Lecture one (Pain)-Exam 1 Flashcards
What is the definition of pain (both for american academy of pain medicine and margo mccaffery)?
- “An unpleasant sensation and emotional response to that sensation”-AAPM
- “Pain is whatever the person says it is, existing when and where the person says it does”-Margo
What is transduction?
Process that converts a pain stimulus to biologic signal
Transduction
- What are the different tissue injuries?
- What does these tissue injuries cause?
Tissue injury
* Mechanical – pinch, stab
* Thermal - burn
* Chemical – strong acid
Inflammatory response releases chemicals that stimulate sensory nerve fibers
* Prostaglandins
* Histamine
* Cytokines
* Bradykinins
What is transmission?
pain action potential from site of injury to cortex of brain
Ascending tract:
* Which horn?
* What happens in the ascending tract?
* Order neurons?
- Dorsal horn of spinal cord
- Stimulated sensory nerve fibers send impulse / action potential to the spinal cord
- 1st, 2nd, 3rd order neurons
What are the first order neuron?
Site of stimulus to dorsal horn of spinal cord
What is the second order neuron
Dorsal horn of spinal cord -> through brainstem -> to thalamus
* Crosses to opposite side of spinal cord
* Travels through spinothalamic tract (pain track)
Right hand injury=left side of brain is processing it
What is 3rd order neuron?
- Thalamus to cerebral cortex
- Region of cortex stimulated correlates to site of injury
- Opposite side stimulated
Impulse transmitted primarily by what two nerve fiber types?
- A-delta – thin, poorly myelinated, fast, sharp, stabbing, localized
- C – thin, unmyelinated, slow, dull, aching
What are the primary NTs of pain? What is it stimulated by?
Primary neurotransmitters of pain – stimulated by chemicals released during pain response
* Glutamate
* Substance P
Explain the whole process of transmission
What is perception?
Consciously perceiving pain and its characteristics
* Location
* Intensity
* Type
What does perception stimulate and result in?
- Stimulates emotional response
- Results in response
Where is perception processed in the brain?
Somatosensory cortex: different regions correspond to different parts of the body
What is modulation?
How the pain signal is altered by the descending pathway
Explain how pain signal is altered by the descending pathway?
- Descending modulatory fibers generally help to inhibit pain signals
- Noradrenaline/serotonin primary neurotransmitters
- Control (inhibit) communication between the 1st and 2nd order neuron
MODULATION
What are the effects of epinephrine and 5-HT?
Inhibit release of substance P and glutamate from presynaptic vesicles
Stimulate interneuron responsible for releasing endogenous opioids (enkephalin)
* Inhibits release of substance P and glutamate from presynaptic vesicles
* Inhibits postsynaptic neuron from depolarizing
What is nociceptive and neuropathic pain?
Nociceptive: caused by an injury to body tissues
* e.g., post-op, trauma, procedural pain
Neuropathic: caused by damage to or dysfunction of nerves
* e.g., neuropathies, post herpetic neuralgia, phantom limb pain
may be a combination
What is psychogenic pain?
psychologic factors such as headaches or abdominal pain caused by emotional, psychological, or behavioral factors
- What is break through pain?
- What are the three different types?
Break through – pain that occurs scheduled pain medications
* Spontaneous: no identifying factor -> give PRN medication
* Incident: after some stimulus -> give PRN medication
* End of dose: increase dose or frequency of scheduled medication
What are the two subtypes of nociceptive pain? What does this type of pain respond well to?
What are the two subtypes of neuropathic pain? What does this type of pain respond well to?
What is acute pain? (how long and associated with what)
- Of short duration; self-limited (< 3 months)
- Often associated with objective physical signs
Chronic pain:
* length?
* may begin as what?
* what is the cause?
* S/S?
- > 3 months
- May begin as acute pain but continues or recurs over a prolonged period
- Cause often unknown
- Does not look like in pain
What are non-pharmacotherapy treatments?
- Heat / cold
- Massage
- Acupuncture
- Physical therapy
- Stretching / yoga
- Exercise
- Hypnosis
- Biofeedback
What are the first line nonopioid analgesics?
acetaminophen and NSAIDs
Acetaminphen and NSAIDs
* What level of pain do these work for?
