Pain and analgesics Flashcards
1
Q
What are the two different types of pain?
A
Nociceptive pain - the result of tissue damage, often acute, short term and relatively easy to treat.
Neuropathic pain- the result of damage to neurons, often chronic and difficult to treat
2
Q
Define hyperalgesia
Define allodynia
A
- Hyperalgesia- increased amount of pain with a mild noxious stimulus (abnormally heightened sensitivity to pain)
- Allodynia - pain evoked by a non-noxious stimulus (Triggering of pain response in abscence of pain stimulus).
3
Q
Give 5 qualities of nociceptive pain
A
- Physiological/ acute pain
- Caused by physical damage or response to inflammatory soup
- responds to analgesics
- Results in the activation of free nerve endings
- Responds to mechanical, chemical, pressure and temperature changes
4
Q
What are some types of nociceptive pain?
A
- Lower back pain
- Myofascial / muscle pain
- Arthritis
- Visceral pain (e.g. pancreatitis, interstitial cystitis, endometriosis)
5
Q
Describe the qualities of neuropathic pain and some common symptoms
A
- Neuropathic pain often chronic, highly debilitating
- Causes by damage to the neurones themselves which leads to hyperexcitability/ hypersensitivity of these neurones
- Common symptoms include:
- Shooting pain
- Parasethesias:
- burning
- tingling
- numbness
- throbbing
6
Q
Give some causes of neuropathic pain
A
- Post stroke (commonly called thalamic pain, damage to thalamic structures)
- Trigeminal neuralgia (damage to facial nerve cause excruciating facial pain)
- Post herpetic (virus sits in dorsal nerve roots)
- Malignant
- Phantom limb
- Complex regional pain syndrome (pain in one limb/ arm, often idiopathic and accompanied by autonomic activation, red limbs and burning pain).
7
Q
Describe how referred pain occurs
How do you treat referred pain?
A
- Sensory information from organs is sent via autonomic neurones and travels to the spinal cord alongside parasympathetic and sympathetic neurones.
- These ANS afferents enter the spinal cord at the same level as somatic sensory afferents coming back from the skin
- As the skin normally has high sensory output and the viscera normally a lower output, the two inputs coming in at the same level are confused by the CNS as only higher output input from the skin.
- Therefore organ pain presents as cutaneous pain in a dermatomal pattern.
- the dermatome the organ pain is referred to is dependent on the spinal cord level at which the somatic sensory afferents and autonomic afferents from the viscera enter.
- i.e MI pain referred to the left arm, neck and jaw as the heart receives autonomic innervation from T1-T5, which is also the level at which sensory information from the left arm, neck and jaw is received.
- Treating referred pain requires you to treat the cause.
8
Q
List 5 different types of headache commonly seen
Suggest how to treat each
A
-
Tension headache:
- Often bilateral, accompanied by muscular pain of the neck
- felt like a band around the head
- most common
- NSAID’s and diary to determine trigger
-
Migraine:
- unilateral presentation often focusses around the eye
- can present with nausea/ vomiting/ visual changes/ sensitivity to light and sound
- thought to be due to change in vasodilation- vasospasm causes migraine
- treated with 3 steps: 1) NSAID and antiemetic 2) Triptans- 5-HT agonists which modulate vasomotor tone (sumatriptan, naratriptan)
- 3) Prophylaxis- beta blocker, amitriptyline
-
Cluster:
- Again unilateral and focussed around the eye
- Excruciating pain
- accompanied by sympathetic involvement - excessive tearing/ running of nose/ facial sweating/ swelling around eye
- Treatment: Triptans (sumatriptan)
- Prophylaxis: verapamil
-
Sinus:
- classic butterfly presentation around sinuses
- Treat with decongestants/antihistamines/ steroid
- Medication overuse headache
9
Q
What type of headache is a sign of a subarachnoid haemorrhage?
A
A “thunder- clap” headache is a sign of subarachnoid haemorrhage- a sudden onset, high intensity headache that takes only minutes to reach peak painfulness. MEDICAL EMERGENCY.
