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Module 4

Terms in this set (74)

Non-opioid analgesics: Examples
Acetaminophen (Tylenol)
Non-acetylated Salicylates
Choline magnesium trisalicylate (Trilasate)
Diflunisal (Dolobid)
Magnesium salicylate
Acetylated Salicylate
Aspirin
Selective COX-2 inhibitor
Celecoxib (Celebrex)
Traditional NSAIDS:
Ibuprofen (Motrin)
Naproxen (Naprosyn)
Oxaprozin (Daypro)
Diclofenac (Voltaren)
Etodolac (Lodine)
Indomethacin (Indocin)
Ketorolac (Toradol)
Nabumetone (Relafen)
Sulindac (Clinoril)
Tolmetin (Tolectin)
Piroxicam (Feldene)
Meloxicam (Mobic)
Flurbiprofen (Ansaid)
Non-Opioid Analgesics
Factors to be considered
First line agents for mild to moderate pain
Ceiling effect of ASA and APAP between 650 and 1300 mg
NSAIDs other than aspirin - analgesic ceiling may be higher
Tolerance does not develop
Acetaminophen
Similar efficacy and potency as aspirin
No anti-inflammatory effect
Overdose can cause serious or fatal hepatic injury
Caution in patients on isoniazid, heavy ETOH users
Maximum safe dose 4 grams per day (> 12 years)
Inadvertent overdose can occur
Taking multiple products containing APAP
Using wrong amount of highly concentration product
The following changes were implemented to prevent accidental overdose of acetaminophen:
New limit of acetaminophen in combination prescription products - 325 mg per tablet or capsule
OTC acetaminophen - maximum dose of 3 g per day unless directed by healthcare professional
Note: 4 g per day continues to be the maximum safe dose
Salicylates
Aspirin effective for most mild to moderate pain
Unlike other NSAIDs, irreversible inhibition of COX
Single dose inhibits platelet function for lifetime of platelet (4-7 days)
Single dose can precipitate asthma in aspirin-sensitive patients
Like other NSAIDs, can cause GI bleeding, PUD
Salicylates: Aspirin
Analgesic vs. anti-inflammatory dosing
Analgesic/antipyretic: 325-650mg
Anti-inflammatory: 1000mg (3-5 g/day)
Increase dose gradually
Follow serum salicylate levels
Rarely used due to GI side effects
Hepatic clearance
Salicylate overdose: metabolic acidosis, tinnitis
Reye's Syndrome
Aspirin should not be used during viral syndromes in children and teenagers
Mechanism unknown
Non-acetylated salicylates
Non-acetylated salicylates have a more favorable toxicity profile
Do not interfere with platelet aggregation
Rarely associated with GI bleeding
Well tolerated by asthmatic patients
Traditional NSAIDs
Analgesic efficacy
More effective than full doses of aspirin or APAP
Equal or greater than usual doses of an opioid combined with APAP
Different NSAIDs
Similar efficacy at equipotent doses
Patient-to-patient differences
Toxicity differences
Anti-inflammatory
NSAIDs MOA
MOA:
Cyclooxygenase (COX) inhibition
Blocks conversion of arachidonic acid to prostaglandins (PGs)
Decreases production and release of PGs
Analgesic, anti-inflammatory, antipyretic activity
Weak acids - well-absorbed
Highly protein-bound
Extensively metabolized and excreted in urine
Half-life varies from <6 hrs to >12 hrs
Comparison of COX-1 and COX-2
Property/COX-1/COX-2

Expression/Constitutive/Inducible; not normally present in most tissues Constitutive in parts of nervous system

Tissue Location/Ubiquitous expression/Inflamed and activated tissues

Cellular Localization/Endoplasmic reticulum/ER and nuclear membrane

Substrate Selectivity/Arachidonic acid, eicosapentaenoic acids/Arachidonic acid, ϒ-linolenate, α linolenate, linolenate, eicosapentaenoic acids

Role/Protection and maintenance functions/Proinflammatory and mitogenic functions

Induction/Generally no induction. hCG can up-regulate COX-1 in amnion/Induced by LPS, TNF-α, IL-1, IL-2, EGF, IFN- ϒ. mRNA rises 20- to 80-fold upon induction Regulated within 1-3 hours

