Pain e.g. Analgesic and anti inflammatory drugs

Question 1

Define nociception.

Answer 1

Process by which nociceptive information is detected by the brain.

Question 2

Define Antinociception.

Answer 2

Blockade of nociception.

Question 3

Define Analgesia

Answer 3

Blockade of pain

Question 4

What are 4 types of Analgesic drugs?

Answer 4

• Local anaesthetics e.g. Lidocaine
• Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. Aspirin, ibuprofen, paracetamol.
• Opioids e.g. Morphine, codeine
• Miscellaneous drugs (These relieve the pain by relieving the cause of the pain) e.g. Nitrates, triptans, angina etc.

Question 5

How does acute pain respond to the 3 types of analgesic drugs?

Answer 5

Responds well to all 3 types of drugs.

Question 6

Define chronic pain?

Answer 6

Pain for more than 3-6months duration.

Question 7

How does chronic pain respond to different analgesic drugs?
For:
- Neuropathic pain
- Nociceptive pain.

Answer 7

• Due to chronic nociceptive activation, responds well to opioids.
• neuropathic pain due to adaptive changes responds poorly to opioids.

Question 8

What are the 4 different types of chronic pain?

Answer 8

• Nociceptive
• Neuropathic
• Visceral
• Mixed

Question 9

Give examples of chronic Nociceptive pain.

Answer 9

• OA

- RA

Question 10

What are the two types of Neuropathic pain, and give examples of each.

Answer 10

Central;

• Post-stroke
• Multiple sclerosis
• Spinal cord injury
• Migraine
• HIV related neuropathic pain.

Peripheral;

• Post-herpetic neuralgia
• Diabetic neuropathy

Question 11

Give examples of chronic Visceral pain.

Answer 11

• Internal organ
• Pancreatitis
• Inflammatory bowel syndrome

Question 12

Give examples of chronic Mixed pain.

Answer 12

• Lower back
• Cancer
• Fibromyalgia

Question 13

How do local anaesthetics work?

Answer 13

• Local anaesthetics are Na+ channel blockers
• They slow the rate at which channels revert to resting state.
• Local anaesthetics block action potential generation by decreasing the number of Na + channels available to open
• They have greatest effect in rapidly firing neurons

Question 14

How can local anaesthetics be administered?

Answer 14

• They’re given topically or infused near to the nerve to be blocked.
• Can be administered locally to spinal cord to produce regional block, either; Epidurally or intrathecally i.e. during child birth.

Question 15

What is the mechanism of action of NSAIDs?

Answer 15

• Activation of the prostaglandins (messengers)
• In the membrane there are phospholipids, which are acted upon by PLA₂, which splits Arachidonic acid from the membrane.
• Arachidonic acid is the substrate for cyclooxygenase, which causes the production of the proteinoid’s (might be wrong term but idk) the three main ones are:
• Tx (Thromboxane)
• PG (Prostaglandin)
• PGI₂ (Prostacyclin)
• These are involved in mediating various phases of the inflammatory response.
• As for the nociceptive effect, PGE₂ that is responsible for nociceptive responses.

Question 16

How do NSAIDs work?

Answer 16

• They inhibit cyclo-oxygenase (COX)

- COX produces eicosanoids e.g. PGE₂ from arachidonic acid.

Question 17

What are the 3 main effects of NSAIDs?

Answer 17

• Anti-inflammatory
• Anti-pyretic i.e. anti-fever
• analgesia

Question 18

What do prostaglandins do?

Answer 18

• They do not stimulate nociceptors, they sensitise them to other mediators.
• NSAIDs produce analgesia by preventing this sensitization.

Question 19

Which are the main NSAIDs that are used as analgesics?

Answer 19

• Aspirin
• Ibuprofen
• Paracetamol

Question 20

What type of inhibitor to COX is aspirin?

And what is its duration?

Answer 20

A irreversible inhibitor, this is because it binds to COX and blocks its active site.

• 4 hours

Question 21

What type of inhibitor to COX is ibuprofen?

And what is its duration?

Answer 21

A reversible inhibitor as it binds to the active site of COX, and is an alternative substrate and is eventually broken down by COX.

• 4 hours

Question 22

What type of inhibitor to COX is paracetamol?

And what is its duration?

Answer 22

A indirect inhibitor of COX, don’t need to know why, seems like they’re not too certain either.

Question 23

What is one way to increase the effectiveness of NSAIDs?

Answer 23

Combine them with a weak opioid such as; Codeine in OTC medicines.

Question 24

How do Opioid analgesics work?

Answer 24

They produce analgesia by interaction with the endogenous opioid system.

• Morphine acts on specific opioid receptors.

Question 25

what is the endogenous opioid system?

Answer 25

- Innate pain-relieving system. It controls pain sensitivity under various conditions.

Question 26

What are the mediators used for the endogenous opioid system? What are the main/ the first 2 to be isolated?

Answer 26

- Peptides which activate the opioid receptors. | - The main 2 are Leu⁵ & met⁵- enkephalin.

