Pain & Pharmacology Of Analgesics Flashcards
What are the 2 types of pain?
- Nociceptive
2. Neuropathic
What is nociceptive pain?
The result of tissue damage, often acute, short-term and relatively easy to treat (physiological)
What is neuropathic pain?
The result of damage to neurons, often chronic and difficult to locate + treat
Define hyperalgesia.
When something that is moderately painful normally becomes excruciating i.e. patient is over-sensitized to it
Define allodynia.
When something that is not noxious, causes a painful response in the patient e.g. putting a T-shirt on when sunburnt - it shouldn’t hurt you but it does!
How does nociceptive pain occur?
Physical damage or response to inflammatory soup (immune response) results in activation of free-nerve endings which respond to mechanical, chemical, pressure + temperature changes
What pharmacological options exist for nociceptive pain?
NSAIDs + opioids:
- Ibuprofen
- Co-codamol
- Morphine (gold-standard opioid)
What are some examples of nociceptive pain?
Low-back pain
Myofascial pain
Arthritis
Visceral pain (pancreatitis, interstitial cystitis, endometriosis etc.)
How does neuropathic pain occur?
Damage/changes in the pain neurons themselves but mechanism is unclear -wind-up of activity through pathways
List some classic symptoms of neuropathic pain.
Shooting/burning pain
Paraesthesias (pins + needles): tingling, numbness, burning + throbbing
Give some examples of conditions that cause neuropathic pain.
Phantom limb Trigeminal neuralgia Post-stroke pain Post-herpetic pain (shingles) Complex regional pain syndrome Malignant pain
What is complex regional pain syndrome (CRPS)?
Massive autonomic activation in 1 limb causing burning pain, redness etc.
What is referred pain?
Sensory info from ANS travels alongside sympathetic (pain/temp) and parasympathetic neurons (other sensation) entering at the same level so pain/temp for example can be referred to cutaneous region where it enters
E.G. heart = T1-5 + kidneys = T10-L1
How do you treat referred pain?
Treat the underlying cause i.e. figure out the organ innervated by this dermatome and treat the organ issue
What is a tension headache? How do you treat it?
Presents on frontal lobe and back of neck
Treat with NSAIDs, maybe codeine + keep a diary to determine trigger factors as avoidance may be possible
What is a sinusitis headache? How do you treat it?
Presents in a typical butterfly pattern across the front of the face
Treat with decongestants, antihistamine or steroids
What are migraine headaches? How do you treat them?
Unilateral headache presenting with nausea and photophobia perhaps due to vaso-constriction
Prophylaxis = β-blockers or amitriptyline
Treat with 3 step approach:
- NSAIDs +/- antiemetics
- Rectal NSAIDs + antiemetic
- Anti-migraine drugs (5HT1B/1D agonists e.g. sumatriptan + naratriptan)
AVOID OPIOIDS
What are cluster headaches? How do you treat them?
Unilateral symptoms behind 1 eye with sympathetic involvement causing runny eyes/nose
Prophylaxis = verapamil
Treatment = sumatriptan
What are the different types of headache?
- Tension
- Sinus
- Migraine
- Cluster
- Medication over-use
- Sub-arachnoid haemorrhage
What are sub-arachnoid haemorrhage headaches? How do you treat it?
Worst ever rapid onset thunderclap headache
This is an emergency so get them a CT scan ASAP
Where in the body can the pain pathway be modulated?
- Periphery
- Spinal cord
- Centrally
Give some drug development targets for pain treatment.
Rubefacients
Capsaicin
Topical analgesics
How do rubefacients work?
Distract area around inflammatory soup e.g. when you rub an area making it less painful - work around the gate control theory
How does capsaicin work?
Causes enough pain to distract focus of pain
How is nociceptive pain sensed and carried to brain?
- Sensed by free nerve endings on C (groan) and Aδ (ouch) fibres (1st order neurons)
- Synapse at substantia gelatinosa onto 2nd order neurons
- Carried via lateral spinothalamic tracts (trigeminothalamic tract if in face) to thalamus and on to cortex
What is the difference between C and Aδ pain fibres?
C: longer and slower pain response as they have no myelin sheath
Aδ: shorter and quicker pain response as they have myelin sheath
What is the gate control theory of pain?
