Pain Flashcards
How can pain be beneficial and life destroying?
- normal pain is life saving
- excessive long lasting pain or neuropathic pain is life destroying
Pain as a condition
- if there is no treatable pathology then the pain itself becomes the pathology that needs to be treated
do we have good biomarkers of pain?
no, there is no biomarker to discern real and psychogenic pain
How many classes of analgesic drugs do we have? What are their drawbacks?
ASA type drugs that work for mild pain
- but have ceiling effect so doesn’t work for serious pain
opioid type drugs
- serious side effects such as sedation and risk of addiction
Simple and IASP definitions of pain
simple: pain is a sensory modality that signals actual or potential damage to the body - thought to be a separate somatosensory system separate from others (ex. from crude touch)
IASP: an unpleasant sensory and emotional experience associated with the actual or potential tissue damage or described in terms of such damage
Types of normal pain
fast pain –> short and stabbing –> first pain
- happens when first injured and is more localized
- more recently evolved
slow pain –> slow and burning –> second pain
- generalized aching after first pain
- older system
these have different central paths using different neurons
degrees of pain
- mild - can go to work
- moderate - stays home
- severe - stays in bed
- psychogenic –> verbal report doesn’t match behaviour –> most likely depression presenting as severe pain but not staying at home
duration of pain
acute - one month or less
chronic - more than 3 months
- chronic can be long lasting or neuropathic (not all chronic pain is neuropathic but almost all neuropathic pain is chronic)
normal vs abnormal pain
normal pain
- “nociceptive”
- there is adequate stimulus and body is responding as it should
abnormal pain
- “neuropathic”
- absent or inadequate stimulus for the pain response
- CNS disorder - pain system is reporting pain when there is no cause
function of normal pain
from the bio physiological perspective - it protects the integrity of the body
- removes you from damage (sharp, stabbing pain) to remove you from the dangerous area
- it immobilizes you for repair (slow and burning) so you can heal
- helps you to get help from a doctor
is normal pain always active?
yes - always active at a low level
- it is what makes you shift your body weight when you are awake and sleeping
- unconscious levels of nociceptive pain
congenital pain insensitivity
- individuals who feel no pain
- often burn themselves, bite off tongue, don’t notice broken bones or ruptured appendices, poke out their eyes and pull teeth out as infants, don’t cough
- also have impairments in the low levels of nociceptive pain and develop orthopaedic problems because they don’t move
3 psychological dimensions of pain
- pain is regularly associated with a motivational state that elicits stereotyped avoidance behaviour –> reflex, instructive and goal oriented behaviour
- this is unlike other sensory systems that can make you feel good or bad like vision and audition, pain can only make you feel bad - pain is variably linked to damage
- pain may be present without damage ex. neuropathic pain, trigeminal neuralgia, phantom limb pain
- damage can be present without pain –> pain is suppressed during hypnosis, placebo, fight or flight, and sex
- this suggests that there is a pain override system - excessive or prolonged nociceptive pain can become neuropathic
- can be due to nerve damage but also the learning-like behaviour of pain that can spread to other parts where nerves are not damaged
- the system can be made hyperactive by damage or overuse (this is controversial)
uncontrolled nociceptive pain: onset, cause, duration, gender, prevalence, treatment
onset: often Middle Ages of later
cause - often disease of ageing ex. inflammation of the joints leads to arthititis
duration - indefinite
gender - more in women than men
prevalence - 1/3 of the population in canada
treatment - usually ASA type drugs, usually not opioids
neuropathic pain
- caused by malfunction of the nervous system due to pain damage or nerve damage
- pain without an appropriate stimulus
- it has no function –> CNS disorder
uncontrolled neuropathic pain terms - allodynia and hyperalgesia
allodenya: touch is painful
hyperalgesia: mild pain becomes severe
- neuralgias (ex. trigeminal neuralgia), causalgias, phantom limb pain
uncontrolled neuropathic pain: onset, cause, duration, gender, prevalence, treatment
onset: any time but often middle or later age
causes: nerve damage, excessive or prolonged nociceptive pain
duration: indefinite
gender: seen equally in men than women
prevalence: unknown - 12-18% of chronic pain in Canada which is partly neuropathic pain
treatment: treated with anti seizure drugs because they opposed hyperactivity of the CNS –> thus there is a hyperactivity component to neuropathic pain
why can neuropathic pain be considered a model for CNS disorders
- disorders where a super-normal pain occurs in presence of a normal stimulus
- anxiety disorders: high anxiety when there is no significant cause
- depression: severe sadness with no adequate cause
- mania
how does chronic pain affect quality of life and comorbidities?