Question 27

What are the 3 families of opioid peptides

Answer 27

- endorphins e.g. b-endorphin - enkephalins e.g. [Met5]enkephalin, [Leu5]enkephalin. - dynorphins e.g. dynorphin A, dynorphin B

Question 28

What are the 3 types of opioid receptor?

Answer 28

- (Mu the symbol of a U but with a tail going down on the right) - δ = delta - κ = Kappa

Question 29

What do opiates do?

Answer 29

They act with receptors to activate inhibitory pathways and inhibits nociceptive transmission.

Question 30

Describe in a flowchart like way the Ascending pathway of pain.

Answer 30

Afferent neurons --> DRG --> Spinal cord dorsal horn --> Thalamus --> Prefrontal cortex/ somatosensory cortex/ cingulate cortex.

Question 31

Describe in a flowchart like way the Descending pathway of pain.

Answer 31

From midbrain= Periaqueductal gray/ Raphe nuclei --> Dorsolateral funiculus (Opioids take effect on the neurons from PAG/RN ---> DF). DF---> spinal cord dorsal horn--> Thalamus---> Prefrontal cortex/ somatosensory cortex/ cingulate cortex.

Question 32

Where are opioid receptors found?

Answer 32

- Periaqueductal gray (PAG) - Nucleus raphe magnus (NRM) - NRPG - dorsal horn of the spinal cord, especially lamina ll

Question 33

Describe in full the ascending pain pathway.,

Answer 33

- Activation of nociceptive primary afferents (Ad or C fibres) which enter dorsal horn and synapse onto interneurons or projection neurons - Activation of projection neurones in the dorsal horn which travel to the brain in the spinothalamic tract - If one records firing of dorsal horn neurones, opioids inhibit firing and stop transduction of the signal to the brain. Inhibit release of glutamate and substance P from primary afferents

Question 34

Describe in full the descending pain pathway.,

Answer 34

- Activation of PAG and NRM by morphine causes increase firing of descending pathway to dorsal horn. - This involves mainly serotonergic neurons and depletion of 5HT or 5HT antagonists decrease anti-nociceptive effect of morphine. - Effect in PAG and NRM is due to inhibition of release of GABA from local interneurons. This leads to dis-inhibition of the descending serotonergic pathway which decreases transmission of nociceptive information through the dorsal horn.

Question 35

At which receptor is Morphine a selective agonist for?

Answer 35

Mu.

Question 36

What are the effects of Morphine? pt.1 | There's 5

Answer 36

ANALGESIA - All kinds of acute & severe pain - Reduces sensation of pain (nociception) and the emotional response EUPHORIA - Depends on circumstances, varies with different opioids RESPIRATORY DEPRESSION - Selective depression of sensitivity to PCO2 MIOSIS - Pin-point pupils, diagnostic for opioid overdose - Parasympathetic stimulation via the Edinger Westphal nucleus EMESIS - Due to stimulation of chemical trigger zone in area postrema

Question 37

What are the effects of Morphine? pt.2 (There's 7) (Includes psychological effects)

Answer 37

CONSTIPATION - Increase in gut tone, decreased gut transit, due to high level of receptors on enteric neurons - Kaolin and morphine used to treat diarrhoea, loperamide (Imodium) OPIOID-INDUCED HYPERALGESIA - Roeckel et al. (2016). Neurosci. 338, 160-182. COUGH SUPPRESSION - All opioids suppress cough reflex, not an opioid effect, possibly due to stimulation of dextromethorphan receptor HISTAMINE RELEASE HYPOTENSION TOLERANCE - Decrease response with repeated administration - High emesis > analgesia Low miosis, constipation DEPENDENCE - Physical dependence - Withdrawal syndrome - Psychological dependence

Question 38

What are some Mu agonists

Answer 38

DIAMORPHINE (diacetylmorphine) – more lipophilic and more potent than morphine   BUPRENORPHINE – very lipophilic, given sublingually, partial agonist OXYCODONE – cancer pain FENTANYL - very lipophilic, very short acting, used as part of pre-medication for surgery. Fentanyl patches used for long term relief in cancer patients. PETHIDINE – labour, minor surgery. No pin-point pupils METHADONE – long acting, once daily dosing, used for maintenance of addicts

Question 39

What are 2 opioid drugs that are mixed opioid agonists/ uptake inhibitors?

Answer 39

mu -receptor agonist and noradrenaline and 5HT uptake inhibitor: - TRAMADOL - TAPENTADOL (cause less respiratory depression?)

Question 40

What are 2 weak opioids used for mild pain.

Answer 40

- CODEINE - DIHYDROCODEINE (combined with NSAID in OTC preparations)

Question 41

What 2 drugs are used to treat opioid overdose as they are antagonists?

Answer 41

- Naloxone | - Naltrexone (Longer duration of action)

Question 42

What drugs are used to treat opioid induced constipation?

Answer 42

Peripherally active antagonist ALVIMOPAM also paralytic ileus QUATERNARY NALOXONE