Inhibition/Pharmacologic: NSAIDs (low-dose aspirin)/In vivo: anti-inflammatory glucocorticoids, IL-1β, IL-4, IL-10, IL-13 Pharmacologic: NSAIDs, COX-2 selective inhibitors
Major Adverse Effects of Nonselective COX Inhibitors and COX-2 Selective Inhibitors
Adverse Effect- Nonselective COX Inhibitors/(NSAIDs) COX-2 Selective Inhibitors

Gastric ulceration- Yes/ Yes*
Inhibit platelet function- Yes/ No
Inhibit labor induction- Yes/ Yes
Inhibit renal function- Yes/ Yes
Hypersensitivity reaction- Yes/ ?
NSAIDs
Salicylate build-up - tinnitis, hearing loss
Reversible inhibition of platelet aggregation
Inhibition of COX blocks synthesis of thromboxane A2 which inhibits platelet aggregation
Unlike opioids, no physical dependence
Pregnancy
Avoid in 3rd trimester, Category D, due to premature closure of ductus arteriosus
NSAIDs GI Adverse effects
Dyspepsia, GI bleeding, PUD
Inhibition of PGs that maintain normal gastric and duodenal mucosa
Increases acid production
Decreases mucus production, gastric blood flow
Local irritation
Lipid soluble at low pH - enter gastric mucosal cells - lose lipid solubility - become trapped in cell
Risk factors
High doses, prolonged use, previous GI ulcer or bleeding, excessive ETOH intake, elderly, corticosteroid use
Prevention of GI Adverse Effects
Prostaglandin analog misoprostil (Cytotec)
Diclofenac/misoprostol (Arthrotec)
Gastric and duodenal ulcers
Proton-Pump inhibitors
H2-receptor antagonists
Sucralfate (Carafate)
Dyspeptic symptoms only
Take with food
Prevention of GI Adverse Effects
Low Risk
Ibuprofen and naproxen at low doses
Etodolac, sulindac
Celecoxib
Moderate Risk
Ibuprofen and naproxen at mod-high doses
Diclofenac, oxaprozin, meloxicam, nabumetone
High Risk
Tolmetin, piroxicam, aspirin, indomethacin, ketorolac
NSAIDs: Renal Adverse Effects
Decreased synthesis of renal vasodilator PGs (PGE2)
Leads to decreased renal blood flow
Fluid and sodium retention
May cause renal failure or hypertension
Interstitial nephritis (rare)
Risk factors
Old age, CHF, HTN, renal insufficiency, ascites, volume depletion, diuretic therapy
Renal Risk of Specific NSAIDs
Can occur with all NSAIDs
Increased risk
Longer half-life
Highly potent COX inhibitors
Ketorolac, indomethacin
Higher dose
"Renal sparing" (lower risk, not devoid)
Sulindac, nabumetone
Celecoxib
NSAIDs: Drug Interactions
Displaces other highly protein-bound agents
Increases levels of warfarin, phenytoin, sulfonylureas, sulfonamides, digoxin
Warfarin least likely to interact with diclofenac, ibuprofen, tolmetin, naproxen
Reduces effect of diuretics, β-blockers, ACEIs via suppression of renal PGs
Increases lithium levels
Probenicid increases levels of most NSAIDs
Avoid with ketorolac
Ketorolac
Only NSAID available in US as injectable for short term until approval of IV ibuprofen
Do not exceed 5 days of use
IM or IV comparable to mild opioids
Serious GI bleeding, ulceration, perforation and/or renal toxicity can occur (especially in the elderly)
Selective NSAIDs
Celecoxib (Celebrex) only agent available today
Withdrawn from the market due to increased MI risk
Rofecoxib (Vioxx), Valdecoxib (Bextra)
Selectively inhibit COX-2 (nonselective NSAIDs inhibit COX-1 and COX-2)
No more effective at reducing pain and inflammation
COX-1: gastric protection and production of TxA2 (vasoconstrictor, platelet aggregator)
COX-2: production of prostacyclin (vasodilator, platelet inhibitor)
Same risk of renal adverse effects
Celecoxib
Use the lowest effective dose
≤200 mg/day
200 mg/day = naproxen 500 mg BID
Consider patient's risk for cardiovascular events
Consider patient's risk for GI events
Weigh risk vs. benefit
PO
Should still be taken with food
Black Box Warnings
Cardiovascular Risk
Increased risk of serious CV thrombotic events, MI, stroke, which can be fatal
CI for tx of peri-operative pain in setting of CABG surgery
Gastrointestinal Risk
Increased risk of bleeding, ulceration, perforation of the stomach or intestines, which can be fatal
Selective and non-selective NSAIDs
Nomenclature opioid
Opiate - naturally occuring drugs (ie. morphine, codeine)
Opioid - anything that acts like an opiate
Narcotics - DEA regulations, "don't call it this"
Opioids - therapeutic agents
Nomenclature opioid
μ (mu) 1
Supraspinal analgesia, bradycardia, sedation
μ (mu) 2
Respiratory depression, euphoria, physical dependence
δ (delta)
Spinal analgesia, respiratory depression
κ (kappa)