- chronic pain can be nociceptive or neuropathic and both are serious
- it is found in 30% of the population
- comorbidities: depression, anxiety, poor sleep, lack of energy, inability to work, substance use
- quality of life is low - suicide rate is 2x normal rate, and about 10% of suicides occur in chronic pain patients
Steps of sensation to the CNS
- sensory/primary afferent neurons encounter a stimulus
- stimulus energy is transducer to a generator potential
- in pain it is by the same cell, in other sensory systems it can be by a separate receptor cell
- the generator potential is a graded potential –> spreads by decremental conduction (like an ESPS) - the generator potential produces an AP in primary afferent neurons
- if it is strong enough it will trigger the opening of VGSC (AP) in primary afferents
- AP spreads non-decrementally towards the CNS
- whole primary neuron acts like an axon - primary afferent synaptically excites a secondary ascending neuron in the CNS
- these trigger local reflexes and send signals to the brain
- in the spinal nerve the synapse is often in the dorsal horn of the spinal grey matter - tertiary and higher order neurons are activated that may provide conscious sensations
strict and general definitions of sensory neurons
strict: primary sensory neuron
general: first few neurons in a sensory system (ex. neurons in the cortex that respond to touch)
what types of primary neurons are there
bipolar
- in the ear, eye, nose
- has one axon and one dendrite
- has cilia that are sensitive to physical stimuli that are on the dendrites
pseudounipolar
- skin
- has one axon that splits, one side travels into PNS and one to CNS
what do skin/cutaneous senses include? what is the stimulus energy?
fine touch, crude touch, hot, cold, vibration, pain
- the stimulus energy for pain are these sense when they are intense - all potentially causing tissue damage
where does pain originate?
deep tissue (muscle and viscera) and the skin (cutaneous)
primary afferents
- pseudo unipolar neurons with one end in skin and the other in the spinal cord, the cell body is in the dorsal root ganglia
- embryologically start as bipolar but the cell body moves to one side
- sometimes called nociceptors (especially used for TRP channels)
what kind of channels are the free nerve ending receptors?
- receptors are cation channels on free nerve endings in the skin and body
- sensory gated ion channels (sensory activated - no separate receptor cell)
- the cation channel opens to produce a generator potential (graded, decremental spread)
- when strong enough the generator potential triggers an AP in the axon of the primary afferent neuron
transient receptor potential channels
- type of channel;
- what they respond to;
- type of sensory gated ion channel
- part of TRP channel superfamily that play a role in touch, temperature, vision, taste, smell, hearing
- cutaneous TRP can respond to chemicals - capsaicin and menthol - that helps researchers study them
- can occur in the brain but their role is unclear because we don’t feel pain in the brain, but blocking them may have side effects
types of TRP channels
- high threshold mechanoreceptors
- TRPV1: heat, inflammation, acid (capsaicin)
- TRPA1: chemical irritant (mustard, radish)
- TRPM8: cold (menthol)
two major types of primary afferents
A-delta: small myelinated, fast pain
- Ab: funny touch
- Ad: fast pain
C: small unmyelinated, slow pain
compound AP
- evoked potential elicited in spinal nerves
- mild stimuli will only activate the A group of primary afferents
- more intense stimulus activates C fibres
what are the specialized channels on primary afferents?
- voltage dependent sodium channels
- the same ones are on A-delta and C fibres –> gives us a target
- Nav1.7 and Nav1.8 are the major pain channels produced by SNC genes
- Nav1.7 is mutated in congenitally pain insensitive patients - seems to be dominant
where do the primary afferents synapse in the spinal cord?