* Severe what?
* _ sparing?
* First line for what?
* What are the two dosages?
* What effect is there?
Explain the mechanism of action of NSAIDs to get the two final enzymes
- Phospholipase A2 released in response to inflammation
- Converts phospholipids into arachidonic acid
- Arachidonic acid is a substrate for two enzymes: 5-lipoxygenase (5-LOX) and Cyclooxygenase (COX-1 and COX-2)
NSAID MECHANISM OF ACTION
COX-1:
* Is the enzyme around all the time or needs to be activated?
* What are two eicosanoids are released? What are their actions?
- COX-1 is alaways circulating and active
- Release Thromboxane which promotes platelet aggregation
- Release prostaglandins and prostacyclins which secretes protective gastric mucosa and maintains renal blood flow (vasodilation)
COX-2:
* Is the enzyme around all the time or needs to be activated?
* What does it mediate?
- COX-2 activated at sites of inflammation
- Mediates inflammation, pain, and fever
What does NSAIDs block? What does this reduce?
NSAIDs block COX-1 and COX-2
* Reduce prostaglandin, thromboxane, prostacyclin synthesis
* Reduce inflammation, pain, and fever
What are the two NSAID classification?
Irreversible COX inhibitors (cannot reverse effects on platelets)
* Aspirin
Reversible COX inhibitors
* Non-selective: Inhibit COX-1 and COX-2
* Selective: Inhibit COX-2
What are the examples of cox1 selective, non-selective and cox-2 selective?
What is the most common adverse effect of NSAID? Explain why this happens
- MC adverse effect = gastric ulcers
- This is because of the inhibition of prostaglandins and prostacyclin which decrease GI mucous production, decreases GI blood flow that leads to Ulcer formation
- This is more common with COX-1 inhibition NSAIDs
What are other GI adverse effects of NSAIDs?
- Dyspepsia
- Abdominal pain
- Nausea / vomiting
NSAID adverse effects
- What is the effects of NSAIDS on blood?
- What drugs have the stongest effect on blood?
Increased bleeding risk
* Due to inhibition of thromboxane which decrease in platelet aggregation
Strongest effect with:
* Aspirin – irreversible inhibition
* Increased COX-1 selectivity
- What are the effects of NSAIDs on clotting and cardiovascular events? Explain the reason why
- What drug is this more common with?
- Increased clotting risk and cardiovascular events
- MC with increased COX-2 selectivity
- Less COX-1 inhibition = less inhibition of thromboxane A2
- More COX-2 inhibition = more vasoconstriction (dt decrease prostacyclin)
What are the effects of NSAIDs on the kidneys? Explain the reason why
Kidney effects
* NSAIDs inhibit prostaglandins -> VASOCONSTRICTION
Causes Decrease renal blood flow
* Kidneys think blood pressure is low and retain fluid -> increase blood pressure / peripheral edema
Causes increase risk of renal injury
* Effect more pronounced with underlying decrease in renal perfusion
What is the effects on skin with NSAIDs?
Rash – hypersensitivity reactions rare / cross sensitivity
What are the different black box warnings for NSAIDs?
- What are the contraindications for NSAIDs?
- What are pregnancy consideration?
Contraindications:
* Aspirin allergy – watch for patients with Samter’s triad
* Peptic ulcer. GI bleed or perforation
* Advanced renal impairment
* Cerebrovascular bleeding
Pregnancy Considerations
* Avoid if possible; especially in first and third trimesters
Ketorolac:
* More or less potent?
* What is this drug used for management?
* What is not recommend?
- More potent
- Short-term management of moderate to severe acute pain requiring opioid-level analgesia
- Do not recommend use of oral product for home use
- What is important about the dosage of ketorolac?
- What are the contraindications of ketorolac?
Warning
* Do not exceed 5 days combined (inj + tabs) therapy
Contraindications
* Hypovolemia
* Incomplete hemostasis
* Bleeding disorders or high risk of bleeding
* Concomitant epidural or intrathecal injections
What is ketorolac Recommended for? What are the SE?
- Recommended for after surgery
- SE: GI bleeds+kidney damage
How does acetaminophen work? (MOA)
Inhibits COX-1 and COX-2 in the central
nervous system
What are the effects of acetaminophen on the body?
