DRUGS IN PAIN MANAGEMENT

Celecoxib

selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1

Celecoxib

associated with fewer endoscopic ulcers than most other NSAIDs.

Celecoxib

May cause rashes probably because it is a sulfonamide

Meloxicam

enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1

particularly at its lowest therapeutic dose of 7.5 mg/d.

Meloxicam

It is not as selective as celecoxib and may be considered “preferentially” selective rather than “highly” selectiv

Meloxicam

It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen.

Meloxicam

its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function

Coxibs (COX-2 inhibitors)

selectively target COX-2 for pain control. They carry black box warnings for cardiotoxicity and are contraindicated in patients with cardiovascular diseases. May rarely cause Stevens-Johnson syndrome

Aspirin

inhibits thromboxane A2, acting as an antiplatelet agent.

Meloxicam

has mild antiplatelet effects, weaker than aspirin.

Diclofenac

phenylacetic acid derivative that is relatively nonselective as a COX inhibitor

Diclofenac

150 mg/d, appears to impair renal blood flow and glomerular filtration rate

Diclofenac

Elevation of serum aminotransferases occurs more commonly with this drug than with other NSAIDs

Flurbiprofen

propionic acid derivative with a possibly more complex mechanism of action than other NSAIDs

Flurbiprofen

Its (S)(–) enantiomer inhibits COX nonselectively

Flurbiprofen

Intravenously, it is effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat

Flurbiprofen

rarely associated with cogwheel rigidity, ataxia, tremor, and myoclonus

Ibuprofen

simple derivative of phenylpropionic acid

Ibuprofen

is often prescribed in lower doses (<1600 mg/d), at which it is analgesic but not anti-inflammatory

concomitant administration of ibuprofen and aspirin

antagonizes the irreversible platelet inhibition induced by aspirin

2400 mg

In doses of about ____ daily, ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect.

Indomethacin

potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T-cell and B-cell proliferation

Indomethacin

It has been used to accelerate closure of patent ductus arteriosus

Ketoprofen

propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase.

Ketoprofen

Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life.

Nabumetone

the only nonacid NSAID in current use; it is given as a ketone prodrug

Nabumetone

resembles naproxen in structure

Nabumetone

Its half-life of more than 24 hours

Permits once-daily dosing

Nabumetone

drug does not appear to undergo enterohepatic circulation.

Nabumetone

Renal impairment results in a doubling of its half- life and a 30% increase in the area under the curve.

Naproxen

naphthylpropionic acid derivative.

Naproxen

the only NSAID presently marketed as a single enantiomer.

Naproxen

free fraction is significantly higher in women than in men, but half-life is similar in both sexes

Oxaprozin

propionic acid derivative NSAID

Oxaprozin

Has a very long half-life (50–60 hours), although _____ does not undergo enterohepatic circulation

Oxaprozin

It is mildly uricosuric

Piroxicam

an oxicam

a nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function

Piroxicam

Its long half-life permits once-daily dosing.

dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding¨

Sulindac

a sulfoxide prodrug.

It is reversibly metabolized to the active sulfide metabolite and has enterohepatic cycling; this prolongs the duration of action to 12–16 hours

Sulindac

In addition to its rheumatic disease indications, it suppresses familial intestinal polyposis and it may inhibit the development of colon, breast, and prostate cancer in humans

Tolmetin

a nonselective COX inhibitor with a short half-life (1–2 hours) and is not often used

It is ineffective (for unknown reasons) in the treatment of gout

Diclofenac

requires regular patient monitoring

Flurbiprofen

rarely used in the Philippines.

Ibuprofen

available in 200 mg (analgesic, antipyretic) and 400 mg (anti-inflammatory) doses.

Aspirin

is no longer used mainly for pain due to adverse effects. Low doses (81–82 mg) serve as antiplatelets, while higher doses (325 mg) increase risk of side effects.

MOA: irreversibly acetylates COX-1 and COX-2.

Indomethacin

used for arthritis and patent ductus arteriosus (failure of ductus arteriosus to close after birth).

Naproxen

used for rheumatoid arthritis; allows once-daily dosing.

Uricosurics

increase uric acid excretion

Piroxicam

contraindicated in ulcer patients; sometimes used in veterinary medicine.

Sulindac

rarely used NSAID.

Acetaminophen

the active metabolite of phenacetin and is responsible for its analgesic effect.

