Exam 2: Acute Pain & Opioid-Free Analgesia Flashcards
What types of somatic pain are there?
- Superficial: skin, SQ, mucous membranes
- Deep: muscles, bones, tendons
S4
Examples are knife cut to finger or a deeper pain like extremity injury jumping from a burning building
What types of visceral pain are there?
- Parietal: sharp, stabbing, localized organ pain.
- Referred: Cutaneous pain from embryological development patterns and convergence of visceral and somatic afferent input to CNS.
S4
expanding bowel gas from injesting certain food. Parietal would be appendicits. Referred would be L shoulder pain from an MI
Is chronic nociceptive pain or neuropathic pain more abnormal?
Neuropathic pain
S7
Red flags for pain
- Constitutional symptoms
- Pain that wakes patient up from sleep
- Immunosuppression
- Severe or progressive neurologic deficit
- Cold, pale mottled or cyanotic limb
- New bowel/bladder dysfunction
- Severe abdominal pain or signs of shock/peritonitis (bc there is so many different things in the abd and its hard to isolate the pain source)
S10
What are some possible cardiac consequences of poorly managed or acute pain?
↑ HR
↑ BP
↑ Cardiac workload
S11
What are some possible respiratory consequences of poorly managed or acute pain?
- Splinting (resp muscle spasm)
- ↓ VC
- Atelectasis
- Hypoxia
- Pulmonary infection risk
S11
What are some gastrointestinal consequences of poorly managed pain?
Ileus
S11
What are some possible renal consequences of poorly managed pain?
- Oliguria
- Urine retention
S11
What are some possible coagulative consequences of poorly managed pain?
↑ clot risk
S11
What are some possible immunologic consequences of poorly managed pain?
Immunosuppression
S11
What are some possible musculoskeletal consequences of poorly managed pain?
- Fatigue & weakness
- Limited mobility = clotting
S11
What is the Specificity Theory?
Who came up with it?
Intensity of pain is directly related to the tissue injury - Rene Descartes
Pain is a specific sensation with its own sensory apparatus independent of touch and other senses
S12
What theory linked pain and emotion?
Intensity Theory (Plato)
Plato defined pain as an emotional experience, rather than a sensory one.
S13
What is the Gate Control theory of pain?
- proposed by Ronald Melzack and Patric Wall
- According to the Gate Control Theory, pain transmission is modulated by a balance of impulses transmitted to the spinal cord and these fibers terminate and inhibitory interneurons in the Substantia Gelatinosa and the cells in this area functions as a gate regulating transmission of impulses to the central nervous system
S14
Where is pain attenuated in the CNS according to gate theory?
Substantia Gelatinosa of the spinal cord
S14
Thermal, mechanical and chemical tissue damage activates nociceptors, which are____?
Free afferent nerve endings of myelinated A-delta and unmylenated C fibers
S15
What chemicals are released upon tissue injury that mediate pain?
- Histamine
- Bradykinin (peptide)
- Prostaglandins (lipids)
- Neurotransmitters like Serotonin
S15
Give an example of first order neurons.
Aδ and C (sensory free nerve endings)
S16
Where do first order Aδ and C fibers synapse at?
Dorsal Root of the spinal cord
S17
Where do second order neurons synapse at?
Crosses lamina X, ascend the spinothalamic tract and synapse at the Thalamus
S18
Where do the third order neurons project to?
Third Order neurons from the thalamus projects through the internal capsule and to the postcentral gyrus of the cerebral cortex
S19
What is the name of the process by which noxious stimuli are converted to action potentials?
Transduction
S21
What is the name of the process by which an action potential is conducted through the nervous system?
Transmission
S21
What is the name of the process by which pain transmission is altered along its afferent pathway?
Modulation
S21
What is the name of the process by which painful input is integrated in the somatosensory and limbic cortices of the brain?
Perception
S21
What is Allodynia?
Allodynia is a pain from a stimulus that does not normally evoke pain (thermal or mechanical)
S22
Hyperalgesia is the process by which tissue trauma releases ____ that produced augmented sensitivity to stimuli.
local inflammatory mediators
hyperalgesia is an exaggerated response to a normally small amount of painful stimuli
S22-23
What is primary hyperalgesia?
Augmented sensitivity to painful response.
or
Allodynia-style misinterpretation of non-painful stimuli.
S23
Primary hyperalgesia is caused by a combination of peripheral and central sensitization, while secondary hyperalgesia is primarily caused by central sensitization
What is secondary hyperalgesia?
Increased neuronal excitability due to glutamate activation of NMDA receptors.