- Decreases pain and fever
- No anti-inflammatory effects because it does not inhibit peripheral COX receptors
- No effects on platelets
When is acetaminophen preferred?
- Bleeding disorders
- Peptic ulcer disease
- Cardiovascular disease
- NSAID allergy
- Children < 6 months of age
What is the adult dosing for acetaminophine
650mg to 1000 mg every 4 to 6 hrs
Acetaminophen
What are the max daily doses for short term, elderly or debiliated, chronic use or alcohol intake?
- Short term (≤10 days): 4 grams/day
- Elderly or debilitated: 3 grams/day
- Chronic use: 3 grams/day
- Alcohol intake ≥ 2 ounces daily: 2.5 grams/day
What are the children dosages?
12.5 to 15 mg/kg/dose every 4 to 6 hours (Max 5 doses daily – 75 mg/kg/day)
What are the dosage forms of acetaminophen?
- Tablets / capsules
- Oral suspension
- Suppositories
- Intravenous-> cannot use on the reg sicne so expensive
Acetaminphen
What are the adverse drug reaction? What are contraindications?
Explain why acetaminophen can be liver toxic
For normal elimination acetaminophen is conjugated to glucuronide or sulfate. When the conjugation hits Vmax, P450 will be used to eliminate the med which turns into NAPQI (TOXIC TO LIVER)
What is the antidote for acetaminophen?
NAC = N-aceylcysteine
What is the MOA of opioids presyn and postsyn?
What type of pain is opioids used for? What receptors does the drug bind to?
- Moderate to severe pain
- Bind to mu, kappa, and delta receptors – in brain, spinal cord, gastrointestinal tract
What are the 4 classes that opiods can be Classified in?
- Full agonist – bind completely to opioid receptors; full response with no ceiling effect
- Partial agonist – bind completely to opioid receptors; partial response with ceiling effect
- Mixed agonist / antagonist: Stimulate one receptor / inhibit another
- Antagonist
What opioid receptor is the most important and is responsible for most of the effects?
Mu!
What opioids are in the natural class?
Codeine and morphine
What opioids are semi-synthetic?
- Hydrocodone
- Oxycodone
-
Hydromorphone
Oxymorphone
Agonist/antagonists
* Butorphanol
* Nalbuphine
Partial agonist
* Buprenorphine
Antagonists
* Naloxone
* Naltrexone
Pay closer attention to highlighted!!!
What opioids are synthetic?
Phenylpiperidines
* Meperidine
* Fentanyl
* Remifentanil
Diphenylpropylamines
* Methadone
* Propoxyphene
* Dextromethorphan
Complex analgesics
* Tramadol – partial agonist
pay attention to highlighted!
What opioids are endogenous?
- Enkephalin
- Endorphin
- Dynorphin
What is the most common adverse effects of opiods?
Constipation
* Most common adverse effect with chronic use
* Dose related (increase dose= increase consitpation) and tolerance rarely develops (does not get better over time when taking it)
What is unlikely to help and what does help the opioid induced consitpation?
Unlikely to respond to increased fiber intake
* Bulk-forming laxatives – psyllium / methylcellulose
* Osmotic laxatives - polyethylene glycol (MiraLAX), lactulose
* Most common^^^^
Stimulant laxative + stool softener (SS does not do anything alone)
* Senna-docusate BID
What side effect of opioids is most common with therapy initation or when increasing the dose?
Nausea and vomiting
* Peripheral and central mechanisms
For the side effect of N/V from opioids, what are non-pharmacologic and pharmacologic management?
Non-pharmacologic management:
* Reduce the dose of the opioid
* Multimodal therapy
Pharmacologic management:
* Ondansetron (Zofran)
* Glucocorticoid (dexamethasone)
* Dopamine receptor antagonist (prochlorperazine, metoclopramide)
- What is an adverse effect of opioids that can be mistaken for allergic reaction?
- What is the effect mediated by?
itchingAdverse effect, not an allergic reaction
* Mediated by histamine, prostaglandins, and serotonin
What are non-pharm and pharm managements for opioid induced itching?
