Pain Flashcards
What is the official definition of pain?
An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage
What is the NICE ladder of analgesia?
1 - aspirin, paracetamol or ibuprofen
2 - codeine
3 - Morphine, fentanyl
What are the main side effects of analgesics?
- Constipation
- Nausea + vomiting
- Depression
- Drowsiness
- Changes in cognition
- Tolerance
- Dependence
- Misuse
- Lack of effect
- Driving impairment
- Opioid induced hyperalgesia
- Sexual dysfunction
- Loss of libido
- Endocrine dysfunction
- Immune dysfunction
- Osteoporosis
- Increased risk of falls
- Renal and hepatic failure
What is analgesic stewardship?
The aims of analgesic stewardship are to improve patient outcomes, reduce analgesic related harm and ensure cost-effective use of analgesics to provide optimal pain management
What is codeine?
Naturally occuring
Analgesic, with around one tenth the potency of morphine
e.g. human parenteral dose of 60-100 mg of codeine is equivalent to 10 mg morphine
but codeine retains most of its activity after oral administration (and therefore can be used in tablet form), whereas morphine suffers from considerable first pass metabolism, making codeine ideal for mild/moderate pain relief and as antitussive agent.
What is heroin?
All other things being equal, fast access to the brain and rapid offset from the receptor leads to higher abuse potential (better ‘rush’)
Heroin accesses the brain more quickly than morphine due to higher lipophilicity (pharmacokinetics)
Compared to morphine, heroin is about 2 times as potent as an analgesic, but heroin has very low affinity to opioid receptors and so,….
Metabolism - rapid to 6-acetylmorphine (~ 4 times more potent than morphine and similar binding affinity) and then further metabolism to morphine.
i.e. heroin acts as a pro-drug
What is morphine?
1805: Active ingredient (morphine) of opium was isolated by Friedrich Serturner (a German pharmacist). (Armand Seguin read a paper to the Institute of France in 1804, but only published it in 1814)
1923: Elucidation of the precise chemical structure by Robinson.
By this time chemists were making analogues and derivatives, in particular to retain the analgesic properties but remove the undesirable side-effects.
Replacement of the nitrogen methyl group
In general: analgesic activity initially decreases as the size of the N-substituent increases but then rises again, reaching a peak at C6.
The most active compound in this series: N-b-phenethylnormorphine
i.e. for agonist activity a small N-substituent (e.g. methyl) or a relatively large, lipophilic substituent like phenylethyl is preferred.
Nalorphine
Administration of nalorphine was shown to reverse the effects of morphine and pre-treatment with nalorphine blocks the effects of subsequently administered morphine. i.e. it acts as an antagonist
,… but in 1950’s it was discovered to relieve postoperative pain in humans. i.e. acts as an agonist
Dual action is a result of action at two opioid receptors –
a) antagonism at the mu opioid receptor and
b) agonism at the kappa opioid receptor
Benzomorphans
have a simplified structure
removal of one/two of the rings
activity is largely retained (compared to morphine)
Serendipity in drug design
The first totally synthetic opiate, pethidine, was discovered by chance.
Identified during research into atropine-like agents.
The structure of morphine was not known at the time of pethidine’s discovery, but the similarities in structure are now clear.
Methadone
synthesised by German chemists during world war II and acquired by the Allies as part of reparation.
No fused rings in the structure
Opioid activity is maintained. Pharmacology typical of a mu opioid receptor agonist.
L-(R)-methadone has the majority of the opioid activity but used clinically as a racemate (D-isomer has NMDA antagonist activity)
Methadone has similar pharmacology to morphine. Both bind and activate the mu opioid receptor to similar levels.
Methadone has much greater lipophilicity than morphine – leads to it being widely distributed around the body.
Has a much longer duration of action in vivo.
Means it need only be taken once per day and
gives it a milder, but more protracted, withdrawal
syndrome.
Used for maintenance of opioid addicts.
Enkephalins
The endogenous opioids.
Leu-enkephalin
Met-enkephalin
It has been suggested that the tyrosine residue and the tyramine moiety in morphine fulfil the same role:
but for this to be strictly true we would need D-Tyr
However it does seem likely that morphine and the tyrosine residue of the enkephalins do access the same site in the receptor and interact with the same aspartic acid residue – possibly due to the high degree of flexibility of the peptide.
More complex opioids
Reckitt & Colman: Theory (in late 1950’s) was that a more complex compound might fit the ‘analgesic receptor’ but be prevented from fitting the receptor which might be responsible for the unwanted effects of morphine.
What is the drug used to knock out elephants?
Etorphine
What is buprenorphine?
mu opioid partial agonist. Analgesic and treatment for opioid dependence
used for treatment of opioid use disorder
The highly lipophilic nature of buprenorphine, and its almost irreversible binding to the mu opioid receptor, mean it has a long duration of action (pharmacokinetic and pharmacodynamic properties working together).
Partial agonist activity (not full efficacy) means it has a good safety profile.
Long duration of action helps minimise any withdrawal syndrome after chronic use/treatment.
What is Diprenorphine?
mu opioid antagonist. Used as Revivon, to reverse effects of opioid sedation in animals
What is the pharmacology of buprenorphine?
Action at NOP opposes
effects at m
Analgesics with lower abuse liability?
Safer on overdose?
Action at NOP is additive/synergistic with effects at m
Only need a partial agonist at both for good analgesia with few side effects?
Cebranopadol
(high affinity and efficacy at mu and NOP receptors)
1: good binding but not high enough efficacy at mu and NOP
2aexhibited strong efficacy in preclinical models of acute (ED50rat tail-flick: 3.63 nmol/kg i.v.)
and neuropathic pain (ED50rat spinal nerve ligation: 1.05 nmol/kg i.v.) but was hampered by
poor pharmacokinetic (PK) properties in rats with high clearance, large volume of distribution,
moderate half-life (Cl = 4.0 L/h·kg; Vss= 7.52 L/kg;t1/2= 1.6 h), and a critically very low oral
bioavailability (F= 4%)
What is the acute thermal antinociceptive effect of BU08028?
Initial results in mice did not look promising – longer duration than morphine, but otherwise quite similar
A full agonist in vivo (we wanted a partial agonist)
Less potent than buprenorphine
Little evidence of an NOP component in vivo
