Opioid Tolerance and Dependence

Question 1

What is tolerance?

Answer 1

The need to increase the dose to maintain a given/therapeutic effect
»> Develops rapidly and compromises therapy with increasing risk of side effects

Question 2

What is dependence?

Answer 2

• Physical dependence: development of a physiological withdrawal/abstinence syndrome
• Psychological dependence: desire/craving to take the drug irrespective of adverse consequences

Question 3

When does normal sensitivity to morphine return after withdrawing treatment?

Answer 3

A few days.

Question 4

When can analgesic tolerance be observed from with morphine?

Answer 4

Detected within 12 - 24 hours of administration

Question 5

Do opioid side effects undergo tolerance too?

Answer 5

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.

Question 6

What is cross-tolerance and what is useful to combat it?

Answer 6

• 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)

Question 7

What is the pharmacokinetic (body handling the drug) hypothesis for opioid tolerance?

Answer 7

• 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

Question 8

What is the pharmacodynamic hypothesis for opioid tolerance?

Answer 8

• Reduction in agonist affinity
• Uncoupling from G-proteins = reduced downstream/intracellular signalling
• Receptor internalisation and downregulation

Question 9

How do Gαi-PCRs react upon morphine binding?

Answer 9

• α and βγ subunits dissociate
• Gαi inhibits adenylyl cyclase
• Inhibits Ca2+ channels (less Glu release)
• Activates K+ channels (hyperpolarisation)

Question 10

What is the relationship between opioid agonist efficacy and tolerance, and how can this be explained?

Answer 10

• 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.

Question 11

How does uncoupling from downstream signalling occur?

Answer 11

• Phosphorylation by several different protein kinases (such as cAMP-dependent PKA, CaMKII, protein kinase C (PKC), P protein-coupled receptor kinases (GRKs) or MAPKs)

Question 12

What are the steps of μ opioid receptor internalisation?

Answer 12

• Rapidly follows agonist activation, receptor phosphorylation and recruitment of β-arrestin protein (seconds-mins)

Question 13

Does the scope of internalisation depend on the agonist?

Answer 13

• Agonist-dependent
• Higher with endogenous peptide ligands, etorphine and dihydroetorphine
  »> Morphine fails to cause much internalisation

Question 14

What occurs during μ opioid receptor downregulation; is this process agonist-dependent?

Answer 14

• 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

Question 15

What is the best supported theory for opioid receptor desensitisation?

Answer 15

Alterations in signal mechanisms: upregulation in adenylyl cyclase expression and the coupling of opioid receptors to both Gi and Gs proteins.

Question 16

What does upregulating the expression of adenylyl cyclase in the CNS result in?

Answer 16

• Increased capacity for cAMP generation (more excitable neurons)
• Reduced sensitivity to inhibition via Gαi

Question 17

What does chronic morphine administration lead to re. adenylyl cyclase?

Answer 17

The increased expression of specific isoforms of AC that are stimulated by Gβγ subunits

Question 18

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?

Answer 18

Opioid receptors couple to Gs (stimulatory) proteins instead of Gi (inhibitory) after chronic opioid treatment; a switch in signalling.

Question 19

Why must care be taken in treating newborns with opioids?

Answer 19

• Parallel increase in coupling of μ-opioid receptors to Gi during post-natal development
• Babies susceptible to opioid abstinence syndrome

Question 20

How can opioid tolerance be combatted?

Answer 20

• NMDA receptor antagonists (e.g. ketamine) reduce opioid tolerance and dependence in animals;
  »> Co-activation with NMDA reduces opioid-dependent inhibition of cAMP formation

Question 21

What are the symptoms of opioid withdrawal/how are they often described?

Answer 21

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”

Question 22

How long do opioid withdrawal symptoms last for/how they do return?

Answer 22

• Maximal at 2 days, disappear by 10 days

- Precipitated in tolerant patients by administration of opioid receptor antagonist (e.g. naloxone)

Question 23

How is acute opioid toxicity treated?

Answer 23

Naloxone (IV) blocks receptor and prevents respiratory depression, but precipitates withdrawal in chronic user

Question 24

How are opioid withdrawal symptoms treated?

Answer 24

• 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)

Question 25

How can cannabis be used for opioid withdrawal?

Answer 25

• Replacing one Gi-coupled receptor with another (cannabinoid)
• cb-receptors not expressed in brain stem = no respiratory depression = replaces severe agent with less severe

Question 26

What substitution therapy is available for heroin?

Answer 26

Methadone/buprenorphine; difficult to treat and requires medical social and psychological intervention (specialist support team)

Question 27

Why is methadone preferred to heroin even though its a full opioid agonist?

Answer 27

• Longer half life; better tolerated re. withdrawal
• Taken PO not IV
• Does not produce IV heroin-like high

Question 28

What’s the danger of methadone overdose?

Answer 28

Respiratory depression

Question 29

What kind of opioid is buprenorphine?

Answer 29

A partial agonist; ceiling effect reduces OD danger but can precipitate withdrawal symptoms if other opioids in system