Non-pharmacologic management:
* Reduce the dose of the opioid
* Multimodal therapy
Pharmacologic management:
* Antihistamines
* Morphine – histamine release by mast cells
* Low dose naloxone/naltrexone
* Risk of reversal and withdrawal
* switch classes
What are other general side effects of opioids? (7)
- Urinary retention (need to watch for this)
- Euphoria
- Bradycardia
- Respiratory depression
- Somnolence / sedation
- Dizziness / lightheadedness
- Miosis-> pin point pupils
What are contraindications of opiods?
- Significant respiratory depression
- Known or suspected GI obstruction, including paralytic ileus
What are the boxed warnings of opiods?
- Addiction, abuse, and misuse – Risk Evaluation and Mitigation Strategies (REMS)
- Life-threatening respiratory depression
- Accidental ingestion
- Risks from concomitant use with benzodiazepines or other CNS depressants
- Use only if alternative treatment options (eg, non-opioid analgesics, opioid combination products) are ineffective, not tolerated, or otherwise inadequate to provide sufficient management of pain.
- Taper dose after prolonged use
Opioids
What are the different routes of administration?
- Oral
- Intramuscular/subcutaneous
- Intravenous – intermittent / PCA § Intranasal
- Buccal / sublingual
- Rectal
- Transdermal
- Epidural – PCEA
- Intrathecal – single injection
Methadone:
* What are the receptors that are used?
* What is the drug used for?
Synthetic opioid: mu, kappa, delta agonist and N-methyl-D-aspartate (NMDA) antagonist (NMDA: responsible for neuropathic pain)
* Used primarily for treatment of chronic pain
* Potential use for treatment of neuropathic pain
Methadone:
* How is the drug metabolized?
* why is the drug variable?
* What happens during the first week of using the drug?
* How is the drug eliminated? What is the half life?
Metabolized via CYP3A4, 2D6, and 1A2
* Variable due to genetic polymorphisms and drug interactions
* Initial auto induction for first week
Eliminated exclusively in feces
* Long elimination half-life (15 to 40 hours)
Methadone:
* What is an side effect on the heart?
* What is difficult to determine?
Potential to prolong the QT interval
* ECG prior to treatment, in 30 days, annually
* Use caution with other agents that can increase the QT interval
Equianalgesic doses difficult to determine
Tramadol:
* Structurally related to who?
* What is the mechanism of action?
Structurally related to codeine
Mechanism of action:
* Central inhibition of norepinephrine and serotonin (decending pathway) reuptake and weak mu receptor agonist
tramadol:
* What does tramadol require to become active?
* Is it more or less potent than morphine?
* What type of drug is it?
- Requires metabolism by CYP2D6 to active metabolite
- 10 to 15 times less potent than morphine
- Partial agonist
Tramadol:
* What is the drug used for?
* What is the dose?
* What are the SE?
- Use: mild to moderate pain
- Dose: 50 to 100 mg PO q6h
- Less side effects compared to opioids
* Decreases seizure threshold
Out of fentanyl, morphine, oxycodone, which one has a longer half life?
oxycodone because it is orally
What is the equivalent dose?
* What is it determined by?
* What is directly proportional to the ED?
Equivalent dose - dose at which two opioids (at steady state) provide approximately the same pain relief
* Determined by opioid potency
* Directly proportional to the receptor binding affinity of the opioid
What does equivalecy charts provide?
* What is recommendations?
* Patient responses may _
Equivalency charts provide analgesic doses which approximate each other in their ability to provide pain relief
* Exact conversion recommendations vary with reference
* Patient responses may vary
What are equianalgesic dose calculations
means for selecting the appropriate initial dosing when
changing from one opioid agent or route of administration to another
Convert IV morphine 4 mg every 4 hours to PO oxycodone
Then you need to check dosage forms and adjust accordingly so oxy comes in 5mg and 15mg tables so 10 mg PO every 6 hours
Higher doses of opioids associated with what?
Higher doses of opioids associated with higher risk of overdose and death
What is MORPHINE MILLIGRAM EQUIVALENTS (MME)? Why is it important (4)?
