Opioid receptors - morphine

Question 1

Naturally occurring opioids from the opium poppy:

Answer 1

Morphine
Codeine (Weak)

Question 2

Simple chemical modifications to naturally occurring one:

Answer 2

Diamorphine
Oxycodone
Dihydrocodeine

Question 3

Synthetic opioids

Answer 3

Pethidine
Fentanyl
Alfentanil
Remifentanil

Question 4

Synthetic partial opioid agonists

Answer 4

Buprenorphine

Question 5

What is the antagonist for opioids?

Answer 5

Naloxone

Question 6

Routes of administration for morphine

Answer 6

Oral - bioavailability is reduced.

First pass metabolism by the liver - 50% is metabolised.

Single dose lasts for ~3-4 hours.

Slow release preparations for palliative care - continuous.

Question 7

How does morphine dosing differ if its given orally vs S/C; IM or IV?

Answer 7

50% of oral dose is metabolised by the liver thus parenteral administration requires half the oral dose.

10mg orally is equivalent to 5mg s/c; IM; IV.

Question 8

What are the parenteral routes for morphine administration?

Answer 8

S/C (third fastest)
IM (second fastest)
IV (fastest)

IV PCA (patient controlled)
Epidural/CSF
Transdermal patches for lipid soluble drugs= fentanyl.

Question 9

Morphine problems

Answer 9

Serious problems with addiction,
the drug companies started
trying to develop non-addictive
(and non-respiratory depressant)
versions of morphine

Question 10

Diamoprhine

Answer 10

Simple chemical transformation to diacetylmorphine.

More potent and faster acting (crosses BBB quickly)

Question 11

Controlled drug legislation

Answer 11

Started in the 1920s

Current legislation:
Misuse of Drugs Act 1971

Class A drugs

Secure storage
CD books (2 signatures needed)

Question 12

How do opioids work?

Answer 12

Review of pain pathways - opioid drugs simply use the existing pain
modulation system.

Natural endorphins (endogenous morphine) and enkephalins.

G protein coupled receptors - act via second messengers.

Inhibit the release of pain transmitters at spinal cord and midbrain - and modulate pain perception in higher centres - euphoria - changes the
emotional perception of pain

Question 13

What do opioids inhibit?

Answer 13

Descending inhibition of pain

Part of the fight or flight response

Never designed for sustained activation

Sustained activation leads to tolerance and
addiction

Question 14

Opioid receptors

Answer 14

MOP, KOP, DOP and NOP (nociceptin opioid-like receptor)

• Receptors now sequenced, all vertebrates have copies of the
  main opioid receptors - unchanged in evolutionary terms for
  millions of years

Question 15

Importance of opioid receptors?

Answer 15

• MOP, KOP, DOP and NOP - what do you need to know?
• Aim remains to develop opioid analgesics without the side
  effects of respiratory depression or addiction
• Kappa agonists cause depression instead of euphoria
• At the moment all the drugs that we use are µ agonists

Question 16

Potency

Answer 16

Whether a drug is ‘strong’ or ‘weak’ relates to how well the drug binds to the receptor,
the binding affinity

Question 17

Efficacy

Answer 17

Is it possible to get a maximal response with the drug or not?

Or even if all the receptor sites are occupied do you get a ceiling response?

The concept of full or partial agonists

Question 18

Relative potencies

Answer 18

Diamorphine 5 mg
Morphine 10 mg
Pethidine 100 mg

Question 19

Tolerance

Answer 19

Down regulation of the receptors with prolonged use
Need higher doses to achieve the same effect

Question 20

Dependence

Answer 20

Psychological - craving, euphoria
Physical

Question 21

Opioid withdrawal

Answer 21

Starts within 24 hours, lasts about 72 hours.

Question 22

Side effects

Answer 22

Opioid receptors exist outside the pain system
e.g.: digestive tract, respiratory control centre

• We can sometimes deliver opioids epidurally, but for the most part we have to
  give them systemically

Respiratory Depression
Sedation
Nausea and Vomiting
Constipation
Itching
Immune Suppression
Endocrine Effects

• Different patients have quite a range of sensitivity to opioids - start with a small
  dose and titrate up as necessary

Question 23

Opioid induced respiratory depression

Answer 23

Call for help

• ABC
• Naloxone
• IV is fastest route
• Titrate to effect - don’t have to give it all once - once you’ve injected a drug you
  can’t get it back!
• Short half-life of naloxone - beware drug addict overdoses in A&E

Question 24

How to titrate naloxone to effect?

Answer 24

Titrate to effect - dilute 1ml in
10ml saline

One ampoule of a drug is
usually about the right adult
dose - if you think you need to
open more than one - check
with a colleague first!

Question 25

Opioid use in chronic non-cancer pain (AVOID if possible)

Answer 25

Opioids for non-cancer pain start to lose effectiveness fairly quickly (within
weeks)

Addiction to the drug leads to manipulative behaviour - easy to start, but can be
very difficult to get patients off them.

• Before prescribing opioids, discuss with the patient the risks and features of
  tolerance, dependence, and addiction - use short term courses.
• Agree a treatment strategy and plan for end of treatment.
• Warnings have been added to the drug labels and packaging of opioids to
  support patient awareness.
• At the end of treatment, taper dosage slowly to reduce the risk of withdrawal effects - may take weeks.

Question 26

What metabolises codeine (prodrug) to morphine?

Answer 26

CYP2D6 enzyme.

CYP2D6 activity is decreased in 10-15% of the Caucasian population

• • CYP2D6 is absent in a further 10% of this population
• Codeine will have a reduced or absent effect in these individuals
• CYP2D6 is overactive in 5% of this population - these individuals may be at
  increased risk of respiratory depression with codeine - not licensed for
  children under 12

Question 27

Morphine metabolism

Answer 27

Metabolised to morphine-6-glucoronide (more potent and is renally excreted).

Careful use in patients with renal function <30%.

Question 28

Tramadol

Answer 28

Weak opioid agonist - slightly stronger than codeine.

Prodrug - CYP2D6

It has a secondary effect in analgesia as a serotonin and nor-epinephrine reuptake inhibitor

• So it interacts with SSRIs, tricyclic antidepressants and MAOIs, sometimes fatally - take care prescribing it to patients on antidepressants