Pain Pharmacology (opioids) Flashcards
Define allodynia
Pain caused by a stimulus that does not normally provoke pain
Define analgesia
Absence of pain in response to stimulation which would normally be painful.
Define dysesthesia
Dysesthesia: An unpleasant abnormal sensation, whether spontaneous or evoked
Define Hyperalgesia
Hyperalgesia: Increased pain response to a stimulus that is normally painful
Define hyperesthesia
Hyperesthesia:Increased sensitivity to stimulation, excluding the special senses.
Define hyperpathia
Hyperpathia: Increased pain reaction to any stimulus, with increased threshold
Define paresthesia
Paresthesia: An abnormal sensation, whether spontaneous or evoked
Define hypesthesia
Hypesthesia: Decreased sensitivity to stimulation, excluding the special senses.
What is first pain and how is it transmitted?
First pain is carried by well myelinated peripheral nerve fibers that enter the dorsal horn of the spinal cord
Where are endorphins found?
From frontal/insular cortex & limbic system
- Role in descending modulation
Where is NE found?
From locus coeruleus (pons)
- Role in descending modulation
What are the main side effects of NSAIDS?
Tinnitis, renal, inhibits platelet function
What is the mechanism of action of NSAIDS?
Inhibition of prostaglandin production (anti-inflammatory) from arachadonic acid
- Reversible or irreversible acetylation of cyclooxgenase (COX- especially COX 2)
What is the mechanism of action of peripheral prostaglandins?
Contribute to hyperalgesia:
- Sensitization of nerve endings to:
- Mediators (histamine, bradykinin)
- Non-nociceptive stimuli (touch)
- Induce COX-2
What is the mechanisms of action of central prostaglandins?
Direct action at spinal cord
- Enhanced nociception at terminal sensory neurons of dorsal horn
What are the different classifications of NSAIDS?
- Carboxylic acids
- Enolic Acids
- Cox-2 inhibitors
- Analine Derivatives (ie tylenol/aceteminophen)
What are the various types of carboxylic acids?
Salicylic Acids & Esters
Acetic Acids
Propionic Acids
Antrancillic Acids
What type of NSAID is aspirin?
Aspirin is a salicylic acid. It irreversibly inactivates COX via acetylation
- Platelets cannot synthesize new COX (no nucleus) unlike other cells
- Effect lasts life of platelet = 10-14 days
Name 3 acetic acid derivatives.
- Indomethacin
- Diclofenac
- Ketorolac (Toradol)
What is the primary use of indomethacin?
Primarily used for: acute gout & osteoarthritis
- IV formulation FDA approved for closure of persistent patent ductus arterioles
- Concentration in synovial fluid is equal to plasma (within 5 hours)
What are the main side effects of indomethacin?
High incidence of side effects, requiring short term dosing
Gastritis, renal dysfunction
What is the mechanism of action of indomethacin?
More potent inhibitor of COX than aspirin
What is the mechanism of action of diclofenac?
COX-2 selectivity (similar to Celebrex)
What should be monitored in patients in diclofenac?
Hepatotoxicity should be monitored
What is the primary use of diclofenac?
Significant post-operative pain relief
- Accumulates in synovial fluid (effect is considerably longer than half life of 1-2 hrs)
What is the mechanism of action of ketorolac?
Mechanism of Action: Non-selective COX inhibitor
What is the clinical use of ketoralac?
Short-term management of pain, can be administered IV, very strong analgesic, post-surgical pain
What are the adverse drug reactions of ketoralac?
- Use must be limited to less than 5 days
- Increased risk of allergic reactions in persons with asthma
- Can precipitate/exacerbate renal failure
What important interactions should be considered in patients on ketoralac?
Adverse GI effects increased by other NSAIDs, use with acetaminophen increases liver toxicity
Name 3 proprionic acids.
1) Naproxen (ie midol, aleve)
2) Ibuprofen (Advil, Motrin)
3) Oxaprozin (daypro)
What are the primary benefits of naproxen?
- Less GI irritation compared to aspirin
- Possibly less CV risk compared to other NSAIDs
What is Ibuprofen (Advil, Motrin) proven effective in?
-Headache and migraine, menstrual pain, and acute postoperative pain
What are the main side effects of ibuprofen?
GI side effects (nausea/dyspesia) at higher doses
What are the mechanisms of action of oxaprozin?
- In addition to good nonselective COX-1&2 activity, additional mechanisms identified:
- NF-ᴋB & metalloproteinase inhibition
- Endogenous cannabinoid modulation
- Long acting medication – once daily dosing
What is Oxaprozin used for?
Superior analgesia & QOL with refractory shoulder pain compared to diclofenac in one study
- uses readily into inflamed synovial tissues
Name an enolic acid.
Meloxicam (Mobic)
What is the mechanism of action of meloxicam?