S23
Primary hyperalgesia is caused by a combination of peripheral and central sensitization, while secondary hyperalgesia is primarily caused by central sensitization
What opioid will potentiate hyperalgesia?
Remifentanil
S23
What is the treatment for hyperalgesia that was mentioned in lecture?
Ketamine
Lecture S23
Differentiate Hyperalgesia and Allodynia.
In chart form.
What is the hallmark “negative” symptom of neuropathy?
numbness
The paradoxical part is that nerve trauma and disease are also frequently associated with positive signs and symptoms
S25
GI blood flow and motility increase as we age. T/F?
False.
S27
Gastric acid secretion ____ as we age thus ____ gastric pH.
Gastric acid secretion decreases ‐ elevated gastric pH
S27
What effect does aging have on nutrient absorption in the GI tract?
Minimal effect but pts have increased complaints about their GI symptoms
S27
What occurs to muscle and fat mass as a patient ages?
Muscle decreases while fat proportion increases
S29
Dr. M slide says fat also decreases and thats why we can’t thermoregulate - this one is the ratios (not contradictory)
A decrease in ____ and ____ affects your protein-bound drugs in aging.
decrease in total body water (for water soluble drugs) and
albumin for protein bound drugs
S29
What occurs with hepatic function in the aging patient?
- ↓ hepatic blood flow
- ↓ liver mass and metabolic activity
S30
What occurs with renal function due to aging?
- ↓ GFR
- ↓ blood flow, kidney mass & functioning nephrons
S31
WHO steps for the pain relief ladder
- pain persisting or increasing = non-opioid pain management (NSAIDS, heat/cold, movement/positioning)
- pain persisting or increasing = opioid for mild to moderate pain + non-opioid
- Relief from pain = opioid for moderate to severe pain + non-opioid
S32
hit multiple receptors
Regaurdless of pain level, always use non-opiods +/- narcs
Do opioids or non-opioids act peripherally?
Non-opioids act peripherally, opioids act centrally and contribute to sedation effects
S33 (table comparing narcotics and non-narcotics)
Do opioids or non-opioids have anti-inflammatory effects?
most non-opioids have anti-inflammatory effects
S33
Do opioids or non-opioid analgesics exhibit a ceiling effect?
Non-opioid analgesics
S33 (table comparing narcotics and non-narcotics)
The μ receptor is responsible for…
analgesia, respiratory depression, euphoria, and reduced GI motility
GEAR
S34
The Kappa receptor is responsible for….
Analgesia, dysphoria, psychosis, miosis, and respiratory depression
DR. MAP
S34
The Delta receptor is responsible for…
analgesia alone when bound by an agonist
S34
4 Characteristics all opioids share
- Derived from opium
- bind to opioid receptors (mu1, mu2, K and D)
- Act directly on the CNS
- reduce the perception of pain, they don’t treat the cause
S35
What drug is described by the following organic structure:
Substitution of methyl group for hydroxyl group on #3 carbon of morphine molecule.
- what is it’s scientific name?
- What is/are the trade names?
Codeine
- 3-Methoxymorphine
- Tylenol #3 and Tylenol #4
S39
____ is much more reliably absorbed than morphine.
Codeine
S39
How is codeine metabolized?
CYP2D6
- 10% of the dose is demethylated in the liver to morphine
- remainder is demethylated to inactive norcodeine
10% of the population is resistant to its analgesic effect
S40
What drug exhibits side effects (without concurrent analgesia) in children?
Why is this?
Codeine
Children lack enzymatic maturity needed to properly break down codeine.
S40
Codeine metabolism is variable due to more than ____ polymorphisms resulting in analgesic variability.
50
S40
What is the adult dose and max of codeine?
15 - 60 mg q4
360mg max per day
S41
Corn says: Tylenol #3=30mg
Tylenol #4 = 60mg
What is the pediatric dose and max of codeine?
0.5 - 1 mg/kg/dose
60mg max per day
S41
60mg of codeine (maximal dose) is equivalent to how much aspirin?
and how long is its ET1/2?
650mg
3-3.5 hours
S41
What drugs does codeine have interactions with?
Opioids, EtOH, and Anticholinergics
S42
What drug is described by the following:
Synthetic 4-phenylpiperidine analogue of morphine and codeine which is composed of a racemic mixture of two enantiomets + and -
Tramadol
S43
Where does the + enantiomer of tramadol have affinity and what does it do?
Centrally acting opioid agonist:
- μ → moderate affinity
- K & δ → weak affinity
- Opposes serotonin reuptake
S43
What does the - entantiomer of tramadol do?
