Opioid Tolerance and Dependence Flashcards
What is tolerance?
The need to increase the dose to maintain a given/therapeutic effect
»> Develops rapidly and compromises therapy with increasing risk of side effects
What is dependence?
- Physical dependence: development of a physiological withdrawal/abstinence syndrome
- Psychological dependence: desire/craving to take the drug irrespective of adverse consequences
When does normal sensitivity to morphine return after withdrawing treatment?
A few days.
When can analgesic tolerance be observed from with morphine?
Detected within 12 - 24 hours of administration
Do opioid side effects undergo tolerance too?
Much less subject: emesis, euphoria, respiratory depression and constipation/pupillary constriction show little tolerance; do not dissipate, thus limiting dose escalation in an attempt to combat analgesic tolerance.
What is cross-tolerance and what is useful to combat it?
- When one drug causes tolerance to a different drug
(usually of the same pharmacological class/target) - Thus opioid rotation is useful e.g. from morphine to hydromorphone or oxycodone (analgesic effects on diff. receptors/mechanisms to maintain analgesia)
What is the pharmacokinetic (body handling the drug) hypothesis for opioid tolerance?
- Reduction in amount of available drug at the receptor due to increased metabolism or increased efflux
- Opioids are substrates of P-glycoprotein
BUT: no evidence of enzyme induction (nor P450s 2DG/3A4 in PI or UGT2B7 in PII) or increased P-glycoprotein expression/activity with prolonged exposure to opioids
What is the pharmacodynamic hypothesis for opioid tolerance?
- Reduction in agonist affinity
- Uncoupling from G-proteins = reduced downstream/intracellular signalling
- Receptor internalisation and downregulation
How do Gαi-PCRs react upon morphine binding?
- α and βγ subunits dissociate
- Gαi inhibits adenylyl cyclase
- Inhibits Ca2+ channels (less Glu release)
- Activates K+ channels (hyperpolarisation)
What is the relationship between opioid agonist efficacy and tolerance, and how can this be explained?
- Inversely proportional
- Due to ‘receptor reserve’; e.g. fentanyl (high efficacy) requiring 5% receptor activation to achieve full response and morphine (low efficacy) requiring 100% receptor activation for the same; an internalisation of receptors etc. would influence morphine’s efficacy a lot more.
How does uncoupling from downstream signalling occur?
- Phosphorylation by several different protein kinases (such as cAMP-dependent PKA, CaMKII, protein kinase C (PKC), P protein-coupled receptor kinases (GRKs) or MAPKs)
What are the steps of μ opioid receptor internalisation?
- Rapidly follows agonist activation, receptor phosphorylation and recruitment of β-arrestin protein (seconds-mins)
Does the scope of internalisation depend on the agonist?
- Agonist-dependent
- Higher with endogenous peptide ligands, etorphine and dihydroetorphine
»> Morphine fails to cause much internalisation
What occurs during μ opioid receptor downregulation; is this process agonist-dependent?
- Disappearance from all cell locations; proteolysis (degradation of) by lysosomes/proteosomes
- Agonist-selective; marked reduction in receptor density with the high efficacy agonist etorphine
- Limited effect of morphine on receptor numbers
What is the best supported theory for opioid receptor desensitisation?
Alterations in signal mechanisms: upregulation in adenylyl cyclase expression and the coupling of opioid receptors to both Gi and Gs proteins.
What does upregulating the expression of adenylyl cyclase in the CNS result in?
- Increased capacity for cAMP generation (more excitable neurons)
- Reduced sensitivity to inhibition via Gαi
What does chronic morphine administration lead to re. adenylyl cyclase?
The increased expression of specific isoforms of AC that are stimulated by Gβγ subunits
How can a shift between initial localised pain to widespread non-specific pain (increased pain sensitivity) w/chronic opioid treatment be explained with Gi/Gs proteins?
Opioid receptors couple to Gs (stimulatory) proteins instead of Gi (inhibitory) after chronic opioid treatment; a switch in signalling.
Why must care be taken in treating newborns with opioids?
- Parallel increase in coupling of μ-opioid receptors to Gi during post-natal development
- Babies susceptible to opioid abstinence syndrome
How can opioid tolerance be combatted?
- NMDA receptor antagonists (e.g. ketamine) reduce opioid tolerance and dependence in animals;
»> Co-activation with NMDA reduces opioid-dependent inhibition of cAMP formation
What are the symptoms of opioid withdrawal/how are they often described?
Severe flu-like symptoms in withdrawal from chronic administration:
- Restlessness, yawning, pupillary dilatation, fever, sweating, piloerection, nausea, diarrhoea and insomnia.
- Involuntary leg movement and goose pimples are the OG of “kicking the habit” and “cold turkey”
How long do opioid withdrawal symptoms last for/how they do return?
- Maximal at 2 days, disappear by 10 days
- Precipitated in tolerant patients by administration of opioid receptor antagonist (e.g. naloxone)
How is acute opioid toxicity treated?
Naloxone (IV) blocks receptor and prevents respiratory depression, but precipitates withdrawal in chronic user
How are opioid withdrawal symptoms treated?
- Loperamide (diarrhoea); peripheral opioid ligand not absorbed into CNS
- Mebeverine (stomach cramps)
- Paracetamol/NSAID (headache, muscle pain)
- Metoclopramide (nausea)
- Short-acting benzodiazepine (insomnia)
- Lofexidine/donidine; α2-adrenoceptor agonists; alleviate symptoms by reducing sympathetic NS activity (increased during withdrawal)
How can cannabis be used for opioid withdrawal?
- Replacing one Gi-coupled receptor with another (cannabinoid)
- cb-receptors not expressed in brain stem = no respiratory depression = replaces severe agent with less severe
What substitution therapy is available for heroin?
Methadone/buprenorphine; difficult to treat and requires medical social and psychological intervention (specialist support team)
Why is methadone preferred to heroin even though its a full opioid agonist?
- Longer half life; better tolerated re. withdrawal
- Taken PO not IV
- Does not produce IV heroin-like high
What’s the danger of methadone overdose?
Respiratory depression
What kind of opioid is buprenorphine?
A partial agonist; ceiling effect reduces OD danger but can precipitate withdrawal symptoms if other opioids in system
