Pain Flashcards
Types of pain fibers
Aβ
- non-noxious – touch, pressure
- innervate the skin
- very fast
Aδ
- pain, cold
- fast
- first pain reflex (sharp, prickly)
C
- pain, temp, touch, pressure, itch
- slow
- 2nd pain (dull, aching)
Quality of Pain ( inflammatory, neuropathic, visceral, referred)
- inflammatory: throbbing, pulsating
- neuropathic: stabbing, shooting, burning, tingling
- visceral: squeezing
- referred: usual distribution of pain with myocardial ischemia
Pain Transmission (MOA)
- pain starts in PERIPHERY, when there is a peripheral stimulus and this signal is conducted to the spinal cord
- once the signal gets to the spinal cord, it is processed and that info is sent up through the ascending input up to the brain for processing effect(central effect)
- then the info gets sent back down through descending modulation, and the idea of this process is to help control the action of the afferent neuron that’s bringing info into spinal cord
Peripheral Receptors (Temperature Sensitive)
- Transient receptor potential cation channel (TRP)
- TRPV (vanniloid) = heat
- TRPM (melastatin) = cold
Peripheral Receptors (Acid Sensitive)
- activated by protons
- acid sensing ion channel (activated by H+, conduct Na+)
Peripheral Receptors (Chemical irritant sensitive)
- Histamine
- bradykinin
Importance of glutamate with nerve transmission
- once the signal gets to the spinal cord, a neurotransmitter gets released, glutamate acts on AMPA, mGluR, NMDAR and they get released and go to the brain or work by reflex
- glutamate plays a huge role in conduction of pain in spinal cord
Repeated stimuli reduces firing threshold
becomes easier for pain conducting neuron to fire and conduct a painful stimuli
Substance P role in heightening pain responding
- when there’s a stimulus, substance P is released, which stimulates the blood vessels
- vasodilation, release of degranulate mast cells, histamine release, and inflammation occur
- these events lead to an increase in signal receiving receptors in the periphery — AMOA and NMDA
(which can then send more signals to the spinal cord and thus to the brain) - this is known as peripheral sensitization
– an example of this is a sunburn
Phenanthrenes
morphine
codeine
thebaine
Benzylisoquinolines
noscapine
papaverine
Types of opioid receptors
- G protein-coupled receptor
- Mu
- Kappa
- Delta
- Nociceptin
- Sigma – not an opioid receptor
GPCR (opioid receptor)
- family A - peptide receptors
- Gi/o coupled (inhibit cAMP production)
- open GIRK potassium channels
- close calcium channels
Mu (opioid receptor)
- M - morphine
- endogenous opioid = endorphin
Kappa (opioid receptor)
- K - ketocyclazocine
- endogenous opioid = dynorphin
Delta (opioid receptor)
- D - deferens -> where identified
- endogenous opioid = enkephalin
Nociceptin, orphaniin FQ receptor
endogenous opioid = nociceptin
Opioid receptor signal transduction (presynaptic)
Presynaptic = inhibit calcium channel (Gi), results in decrease in neurotransmitter release
- decreases conduction ( of primary neuron bringing info to spinal cord)
Opioid receptor signal transduction (postsynaptic)
Postsynaptic = activate GIRK channel (Gbetagamma), efflux of K+ which causes hyperpolarization
- causes an increased difficulty for action potential to reach threshold, thus reduction of neurotransmitter release of painful stimuli
Mu opioid receptor
- most drugs work here
- beta-endorphins (endogenous morphine) – runner’s high
- therapeutic use for analgesic (acute)
- not as effective for chronic pain
- also used for sedation and antitussive
opioid induced SE at Mu receptor
- respiratory depression
- constipation
- pruritus (itch) - SE not allergic response
- addiction
- urinary retention
- N/V
- miosis
Kappa opioid receptor
- dynorphins natural ligand (though that drug therapy is less addictive)
- activation is dysphoric, aversive
- use in treatment of addiction because it results in reduction of dopamine release (decreases abuse potential)
- counterbalance mu opioid receptor effects
Delta opioid receptor
- no FDA approved opioid receptor agonists for delta receptor
- therapy - reduce anxiety, depression, treat alcoholism, relief hyperalgesia
SE: seuzures!!