Acetaminophen

It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant antiinflammatory effects

Acetaminophen

Although said to be equivalent to aspirin as an analgesic and antipyretic agent, acetaminophen lacks antiinflammatory properties. It does not affect uric acid levels and lacks platelet-inhibiting effects.

Acetaminophen

Dose greater than 4 g/d are not usually recommended

Acetaminophen

Acute pain and fever may be effectively treated with 325–500 mg four times daily

Ketorolac

an NSAID promoted for systemic use mainly as a short-term analgesic (not longer than 1 week), not as an antiinflammatory drug

Ketorolac

effective analgesic and has been used successfully to replace morphine in some situations involving mild to moderate postsurgical pain.

Ketorolac

When used with an opioid, it may decrease the opioid requirement by 25–50%

Ketorolac

Renal toxicity is more common with chronic use.

Tramadol

a centrally acting synthetic analgesic, structurally related to opioids

Tramadol

Since naloxone, an opioid receptor blocker, inhibits only 30% of the analgesic effect of ___ the mechanism of action of this drug must involve both nonopioid and opioid receptors

Tramadol

does not have significant anti-inflammatory effects.

Tramadol

The drug may exert part of its analgesic effect by enhancing 5-hydroxytryptamine (5-HT) release and inhibiting the reuptake of norepinephrine and 5-HT

N-acetyl-p-benzoquinone imine

The toxic metabolite of Phenacetin

Ketorolac

for short-term pain management; reduces dependence on morphine.

may cause drowsiness.

Side effect of Tramadol

Morphine, Methadone, Fentanyl

Strong myu-receptor agonists • variable affinity for delta and kappa receptors

Hydromorphone, oxymorphone

Like morphine in efficacy, but higher potency

Meperidine

Strong agonist with anticholinergic effects

Oxycodone

Dose-dependent analgesia

Sufentanil, alfentanil, remifentanil

Like fentanyl but shorter durations of action

• Codeine

• Hydrocodone

Less efficacious than morphine

can antagonize strong agonists

Buprenorphine

Partial myu agonist

kappa antagonist

Nalbuphine

kappa Agonist • myu antagonist

Tapentadol

Moderate myu agonist, strong NET inhibitor

Tramadol

Mixed effects: weak myu agonist, moderate SERT inhibitor, weak NET inhibitor

OPIOID AGONISTS

Very limited data support the safety and efficacy of opioids for chronic noncancer pain

Prone for misuse and abuse:

45 minutes, 1 to 2 hours.

The onset of action of oral opioids is about ___ , and peak effect usually is seen in about ____

Opioids

prone to dependence, misuse, and abuse. Patients should be counseled on proper use and withdrawal symptoms such as agitation and irritability. Increasing doses may be required over time due to receptor saturation.

Morphine

the first-line agent for moderate to severe pain.

Morphine

It is often considered the opioid of choice for pain associated with myocardial infarction, as it decreases myocardial oxygen demand

Morphine

In patients with head trauma who are not ventilated, morphine-induced respiratory depression can increase intracranial pressure and cloud the neurologic examination results.

Morphine

Patients with underlying pulmonary dysfunction are at increased risk for respiratory depression, which can be reversed by naloxone

Codeine

alone or combined with other analgesics (eg, acetaminophen) is commonly used for mild to moderate pain.

Oxycodone

useful for moderate to severe pain, especially when combined with nonopioids

Morphine

given in fixed daily doses; may cause allergic reactions (antihistamines given beforehand). Also used in myocardial infarction to reduce oxygen demand.

Patient-Controlled Analgesia (PCA):

allows controlled self-administration within safe limits

pinpoint pupils, respiratory depression, coma.

Opioid Toxicity Triad

Naloxone

Morphine toxicity is reversed with

Morphine

Used in some countries for euthanasia (obsolete term: mercy killing)

Meperidine

less potent and has a shorter duration of action than morphine.

Meperidine

Do not combine meperidine with monoamine oxidase inhibitors because severe respiratory depression or excitation, delirium, hyperpyrexia, and convulsions may occur.

Fentanyl

often used as an adjunct to general anesthesia, is more potent and faster acting than meperidine.

Fentanyl

It is used for breakthrough cancer pain

Methadone

has extended duration of action. Studies show a growing number of methadone-related deaths.

Methadone

High doses cause cardiac arrhythmias. Do not titrate more frequently than every 5 to 7 days

Methadone

Although effective for acute pain, it is used for chronic cancer pain.

Naloxones

a pure opioid antagonist that binds competitively to opioid receptors.

Naloxones

does not produce analgesia or opioid side effects.