Pain and Analgesia Flashcards
what is pain?
an unpleasant sensory and emotional experience associated with actual or potential tissue damage
are pain and nociception the same?
NO! pain cannot be inferred solely from activity in sensory neurons, and pain has a consious component
what is nociception?
the neural process of encoding noxious stimuli
what are the 3 big categories of pain control?
- anti nociception (abscence of response to a normally painful stimulus, aka there is an inability to respond but there could still be pain)
- analgesia (abscence of pain in response to a stimuli which would normally be painful)
- general anesthesia (drug induced unconsiousness by reversable depression of the CNS and perception)
nociceptors are capable of detecting different types of stimuli, such as: __________. Most are _______
- mechanical
- chemical
- thermal
polymodal, meaning they can detect multiple types of stimuli
which sensory nerve fibers are myelinated and which are not?
A fibers are myelinated (including A alpha, beta, and delta fibers)
C fibers are not myelinated
which sensory nerve fibers can perceive nociception?
A delta and C fibers. A delta is fast ad C is slow
considering A fibers are faster conducting than C fibers, what kind of pain does each sense?
A fibers: sharp, well localized pain (skin, SQ, fascia, bone)
C fibers: dull, diffuse pain (muscle, viscera)
what is the primary excitatory neurotransmitter released by A and C fibers?
glutamate (some C fibers can express substance P)
explain inflammatory soup and why inflammation can be a bad thing sometimes!
nociceptors are very sensitive to inflammatory mediators like cytokines, and when these mediatorys are around they increase nociception. The stimulation of these nociceptors also increases local production of inflammatory mediators which makes a positive feedback loop.
what does inflammation do to the pain threshold? how about analgesics?
inflammation will decreases the pain threshold, making it easier to feel pain
analgesic therapy will increase the pain threshold, which means it takes more to feel or preceive a certain level of pain
define hyperalgesia and allodynia
hyperalgesia: increased sensitivity to noxious stimuli
allodynia: when normally non noxious stimuli become capable of eliciting a pain response
explain where each of the following drug classes works at the CNS levels:
- antidepressants and opiods
- opiods and alpha 2 agonists
- local anesthetics
- works at the level of the cerebral cortex
- works at the level of the spinal cord (modulation)
- works at the level of transmission of sensory nerves
explain what wind up is
spinal facilitation of pain, aka high frequency action potentials train the second order neurons to respond more vigorously to subsequent stimulation, the increase in pain intensity over time when a given stimulus is delivered repeatedly above a critical rate.
does general anesthesia prevent wind up?
no! this is why you MUST provide analgesia as well as anesthesia
explain the process step by step of what happens at the receptor/nerve level of wind up. where does this process all happen?
high frequency of action potentials in primary afferent nerves–>increased glutamate and other neurotransmitters–>activation of normally inactive NMDA receptors–>influx of calcium into the post synaptic cell–>upregulation of receptors on the post synaptic membrane –>this nerve becomes hypersensitive
this all happens at the level of the dorsal horn of the spinal cord
explain why you should do pre-emptive analgesia
because we know pain leads to increased sensitivity which will lead to wind up, so if we use pre-emptive analgesia we can control the pain before it actually starts
are anesthetics good analgesics too?
NO this is why you MUST provide analgesia in surgery before your patient wakes up!
what is a descending inhibitory pathway in regards to pain?
these are descending pathways from the brain that modulate pain by either excitatory action or inhibatory action via endogenous/exogenous opiods. Whether they are pro-nociception or anti-nociception depends on the neurotransmitter, for example norepinephrine is always anti nociception, but dopamine and serotonin can be both.
what are the 3 big physiological pain inhibion mechanisms?
- endogenous opiods agonists: endorpins, enkephalins, etc
- upregulation of peripheral opiod receptors at site of injury: triggered by inflammation
- migration of opiod producing leukocytes to site of injury: triggered by selectin expression at injury site
what are the 4 sites of analgesia?
- block nociception at peripheral nociceptiors
- prevent transmission to the spinal cord
- prevent transmission to brain
- enhance descneding inhibitory pathways
what is the best way to manage pain?
to affect all of the different levels, referred to a balanced or multimodal approach, use drugs or techniques with different mechanisms of action to acheive optimal pain control, use lower doses of multiple drugs
what are the 3 kinds of opiod receptors? where are they expressed?
Mu, kappa, and delta (there are other subtypes as well but these are the big 3)
they are expressed in the CNS and PNS as well as the intestinal tract, immune cells, etc
what kind of receptor are opiod receptors? generally, what are their 3 mechanisms of action?
