Nociception, Pain, and Analgesia Flashcards
How can pain be classified?
Acute and chronic.
What is acute pain?
Pain that lasts less than 3-6 months. Can be caused by tissue injury, trauma, and childbirth.
What is chronic pain?
Pain that lasts longer than 3-6 months, outlasting tissue injury.
What is hyperalgesia?
Enhanced pain response to noxious stimuli, due to sensitization of peripheral nociceptors.
What is allodynia?
Pain caused by innocuous stimuli.
What are the pain classifications based on cause?
Nociceptive pain, inflammatory pain, neuropathic pain.
What is nociceptive pain?
Direct activation of pain fibres by noxious stimuli.
What is inflammatory pain?
Pain caused by inflammatory mediators.
What is neuropathic pain?
Pain to the somatosensory nervous system.
What are nociceptors?
Nociceptors work like pain signal generators that convert damaging stimuli into nociceptive signals.
Describe TRPV1 nociceptors.
Heat activated ion channels, also activated by capsaicin, H+ ions (pH <5.5). Permeable to Na+ and Ca2+.
Describe TRPM8 nociceptors.
Cold (<26°C) activated ion channel also activated by menthol.
Describe TRPA1 nociceptors.
Detects noxious cold (colder than above) and mechanical stimuli, oxidative stress, lipopolysaccharide (LPS), irritating chemicals (e.g. AITC from wasabi, mustard oil and cinnamon, allicin from garlic), Δ-9-tetrahydrocannabinol (marijuana), Methylglyoxal (DN), bradykinin etc.
Describe TRPV4 nociceptors.
Senses hypo-osmolarity and arachidonic acid metabolites.
Describe ASICs (acid sensing ion channels).
Activated by acid (pH <6.4).
Describe P2X3 nociceptors.
ATP-gated ion channels; detects ATP released during tissue damage.
Name some mechanically activated ion channels implicated in nociception.
ENac, PIEZO.
What neurotransmitters are involved in nociception?
Glutamate, tachykinins.
What neurotransmitters are involved in analgesia?
Opioid peptides, 5-HT, noradrenaline, GABA, adenosine.
Describe glutamate’s role in nociception.
Released from primary afferents, Fast transmission (AMPA subtype of receptors), Slower, NMDA (component is important in wind up).
What are inflammatory mediators?
These are mediators released from damaged cells and trigger the nociceptive pathway. There is an element of positive feedback (Substance P, Mast Cells, Histamine) which increases the pain response.
Describe bradykinin’s role in nociception.
Generated in damaged tissue, couples to the B1 and B2 receptors, sensitizes TRPV1, TRPA1, and TRPV4 via activating PKC.
Describe the role of prostaglandins E and F in nocicaption.
Increase the excitability of afferents by acting on Na+ and K+ ion channels, and sensitized TRPV1 and TRPV4 via activating PKA.
Describe the role of NGF (nerve growth factor) in nociception.
Sensitizes TRPV1, Na+, and K+ channels, increasing the expression of these ion channels. Released from damaged and inflamed tissues, and cells.
What metabolites, involved in nociception, are released from damage cells?
Acid, ATP, 5-HT, histamine.
What neuropeptides are involved in nociception?
Substance P and calcitonin gene-related peptide (CGRP) released from afferent nerve fibres. Bidirectional signalling.
What are the two types of afferent nerve fibres used in nociception?
A-delta and C fibres.
Describe the characteristics of A-delta afferent nerve fibres used in nociception.
Myelinated, high conduction velocity, cause a sharp, localised, and fast pain.
Describe the characteristics of C afferent nerve fibres used in nociception.
Non-myelinated, low conduction velocity, cause a dull, burning, non-localised, slow pain.
Different nerve fibres synapse with different parts of the dorsal horn of the spinal column. Where is pain processed?
Pain is mainly processed in the superficial layers of the dorsal horn.
How are interneurones in the spinal cord involved in the modulation of the pain response?
Interneurones in the dorsal horn release inhibitory neurotransmitters (e.g. GABA) to inhibit the pain response.
Describe the gate control theory of pain modulation.
Spinal transmission (T) neurones receive input from nociception to evoke nociception. T neurones concurrently receive other innocuous inputs from Aβ fibres, which also activate inhibitory interneurons in the substantia gelatinosa (SG) to reduce nociception; hence the activation of the SG ‘closes the gate’. This determines whether nociceptive input from the peripheral nervous system is relayed through the spinal transmission neurones (T) to higher CNS areas where pain is consciously perceived.
What is wind up theory?
Wind-up is a progressive, frequency dependent facilitation of the response of a neuron evoked by repetitive (usually electrical) stimulation of constant intensity. Pain increases over time in response to repetitive stimuli.
What is the mechanism of wind up theory?
