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

 

List:

Tolerance: definition, mechanism, time course, implications, treatment

Dependence: definition and types, associations, cause, risk factors, withdrawal, treatment

 

Tolerance:

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 (Gi -> quasi Gs)

·  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)

 

Dependence:

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