Input from 1st order pain fibres (Aδ/C) activates 2nd order cells and inhibit local interneurons so pain signal can travel onwards
However, mechanical stimulation of area activates inhibitory interneurons reducing pain transmission by inhibiting 2nd order cells
What are the main higher pain centres sending output to descending tracts?
Hypothalamus
Periaqueductal gray (defense region)
Brainstem nuclei
What brainstem nuclei send output to descending pain tracts?
Nucleus raphe paragigantocellularis, nucleus raphe magnus + locus coeruleus that produce 5-HT
Dorsolateral funiculus which contains descending inhibition tract
What are some important higher integration centres?
Parietal lobe:
Frontal cortex
Prefrontal cortex
Amygdala
What is descending inhibition?
Higher centres (e.g. limbic system) modify response to painful stimuli and this travels to ANS and spinal lamina of dorsolateral funiculus (brainstem nuclei) dampening down the pain
Many transmitters and neuromodulators involved particularly 5HT and NA
Why does neuropathic pain remain chronic?
Because so much information is going through that there is reduced descending inhibition due to confusion and pain gate is left open
Why does neuropathic pain occur?
Badly managed acute pain Emotionally sensitive patient Poor coping skills Previous bad pain experiences Pain goes on for longer Surgical complications Genetic predisposition
What part of the spinal cord does pain travel through?
Dorsal horn
Describe the biopsychosocial model of pain perception.
Incorporates all aspects of pain and associated behaviour such as:
- Biological pain (varies e.g. when women are on cycle + thought that women have higher pain thresholds than men)
- Psychological e.g. attitudes/beliefs, psychological distress + illness behaviour
- Social
What are the non-pharmacological options used to treat pain?
Exercise Physiotherapy Acupuncture Transcutaneous Electrical Nerve Stimulation (TENS) Behavioural therapy
What are the invasive procedures used to treat pain?
Nerve blocks/injections at trigger points or joints
Ablation
Implants of pumps releasing drugs e.g. neuromodulators
What pharmacological options exist for neuropathic pain?
TCAs and anti-epileptics:
- Nortriptyline/amitriptyline
- Gabapentin/pregabalin +/- nortriptyline (better tolerated in combo than amitriptyline)
- Carbemazepine alone (never in combo - good for trigeminal neuraligia)
Describe the WHO ladder for cancer pain control.
- Pain-free: no medication
- More pain: administer non-opioid analgesic (paracetamol/NSAID) +/- adjuvant (e.g. caffeine)
- More pain: administer weak opioid (e.g. codeine, co-codamol) +/- non-opioid +/- adjuvant
- More pain: strong opioid (morphine + related e.g. fentanyl, methadone) +/- non-opioid +/- adjuvant
How do non-steroidal anti-inflammatory drugs (NSAIDs) work?
- Rapid uptake into stomach + SI
- Block production of pro-inflammatory PGs by inhibiting COX so AA is not broken down
- Metabolites excreted in urine
What are the different forms of cyclooxygenase (COX)?
COX1: normal cell function
COX2: inflammation
COX3: fever? Does it exist?
What are the commonly used non-steroidal anti-inflammatory drugs (NSAIDs)?
Aspirin (also used as CV drug)
Ibuprofen (weak)
Naproxen (strong + lower side effects)
Diclofenac (stronger but like naproxen)
Indomethacin (strong, good for arthritis but high side effects)
What non-steroidal anti-inflammatory drugs (NSAIDs) can a patient with gut problems take?
COX-2 inhibitors e.g. Celecoxib, Etoricoxib + Paracoxib
Similar to naproxen but with lower GI effects
What class of drug does paracetamol come under?
It is part of the NSAID family but it is kind of isolated - thought that it might be working on COX-3 if it exists - it is a anti-pyretic but not anti-inflammatory which is why it doesn’t quite fit into NSAID category
What do prostaglandins (PGs) do?
PGs work on prostanoid receptor increasing activation of Na channels casing depolarisation, AP firing + pain
List the side effects of non-steroidal anti-inflammatory drugs (NSAIDs).
GI problems (heartburn, nausea, vomiting, diarrhoea, bleeding/ulceration) CV incidents (thrombosis esp. COX-2) Headache Tinnitus Dizziness Insomnia Nervousness Depression Vertigo Photosensitivity Renal impairment Hypertension Hypersensitivity (skin rashes + eruptions, angioedema, bronchospasm)
What is a common indicator of salicylate toxicity?
