> ↑↓effect

·  Tolerance: beta arrestin binds to phosphorylated carboxyl terminal in ICF -> downregulation -> ↓effect

Intracellular signalling

·  Polymorphism -> ↑↓amplification -> ↑↓effect

·  Tolerance: chronic opioid use -> upregulation of cAMP -> ↓effect

·  Opioid-induced hyperalgaesia: e.g. ↑NMDA activity

Drug interactions

·  Additive: e.g. fentanyl + morphine

·  Synergistic: e.g. fentanyl + midazolam -> ↑↑respiratory depression

o i.e. effect of drug A + B together > drug A alone + drug B alone

·  Antagonistic: e.g. fentanyl + naloxone

Special physiology

·  Neonate: immature respiratory centre -> ↑sensitivity

·  Elderly: ↑sensitivity (? cause)

Pathology

·  ↑Resp centre sensitivity -> ↑opioid toxicity

o Sleep disordered breathing

o Severe COPD

Psychosocial factors

·  Differing individual perceptions of pain

o Mental illness: physical and psychological effects

o Other life stressors

o Cultural differences