COX-2 preferential, especially at low doses
What are the benefits of meloxicam?
- As effective as piroxicam (Feldene), diclofenac, & naproxen, but with fewer GI symptoms
- Lower perforations, obstructions, bleeds
- Not altered by renal or hepatic insufficiency
- Dose adjustment not needed in elderly
Name a coxib.
Celecoxib (Celebrex)
What is the mechanism of action of celecoxib?
Selective COX-2 inhibitor and synthesis of PGs causing pain, fever and inflammation
What is the clinical use of celecoxib?
Mild to moderate pain
What are the adverse drug reactions of celecoxib?
GI bleeding but may be less than nonselective COX inhibitors.
What interactions should be noted in patients on celecoxib?
- Levels increased by drugs that inhibit cytochrome P450 2C9
- Decreases effects of angiotensin-converting enzyme inhibitors and diuretics
- Increases lithium levels.
What are the benefits of celecoxib?
Does not interfere with platelet aggregation
- Perioperative administration possible without increased bleeding
- Less GI & CV complications
What is the main contraindication of celecoxib?
Contraindicated w/ sulfa allergy
Name an analine derivative.
Acetaminophen (Tylenol)
What is the mechanism of action of acetaminophen?
- Not entirely clear; may act centrally to inhibit cyclooxygenases
- Lacks antiplatelet activity
- Inhibits central prostaglandin synthesis with minimal effect peripherally (weak anti-inflammatory effect)
What is the clinical use of acetaminophen?
Mild to moderate pain, fever
- Safest and most cost-effective nonopioid analgesic
What are the adverse drug reactions of acetaminophen?
None usually, overdose can cause fatal hepatic failure especially in combination with alcohol
What interactions should be noted in patients on acetaminophen?
Additive liver toxicity with NSAIDs.
Describe the pharmacokinetics of acetaminophen.
- Peak serum concentrations 0.5-3 hrs (orally)
- Only 10%–50% is protein bound and has an estimated
- Half-life = 2-3 hrs, duration of action 4-6 hrs
- Metabolized in the liver
What is the major concern of all NSAIDS?
All NSAIDs (including Aspirin) may induce hypersensitivity reactions - Related to the inhibition of PG synthesis
What are the two types of NSAID induced hypersensitivity reactions?
1) Syndrome of asthmatic attacks
- Patients with vasomotor rhinitis, nasal polyposis, and bronchial asthma
2) Syndrome of urticaria and angioedema
- Prostaglandin E2 is a bronchodilator
- Stabilizes histamine stores in mastocytes, inhibiting inflammatory response
What are the major GI effects of NSAIDS?
- Gastric distress
- Superficial mucosal lesion
- Serious Ulceration
What increases the risk of GI effects related to NSAIDS?
SSRIs increase risk 12-15 fold
What are the renal effects of NSAIDS?
- Renal impairment
- Acute renal failure
What are the risk factors for renal effects related to NSAID use?
- Chronic NSAID use
- High-dose/multiple NSAIDs
- Volume depletion
- CHF, vascular disease
- Hyperreninemia
- Shock
- Sepsis
- SLE
- Hepatic disease
- Sodium depletion
- Nephrotic syndrome
- Diuresis
- Concomitant drug therapy (diuretics, ACE inhibitors, beta blockers, potassium supplements)
- Advanced age
What is the proposed mechanism of renal impairment with NSAID use?
Decrease in prostaglandin production–> reduced renal blood flow –> medullary ischemia
What causes the hepatic effects of NSAIDS?
- Rare complication of most NSAIDs
- Dose-related toxicity - aspirin & acetaminophen
What is the mechanism of action of the hepatic effects of NSAIDS?
- Almost entirely metabolized in the liver
- Depletion of hepatocyte glutathione –> accumulation of the toxic metabolite NAPQI –> mitochondrial dysfunction, and alteration of innate immunity
What are the risk factors for hepatic side effects due to NSAIDS?
Concomitant depression, chronic pain, alcohol or narcotic use, and/or using several preparations simultaneously
What are the cardiac effects of NSAIDS?
- 10 fold increase in heart failure exacerbation
- induce systemic vasoconstriction: increase after load and decrease cardiac contractility and decrease cardiac output
- Hypertension
- MI
What are the other side effects of NSAIDS?
- Impaired fracture healing
- Interference with Aspirin
- Competition for COX-1 binding of platelets
- Administered NSAIDs 2 hours after aspirin
- No interference with COX-2 inhibitors
Why should NSAIDS be avoided in the 3rd trimester?
Avoid NSAIDs in 3rd trimester
=> in utero constriction of the fetal ductus arteriosus
What are the effects of NSAIDS at term?