G protein coupled receptors
1. decreased cAMP formation and adenyl cyclase inhibition leading to reduction in cAMP modulated Ca2+ influx (preventing neurotransmitter release)
2. inhibition of calcium channels in presynaptic neurons (reduced neurotransmitter release)
3. increased K+ outflow in post synaptic neurons, leading to hyperpolarization which makes it harder for neurons to depolarize
what can happen if you chronically take opiods?
it causes downregulation of opiods receptors, meaning you have to gradually increase the dose to get the same effects
all opiod receptors provide analgesia, but which one is the “big gun receptor” that has the most effects, including respiratory depression, euphoria, nausea and vomitting?
Mu receptors
what broad 4 categories of drugs interact with opiod receptors?
analgesics, sedatives, antiussive, antidiarrheal
are all opiods full agonists?
no, they are split into categories:
- full agonist
- partial agonist
- agonist-antagonist
- antagonist
list 4 clinical uses of opiods
- pre-anesthetic (analgesia, sedation, induction)
- intra-operative (analgesia, minimize the anesthetic dose)
- post-operative (analgesia, +/- sedation, may be adverse side effects)
- epidurals and intra-articula blocks
opiods are better at inhibiting nociceptive transmission via _____ fibers than through _____ fibers, therefore:
C, A
opiods alone may not provide sufficiency surgical analgesia
what are the 6 clinically important adverse effects of opiods
- respiratory depression (esp in animals with resp disease and neonates)
- vomitting (usually with morphine or hydromorphone)
- constipation/ileus (important for horses, SA less susceptible)
- severe pruritus
- histamine release (esp IV morphine)
- hyperthermia in cats
- CNS excitation/dysphoria/seizures, esp in horses and cats
what are some contraindications of opiods?
- don’t use morphine in animals with congestive heart failure because of effects on coronary blood flow and it can cause bradycardia
- use opiods with caution in head trauma patents as respiratory depression can increase cranial PCO2 and cause cerebral vasodilation
what are two important things to remember regarding pharmakokinetics of opiods
- their half life is generally short
- duration of action depends on the dose/pain
opiod receptor expression is upregulated by _____
inflammatory cytokines, mostly the Mu receptors
what kind of drug is morphine?
Mu agonist, Kappa partial agonist, considered the gold standard opioid. Used for analgesia, anesthtic pre med, sedative combo. Not good for cats, good for dogs, not used in horses due to CNS effects. Adverse effects are pain dependent, meaning if the animal is painful there will be less adverse effects
what kind of drug is hydromorphone?
a Mu agonist, emetic. less of a histamine response than morphine. short half life and half life is longer if the dose is larger
what kind of drug is methadone?
Mu agonist, NMDA antagonist, NE and serotonin reuptake inhibitor. causes fewer CNS effects and less vomitting than other Mu agonists esp in cats!!!
what kind of drug is fentanyl?
synthetic Mu agonist, 1000x more lipophilic than morphine and 100x more potent too! given IV or via skin patch. generally safe for dogs, generally fewer adverse effects than with other opiods
what kind of drug is Buprenorphine?
partial Mu agonist and a Kappa antagonist. has a ceiling effect on analgesia and respiratory depression effects. good for cats given transmucosally, not good for dogs. Very high affinity for Mu receptors but lower efficacy.
What kind of drug is Butorphanol?
kappa agonist, mu antagonist/partial agonist. effective analgesia for mild to moderate pain, also a sedative, commonly used in combo with sedatives in LA for sedation and analgesia like castrations, very good sedation in camelids!!
what kind of drug is tramadol?
centrally acting multimodal analgesic, but the active metabolite is a Mu agaonist. do not use as sole analgesic in dogs but can be used as adjunct. more effective in cats.
what broad class of drug should you use to reverse opiods?
competitive opiod receptor antagonists
what kind of drug is Naloxone?
a competitive antagonist for all opioid receptors (greatest at Mu), and a GABA antagonist (which can induce seizures!), give small doses every few minutes to reverse any resp depression
in large animals, the most commonly used systemic opiod is
butorphanol
alpha 2 agonists are useful sedatives, analgesics, and muscle relaxants. How do they work on descending inhibitory pathways?
alpha 2 receptors are normally expressed by primary afferent neurons, and normally norepinepherine binds and reduced NT release via calcium, so alpha 2 agonists will have the same effects and act to inhibit NT release
all currently used veterinary alpha 2 agonists have some _______ activity. What does this mean for the drug effects?
alpha 1. alpha 1 activation usually causes excitation and increased motor activity
what kind of drug is ketamine?
a short acting general anesthetic commonly used for field procedures. safe for cardio and resp systems and usually combined with alpha 2 and opiod
it is also an analgesic: NMDA receptor antagonist, effective at the level of the spinal cord
what are the 3 local anesthetics that I care about? how do these drugs work?
lidocaine, bupivacaine, mepivacaine
they block sodium channels and stopping action potential conduction in nerve fibers, aka they stop nerve conduction
what are the main side effects of local anesthetics?
**local anesthetic toxicity can occur and is a very real concern in small animals
CNS effects: gradually becomes generalized CNS depression
CV effects: arrythrmias and collapse
