Pain Medicine
These drugs classically work by preventing the synthesis of Prostaglandin E2 or by stimulating opioid receptors, activating brains endogenous analgesic pathways.
Opioids
Morphine
This is the most famous opioid which provides analgesia in a variety of situations.
It is available in many formulations. The most common oral ones are morphine MST (which is given 12-hourly) and an immediate release oral formulation, Oramorph.
Diamorphine
This has high blood-brain barrier penetration which provides a euphoric sensation.
Methadone
This is used as a treatment for physical dependency in heroin addicts.
Fentanyl/Sufentanil
These are given parenterally and have a very short half-life.
They are typically used as pre-anesthetic and intraoperatively due to their fast action.
They are also the preferred opioids in renal impairment as they are nephroprotective.
Oxycodone
This is often used for patients who require an opioid but cannot tolerate morphine.
Buprenorphine
An opioid which is also given to people with renal impairment as it is nephroprotective.
Codeine
This is a prodrug which is metabolised to morphine in the liver, used to treat mild pain.
Tramadol
This has weak opioid μ-receptor activity and is used for moderate pain.
– It also has serotonergic activity, and so can precipitate serotonin syndrome.
Side effects
Respiratory depression – due to direct inhibition of the respiratory centre. Hence opioids not used in patients with significant respiratory problems
Constipation – inhibits ACh release in GI
Pupil constriction (pin-pick pupils)
Nausea – due to direct stimulation of the chemoreceptor trigger zone
Postural hypotension
Sedation and drowsiness (yawning)
Urine retention, especially in the elderly
Withdrawal symptoms
A key thing about opioids is that prolonged use can lead to dependence. If, patients suddenly stop taking their opioids, they can get a number of physical withdrawal symptoms. These are the opposite of the side effects.
– Dilated pupils
– Diarrhea
– Piloerection
– Increased anxiety
– Sweating and confusion
– Muscle pain
Drugs used for neuropathic pain
Gabapentin/pregabalin
These drugs have a similar structure to GABA and are used to treat neuropathic pain.
Their exact mechanism of action is unclear, but they are thought to decrease cell expression of Ca2+ channels which are upregulated in neuropathic pain.
Amitriptyline
This inhibits the NET (Na transporter) and SERT (5-HT reuptake).
It also has a lot of side effects as it blocks many other receptors in the brain.
Side effects
ACh effects – Memory dysfunction + dry mouth, blurred vision, constipation + urinary retention
H1 effects – Weight gain, sedation
Alpha-receptors — ostural hypotension giving reflex tachycardia and arrhythmias
Lengthen QTc interval
Block Na+ channels in heart/brain – cause seizure, coma, arrhythmia and delirium in overdose
SIADH and Discontinuation syndrome
Duloxetine
This inhibits both the serotonin and noradrenaline (NA) transport to potentiate 5-HT and NA transmission.
It acts as an SSRIs at low doses, whereas a higher dose is needed to achieve the NA effects.
It is often used for neuropathic pain associated with diabetic peripheral neuropathy.
NSAIDs
These drugs are inhibitors of the cyclo-oxygenase enzymes (COX-1 and COX-2) and act to reduce prostaglandin E2 and thromboxane A2 synthesis.
They are often used first line in many inflammatory diseases and are effective at alleviating mild-to-moderate pain.
Ibuprofen/Naproxen/Diclofenac
These are non-specific inhibitors of cyclo-oxygenase.
Celecoxib/Etoricoxib
These are COX-2 selective NSAIDs, used to reduce incidence of GI adverse effects.
Indomethacin
This is the drug of choice for ankylosing spondylitis and reactive arthritis. It is also used to treat patent ductus arteriosus in premature infants.
Side effects
GI bleeding (most common) – as they inhibit production of protective prostaglandin
Renal insufficiency – as inhibits PGE2/I2 which help maintain renal blood flow
Stroke/heart attack – due to inhibition of COX-2 in endothelium which makes PGI2
Bronchospasm – need caution in asthma
Other anti-inflammatories
Aspirin
This is a salicylate which works by irreversibly acetylating serine 530 in the active site.
It also inhibits the COX enzymes, but in a different mechanism to classical NSAIDs.
Aspirin also reduces platelet aggregation as it inhibits TXA2 production in platelets.
Platelets are unable to regenerate new COX-1 as they do not have a nucleus.
Conversely, the endothelial cells of blood vessels can regenerate COX-1, meaning they can still produce PGI2 which causes vasodilation, reducing thrombus formation.
Side effects
Similar to NSAIDs (GI bleeding, renal insufficiency)
In addition to its usual side effects, aspirin can cause 2 other syndromes:
Reye's syndrome
This is a syndrome which is usually seen in children < 16 years.
It can lead to liver toxicity and leads to hepatic encephalopathy.
Death occurs in up to 20–40% of those affected and many survivors will be left with permanent brain damage.
Symptoms include vomiting, personality changes, confusion, seizures and death
Symptoms
Adults – initial tinnitus and vertigo before proceeding to hyperventilation
Children – hyperventilation is more pronounced
Management
Urinary alkalisation with or without haemodialysis
Salicylism
This is a potentially life-threatening condition which is seen in aspirin overdose.
Aspirin overdose causes Krebs’ cycle inhibition and uncoupling of oxidative phosphorylation.
This leads to increased O2 consumption and CO2 production causing a metabolic acidosis.
It also triggers the respiratory centers to cause hyperventilation, resulting in a respiratory alkalosis.
Eventually, respiratory depression occurs causing a metabolic and respiratory acidosis with a high risk of mortality.
Paracetamol
Paracetamol inhibits prostaglandin synthesis by reducing the active form of COX-1 and COX-2 enzymes.
It is considered a weak anti-inflammatory but provides very good analgesia and works well as an antipyretic.
It is usually eliminated by conjugation in the liver. However, when the liver enzymes are saturated, it is metabolised to the toxic product NAPQI.
Alcohol stimulates liver cytochromes, converting more paracetamol to NAPQI.
Paracetamol overdose leads to a buildup of NAPQI causing renal and hepatic toxicity.
Side effects
Renal toxicity
Acute liver failure (jaundice, coagulopathy, encephalopathy).
The antidote for overdose is N-acetylcysteine, which works by regenerating reduced glutathione (used to conjugate the toxic product NAPQI).
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