Opioid site of action
- inhibit gabanergic neuron which increases dopamine and increases reward pathway
- Ventral Tegmental Area –> Nucleus Accumbens
dopamine release
- opioid binds at Mu receptor
- Gi signaling inhibits neurotransmitter release
- less GABA to activate GABAa
- less inhibition of dopamine neuron activity
- increase dopamine release
- increase activation of dopamine receptors
Morphine PK
- readily absorbed - 1st pass metabolism (bioavailability 25%)
- CYP2D6 and CYP3A4
- elimination t1/2 increased with liver disease
CYP3A4 makes opioids starting with ____
NOR
CYP2D6 Metabolizers
- UM: ultra-rapid metabolizers will activate morphine at a quicker rate, so will have higher concentrations when given codeine
- PM: poor metabolizers won’t be able to convert codeine to its active form of morphine so will have no effect from codeine
tramadol
- mild opiate analgesic
- has SNRI properties
- increases NE and 5HT which then influences descending pathways of pain and can regulate pain
Meperidine
- used to treat rigors (shivering)
- has toxic metabolite (normeperidine)
- renally excreted so dangerous in patients with decreased renal function
not recommended without good justification
Methadone
- primarily used for opioid dependence
- QTc prolongation
- NMDA antagonist
- used for chronic pain
Methadone (full agonist)
- full Mu opioid receptor agonist
- relief from withdrawal
- slow acting (reduced risk of ‘high’ to deter overall opioid use)
- accumulates with repeated dose
- NMDA antagonist
Buprenorphine (partial agonist)
- Mu opioid receptor partial agonist
- blocks full agonist effect of drugs like heroine or oxycodone
- provides some activation to help with withdrawal
- abuse potential with Subutex
Naltrexone (agonist)
- IM injection monthly or PO daily
- decent oral bioavailability
- will cause withdrawal
- used later in treatment when withdrawal is not a concern, patient should be drug free for 1 month
- blocks high and reinforcement
Naloxone
- IV or intranasal
- treat overdose (antidote)
- short half-life, rapid onset
classifying pain (acute, chronic, malignant)
- acute: <3 months
- chronic: >3 months
- malignant: mixed tissue and nerve
stepwise treatment approach for non-malignant pain
1- non opioid and adjunctive if needed
2- opioid for mild-moderate pain + non-opioid plus adjuvant analgesic if needed
3- opioid for moderate-severe pain + non-opioid plus adjuvant analgesic if needed
Non-opioid analgesics
non-opioids: acetaminophen, NSAIDS
adjuvant therapies: gabapentinoids, SNRIs, TCAs, skeletal muscle relaxants, antiepileptics, topical agents
acetaminophen (tylenol)
- tablet, capsule, chewable, liquid, IV solution, suppository
- 4g/day max
- peds: 10-15 mg/kg q4h max is 75 mg in day
- gold standard for osteoarthritis
NSAIDS
- analgesic, anti pyretic, anti-inflammatory
- SE: GI bleed, nephrotoxicity, fluid retention, increase CV events
- take with food, caution in geriatric pts, avoid systemic NSAIDs with cardiac history, avoid in liver disease and CKD
aspirin
- capsule, tablet, chewable, suppository
- avoid in pediatrics bc Reye’s syndroms
- avoid in blood thinners or antiplatelet use
ibuprofen
- capsule, tablet, chewable, suspension, IV solution
- max is 3200 mg/day
- pediatrics: 5-10mg/kg q4-6h, max is 2400mg/day
diclofenac
- capsule, tablet, IV, suppository, topical, opthalmic, patch
- 50mg PO q8h or 2-4 g applied QID
naproxen
- capsule, tablet, suspension
- 220-500 mg PO q6-12h
ketorolac (toradol)
- tablet, IV/IM, nasal spray, opthalmic solution
- max duration is 5 days – increased risk of GI bleeding
celecoxib
- capsule, oral solution
- 200mg PO BID
- cox 2 selective, so less GI toxicity
gabapentinoids: gabapentin (neurontin) and pregabalin (lyrica)
- uses: fibromyalgia, neuropathies, post-op pain
- tablet, capsule, liquid solutions
- gabapentin dosing: 100-300 mg PO TID (max 3600mg/day)
- pregabalin dosing: 75mg PO BID (max 600 mg/day)
- SE: sedation, dizziness, peripheral edema
SNRIs for adjunctive therapy for pain
- venlafaxine & duloxetine
- fibromyalgia and neuropathy
- capsule and tablet
- SE: headache, nausea, hypertension, sedation, weakness