- Inhibits NE reuptake
- Stimulates α2 receptors
S43
Dexmetatomadine will be potentiated
What is tramadol metabolized into and what is the relevance of its metabolite?
Tramadol → CYP3A4 & 2D6 → O-desmethyltramadol (2-4 times more potent)
S44
What is tramadol’s potency compared to morphine?
1/5 to 1/10 potency of morphine
S45
What is the oral onset for tramadol?
1-2 hours
S45
What is the half life of tramadol?
6.3 hours (7.4 hoursfor metabolite)
S45
When is tramadol contraindicated?
- Seizure Disorders
- PONV (high incidence)
S46
What are the benefits of tramadol vs other opioids?
- Minimal respiratory depression
- Minimal-none addiction
- Minimal constipation
S46
Oral morphine dose requirement is ____ times the IM or IV route.
3
S47
What receptors are primary affected by morphine?
μ-1 and μ-2
S47
What are the two principle active metabolites of morphine? (also list effects)
- Morphine-6-glucuronide → analgesia
- Morphine-3-glucuronide → neurotoxicity & hyperalgesia
S48
How is morphine metabolized?
- Hepatic → conjugation w/ glucuronic acid
- Extrahepatic = Kidneys
S48
What 3 factors contribute to morphine’s minimal CNS absorption?
- poor lipid solubility
- high protein binding
- high Ionization at normal bodily pH
S48
What is the IV/IM onset and peak of action for morphine?
Onset: 15-30 min
Peak: 45-90 min
S49
What differences does morphine exhibit in women vs men?
In women:
↑ potency
↓ speed of offset
S49
What is the protein binding of morphine?
What about the half-time?
35% protein binding
1.7 - 3.3 hours
S49
What is released from morphine administration?
What is the result?
Histamine → vasodilation and hypotension
S50
Morphine should be avoided in patients with ____ impairment as the metabolite morphine–6-glucuronide can accumulate and lead to _________ ________.
Renal : respiratory depression
S50
What drug is a synthetic derivative of thebaine?
Oxycodone
S51
What are the metabolites of oxycodone?
Oxymorphone (active)
Noroxycodone (inactive)
Oxycodone is primary a prodrug.
S52
What is the site of action of oxycodone?
μ and κ receptors of the CNS
S52
What are the two types of PO oxycodone?
IR = Immediate release
CR = Controlled release
S51
What is the dose of oxycodone? and what is the morphine equlvalent?
Dose: 5mg PO
10 - 15mg is equilvalent to 10mg morphine (rough 1 to 1 equivalence with morphine)
S53 (dose comes from S88)
What is the onset of action of oxycodone?
< 1 hour
S53
Opioids (in general) exhibit an ____ effect with other drugs that are CNS depressants
additive
S54
Why is methadone used for opioid addiction maintenance?
is it synthetic or natural?
- 60-90% oral bioavailability
- High potency
- Long duration of action
- Synthetic borad-spectrum
S55
What should be known about methadone’s half life?
Very long and unpredictable ET1/2 (up to 36 hours)
Can accumulate w/ repeated doses
S55
What various receptors affinities does methadone have?
- Weak noncompetitive NMDA antagonist
- Serotonin reuptake inhibitor
- Monoamine reuptake inhibitor
- High μ receptor affinity
S55
What would occur with concurrent methadone and carbamazepine use?
Carbamazepine (Tegretol) is a CYP450 inducer thus methadone will be metabolized faster.
S56
What agents can decrease the metabolism of methadone?
CYP450 Inhibitor:
- Antiretrovirals
- Grapefruit juice
S56
How much is methadone clearance affected by hepatic and renal impairment?
Not much
* Excreted in urine and bile with small amounts of unchanged drug
S56
What is the dose of methadone?
2.5 - 10 mg PO/IM/SC q4-12 hours
S57
Why are standardized simple dosing guidelines unachievable for methadone?
High variable half life (8-80 hours)
S57
What is the most severe and unpredictable medication interaction associated with methadone?
MAOI’s
S58
What drugs are known to increase the concentration/effects of methadone?
- Cipro
- Diazepam
- Acute EtOH use
S58
What drugs are known to decrease concentration/effects of methadone?
- Amprenavir
- Phenobarbital
- Phenytoin
- Rifampin
- MAOI’s
S58
What cardiac complications can occur in rare cases with methadone usage?
- Pause dependent dysrhythmia associated with bradycardia
- QT prolongation
- Torsades
S58
What drug is fentanyl structurally similar to?
Meperidine
Fentanyl is a Phenylpiperidine-derivative synthetic opioid agonist
S59
Fentanyl has ____ potency, ____ onset of action and ____ duration of action.