Wind-up occurs in dorsal horn neurones. It is caused by inputs from peripheral nociceptive C fibres, leading to increased excitability of dorsal horn neurones. Glutamate (NMDA) and neurokinin NK1 receptors are required to generate wind-up.
Where are mu type opioid receptors found?
Cortex LIII, IV, Thalamus, PAG, Substantia gelatinosa, Spinal cord, DRG.
What are mu type opioid receptors implicated in?
Supraspinal analgesia, dependence, respiratory depression, miosis, euphoria, constipation.
Where are kappa type opioid receptors found?
Hypothalamus, PAG, Substantia gelatinosa, Spinal cord.
What are kappa type opioid receptors implicated in?
Spinal analgesia, sedation, miosis.
Where are delta type opioid receptors found?
Pontine nucleus, Amygdala, Olfactory bulb, Deep cortex, Spinal cord, DRG.
What are delta type opioid receptors implicated in?
Analgesia, euphoria, dependence.
What is referred pain?
Referred pain is pain that reflects where the pain/problem originated from, giving information on the causes of the pain.
What is phantom limb pain?
Phantom limb pain is pain reported to be coming from amputated limbs. It is not nociceptive pain but is neuropathic pain and is very hard to treat.
SOCRATES is a mnemonic used for describing pain, what are the categories for this description?
Site, Onset, Character, Radiation, Associated symptoms, Timing (duration, course, pattern), Exacerbating and relieving factors (Positioning, analgesia (dose), etc), Severity (Pain scales).
When asking a patient about the character of their pain, what should one avoid?
Putting words into the patients mouth.
Describe the WHO analgesia ladder.
1 (non-opioid and adjuvant), 2 (weak opioid, non-opioid, adjuvant), 3 (strong opioid, non-opioid, adjuvant).
What are the 4 drugs recommended first line for neuropathic pain?
Gabapentin, pregabalin, amitryptaline, duloxetine.
Why should analgesia be given at regular intervals?
Analgesia should be given at regular intervals in order to break the pain cycle and give consistent coverage.
What should analgesia prescribing be done in accordance with?
Prescribing should be done in accordance with the patients’ pain; pain is a very personal and subjective thing and differs for each patient. Thus, if a patient’s pain increases, the analgesia regimen should also increase. And vice versa.
How does paracetamol work?
Paracetamol is thought to act through the inhibition of CNS prostaglandins.
How do NSAIDs work?
NSAIDs act through inhibition of the enzyme cyclo-oxygenase (COX) which in turn inhibits the production of prostaglandins.
How long does it take for the full anti-inflammatory effect of NSAIDs to present?
Up to 3 weeks.
What are the side effects of NSAIDs?
The side effects are mediated through systemic inhibition of prostaglandins; this is regardless of the route of administration hence over use of an NSAID gel can lead to gastrointestinal side effects.
The cardiac side effects are mediated through the retention of water and sodium ions, reducing blood pressure control and worsening heart failure.
What are the side effects of opioid analgesics?
Respiratory depression, pupillary constriction, cough supression, sedation, nausea and vomiting, constipation, euphoria/dysphoria, tolerance, addiction/physical dependence.
Codeine is a pro-drug of morphine, how much of it is demethylated to form morphine?
10%.
What are the main side effects of codeine?
Codeine can have side effects such as constipation, cough suppression, and respiratory depression.
Why is tramadol different to other opioid analgesics?
Tramadol is an odd opioid analgesic as it doesn’t just act at the opioid receptor but also acts through pre-synaptic re-uptake blockade of noradrenaline and serotonin.
Compared to morphine, what is the potency of tramadol?
It has a potency 1/10th of that of morphine.
Who should tramadol be used in caution with?
Tramadol should be used in caution in patients with a low seizure threshold (e.g. epileptic patients’).
When prescribing morphine, what form should be used initially? Why?
One should start with an immediate release preparation and move onto MR preparations with immediate release for breakthrough pain. This is titrate the dose up to provide effective analgesia.
Why should MR formulations of morphine be prescribed by brand?
They have different bioavailabilities.
What is the potency of diamorphine compared to morphine?
2.5x.
What is diamorphine a pure form of?
Street heroin.
How much more potent than morphine is fentanyl?
100x.
Why should fentanyl patches be prescribed by brand?
They have pharmacokinetic differences.
What is the potency of oxycodone compared to morphine?
2.0x.
As well as treating opioid addiction, what else is methadone used for?
It is used by specialists to treat difficult to control pain (specialist pain or palliative care units).
Can the action of buprenorphine be reversed by naloxone?
No.
What compound is used to treat opioid overdose?
Naloxone.
What are adjuvents?
They are additions to pain treatment, used to treat neuropathic pain rather than nociceptive pain.
Give some examples of adjuvants.
Tricyclic antidepressants, Anticonvulsants, Benzodiazepines, Lidocaine (only licensed for shingles), Corticosteroids, Ketamine, Bisphosphates, Membrane stabilisers.