MME: amount of morphine milligrams an opioid dose is equal to when prescribed
* Calculating MME accounts for differences in opioid drug type and strength
* MMEs are increasingly being used to indicate abuse and overdose potential
* Allows all stakeholders a single metric to compare data and compare metrics
* Helps identify high risk patients
More chronic pain situations
MORPHINE MILLIGRAM EQUIVALENTS (MME)
- What dose increases risk for overdose?
- Patients who died from opioid overdose were prescribed an average of what?
- What patietns should receive close monitory, eduction and nalonxone?
- Opioid doses > 50 MME/day->at lease 2 times increased risk for overdose
- Patients who died from opioid overdose were prescribed an average of 98 MME/day
- Patients on doses > 50 MME should receive close monitoring, extensive education, naloxone
- What are opioid antagonists?
- Agoist or antagonist stronger binding?
- Binds to opioid receptors and inhibit or reverse the effects of opioid agonists
- Stronger binding affinity at opioid receptor causes preferential binding-> will kick it off
Naloxone:
* what are the characteristics of the drug?
* What is it used for ?
* What can low doses be used for?
Naloxone – short half-life / fast onset / short duration of action (1-2 hours)
* Used for acute toxicity – respiratory depression
* Low doses can be used for urinary retention / pruritis
Naltrexone:
* What are the characteristics of the drug?
* What is the drug used for?
Naltrexone – longer half-life / longer duration of action
* Used for relapse prevention - addiction
Methylnaltrexone / alvimopan:
* What is a characteristic of the drug?
* What is it used for?
Methylnaltrexone / alvimopan – do not cross blood-brain barrier
* Used for GI side effects of opioids / postoperative ileus
What does FDA required for naloxone (narcan)?
Labels for all opioids include the recommendation that care providers discuss availability of naloxone with all patients who are prescribed opioids
Consider co-prescribing in high-risk patients or households
* Patients who take benzodiazepines or other central nervous system depressants
* Patients with a history of prior opioid overdose
* Patients with household members at risk for accidental ingestion
Naloxone (narcan):
* Naloxone prescription recommended for who?
* What about some states? (2)
* Some states require what?
- Naloxone prescription recommended for patients with daily opioid dose > 50 MME
- Required in some states for all opioid prescriptions (Florida)
- Required in some states for opioid doses > 90 MME
- Some states require opioid prescribers to provide education on overdose prevention, including use of naloxone
What is used for chronic or neuropathic pain/fibromyalgia?
Antidepressants
* Serotonin norepinephrine reuptake inhibitors (SNRI)
* Selective serotonin reuptake inhibitors (SSRI)
* Tricyclic antidepressants (TCA)
Anticonvulsants
* Gabapentin
* Pregabalin
Topical
* Lidocaine 4 / 5% patch
Other
* Muscle relaxers / steroids
How does antidepressants like SNRIs and SSRIs?
Inhibit reuptake of norepinephrine and serotonin – prolonging duration in synapse
* Increases the release of endogenous opioids
Block sodium channels at local post synaptic neurons
* Stops depolarization and signal transduction
What are examples of SNRIs?
- Duloxetine (Cymbalta)
- Venlafaxine (Effexor)
SSRIs:
* Characteristics?
* Better SE profile than _
- SSRI fewer side effects but less effective, often ineffective in treating chronic pain
- Better side effect profile than TCAs
ANALGESIC ANTIDEPRESSANTS: TCA
* MOA?
* What are tertiary amines? SE and effiacty compared to secondary amines?
Mechanism – like SNRIs and SSRIs
* Also block calcium channels – stops release of presynaptic neurotransmitters
Tertiary amines: Norepinephrine and serotonin
* Increased efficacy compared to secondary amines with increased side effects
* Examples: Imipramine and Amitriptyline
What are the secondary amines?
norepinephrine > serotonin
* Nortriptyline
* Desipramine
What is the SE profile of TCAs?
Cardiovascular effects
* Tachycardia, heart block, orthostasis
* Prolonged QT interval – baseline / periodic EKG
Anticholinergic properties – postural hypotension, sedation
* Problematic in elderly patients
Antieplieptics:
* What is the MOA?
* What are the two examples of drugs with their dosages?
TOPICAL AGENTS: lidocaine
* How does this drug work?
* What are different forms of the drug?
