9. Management of Pain - NSAIDS and Paracetamol Flashcards
What are the 3 main types of pain?
Pain Types
- There are three main types of pain – not all respond well to analgesics
- Nociceptive pain
- Neuropathic pain
- Nociplastic pain
What are the 3 types of pain by duration?
Pain types by duration
- Acute pain = lasts less than 3 months, and usually has a nociceptive component
- Recurrent pain = occurs episodically over 3 months or more
- Chronic pain = lasts for more than 3 months
What is Nociceptive Pain?
2 types?
Nociceptive Pain
- Is the most common type of pain and results from the stimulation of nociceptors (pain receptors)
- It tends to be the typical, everyday pain
- Can be either:
- somatic or
- visceral
- in origin
Where does nociceptive somatic pain arise?
Character of nociceptive somatic pain?
7 Examples?
Nociceptive Somatic Pain
- Nociceptive somatic pain arises in areas such as the skin, bones and muscles
- Described as dull, aching, throbbing, stinging or sharp
- Examples:
- Common headaches
- Abrasions, sprains
- Burn
- Musculoskeletal pain
- Toothache
- Osteoarthritic pain
- Broken bones
What is Nociceptive Visceral Pain?
Character of nociceptive visceral pain?
7 Examples?
Nociceptive Visceral Pain
- Nociceptive visceral pain arises from internal organs such as the gastrointestinal tract, liver, heart, lungs and uterus
- Often described as deep, dull, cramping or colicky
- Examples:
- Appendicitis
- Diverticulitis
- Myocardial infarction
- Dysmenorrhoea (period pain)
- In general nociceptive pain responds well to traditional analgesics such as NSAIDS, paracetamol and opioids
What is Neuropathic Pain?
Character?
Examples?
Treatment?
Neuropathic Pain
- Results from nerve injury or dysfunction
- Often described as burning, shooting, stabbing, knife-like or electric
- Examples:
- Post herpetic neuralgia
- Diabetic neuropathy
- Trigeminal neuralgia
- Phantom limb pain
- Allodynia and pins and needles may also occur
- Can be difficult to treat and often does not respond well to NSAIDS, paracetamol or opioids
- Use of analgesic adjuvants such as amitriptyline, gabapentin and pregabalin
What is Nociplastic Pain?
Nociplastic Pain
- Characterised by altered or abnormal function of the nociceptive pathways or cerebral cortex in the absence of a nociceptive stimulus or damage, or neuropathic lesion
- Sensitisation refers to an increased responsive of neurons to their normal input, or a response to subthreshold inputs
- Central sensitisation is the key contributor to nociplastic pain, rather than ongoing pathology
- Peripheral sensitisation may also occur and refers to a reduced threshold and increased responsiveness of nociceptive neurons to stimuli in the periphery
- You feel pain but you can’t find a reason for it to be there = a sensitisation process in PNS + CNS
- Normal input registers as pain
- Examples - fibromyalgia? irritable bowel syndrome?
- Which analgesics? = difficult to treat - Cognitive Behaviour Therapy etc.
What are the Origins of stimulus and descriptions for:
- Nociceptive pain?
- Neuropathic pain?
- Nociplastic pain?
What are the 2 types of NSAIDs and examples of each (4&2)?
Nonsteroidal Anti-inflammatory Drugs (NSAIDS)
- Traditional NSAIDS
- Aspirin
- Diclofenac
- Ibuprofen
- Naproxen
- COX 2 inhibitors
- Celecoxib
- Meloxicam
What are NSAIDs used for?
Nonsteroidal Anti-inflammatory Drugs (NSAIDS)
- NSAIDS are used in a wide variety of conditions including
- backache, headache, toothache
- muscular aches and pains
- osteoarthritis, rheumatoid arthritis
- dysmenorrhoea, gout, some cancer pain - thrombotic events (low dose aspirin)
- Some NSAIDS are only available on prescription, some only through pharmacy and some are unscheduled and available through supermarkets and other outlets
What 4 effects do NSAIDs have on the body?
What is their main mechanism of action?
Nonsteroidal Anti-inflammatory Drugs (NSAIDS)
- NSAIDS exert the following activities
- Analgesic
- Anti-inflammatory
- Antipyretic = won’t bring down a normal temp but will bring down a fever
- Anti-platelet
- Block the production of prostaglandins by inhibiting the enzyme cyclooxygenase
What are prostaglandins?
Prostaglandins = a group of lipids made at sites of tissue damage or infection that are involved in dealing with injury and illness.
They control processes such as inflammation, blood flow, the formation of blood clots and the induction of labour.
- Prostaglandins act on prostaglandin G-protein coupled receptors (DP, EP, FP, IP and TP)
- Prostaglandins such as PGE2 and PGI2 are involved in pain and inflammation:
- produce vasodilation
- potentiate the increased permeability of blood vessels caused by substances such as histamine and bradykinin
- sensitise nerve terminals and potentiate the pain producing effects of substances such as bradykinin and 5-hydroxytrypamine (they do not directly produce pain themselves)
What is Cyclooxygenase (COX)?
Which 2 forms does it exist in?
Cyclooxygenase (COX) = an enzyme that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid.
Cyclooxygenase exists in two forms:
- cyclooxygenase 1 (COX 1)
- cyclooxygenase 2 (COX 2)
Where is COX1 found?
Where is COX2 found?
