2002B06 Write brief notes on tolerance and dependence in relation to opioid analgesics.

Definition

·   Reduced intensity and duration of effect of a given dose of opioid with chronic use

·   No change in efficacy

·   i.e. Right shift in log(dose) response curve

·   Occurs to variable extent

Representation

(individual graded log-dose response curve)

Mechanisms

·   Receptor downregulation (β-arrestin binds COOH terminal of phosphorylated activated G-protein coupled receptor, triggering downregulation and destruction)

·   Change in receptor effect (G_i -> quasi G_s)

·   Upregulation of cAMP system

·   ↑NMDA activity (↓NMDA transport -> ↑synaptic [glutamate] -> tolerance and opioid-induced hyperalgaesia)

Time course

·   Onset and offset rapid for inhibitory effects (analgesia, respiratory depression)

·   Onset and offset slow for excitatory effects (miosis, constipation)

Implications of time course

·   Use of previously effective dose after a short layoff may cause overdose and death

·   Patients with chronic pain on opioids require very high dose for same effect

o Hence more GIT side effects

o Hence importance of use of adjuvants e.g. ketamine

Treatment

·   Opioid rotation

·   Opioid weaning, esp with ketamine infusion (‘re-sets’ opioid receptors)

Definition

·   Reliance on drug for normal functioning

·   Physical: withdrawal symptoms on cessation

·   Psychological: craving for drug on cessation

Associated features

·   Dependent patients often tolerant; tolerant patients not always dependent

·   Addiction (harmful drug-seeking behavior) – especially if psychological dependence

Cause

·   As for tolerance

·   Pathological adaptation in dopaminergic reward pathways

Risk factors

·   Drug characteristics:

o Rapid onset (high lipid solubility, high % unionised (e.g. alfentanil)

o Highly euphoric (e.g. diacetylmorphine)

·   Administration: prolonged use (e.g. chronic pain)

·   Patient: psychiatric history, unemployment etc.

Withdrawal features

·   Physical: nausea, sweating, cholinergic (salivation, lacrimation, GIT cramp)

·   Psychological: craving, dysphoria, restlessness, insomnia

Treatment

·   Opioid replacement (e.g. methadone, buprenorphine/naloxone)

·   Psychosocial intervention