Pharmacology
4,5 Epoxymophinan ring = Morphine, codeine, oxymorphone, oxycodone, buprenorphine, hydromorphone, and hydrocodone.
Phenylpiperidines = Fentanyl
Diphenylheptylamines = Methadone
Pharmacokinetics
Majority of opiates have high gastrointestinal permeability and good bioavailability EXCEPT fentanyl and buprenorphine - which are metabolised at high levels in hepatic first-pass metabolism.
Most opiates will undergo some first-pass metabolism however by liver enzyme CYP3A4.
Opiates in the 4,5 epoxymorphinans group are subject to O-dealkylation - this is how... codeine --> morphine
hydrocodone --> hydromorphone
oxycodone --> oxymorphone.
However! This dealkylation is quite variable which explains different peoples responses to these prodrugs (e.g. 10% of Caucasians lack the enzyme for this process AND 3% have a SUPER (duplicated) system leading to much faster metabolism).
These metabolites - are more analgesic than their prodrugs and bind mu receptor more readily.
Methadone is metabolised by the cytochrome P450 system - so keep this in mind!
Opioids are excreted through the kidneys (hence renal adjustment is required!)
Regarding binding - just remember that nearly all bind Mu. Morphine binds kappa a little bit. Oxycodone and buprenorphine bind kappa a lot.(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555047/table/tbl2/)
All this different metabolism and binding leads to different clinical strengths of the opioids. This table is a good starting point.
Different types:
Mechanism of action
- The opioid drugs produce analgesia by actions at several levels of the nervous system, in particular, inhibition of neurotransmitter release (such as glutamate, substance P, and calcitonin gene-related peptide) from the primary afferent terminals in the spinal cord and activation of descending inhibitory controls in the midbrain.
- They also activate presynaptic receptors on GABA neutrons inhibiting release of GABA in the ventral tegmental area leaving dopaminergic neutrons to fire more readily and leading to 'pleasure'
Neurotransmitter release from neurons is normally preceded by depolarisation of the nerve terminal and Ca++ entry through voltage-sensitive Ca++ channels. Drugs may inhibit neurotransmitter release by a direct effect on Ca++ channels to reduce Ca ++ entry, or indirectly by increasing the outward K + current, thus shortening repolarisation time and the duration of the action potential. Opioids produce both of these effects because opioid receptors are apparently coupled via G-proteins directly to K+ channels and voltage-sensitive Ca++ channels. Opioids also interact with other intracellular effector mechanisms, the most important being the adenylate cyclase system.
Trescot, A. M., Datta, S., Lee, M., & Hansen, H. (2008). Opioid pharmacology. Pain physician, 11(2 Suppl), S133-53.
Idiosyncrasies of Methadone
- It is a racemic mixture - L isomer has 50 times higher affinity for the opioid receptors than S isomer
- Methadone is an antagonist at NMDA receptor and is also an SNRI reuptake inhibitor (might help with decreased tolerance and improved efficacy)
- Has large inter individual bioavailability (36 to 100%) and half-life (8 to 59 hours)
- Accumulation can occur independent of 6-12 hr duration of analgesia
- Methadone is metabolised by a large amount of cytochrome P450 enzymes - hence can have significant drug interactions
- Methadone has minimal active metabolites and minimal accumulation in renal disease. However liver disease patients may accumulate (but not well studied)
- Research on methadone, particularly long term or different pain types, is limited.
- Methadone requires starting low and titrating slow
(E.g. 2.5 mg every 8 hours and minimum of 1 week between titrations. Can go up 5mg per dose increments every 5-7 days)
- Conversion from other opiates is difficult. That is required to have a 'washout' time and then methadone commenced at the below amounts (Stop and Go method)
- Patients should also be given 10% daily methadone dose as breakthrough
- Between 1999 and 2002, methadone deaths increased 200%. Exam cause of methadone-related mortality is unknown
- Can cause nausea, constipation, and sedations (but less with methadone cw morphine)
- However, methadone has been associated with respiratory depression and cardiac conduction abnormalities (QT prolongation). All patients need an ECG before commencement
https://www.practicalpainmanagement.com/treatments/pharmacological/opioids/methadone-pain-management
Idiosyncrasies of Buprenorphine
Indications
- Acute pain
- Chronic pain
- Cancer pain
- Non-cancer pain
Dosing
Common side effects
- Confusion and drowsiness
- Hallucinations and bad dreams
- Dry mouth and constipation
- Nausea and vomiting
(Due to Mu opiate receptor stimulation outside of pain pathway)
(Anything over oMEDD > 40 mg leads to more side effects. Greater than 100mg > risk of death)
Rare side effects - be aware!
- Itch and sweating
- Hyperalgesia
- Myoclonus
- Delirium
Liver and kidney issues
- Opioids and their active/toxic metabolites are excreted by the kidney
- Dose adjustment rarely needed when eGFR >50 ml/min
-
In renal impairment...
- Active/toxic metabolites may accumulate
- Altered drug distribution - affected by changes in hydration
- Hypoproteinaemia/altered drug binding in uraemia
- Increased permeability of blood brain barrier
- Increased sensitivity to CNS side effects of opioids e.g. drowsiness
Tolerance / Dependence
- Thought to be (in part) due to activation of the glutaminergic system via the NMDA receptor
- Tolerance to the different side effects can also occur (though rarely to constipation or mitosis)
Opioid induced hyperalgesia
- Varies between opiates (hence opiate rotation is useful)
Choice of opioid:
Golden pearls
- Tapentadol may have similar efficacy but less GI side effects (BUT STUDIES SPONSORED) (https://pubmed.ncbi.nlm.nih.gov/21797962/)
- Tapentadol also does NOT involve serotonin - so less risk of serotonin syndrome
- Up to 30% of cancer patients given morphine are 'non-responders'!
References:
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