COX1
- COX 1 is found in most cells
- It is a constitutive enzyme which synthesises the production of prostaglandins which are involved in homeostasis - “housekeeping” or “good” prostaglandins
COX2
- COX 2 is induced by inflammatory stimuli and synthesises prostaglandins which are involved in pain and inflammation - “bad” prostaglandins
- COX 2 is also a constitutive enzyme in some areas e.g. kidney, vascular tissue
- COX 2 is also thought to be involved in some cancers e.g. breast, colorectal
Are COX1 & COX2 both constitutive enzymes?
NSAIDS & COX
- Initial hypothesis was that
- COX 1 was a constitutive enzyme which synthesised prostaglandins involved in homeostasis
- COX 2 was only induced by inflammatory stimuli and synthesised prostaglandins involved in inflammation and pain
- In reality, however, COX 2 is also a constitutive enzyme in some areas e.g. kidney, vascular tissue
Which COX type do Traditional NSAIDS inhibit?
Traditional NSAIDs & COX
- Traditional NSAIDS (e.g. aspirin, diclofenac, ibuprofen, naproxen) inhibit both COX 1 and COX 2
- Traditional NSAIDS block the production of all prostaglandins
- Traditional NSAIDS thus block the production of both “bad” prostaglandins and “good/housekeeping” prostaglandins
What is the rincipal chemical activity of the stomach?
pH of the stomach?
The Stomach
- The stomach is part of the gastrointestinal tract and lies between the oesophagus and the duodenum
- The principal chemical activity of the stomach is to begin the digestion of proteins, primarily through the action of pepsin
- The stomach also has gastric juice which is very acidic (the lumen of the stomach has a pH 1-2)
- The stomach mucosa is exposed to some of the harshest conditions in the body
- So why does the stomach not digest itself? = Gastric mucosal barrier!
What is the Gastric Mucosal Barrier?
Structure?
Gastric Mucosal Barrier
- The gastric mucosal barrier protects the underlying tissue from the acid and enzymes in the lumen of the stomach
- Epithelial cells of the stomach mucosa are joined together by tight junctions which prevents gastric juice from reaching the underlying tissue
- Damaged epithelial cells are replaced very quickly
- Mucus secreted by surface epithelial cells coats the surface of the gastric mucosa
- Bicarbonate ions secreted by epithelial cells neutralise acid
- Protects the stomach and also extends into the duodenum
What is another example of a good “housekeeping” prostaglandins that is targeted by NSAIDs?
Examples of “housekeeping” prostaglandins include those that regulate platelet function - e.g. TXA2 (COX 1) and PGI2 (COX1 and COX 2)
- Thromboxane A2 (TXA2) and prostacyclin (PGI2) are involved in platelet function and blood flow
- TXA2 is formed in platelets by COX 1 → It induces platelet aggregation and produces vasoconstriction
- PGI2 is formed in vascular tissue by COX1 and COX 2 → It inhibits platelet aggregation and produces vasodilation
How does Low Dose Aspirin block platelet aggregation?
Clinical Significance?
Low Dose Aspirin
- In platelets the enzyme cyclooxygenase 1 (COX 1) converts arachidonic acid to thromboxane A2
- Thromboxane A2 induces platelet aggregation and vasoconstriction
- Aspirin irreversibly inhibits COX 1, inhibits the production of thromboxane A2 and reduces platelet aggregation
- Platelets do not have a nucleus and cannot regenerate COX 1
- Vascular tissue can regenerate COX1 and COX2
- Low dose aspirin (50-150mg) is used clinically to inhibit platelet aggregation
- Stop a few days before surgery
- Any platelet that has met aspirin will not function (7 day life)
What are 6 adverse consequences of NSAIDs blocking good prostaglandins?
Why should some asthmatics not take NSAIDs?
Nonsteroidal Anti-inflammatory Drugs (NSAIDS)
Blockade of “good/housekeeping” prostaglandins may result in adverse effects such as:
- Gastrointestinal bleeding and ulcers
- ↑ tendency to bleed
- ↓ renal function
- Sodium and water retention
- Early miscarriage and prolongation of labour
- Asthma symptoms/acute asthma attack in some patients with asthma (approximately 10%) → Some asthmatics shouldn’t take NSAIDs
- The prostaglandins are helping hold their airways open = bronchodilator prostaglandins
What are COX 2 Inhibitors?
2 examples?
COX 2 Inhibitors
- COX 2 inhibitors are selective for COX 2
- Some are more selective than others
- Examples of COX 2 inhibitors currently on the market are:
- Celecoxib (eg. Celebrex)
- Meloxicam (eg. Mobic)
COX 2 inhibitors produce the same analgesic and anti-inflammatory effects as traditional NSAIDS - they are no more effective than traditional NSAIDS
How does Paracetamol cause toxicity in overdose?
Paracetamol Toxicity
- Although it is well tolerated in therapeutic doses, paracetamol may cause serious toxicity and even death if taken in overdose
- Paracetamol normally undergoes glucuronidation (45-55%) and sulphation (20- 30%) with a small amount being converted to N-acetyl-p-benzoquinoneimine (NABQI) by CYP450 2E1
- NABQI is toxic, but is normally conjugated with glutathione and inactivated
- When taken in overdose the normal glucuronidation and sulphation pathways may become saturated, and more NABQI is formed
- Glutathione stores may become depleted
- If the glutathione stores do become depleted, NABQI is no longer inactivated and it may combine with cellular components to cause cell death and liver failure (hepatic necrosis)
- Renal damage may also occur