Block ascending pain pathways to the brain
* Blocks voltage-gated sodium channels in the cell membrane
* No depolarization, no pain signal
Creams / gel / patches
* 4 or 5%
* Directions vary by produc
topical agents: Capsaicin
* How does the drug work?
* What does it results?
* What is prolonged exposure?
* When is pain decreased?
* What form is it in?
Binds to TRPV1 receptors located on A-delta and C-nerve fibers
* Results in release of substance P and nerve depolarization
* Prolonged exposure = depletion of substance P, desensitization of nerve, and reversible nerve degeneration
30 to 50% pain reduction at 12-weeks
8% cream
Fill in the neuropathic pain pathway
What is the first and second general principles of figuring out what drug to use? (Source WHO)
Oral administration of analgesics.
* The oral form of medication should be utilized whenever possible.
Analgesics should be given at regular intervals.
* Have a base in place
* Adjust dose based on pain level
* PRN may be appropriate for mild intermittent pain
What is the third and fourth general principles of figuring out what drug to use? (Source WHO)
Analgesics should be prescribed according to pain intensity as evaluated by a scale of intensity of pain.
* Evaluate your patient first!
* Caution with just using pain scales
* Treat the patient’s pain – not your perception of their pain
Dosing of pain medication should be adapted to the individual.
* There is no standardized dosage -every patient responds differently
* Correct dosage = allow adequate relief of pain
* Balance pain control with side effects
What is the fifth general principle of figuring out what drug to use? (Source WHO)
Analgesics should be prescribed with a constant concern for detail.
* Compliance is key
* Provide a written plan
What are the functional goals of drugs?
What is the chart that addresses how to approach pain?
- Originally proposed by theWHO in the 1980s
- Indicated for the treatment of nociceptive and neuropathic pain (cannot use for only neuropathic pain)
- Two-way ladder allows for escalation or de-escalation
- Newest edition is step 4
Explain the pyramid for multimodal therapy
Mild pain
* What is mild pain?
* When is it expected?
* What drugs should you use?
- Nagging, annoying – does not interfere with activities of daily living (ADLs)
- Expected after sprains, nonspecific low back pain, dental extraction, and headaches
- Opioids NOT indicated
- Drugs of choice:
* Acetaminophen
* NSAIDs: Musculoskeletal pain and Dental pain
* Combination
- What is moderate pain?
- What are example?
Interferes with ADLs; can be distracted if deeply concentrated on a task
Examples:
* Laparoscopic and minimally invasive surgery
* Most soft tissue surgeries
* Non-compound and non-comminuted fractures
* Severe sprains
What are the choices of drugs for moderate pain?
Acetaminophen and NSAIDs
* Generally in combination if not contraindicated
Additional alternatives:
* Low dose oral opioids as needed for breakthrough pain
* Three to five-day supply should suffice
* Oxycodone
* Hydrocodone (only available in combination with acetaminophen)
* Tramadol - not recommended as first line therapy
What is severe pain and what are examples?
Disabling, unable to perform ADLs
Examples:
* Major, non-laparoscopic surgery
* Maxillofacial surgery
* Total joint replacement
* Compound and long bone fractures
* Cancer pain
What is the pain meds that are used for severe pain?
Multimodal therapy crucial
* Move if possible
* Acetaminophen / NSAIDs plus….
Opioid analgesics
* Initially parenteral – scheduled versus PCA
* Intravenous vs epidural or intrathecal
* Convert to oral ASAP
* administration frequency and/or dose reduction as tolerated
* Generally require five to seven days of oral opioids after hospital discharge
* Oxycodone
* Hydrocodone
* Morphine
* Hydromorphone
Adjuvant therapies often used
* Gabapentin / pregabalin
* SNRIs
What is patient controlled analgesia?
- Severe, intractable pain
- Oral/transdermal route not available
- Not appropriate for PCA: dementia, delirium, cognitive impairment
- Very low risk of respiratory depression
- Lower pain scores; higher pt satisfaction
What are the important key concepts she had on her slide?
FLORIDA-HB 21 FROM FLORIDA:
* Florida Legislature placed limits on what?
* A prescription for a Schedule II opioid for the treatment of acute pain may not exceed what?
* Why might The legislation does allow a seven-day supply to be prescribed?
* Why might the legislation allow a 30-day to be prescribed if?