- May delay labor onset 3-10 days
- May cause serious pulmonary vascular disease
- Increased bruising of newborn
Which NSAIDS are approved for children?
naproxen, ibuprofen, aspirin
Why should NSAIDS be avoided in pediatric viral cases?
Avoid w/ viral illness –>Reyes Syndrome (especially Aspirin)
What risks of NSAIDS are pertinent in the elderly population?
- Hypoalbuminemia –> toxicity
- Longer half-lives of some NSAIDs
- Higher risk for drug interaction
How do NSAIDS interact with lithium and warfarin?
- Lithium: may increase lithium plasma levels and decrease its renal clearance
- Warfarin: may increase the risk for bleeding
What is the class and mechanism of action of Gabapentin/pregablin?
Class: Anticonvulsants
Mechanism of Action: preventing Ca++ influx in dorsal horn
What are the clinical uses of gabapentin?
Neuropathic pain.
- Can be used prn
What are the adverse drug reactions of gabapentin?
Dizziness, fatigue, weight gain, drowsiness, and peripheral edema
* BUT NO INTERACTIONS
What is the mechanism of action of tricyclic antidepressants (TCA)?
Mechanism of Action: Norepinephrine and serotonin reuptake inhibitors
What is the clinical use of TCAs?
Neuropathic pain, appetite stimulant, sleep aide
What are the adverse drug reactions of TCAs?
Innumerable- sedation, increased appetite, dry mouth, sexual dysfunction, orthostatic hypotension
What are the major interactions of TCAs?
- Use with caution in elderly.
- Chronic pain patients do not want to gain weight.
- Use with caution with other serotonin reuptake inhibitors
What SNRIs are used in pain management?
Venlafexine, duloxetine, milnaciprin
What is the mechanism of action of SNRIs?
Norepinephrine and serotonin reuptake inhibitors
What are the clinical uses of SNRIs?
Neuropathic pain, appetite stimulant, sleep aide, depression, anxiety
What is the major side effect of SNRIs?
Many- appetite stimulation
What are the primary interactions of SNRIs?
- Chronic pain patients do not want to gain weight.
- Use with caution with other serotonin reuptake inhibitors
Name 2 natural forms of opium.
1) Codeine
2) Morphine
Name 5 types of semisynthetic opioids.
1) Hydrocodone
2) Oxycodone
3) Hydromorphone
4) Oxymorphone
5) Buprenorphine
Name 5 types of synthetic opioids.
1) Meperidine
2) Fentanyl
3) Sufentanil
4) Methadone
5) Propoxyphene
What is the mechanism of action of morphine?
Prototypic mu opioid receptor agonist
What are the adverse side effects of morphine?
Sedation, confusion, constipation, respiratory depression, sexual dysfunction, fracture, physical dependence (withdrawal syndrome), abuse, misuse, addiction, infection, tumors
What are the major interactions for patients on morphine?
- Additive effects with CNS depressants
- MAO inhibitors can cause severe or fatal reactions
- Can be used in patients with hepatic failure
What is the mechanism of action of meperidine?
mu opioid receptor agonist => same as morphine
What is the clinic use of meperidine?
Clinical Use: Severe pain. Not recommended for routine use!
What are the adverse drug reactions of meperidine?
ADRs: Same as morphine plus increased heart rate
What are the major interactions for patients on meperidine?
MAO inhibitors can cause severe or fatal reactions
What is a distinguishing factor of meperidine that is different from other opioids?
Causes mydriasis while all other opioids cause meiosis.
What is oxycodone?
Strong Opioid analgesic
What are the major adverse drug reactions of oxycodone?
Sedation, confusion, constipation, respiratory depression, sexual dysfunction, fracture, physical dependence (withdrawal syndrome), abuse, misuse, addiction, infection, tumors
What are the interactions of oxycodone?
Interactions: Additive effects with CNS depressants
How is oxycodone metabolized?
- Metabolized to oxymorphone by CYP2D6 and noroxycodone by CYP3A4
- Oxycodone and noroxycodone are excreted in urine unchanged and oxymorphone is conjugated and excreted
- Concentrated in breast milk
- Breastfed infants may receive 10% of therapeutic infant dose
What is the half life of oxycodone?
T ½ 2-3 hours
- longer half life in hepatic disease
- safer for patients with renal disease
What is the mechanism of action of oxymorphone?
- Oxymorphone is a strong Opioid analgesic used for severe pain and with the same ADRs as morphine
- Mechanism of Action: Works in modulation phase of nociception.
What are the interactions associated with oxymorphone?
Interactions: Additive effects with CNS depressants
How does oxymorphone compare to morphine and oxycodone?
- Metabolic end product of oxycodone.
- High abuse potential. Twice as strong as morphine
What is the mechanism of action of Methadone?
- Methadone is a strong opioid analgesic.
- Mechanism of Action: Works in modulation phase of nociception. Has NMDA receptor antagonist properties. Can inhibit the reuptake of serotonin. Long elimination half life.