10
Q
Describe how pain can be modulated in the periphery via different drugs
A
- Tissue damage induces the inflammatory response and the release of proinflammatory cytokines/chemokines that can directly activate nociceptive free nerve endings.
- Many chemicals involved e.g Serotonin/ Bradykinin/ prostaglangins/ leukotriene/Histamine
- These can directly activate or sensitise the free nerve ending to send an impulse
- This impulse is sent to the dorsal horn and is carried to the cortex
- Many drug targets act to modulate this:
- Rubefacients - Thought to alleviate muscle/joint/tendon pain by activation of irritant receptors in the skin via vasodilation.
- Capsaicin - induces topical hypersensitivity reaction on skin which defunctionalises nociceptors.
- Topical analgesics- act by inhibiting activation of free nerve endings
11
Q
Describe the pain fibres of nociceptive pain
What pathway is nociceptive pain carried by? Describe its route to the cortex.
How is pain from the face carried?
A
- Nociceptive pain fibres have two types:
- C fibres (groan)- unmyelinated, slower transmission and slow response to pain. Slower onset and longer duration
- A- delta fibres (ouch)- lightly myelinated fibres with a faster transmission, pain has quick onset and quick to die down.
- These pain fibres are part of the spinothalamic pathway, 1st order neuron enters spinal cord and ascend 1-2 levels in tract of lissauer before synapsing with 2nd order neurone in rexed area 1 of dorsal horn.
- 2nd order neurone decussates via anterior white commisure and ascends to thalamus. Here it synapses with a 3rd order neuron that carries pain sensation to the cortex.
- Pain fibres from the face are carried by the trigeminothalamic tract.
12
Q
What is the gate control theory of pain?
What is this an example of?
A
- The gate control theory of pain is an example of pain modulation at the level of the spinal cord
- When nociceptive pain signals are transmitted to the CNS via C and Alpha delta fibres these signals enter the spinal cord, ascend and synapse with 2nd order neurones in the substantia gelatinosa in the dorsal horn.
- Input from pain fibres activates 2nd order cells and inhibits local interneurones.
- These 2nd order neurons ascend to the thalamus and synapse with 3rd order neurones which take pain signal to the cortex.
- In gate control theory, collaterals of large sensory fibres carrying cutaneous sensory input activate inhibitory interneurones which inhibit pain transmission information carried by the pain fibres.
- At the spinal cord level non noxious stimulation produces pre synaptic inhibition on dorsal root nociceptor fibres that synapse on nociceptor spinal neurons, reducing pain transmission to the CNS. I.e closes the “gate”.
13
Q
Describe the higher brain centres involved in pain processing
A
- Multiple brainstem and cortical centres that process pain.
- Pain received as primary somatosensory cortex and information can also be sent to integration centres within the parietal lobe.
- Information from primary somatosensory cortex can also be forwarded to the frontal lobe (positivity response) and the amygdala (negative emotions and fear). It is the interplay between the frontal cortex and amygdala that will determine your response to a particular stimulus.
- Information also sent on to the hypothalamus which is key in controlling autonomic output (hypothalamic- pituitary- adrenal axis). Activate fight or flight response in response to pain transmission.
- Hypothalamus can forward information to the periaqueductal gray which is responsible for defensive behaviours- crucial in ensuring damage isnt done.
- periaqueductal gray can also be activated by pain directly, and is involved in the descending inhibitory pain pathway.
- Other brainstem centres such as the cardiorespiratory centres are also stimulated to modulate response to pain.
14
Q
What is descending inhibition in pain?
A
- Descending inhibition refers to modulation of pain sensation at the spinal cord level by inhibitory signals sent down the dorsal lateral funiculus to the nociceptive afferent neurone at its point of synapse with 2nd order neurone.
- Blocks the transmission of pain presynaptically.
- Dorsal lateral funiculus is comprised of fibres originating from several brainstem nuclei. To note:
- 5HT neurones from nucleus raphe magnus (NRM)
- NA neurones from locus coerulus (LC).