Spinal analgesia, respiratory depression, sedation, dysphoria
σ (sigma)
Dysphoria, delirium, hallucinations
Opioid Characteristics
Moderate to severe pain
Agonists vs. partial agonists vs. antagonists
No max dose vs. ceiling effect
All are hepatically metabolized
Non-CYP450 pathways
Inactive or active metabolites
Tolerance and cross-tolerance
Opioid Drugs
Full Agonists
Morphine
Oxycodone (OxyContin)
Hydromorphone (Dilaudid)
Methadone (Dolophine)
Meperidine (Demerol)
Fentanyl (Sublimaze)
Oxymorphone (Opana)
Full Agonists
Codeine
Hydrocodone (Hycodan)
Propoxyphene (Darvon)
Partial Agonists, Mixed Agonist-Antagonists
Pentazocine (Talwin)
Butorphanol (Stadol)
Nalbuphine (Nubain)
Buprenorphine (Buprenex)
Morphine
PO, IM, IV, SubQ, rectal, epidural, intrathecal
Not as effective orally due to 1st pass metabolism
Two main metabolites (active)
Morphine 6-glucuronide
Morphine 3-glucuronide
SE from build-up of metabolites
Nausea, myoclonus, hallucinations
Causes histamine release - pruritis
Codeine
PO, IV, IM, SubQ
PO combined with APAP, guaifenesin, promethazine
Prodrug: 10% metabolized by CYP2D6 to its active form
Active form = morphine
10% Caucasians, 30% Asians lack 2D6 -- no analgesic effect
Antitussive effect without conversion
Better for cough (lower dose) than pain relief
Hydrocodone
PO
Always combined with either APAP, ASA, ibuprofen, antihistamine
Analgesic and antitussive
Oxycodone
PO
Also in combination with APAP and ASA
No active metabolites - safer in patients with renal dysfunction
Hydromorphone
PO, IM, IV, SubQ, rectal, epidural
Semi-synthetic
No major metabolites - safer in patients with renal dysfunction
Methadone
PO, IV, SubQ
Synthetic
Long half-life elimination
Opioid addiction treatment (maintenance) dosed once daily
No active metabolites - safer in patients with renal dysfunction
Pain management doses bid-tid
Meperidine
PO, IM, IV, rectal, epidural, intrathecal
Synthetic
Use post-op for shakes/chills caused by volatile anesthetic agents, epidural and spinal analgesia (short-term 24-48 hrs)
Main metabolite - normeperidine
Long half-life (15-20 hrs)
Accumulation = CNS excitation/anxiety and convulsions
Caution: elderly, renal dysfunction
Propoxyphene
PO
Also combined with APAP
Metabolized to norpropoxyphene
Long half-life (30-36 hrs)
Can cause stupor, coma, convulsions
NOV 2010: Manufacturer agreed to remove from market due to serious cardiac toxicity
Fentanyl
IV, transdermal patch, transmucosal lozenge, buccal tablets
Patch q72h
80-100x more potent than morphine
Transdermal for chronic pain only after titration with short-acting opioid
Transmucosal for breakthrough pain - 35-50% bioavailable
Buprenorphine
SL, parenteral
Partial agonist
Similar to pentazocine, butorphanol, nalbuphine
Ceiling effect - can precipitate withdrawal symptoms if already on a full agonist
Less likely than full agonist to cause dependence
Not free of dependence liability
Sublingual tablets for treatment of opioid dependence - alone (Subutex) or combined with naloxone (Suboxone)
Non-therapeutic Opioids Drugs of Abuse
Heroin
3x more potent than morphine due to greater lipid solubility
Metabolized to morphine
3-methylfentanyl (China White)
1000x more potent than morphine
Metabolites can accumulate during chronic use
Adverse Effects
Most common
Sedation, dizziness, nausea, vomiting, itching, sweating and constipation
Most serious
Respiratory depression
Tolerance to Adverse Effects
Tolerance to sedative and emetic effects develop rapidly but not constipation
Stimulant laxative with or without a stool softener-start early
E.g. senna/docusate
Chronic COPD, decreased respiratory reserve-susceptible to respiratory depression
Dosage
Wide dosing range
No minimum or maximum dose except limitation by the dose of APAP or aspirin
"Weak" vs. "strong" terminology inaccurate
Use dose required to maintain optimum pain relief with tolerable side effects
Initial titration with short-acting opioid, then dose determination by around-the-clock dosing
A sustained release formulation should be used in chronic pain
Immediate release for breakthrough pain
PCA (IV, SQ, or other routes) when the oral route not feasible
Formulation
A sustained release formulation should be used in chronic pain
Immediate release for breakthrough pain
PCA (IV, SQ, or other routes) when the oral route not feasible
Equianalgesic Doses for Control of Chronic Pain
For potency comparison