Tinnitus (esp. with salicylate NSAIDs e.g. aspirin) - common in patients on consistent low doses but also high acute dose
Salicylism has 1% mortality
What happens to the gut with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs)?
Holes start to form in gut lining, mucus becomes stringy with bacteria on it and ulcer formation occurs
After a very long-time, the reticular structure underlining the normal gut cells has come out to the surface
What is Reye’s syndrome?
A condition causing swelling in liver and brain (can cause death) as a result of aspirin use in children under 16 years old if they have had a virus before hand
What can you prescribe non-steroidal anti-inflammatory drugs (NSAIDs) with to reduce side effects?
PPIs
What are the symptoms of severe non-steroidal anti-inflammatory drugs (NSAIDs) toxicity?
Auditory (ototoxicity, tinnitus, deafness)
Pulmonary (apnoea, aspiration pneumonitis, pulmonary oedema, alkylosis, respiratory arrest)
CV (tachycardia, hypotension, asystole, dysrhythmias)
CNS (depression, seizure, encephalopathy, delirium, hallucinations)
GI (pancreatitis, hepatitis)
Renal failure
Coma
What is chronic non-steroidal anti-inflammatory drugs (NSAIDs) intoxication? How is it treated?
Plasma levels more than 300mg/kg
Treatment:
- Fluid replacement
- Haemodialysis
- Activated charcoal
- Lorazepam/diazepam i.v. for seizures
What are the 4 opioid receptors?
μ (MOP/OP3)
κ (KOP/OP2)
δ (DOP/OP1)
ORL1 (OP4)
What are the opioid agonists?
Strong: morphine (T1/2 = 3-4hrs) , diamorphine (T1/2 = 3-4hrs) + tramadol (acts on 5-HT receptor + has disturbing hallucinogenic side effects)
Weak: codeine (T1/2 = 3-4hrs)+ dihydrocodeine
What are the opioid partial agonists/mixed agonist-antagonists?
Nalorphine
Pentazocine
Buprenorphine (T1/2 = 12hrs)
= mixed affect
What are the opioid antagonists?
Naloxone (T1/2 = 1-2hrs like Fentanyl)
Naltrexone (T1/2 = 10hrs)
What are the 4 main groups of opioid synthetic derivatives?
- Phenylpiperidine e.g. pethidine (T1/2 = 2-4hrs)
- Methadone e.g. dextropropoxyphene (T1/2 = more than 24hrs)
- Benzomorphan e.g. cyclazocine
- Thebaine e.g. buprenorphine (T1/2 = 12hrs)
How do opioids work?
Thought to act by mimicking endogenous opioids in the CNS e.g. brainstem pain nuclei
How do opioids decrease neuronal transmission?
Decreasing opening of voltage-dependent Ca2+ channels
Increasing K+ outflow via K/ATP + K/IR channels hyperpolarising cell so less likely to fire when stimulus appears
Decreasing Ca2+ release from IC stores via cAMP reduction (can increase it too)
Decreased exocytosis of transmitter vesicles
What are the side effects of opioid toxicity?
Cardinal: respiratory depression, conscious depression/mood alterations, miosis + coma (GCS less than 7)
Others: reduced gastric motility, nausea/vomiting, SM spasm, anaphylaxis, psychiatric changes (pentazocine, tramadol) + tolerance/dependency (addiction/withdrawal)
If a white Caucasian person is not responding to a opioid dose, what should you do?
Do not just keep upping the dose as a high % of the Caucasian population are unresponsive and you will induce toxicity
How do you treat opioid overdose?
Opioid antagonists: naloxone (short-lasting) + naltrexone (longer-lasting)
If conscious and within 1hr of OD give activate charcoal + 0.8-2mg naloxone every 2-3mins for respiratory depression
Combo to resolve coma = naloxone, O2, glucose + thiamine(in case there is more than 1 cause)
What is the problem with including barbiturate antagonist flumazenil or benzo clomazinole in the coma cocktail?
Can result in rebound seizures or potentiate seizures in susceptible people
What other drugs can be used for trigeminal neuralgia if carbamazepine is not well tolerated?
Oxcarbazepine
Gabapentin
Pregabalin