High potency
Rapid onset
Short duration
S59
What is the priniciple metabolite of fentanyl?
Norfentanyl
Detectable in urine up to 72 hours after single dose.
S60
Why is elimination of fentanyl slightly prolonged despite very short duration of action?
Lungs serve as large inactive reservoir (up to 75% of initial dose undergoes first pass pulmonary uptake).
S61
Why is fentanyl more potent and rapid than morphine?
Greater lipid solubility
S61
What is responsible for fentanyl’s short duration of action?
Rapid redistribution to fat and muscle
S61
What is the protein binding of fentanyl? what is it’s ET1/2?
84%
3.1-6.6 hours
S61
What is hydromorphone and how is it formed?
semi-synthetic agent and hydrogenated ketone of morphine formed by N-demethylation of hydrocodone
- Dilaudid is hydrophilic but it is also 10x more lipophilic than morphine which increases its potency
S63
Hydromorphone is ____ times as potent as morphine when administered orally.
3 - 5 times
S63
Hydromorphone is ____ times as potent as morphine when administered parenterally.
8.5 times
S63
What is hydromorphone’s primary metabolite?
Hydromorphone-3-glucuronide
S64
What should be known about Hydromorphone-3-glucuronide?
- Lacks analgesic effects
- May potentiate neurotoxic effects (allodynia, myoclonus, seizures).
S64
When is Hydromorphone-3-glucuronide’s neurotoxic side effects an actual concern?
Patients with renal insufficiency
S64
What is the typical parenteral dose of parenteral Hydromorphone?
0.2-2mg Q3-5 min parenterally for post op pain
S65
What is the typical oral dose of hydromorphone?
2 - 8 mg
S65
What is the duration of action and ET1/2 of hydromorphone?
3 - 4 hours
ET1/2 if 2.3 hrs
S65
What is hydrocodone derived from?
Codeine
- semi-synthetic opioid
S67
How does the potency of hydrocodone and codeine compare?
Hydrocodone is 6 - 8 x more potent than codeine
S67
What are the two most abused opioids?
1st = Oxycodone
2ⁿᵈ = Hydrocodone
Lecture S67
What are the two metabolites of hydrocodone metabolism?
- Hydromorphone (via CYP2D6)
- Norhydrocodone (inactive) via CYP3A4 (catalyzed oxidation)
S68
What is the morphine equivalent of hydrocodone?
1 mg morphine = 3 mg hydrocodone
S69
What is typical hydrocodone dosing?
2.5 - 10mg Hydrocodone with 300 - 750mg acetaminophen
q4-6hours
S69
Hint: Same mg dosing as hydromorphone with tylenol added
What receptors does buprenorphine have affinity to?
Semi-synthetic agonist-antagonist derived from alkaloid thebaine
μ - partial agonist (strong)
κ - antagonist (strong)
δ - agonist (weak)
S71
What benefits does buprenorphine provide?
- ↓ respiratory depression
- ↓ immune suppression
- ↓ constipation
- No accumulation in renal patients
S71
What is the primary metabolite of buprenorphine?
Norbuprenorphine from CYP3A4
S72
What should be known about norbuprenorphine?
- Full agonist at Mu, Delta and ORL-1 receptors and partial agonist at Kappa
- 1/50th analgesic activity of buprenorphine
- ↑↑↑ Respiratory depression
S72
What is the IV/IM buprenorphine dose equivalence for morphine?
0.3mg IM buprenorphine = 10mg morphine
S73
What is the half life of buprenorphine?
Long
20 - 73 hours
S73
Should buprenorphine be avoided in patients with renal impairment?
No. Hepatic elimination primarily
S73
What are the differences in side effects of buprenorphine compared to other agonists-antagonists?
- may be resistant to naloxone
- pulmonary edema has been observed
- dysphoria unlikely compared to other agents
S74
What receptors do NSAIDs bind to?
Trick question. NSAIDs inhibit COX pathway as their method of pain modulation.
S78
What is the recommended dose for each NSAID:
- Ibuprofen
- Celecoxib
- Naproxen
- Diclofenac
- Ibuprofen: 200mg three times daily
- Celecoxib: 100 mg daily
- Naproxen: 220 mg twice daily
- Diclofenac: 50mg twice daily
S80
How might antidepressants work as pain medication adjuvants?
Increase transmission in spinal cord to reduce pain signaling
doesn’t work right away, dizziness, decreased appetite and dry mouth
S81
Whats the IV dose of fentanyl for pain?
20 - 50 mcg
S88
What anticonvulsants are used as adjuvant medication to relieve pain?