Opioid Analgesic/Oral/Parenteral
Morphine immediate release/30mg /10mg
Morphine controlled release (MS Contin, Kadian)/30 mg/NA
Morphine extended release (Avinza, in Embeda)/30mg/NA
Hydromorphone (Dilaudid)/7.5-8mg/ 1.5- 2mg
Oxycodone immediate release (Roxicodone, in Percocet)/20- 30mg /NA
Oxycodone controlled release (OxyContin)/20- 30mg/NA
Oxymorphone (Opana) /10 mg /1 mg
Oxymorphone extended release (Opana ER) /10mg /NA
Hydrocodone immediate release (Lortab,Vicodin) /30- 45mg /NA
Codeine /200mg/ 100- 130mg
Methadone (Dolophine)/Variable/ Variable
Meperidine (Demerol) [Avoid for pain management]/ 300mg /75mg
Fentanyl/ NA /0.1mg
24-hour equianalgesic around the clock dosing for morphine is as follows:
Morphine IR 10 mg q4hours
Morphine CR (MS Contin) 30mg q12 hours
Morphine ER (Avinza) 60mg q24 hours
The total daily dose for each one is the same: 60mg
Tramadol
PO
Non-opioid, unrelated to natural or synthetic opioids
Metabolite: 200x greater affinity for μ receptor, 6x more potent than the parent compound
Blocks reuptake of norepinephrine and serotonin
Indicated for moderate to severe pain
Effectiveness in combination with ASA or APAP comparable to codeine and propoxyphene combination
Analgesia only partially reversible with naloxone
Seizures possible in patients taking MAOIs, antipsychotics
Tolerance
Reduction in adverse effects
Shorter duration
Lower efficacy
Increase the dose
Cross-tolerance
Switching to another opioid
Switching to methadone
Dependence
Physical dependence - withdrawal symptoms
Clinically significant physical dependence
Addiction - psychological dependence, biologic and social factors
Rare development of euphoria, psychological dependence, addiction in patients with true, severe pain
Naloxone (Narcan)
Pure competitive opioid antagonist
No opioid activity at therapeutic doses
DOC for reversal of opioid overdose associated with respiratory depression, sedation, coma, hypotension, opioid-induced psychotomimetic effects
Precipitates withdrawal in opioid dependent subjects
Reversal of opioid-induced anesthesia
Half-life 30-90 min
Parenteral only (not absorbed orally)
Naltrexone (Revia)
Pure competitive opioid antagonist
Longer half-life (4 hrs) with an active metabolite
Effective PO
Maintenance of opioid-free state in detoxified, formerly opioid-dependent patients
Approved for treatment of alcoholism
Nalmephene (Revex)
Pure opioid antagonist
Post-operative reversal of opioids and treatment of opioid overdose
Longer half-life (10 hrs)
Treatment of Opioid Withdrawal & Dependence
Hydration, nutrition, supportive care
Treatment program
Somatic symptoms
Clonidine
Benzodiazepines
Antiemetics
Antidiarrheals
Analgesics (non-opioid)
Maintenance treatment
Methadone
Buprenorphine
Buprenorphine/naloxone SL (Suboxone)
Adjuvant Analgesics: Antidepressants
Neuropathic pain
TCAs (amitriptyline, nortriptyline, etc.)
Diabetic neuropathy, postherpetic neuralgia, polyneuropathy, and nerve injury or infiltration with cancer
May also improve underlying depression and insomnia
Venlafaxine (Effexor)
Neuropathic pain, headache, fibromyalgia, postmastectomy pain