- Noxious stimuli can activate the periaqueductal gray which activates other nuclei (NRM) which stimulates the descending pathway to dampen down pain transmission.
15
Q
Describe the pathway of normal sensation
A
- When skin is stimulated, receptors within the skin send sensory afferents to the dorsal horn where these 1st order neurones synapse with 2nd order neurones.
- 2nd order neurones travel up to the brainstem and thalamus where the input is sent further to the sensory cortex which allows us to perceive the sensation.
- At the same time, signals from the brainstem are also sent to CVS/RS centres, which allows maitenance of normal HR/BP/RR/skin temp
- Signals from the brainstem are also send on to the limbic system allowing us to feel happy.
16
Q
Describe the pathway of nociceptive/acute pain (Not anatomical pathway, more the other interactions with other systems)
A
- Tissue injury occurs, pain signals are sent to the dorsal horn of the spinal cord which becomes sensitised
- Synapses with second order neurone that sends signal to the brainstem and up to the sensory cortex, allows the perception of pain.
- At the same time pain signals are forwarded from brainstem to CVS/RS centres to increase HR, BP, RR, Temp. Increase autonomic output to protect ourselves.
- Pain signals from brainstem also forwarded to limbic system to induce pain behaviour - avoidance, defensive behaviour
- Activation of limbic system also activates descending inhibitory pathways to modulate pain as tissue heals
- Closes the gate and the tissue heals
17
Q
Describe the pathway of neuropathic (chronic) pain:
A
- In neuropathic pain there is constant stimulation of the dorsal horn due to nerve damage, which becomes continuously sensitised.
- This sensitisation can occur at the neuronal level with more channel expression/ sensitive channels and increasing stimulus reaching cortex, increased pain perception to chronic level.
- At the same time, the brainstem again activates the CVS/ RS centres which increases HR/BP/RR/Temp.
- This can lead to predisposition to cardiovascular disease and hypertension
- Constant stimulation of the brainstem with pain also activates the limbic system response- leading to chronic pain behaviour - depression and anxiety
- The descending inhibitory pathways from the limbic system become desensitised leading to reduced descending inhibition and worsening of chronic pain
25
Q
Name 2 other types of NSAID’s
Why are they different?
A
eTORI’s are very CELEctive
Selective COX2 inhibitors: Celexicoxib and Etoricoxib
Are different to other NSAID’s as they inhibit the COX2 enzyme specifically. Cox 1 is expressed ubiquitously thoughout the body and is required in tissues such as the stomach and gut where the production of prostaglandins is cytoprotective (inhibit acid secretion, protect gastric mucosa). (COX1 also involved in platelet activation/ renal blood flow autoregulation). COX2 is thought to be more specific to inflammation and therefore show fewer GI side effects.
26
Q
What is the mechanism of action of NSAID’s?
A
- NSAID’s block the cyclooxygenase enzyme from converting arachidonic acid into prostaglandins by binding to the active site. Particularly useful to block the COX-2 inducible form that is associated with inflammation.
- Blocking prostaglandin production:
- Antiinflammatory- reduces prostaglandin mediated vasodilation and oedema
- Antipyretic by inhibiting prostaglandin mediated increase in set temperature point within the hypothalamus
- Analgesic by inhibiting the prostaglandin mediated sensitisation of nociceptors to inflammatory mediators (E.g. bradykinin).
27
Q
How do prostaglandins act at the neuronal level?
How do NSAID’s act at the neuronal level?
A
- Prostaglandins bind to the prostanoid receptor on the neuronal cell membrane
- Prostanoid R = GPCR that via internal signalling p/w activates a VG sodium channel
- Increases activation of VGSC, increasing Na+ influx into the cell and depolarisation of the nociceptive neuron, increases AP firing.
- NSAIDS inhibit the production of prostaglandins, reducing the amount of prostaglandin that can bind the prostanoid R and therefore decrease the sensitisation of nociceptors to firing.
28
Q
What is the WHO ladder for cancer pain control?