- the primary afferent neurons synapse in the dorsal horn of the spinal grey matter of the spinal cord
- in Rexed’s laminae 1 and 2 (some references say 5 as well)
rexed’s laminae
sensory are dorsal
- laminae 1-5
- laminae 1 and 2: zona marginalis
- laminae 2-3: substantia gelitinosa: dendritic trees of neurons in laminae 1 and 2 - there are inhibitory neurons here as well (one of the sites of opioid action)
- lamina 4-6: nucleus proprius
motor are ventral
primary afferent/secondary neuron synapse
- primary afferent releases glutamate, substance P and CGRP
- triggers ESPS that produce AP in secondary neuron
- AP triggers local nociceptive reflexes in the spinal cord and sends collaterals towards the brain in while matter of spinal cord
- primitive reflexes: primary connects to secondary motor neuron first
- complex reflexes: primary connects to secondary interneuron first
secondary/tertiary neurons in fast pain
- fast pain impulses ascend in the NEOSPINOTHALAMIC pathway (ventrolateral and anterolateral pathway) (originates in spinal tract and ends in thalamus)
- synapse in the ventrobasal nuclei of the thalamus
- vasobasal nuclei projects up to the somatosensory cortex - post central gyrus
secondary/tertirary neurons in slow pain
- ascends in paleo-spinothalamic and archi-spinothalamic pathways
- older pathways - may fibres reach brain stem not the thalamus
- often brain-stem pathways are polysynaptic - particularly archi-spino –> many synapses up to the cortex
- they activate arousal and autonomic responses, and the limbic system (amygdala - fear)
- triggers the pain override system
higher sites in the forebrain related to three components of pain experience
Carlson’s theory
- sensory component: S1 and S2
- emotional component (suffering): insula and anterior cingulate (pain, anxiety, depression - older cortex)
- long term emotional component (worry): prefrontal cortex
the pain override system - disinhibition
descending inhibitory system from the central grey of the midbrain (the periaqueductal grey is the origin of this system)
- in the periaqueducatal grey matter opioids inhibit the activity of inhibitory neurons –> which allows excitatory neurons to excite neurons in the raphe nucleus –> which excites a neuron in the dorsal horn of the spinal cord –> these neurons excite interneurons that inhibit neurons that transmit pain signals to the brain
- the interneurons work presynaptically on primary afferent neurons and post synaptically in secondary neurons
What are the causes of neuropathic pain?
- presumably mediated by the normal pain pathway (slow burning pain especially)
- the pathways are hyperactive –> pain neurons overactive
- hyperactivity occurs usually due to damage or lease of the nerves or CNS - central sensitization
- pain can get worse over time and can be extraterritorial (can spread throughout body and isn’t localized anymore)
What are the speculated mechanisms of central sensitization?
recruitment of inactive pain pathways
- pathways that did not carry pain/silent pain pathways now do
- gain in excitation
death of inhibitory neurons due to excitotoxicity
- intense pain overexcites the system and causes excitotoxicity leading to the death of inhibitory neurons
- loss of inhibitory neurons –> gain in excitation
inflammation
- can spread from initial site (extraterritorial)
- effects neuronal firing
pain targets for pharmacologists
- the receptors/cation channels
- TRPV1, TRPA1, TRMP8 - we would have to block several
- the channels are found centrally so this may have side effects
- peripheral acting drugs can be made - spinal TRPs so they do not get into the CNS to exert side effects - can be done with charging the drug so it does cross the BBB - sodium channels in primary afferents
- Nav1.7 especially - known to take away pain - it is mutated in congenitally pain insensitive people who are still cognitively and emotionally normal - transmitters of primary afferents
- CGRP (drug would have to not cross BBB)
- NOT OPTIONS: glutamate - it is a major excitatory neuron in the brain and inhibiting it would block cognition), substance P - has central and peripheral actions - pain override system
- already targeted with opiods
- potential to find something more specific so they don’t act on other systems such as respiratory depression
theory that pain may originate below S1 and S2
- sharp pain reports to the somatosensory cortex
- S1 and S2 light up in response to pain
- people report less pain after hypnotic suggestion that their pain is less intense result in a decrease in activity in S1 and S2
- people with seizures in parietal cortex (S1 and S2) rarely report pain
- people stimulated in the thalamus and insula do
- shows pain sensation may arise below S1 and S2 - real pain experience may be below the cortical level
how do we stop neuropathic pain?
- anti seizure drugs: to stop the over activation of the brain (lessens pain)
- antidepressants (lessens pain)
- opioids/NSAIDs: second/third line - usually don’t work well
- cannabinoids: has been shown to be effective
- analgesics don’t work very well even though they work on normal pain - they usually only work for nociceptive pain