Duloxetine (Cymbalta)
Adjuvant Analgesics: Anticonvulsants
Gabapentin (Neurontin)
Pregabalin (Lyrica)
Carbamazepine (Tegretol)
Phenytoin (Dilantin), Sodium Valproate (Depakote),
Clonazepam (Klonopin), and Topiramate (Topamax)
Lamotrigine (Lamictal)
Other Agents
Hydroxyzine
Low-dose IV/IM
Analgesic for cancer and post operative pain
Reduces n/v
Corticosteroids
Inflammatory diseases
Tumor infiltration of nerves
Topical Analgesics
5% Lidocaine (lidoderm)
Topical lidocaine/prilocaine (EMLA)
Topical steroids
Capsaicin cream (Zostrix)
Transdermal clonidine patch
Osteoarthritis
Pharmacologic Therapy
Analgesia
APAP
NSAIDs
COX-2 Inhibitors
Relief of inflammation, if present
NSAIDs
COX-2 Inhibitors
Intra-articular corticosteroids
Pharmacologic Therapy for RA
APAP not effective due to inflammatory component of RA
Non-acetylated salicylates less effective but more effective than APAP
ASA at inflammatory doses - rarely used due to adverse effects
Symptomatic therapy
NSAIDs
Corticosteroids - systemic, intra-articular
Prevent or slow disease progression
DMARDs
Corticosteroids
Effective anti-inflammatory effect
Avoid long-term
Indicated for life-threatening complications of RA such as vasculitis
Can use temporarily to bridge time to onset of action of DMARDs
Pulse therapy for acute flare-ups
Intra-articular therapy for very acute
inflammation-not on a recurrent basis
Corticosteroids: Long-term AEs
Hyperglycemia
Cataracts
Glaucoma
Aseptic necrosis of weight-bearing joints
Osteoporosis
Cushing's syndrome
Adrenal suppression
Sodium and water retention
CNS side effects with high doses
Corticosteroids: Systemic Dosing
Use lowest dose possible
Try to dose "physiologically" to minimize adrenal suppression
Multiple daily doses often needed for acute flares
Taper slowly if prescribed for > 2 weeks
Corticosteroid Product Selection
Systemic versus local use
Mineralocorticoid activity
Promotes sodium/water retention
Use low mineralocorticoid activity products in patients with CHF, HTN
Dosing equivalency
Duration of biologic action
Disease Modifying Anti-Rheumatic Drugs (DMARDs)
Standard of care
Ideally used when diagnosis of RA is established
Prevent or slow progression of joint destruction or deformities
Relatively toxic, potent, very expensive
Disease Modifying Antirheumatic Drugs
Conventional DMARDs
Hydroxychloroquine (Plaquenil, Quineprox)
Methotrexate (MTX)
Azathioprine (Imuran, AZA)
Gold
Penicillamine
Sulfasalazine (Azulfidine)
Leflunomide (Arava)
Minocycline
Cyclophosphamide
Biologic DMARDs
Etanercept (Enbrel)
Infliximab (Remicade)
Adalimumab (Humira)
Certolizumab pegol (Cimzia)
Golimumab (Simponi)
Tocilizumab (Actemra)
Rituximab (Rituxan)
Abatacept (Orencia)
Anakinra (Kineret)
DMARDs: Efficacy Monitoring
May take 3-6 months for response
Maintain anti-inflammatory therapy for this period (NSAID or corticosteroid)
If good response, may be able to discontinue anti-inflammatory therapy
Response is often incomplete
Continue NSAIDs, may be able to decrease dose
Monitor range of motion, activities of daily living
DMARDs Seldom Used
Gold (oral or parenteral)
Penicillamine