A
Describes a ladder of treatment in which you start at the lowest form of pain management until pain becomes more serious.
First Paracetamol and NSAIDS
Then weak opiods such as codeine and cocodamol (codeine/paracetamol combo).
Followed by strong opiods and related compounds- morphine, fentanyl methadone
29
Q
What are the side effects of NSAID’s?
A
- GI disturbance:
- nausea/ vomiting
- Diarrhoea
- heartburn
- ulceration/ bleeding
- Cardiovascular events:
- Renal impairment (Block COX2 in renin-secreting macula densa)
- Hypertension
- Thrombosis
- MI/ Stroke
- Hypersensitivity reactions:
- Bronchospasm
- skin reactions- rashes, angiooedema
- photosensitivity
- Psychological/ head:
- Headache
- Depression
- Anxiety
- Insomnia
- Balance/ Hearing:
- Tinnitus
- Vertigo
- Dizziness
34
Q
What receptors do the opiods act on?
What is the general mechanism of action of synthetic opiods?
How do opiods have their analgesic effect at the neuronal level?
A
-
There are 4 classes of opiod receptor all of which are GPCR’s:
- mu (MOP)
- kappa (KOP)
- delta (DOP)
- ORL1
- Synthetic opiods have their effect by mimicking endogenous opiods.
- At the neuronal level, activation of the opiod receptors leads to intracellular signalling pathways that modulate the activity of certain ion channels, reducing neuronal AP firing:
- Increasing K+ conductance out the cell via KATP and Kir channels- hyperpolarising the cell
- Decreases opening of voltage gated Ca2+ channels- hyperpolarise cell
- Decreases Ca2+ release from IC stores- prevents the release of neurotransmitter from IC vesicles fusing with PM (exocytosis)
35
Q
How are the opioids differentiated into different classes?
A
- Opioids have different selectivity and efficacy for different opioid receptors therefore are split into different classes:
-
Agonists:
- STRONG- MORPHINE, DIAMORPHINE (HEROIN) (T1/2 - 3-4 HOURS)
- STRONG- TRAMADOL- blocks 5HT and NA reuptake, inhibits pain transmission in spinal cord
- WEAK- CODEINE, DIHYDROCODEINE
-
Partial agonists/ Mixed agonist/antagonists:
- NALORPHINE + BUPRENORPHINE
- PENTAZOCINE
-
Antagonists:
- NALOXONE (T1/2 1-2 hours)
- NALTREXONE (T1/2 10 hours)
-
Agonists:
37
Q
What are the sites of action of opioids in the CNS?
A
- Opioid receptors widely expressed in both brain and spinal cord
- Found in a number of brain regions: insular cortex, amygdala, hypothalamus
- Found in a number of brainstem nuclei: PAG, NRM, LC (periaqueductal gray, nucleus raphe magnus, locus coerulus)
- Activates descending inhibition via dorsolateral funiculus
- Inhibit nociceptive neurones presynaptically (prevent NT release) and postsynaptically (reduce excitability) in dorsal horn of the spinal cord.
38
Q
What are the side effects and signs of opiod intoxication?
A
- CARDINAL SIGNS of OD:
- Respiratory depression
- COMA (GCS < 7)
- Mioisis (“Pinpoint Pupils” - key diagnostic sign)
- GI:
- reduced GI motility
- Nausea/ Vomiting
- Hypersensitivity:
- Histamine release from mast cells
- Smooth muscle spasm
- Bronchoconstriction
- Anaphylaxis
- Pyschiatric:
- Euphoria
- Sedation
- Mood changes
- Tolerance and dependecy:
- desensitisation of the opioid R’s
- physiological withdrawal
39
Q
What are the management steps for Opioid OD?
A
- Oh God Take No drugs CHildren
To resolve coma:
- Oxygen
- Glucose
- Thiamine
- IV Naloxone (shorter acting 2-4 hrs)/ naltrexone (longer acting 10hrs)
- Activated CHarcoal (if concious and within 1 hr of OD, give charcoal and 0.8-2mg i.v naloxone every 2-3 mins)
