Pain, Nociception and analgesia 3 Flashcards
What can Analgesic drugs do
- Mechanism to sensitise the nociception
- Peripheral sensitisation
- Central sensitisation- Form of synaptic plasticity
- Descending inhibition of nociception
- Analgesic drugs could boost descending inhibition, inhibit central sensitisation or peripheral sensitisation
What is peripheral sensitisation
- Inflammatory immune response
- Threshold decreases- more pain
- Protects bodies
What is Descending inhibition of nociception
- Inhibits pain
2. When don’t have time to deal with it
Give some examples of Analgesic drugs
- Opiate drugs
- NSAIDs (non-steroidal anti-inflammatory drugs)
- Other analgesics – already used, and in the pipeline
What do opiates do
- act on opioid receptors
2. mimic endogenous opioids
Give example of opiates
- Morphine
- Heroin (Diamorphine)
- Codeine- lower efficacy
- Methadone
- Pethidine lower efficacy
- (Etorphine)- most potent, not clinical use for humans but used in veterinary practice
- Fentanyl
- Remifentanyl
- Butorphanol
- Buprenorphine- lower efficacy
- Naloxone mu, d, k antagonist- used in case of overdose of opioids
What does the World Health Organisation Pain Ladder suggest to take for different pains
- Mild pain – NSAIDs e.g. aspirin, ibuprofen
- Moderate pain – codeine, buprenorphine
- Severe pain – morphine, fentanyl- more effective but more side effects
What type of opioid receptors are most important and where are they found
- Mu receptors are most important in endogenous anti-nociception
- Mu in brain, spinal cord and peripheral
What are side effects of Mu receptor opioids
- The better the opioid receptors agonist the more euphoria- hard to separate
- Respiratory depression- opioid overdose cause
What are side effects of Kappa opioid receptor agonist
- Dysphoria- miserable
2. Risk of overdose very low
What are side effects of Delta opioid receptor agonist
- Proconvulsant- risk of fits
What are desirable effects of mu receptor opioids
- Analgesia
- Euphoria
- Constipation
- Sedation
- Cough suppression
What are Undesirable effects of mu receptor opioids
- Respiratory depression
- Euphoria
- Constipation (methylnaltrexone)- binds to mu opioid receptor in gut and so agonist can’t bind and cause constipation
- Sedation
- Nausea & vomiting
- Tolerance
- Itching
- Psychological dependence
- Physical dependence
What is tolerance
- Continued use of a drug requires increased doses for equivalent effect
- Analgesic experiment on mice
- Does response to morphine first time is much higher than 3 days later- shift to right in potency of morphine
- Effect of drug wears off
What is main active ingredient in opium and how was opium first used
- Main active ingredient in opium is morphine
- Codeine as well but morphine is main
- Heroin- first attempt at safer drug
- Two acetyl groups replace alcohol
- But mean they cross blood brain barrier more effectively
- Acetyl groups cleaved once passed and left with morphine
Describe routes of administration of opiates
- Pills
- Intravenous injection
- Epidural
- Transdermal patch
- Lollipop
What can be taken as pills
- morphine / codeine
What is an intravenous injection
- patient controlled injection
2. morphine / diamorphine / fentanyl
What is an epidural
- fentanyl / pethidine
- way of local delivery just at spinal level
- useful for childbirth and surgery
- activates opioid receptors in specific part of spinal cord that receives nociceptor input – means doesn’t pass into mothers’ bloodstream and then into babies
What is transdermal patch
- Fentanyl
2. Steady state levels of opioid- if pain is constant it is good
What is lollipop
- Fentanyl- lipophilic so can be delivered through mouth
2. Steady level and then breakthrough level of pain- lollipop along side steady levels of opioid
What are Non-steroidal anti-inflammatory drugs (NSAIDS) used for
- Most widely used therapeutic agents
- Over 50 types available
- eg. aspirin, ibuprofen, diclofenac, paracetamol
- Anti-inflammatory- paracetamol is not
- Anti-pyretic
- Analgesic
- All effects related to decreased prostaglandin synthesis
What do prostaglandins do
- Prostaglandins are part of immune inflammatory response
- Various factors try to heal it
- Prostaglandins act on Prostanoid receptor which sensitise nociceptors
What do NSAIDs inhibit
- NSAIDs are COX inhibitors
- COX- key enzyme in producing prostaglandins
- NSAIDS mean less prostaglandins – less peripheral sensitisation
What are Disadvantages of NSAIDS
- PGs involved in many processes
- multiple side effects
- severe gastric irritation
- kidney disorders
5 paracetamol overdose - Specific COX-2 inhibitors have Less side effects.
What do Specific COX-2 inhibitors do
- COX-1 is widespread throughout the body- leads to gastric side effects
- COX-2 is just involved in the inflammatory response- gives desired effect
- Traditional block COX-1 and COX-2
- Some drugs on market which block COX-2 only
- But Vioxx- sudden death syndrome- caused people’s hearts to stop
- Not found COX-2 specific that doesn’t have cardiac side effects now
What is Neuropathic pain
- Pain unrelated to peripheral nociception
2. Sometimes called pathological pain – serves no purpose
What is neuropathic pain caused by
- Peripheral nerve damage- (eg. Diabetic neuropathy)
- Peripheral nerve terminal damage or infection - (eg. Post-herpetic neuralgia)
- Spinal damage
- Thalamic stroke
- Generally don’t respond to opioids / NSAIDs
What are some other analgesic approaches
- Tricyclic antidepressants (e.g. imipramine)
- Antiepileptic drugs (e.g. gabapentin)
- Cannabinoid receptor agonists
- Glutamate receptor blockers (MK801)
- Neurokinin receptor blockers
- Nociceptor blockers (TRPV1, P2X3, sodium channel)
What do Antiepileptic drugs do
- Neuropathic pain
2. Unknown mode of action
What do Cannabinoid receptor agonists do
- Central and peripheral effects
2. Neuropathic pain (esp. multiple sclerosis)
What do Glutamate receptor blockers (MK801) do
- Block afferent transmission
2. Severe side effects
What do Neurokinin receptor blockers do
- Block central sensitization
2. In development
What do Nociceptor blockers do
- Block detection of noxious signals
2. In development