Standard of care at one time
More recently second- or third-line
High incidence of toxicity requiring discontinuation
Myelosuppression, proteinuria, stomatitis, rash, altered taste perception (penicillamine), visual changes (gold)
Azathioprine (PO)
Also for Crohns Disease
Prodrug for mercaptopurine
Immunosuppressant
Toxicities: myelosuppression, hepatotoxicity, rash, infection
Reserved for aggressive disease or serious complications such as vasculitis
Hydroxychloroquine (PO)
Primarily for mild RA
May take 6 months before clinical effect seen
Also an anti-malarial drug
MOA unknown
Toxicities
Well tolerated (some GI upset)
Retinopathy rare (but ophthalmology exams recommended every 6-12 months)
Sulfasalazine (PO)
Effective for mild to moderate RA
Also for Crohns Disease, Ulcerative Colitis
Cleaved by intestinal bactaria to sulfapyridine (active metabolite) and 5-aminosalicylic acid (5-ASA)
"Sulfa" drug
Side effects: GI upset, rash, bodily fluids can turn yellow-orange (no clinical significance)
Sulfasalazine can bind iron and decrease absorption.
If the patient is taking an antibiotic, intestinal flora may be destroyed, reducing conversion to its active form
Leflunomide (PO)
Inhibitor of pyrimidine synthesis = altered lymphocyte activation and decreased inflammatory response
Toxicities: hepatotoxicity, reversible alopecia, GI distress
Teratogenic (Category X) - contraindicated in pregnant women; may discontinue in men who want to father a child
In cases of toxicity or in patients who wish to have a child, cholestyramine can quickly lower drug levels, which could otherwise take months (half-life of active metabolite = 2 weeks)
Methotrexate (PO, IM, subQ)
Folate antagonist = purine biosynthesis inhibition, cytokine production inhibition, adenosine production stimulation = anti-inflammatory effect
Symptomatic relief within 1 month for many patients
Well-tolerated
Cheapest
Toxicities: GI upset, megaloblastic anemia, hepatotoxicity
Patients should receive folic acid replacement
Biologic DMARDs
Genetically developed proteins
Various effects on the pathogenesis of RA
Advantage - no routine laboratory monitoring
Disdvantages
Risk of infections and malignancy
Temporarily suspend treatment if infection occurs
TB skin test prior to use
Very expensive
Parenteral (IV, subQ) - injection site reactions common
Biologic DMARDs: TNF-α Blockers
Etanercept, infliximab, adalimumab, certolizumab pegol, golimumab
Many used in combination with methotrexate or other DMARDs
Downregulate or antagonize TNF-a, a key cytokine contributing to RA
Black box warnings
Serious risk of infections (invasive fungal infections, active TB and reactivation of latent TB, bacterial infections, viral infections, opportunistic infections)
Lymphoma and other malignancies in children and adolescents
Biologic DMARDs: Rituximab
Depletes B-cells, which have been shown to be responsible for inflammation in RA
Use when patients fail traditional DMARDs and anti-TNF agents
Black box warnings: fatal infusion reactions, severe mucocutaneous reactions, PML
Other Biologic DMARDs
Abatacept
Inhibits T-cell activation
Use when patients fail traditional DMARDs and anti-TNF agents
Anakinra
Antagonizes IL-1 receptors, a proinflammatory cytokine
Use when patients fail traditional DMARDs and anti-TNF agents
Can use in combination with conventional DMARDs but not with anti-TNF drugs (no added benefit, potential increased risk of infections)
Other Biologic DMARDs
Tocilizumab
Inhibits IL-6
Use when patients fail anti-TNF drugs
Black box warning
Serious risk of infections (invasive fungal infections, active TB and reactivation of latent TB, bacterial infections, viral infections, opportunistic infections)
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