- start low dose and titrate up to minimize SE
- renally dose adjust venlafaxine and if CrCL is <30 avoid duloxetine
TCAs for adjunctive therapy for pain
- amitriptyline, nortriptyline
- off label uses: fibromyalgia, neuropathy, migraine prophylaxis
- tablet, capsule, oral solution
- anti-cholinergic SE, sedation
- last line option due to side effects
carbamazepine (tegretol)
- neuropathic pain
- tablet, capsule, chewable, suspension
Geriatrics
- avoid chronic use of non cox 2 selective NSAIDs
- indomethacin has most risk
- avoid muscle relaxants (carisoprodol, cyclobenzaprine, methocarbamol)
- use SNRIs, TCAs, and carbamazepine with caution
- avoid opioids and benzos together
- avoid opioids and gabapentin/pregabalin
- avoid anticholinergics (TCA or muscle relaxant and another anticholinergic medication
- avoid concurrent use of 3 or more CNS active agents
pain medications that can be used in elderly to minimize side effects
- acetaminophen
- topical agents
- SNRIs
- gabapentinoids
opioid overdose signs and symptoms
- sedation
- pinpoint pupils
- bradycardia
- decreased respiratory rate
- hypotension
- pale, clammy skin
signs and symptoms of opioid withdrawal
- insomnia/aggitation
- dilated pupils
- increased respiratory rate
- tachycardia
- hypertension
- sweating
opioid withdrawal treatment
- clonidine - helps with symptoms of withdrawal such as HTN, sweating, vomiting, anxiety
- buprenorphine
- methadone
opioid antagonist
naloxone
opioid weak agonist
- codeine
- tramadol
opioid full agonist
- morphine
- hydrocodone
- hydromorphone
- oxycodone
- meperidine
- fentanyl
- methadone
opioids
- use: acute and chronic pain
- SE: antitussive, constipation, N/V, itching, orthostatic hypotension, urinary retention, sedation, respiratory depression
- consider starting stool softener or stimulant laxative
- potential for tolerance, dependence, addiction
codeine
- tablet, cough syrup
- metabolized by 2D6
- poor metabolizers will get no effect from codeine
- ultrarapid metabolizers can experience overdose
- not recommended for breastfeeding mothers or children < 12
tramadol
- capsule, tablet, oral solution
- one of the weaker opioids
- risk of serotonin syndrome when used with other serotonergic meds
- renally dose adjusted
- 3A4 and 2D6
morphine
- capsule, tablet, oral solution, injection, suppository
- itching more prominent compared to other opioids
- avoid alcohol with ER capsules bc can overdose
hydromorphone (dilaudid)
- IR and ER tablets, oral solution, solution for injection, supposityry
oxycodone and hydrocodone
- tablet, capsule, oral solution
- counsel abt APAP containing products
- use with 3A4 inhibitors increase oxycodone concentrations
fentanyl (duragesic)
- buccal tablet, SL, lozenge, injectable, patch
- 3A4 substrate
- can use in renal impairment
- less hypotension than morphine or hydromorphone at similar doses
- patch only for later more stable pain
methadone (methadose)
- last line treatment for chronic pain
- opioid detoxification
- QTc prolongation
- 3A4 substrate
meperidine (demerol)
- not really used bc SE
- avoid in elderly
- 3A4
- do not use within 14 days of MAOi
tramadol SE (bc serotonergic activity)
- can lower seizure threshold
- cause serotonin syndrome when used with other serotonergic agents
- check if pt has history of seizures, and if so prob done use tramadol
CDC recommendations
- maximize non-opioids first
- start with IR opioid when starting one
- lowest effective dose for opioid naive
- carefully weight risk/benefit and care when changing dosage
- prescribe no greater quantity than needed for expected duration of pain
- follow up and evaluate risk/benefit in 1-4 weeks
- offer naloxone and strategies to mitigate risk
- review if pt has other opioid scripts and risk for overdose
- consider toxicology testing
- caution when prescribing opioid with BZDs or other CNS depressants
- detoxification on its own is not recommended for opioid use disorder because increased risks
reducing/tapering opioids
- decrease by 10% per week if on opioid less than 1 year
- decrease by 10% per month if greater than 1 year