What are the adverse drug reactions of methadone?
Same as morphine plus => Can prolong QTc and cause arrhythmia (get EKG before use)
What are the interactions of methadone?
Additive effects with CNS depressants. Beware using with other serotonin reuptake inhibitors
What is methadone used for?
- severe pain
- used to treat addiction
In what population should we use methadone cautiously?
Exercise tremendous caution in using in elderly
Describe the major pharmacokinetic concern with methadone.
Pharmacokinetics indicate dose should not be increased more frequently than every 14 days
What is the importance of the two enantiomers of Methadone?
Two enantiomers- Levo mu agonist and dextro blocks NMDA receptor
Describe the pharmacokinetics/dynamics of methadone.
- Bioavailability range broad and variable 40-90% due to variable expression of CYP3A4 and CYP3A5
- T ½ beta 8.5-47 hours
- Variable potency dependant on dosage
What is the mechanism of action of fentanyl?
- Strong Opioid analgesic
- Mechanism of Action: Works in modulation phase of nociception.
- 80 times stronger than morphine
What is the clinical use of fentanyl?
severe pain
What are the adverse drug reactions of fentanyl?
Same as morphine
What are the major interactions of fentanyl?
Additive effects with CNS depressants
What is the major hepatic effect of fentanyl?
Hepatic failure alters skin permeability and regional blood flow to skin so can alter absorption of patches
What is the mechanism of action of hydrocodone?
- Not as potent analgesic as others
- Mechanism of Action: Works in modulation phase of nociception.
What is the clinical use of hydrocodone?
severe pain
What are the ADR of hydrocodone?
same as morphine
What interactions should be considered for hydrocodone?
Additive effects with CNS depressants
What is the most abused prescription drug in the U.S.?
Hydrocodone
What is the mechanism of action of hydromorphone?
Mechanism of Action: Works in modulation phase of nociception to treat severe pain but 7.5 times more potent than morphine
What is the clinical use of hydromorphone?
severe pain with similar ADR as morphine
What are the major drug interactions of hydromorphone?
Additive effects with CNS depressants
In what patient group is hydromorphone effective in?
Useful in renal failure patients
How does hydromorphone act in hepatic disease?
- Reduced first pass clearance because of shunting and increased bioavailability
- Avoid sustained release versions
What is the mechanism of action of tapentadol?
- Strong Opioid analgesic
- Mechanism of Action: Works in modulation phase of nociception.
What is the clinical use of tapentadol?
Clinical Use: Severe pain. May be more useful to treat neuropathic pain
What are the adverse drug effects of taptentadol?
Same as morphine plus inhibits reuptake of norepinephrine and to a much lesser degree serotonin
- Additive effects with CNS depressants
What is the mechanism of action of tramadol?
- Not as potent analgesic as others and used in MODERATE pain
- Mechanism of Action: Works in modulation phase of nociception and inhibits reuptake of norepinephrine and serotonin.
What adverse drug reactions are associated with tramadol?
Beware combing with methadone or antidepressants that inhibit the reuptake of serotonin
- Interactions: Additive effects with CNS depressants
What is the mechanism of action of naloxone?
Mechanism of Action: Competitively blocks mu, kappa and delta opioid receptors; rapidly reverses effects of opioid agonists.
What is the clinical use of naloxone?
Clinical Use: Opioid overdose, opioid dependence.
- Can precipitate withdrawal in opioid-dependent persons
What are the major interactions of naloxone?
Interactions: Large, repeated doses are needed to antagonize mixed agonist-antagonist opioids, Naltrexone has a longer half-life.
What is Buprenorphine used for?
Used to treat opioid addiction/ moderate to severe pain.
- 30 times as potent as morphine (24 mg of buprenorphine is equivalent to 720 mg of morphine)
What is the safest drug to use in the hepatorenal system?
Buprenorphine
What is the mechanism of action of buprenorphine?
Buprenorphine is a mixed agonist/antagonist blocks the activity of other opiates and induces withdrawal in opiate dependent individuals who are currently physically dependent on another opiate.
What may be safer in elderly than NSAIDS?
Opioids
- Begin opioids cautiously, titrate carefully, monitor frequently because elderly are more susceptible to side effects
What methods are most commonly used to test for drugs?
Initial (immunoassay-screening) and confirmatory (gas chromatography-mass spectrometry
What food product contains trace amounts of codeine and morphine?
- Poppy seeds contain trace amounts of morphine and codeine
- It is possible to obtain levels high enough to result in positive GC/MS for morphine and codeine
- Morphine levels greater than 1000 ng/ml and no codeine detected (not just below cut-off levels) are not compatible with poppy ingestion.
How do we differentiate morphine use from poppy seed consumption?
Morphine is not metabolized into codeine