- Gabapentin (Neurontin): watch for sedation/ respiratory depression in older patients
- Phenytoin (Dilantin)
- Carbamazepine (Tegretol)
- Topiramate (Topamax)
S81
What skeletal muscle relaxants are used as adjuvant medication to relieve pain?
- Baclofen (Lioresal®)
- Carisoprodol (Soma®)
- Cyclobenzaprine (Flexeril®)
- Methocarbamol (Robaxin®)
- Tizanidine (Zanaflex®)
S82
What is Opioid Free Anesthesia?
- Technique where no intra-operative systemic, neuraxial, or intracavitary opioid is administered during the anesthetic.
Opioid slides S2
Opioids acting on the Mu receptor will produce these unwanted effects.
- Respiratory depression
- Decrease GI motility/ constipation
- Urinary retention
- Prurititis
- Physical dependence
Opioid free S4
Opioids acting on the Kappa receptor will produce these unwanted effects.
- Respiratory depression
- Dysphoria
Opioid Free S4
Opioids acting on the Delta receptor will produce these unwanted effects.
- Respiratory depression
- Urinary retention
- Prurititis
- Physical dependence
Opioid Free S4
In general, all opioids can cause these side effects
- Respiratory depression
- dysphoria
- N/V
- Skeletal musle rigidity
- Smooth muscle spasm
- constipation
- Urinary retention
- biliary spasm (treat with glucagon remember?)
- Pruritus
- histamine release
- Chronic: tolerance
- chronic: physical dependence
- Chronic: constipation
opioid free S5
What is opioid-induced hyperalgesia (OIH)?
- State of nociceptive sensitization caused by exposure to opioids.
- The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain might actually become more sensitive to certain painful stimuli.
Opioid free S10
Absolute and relative contraindications for using opioid free techniques
- Absolute: Allergy to any adjuvant drugs
- Relative
- Disorders of autonomic failure
- Cerebrovascular disease
- Critical coronary stenosis acute coronary ischemia
- Heart block / extreme bradycardia
- Non-stabilized pypovolemic shock or polytrauma patients
- Controlled hypotension for minimal blood loss
- Elderly patients on beta-blockers
S13
Opioid free toolbox: Ketamine (doses and highlights)
- Doses less than 0.5 mg/kg reduces postoperative analgesic needs and especially seen in opioid-tolerant patients
- It has anti-hyperalgesic and anti-allydonic and anti-tolerance effects.
- decreases PONV
S14
Opioid Free toolbox: Gabapentinoids (dosing and highlights)
- Act on alpha-2-deta-1 subunit of presynaptic calcium channels and inhibit neuronal calcium channel influx. Results in reduction in release of excitatory neurotransmitters such as glutamate, substance P and calcitonin
- Pregabalin: 225-300mg (lowest effective dose)
- Gabapentin: we see ceiling effect at 600mg (this was on last year’s test)
S15
Opioid free toolbox: IV lidocaine (dose and highlights)
- Na-channel blocker
- Analgesia: supresses nerve fiber impulses
- anti-inflammatory: neural transmission blockade
- anti-hyperalgesic: suppression of peripheral and central sensitzation
- Dose: bolus of 100mg or 1.2-2mg/kg followed by infusion 1.33-3mg/kg/hr
S16
Opioid free toolbox: magnesium (dose and highlights)
- noncompetative NMDA antagonist on glutamate receptors: decreases Ca and Na ion entry and prevents efflux of K
- prevents depolarization and transmission of pain signals: blunts somatic, autonomic and endocrine reflexes
- Dose: loading dose of 30-50mg/kg then maintance of 6-20mg/kg/hr
S17
Opioid Free toolbox: Alpha2 agonists (doses and highlights)
- both presynaptic (inhibits NE negative feedback loop) and postsynaptic activity (sympathectomy) in CNS and PNS
- activated G1-K channels causing hyperpolarization of neurons
- reduces Ca conductance at voltage gated Ca channels
- Dose for dexmetatomadine: 0.5mgc/kg loading dose over 10 min
- then 0.1-0.3 mcg/kg/hr
S18
8x more specific at the alpha2 receptor than clonadine
opioid free toolbox: beta blockers (highlights)
- Esmolol is a selective β1-adrenoreceptor antagonist that controls HR, contractility and conduction - but may also be a good opioid-sparing adjunct (reasons specifically unclear)
- One theory: Esmolol does slow heart rate; thereby it decreases cardiac output, which decreases hepatic blood flow, so this may slow metabolism of other drugs that are hepatically metabolized, such as fentanyl.
S19
