Eicosanoids and Pain Management

Lecture Overview

• The lecture reviews eicosanoids, aspirin, acetaminophen, headache pain, and migraines

Drug Targets on Prostanoid Biosynthesis

• Phospholipase A-2 is a target of Glucocorticoids
• Glucocorticoids prevent the production of PGs, LTs, HETES, Tx, and are effective, but should only be used for acute use, due to side effects
• Cyclooxygenases are also drug targets
• COX-1 acts in peripheral tissues
• COX-2 is produced locally in response to inflammation
• NSAIDs are drug targets
• Most NSAIDs target both COX-1 and COX-2
• COX-2 selective inhibitors affect inflammation without affecting prostaglandins elsewhere
• Aspirin is an irreversible COX-1 inhibitor

COX1 and COX2 Inhibition Among NSAIDs

• Aspirin inhibits COX-1 more than COX-2 by a factor of 166x
• Indomethacin inhibits COX-1 more than COX-2 by a factor of 60x
• Ibuprofen inhibits COX-1 more than COX-2 by a factor of 15x
• Celecoxib inhibits COX-2 more than COX-1 by a factor of 1,000x
• Rofecoxib inhibits COX-2 more than COX-1 by a factor of 1,000x

Prostaglandins and Pain

• Prostaglandins mediate peripheral (PGE2, PGI2) and central pain (PGE2)
• Aspirin prevents the induction of pain and act on peripheral and central pain
• Acetaminophen only acts on central pain
• Prostaglandins mediate inflammation (PGE2 and PGD2)
• Aspirin prevents prostaglandin mediated inflammation, which is important for arthritis and RA
• Prostaglandin (PGE1) inhibits stomach acid production
• Aspirin prevents this effect, resulting in gastric hyperacidity and ulceration with chronic use
• Aspirin also directly irritates the stomach lining
• Misoprostol (PGE analog) is administered along with aspirin to inhibit stomach acid production
• Prostaglandins mediate fever
• PGE2 increases thermoregulatory set point in the brain
• Aspirin and acetaminophen lower prostaglandin production in the brain
• The reduction of production is useful for patients with fever
• Thromboxane A2 mediates platelet aggregation
• Aspirin prevents TxA2 production, which acts as a blood thinner and can cause bleeding

Aspirin

• Aspirin is an analgesic for mild to moderate pain that provides symptomatic relief
• Aspirin can treat headache, myalgia, arthralgia, dysmenorrhea, and achiness from cold and flu
• Aspirin can be combined with narcotics to treat severe pain
• It also reduces fever
• Aspirin is an anti-inflammatory for arthritis and an anti-platelet blood thinner
• It can decrease heart attack rates, strokes, and colon cancer

Aspirin and Heart Attack/Stroke

• A meta-analysis of 100,000 patients found that baby aspirin (around 80mg per day) significantly reduces thrombotic events with no major side effects
• Aspirin may have some qualities regarding cancer/metastasis

Aspirin, Side Effects

• Aspirin increases gastric acid production
• Aspirin is the second leading cause of gastric ulcers and gastric bleeding
• Increased bleeding can occur so it should be avoided in patients with bleeding disorders
• Increased bleeding can also happen when it is combined with anticoagulants
• Patients should stop taking aspirin one week before surgery
• Aspirin can shut down kidneys in patients with renal insufficiency, due to the renal toxicity
• A cross-allergic reaction can occur so avoid aspirin if allergic reaction is severe
• 5% of patients with aspirin allergies will have an asthmatic attack triggered by aspirin
• Aspirin intolerance can cause allergy which results in rhinitis, urticaria, bronchoconstriction, hypotension, and vasomotor collapse
• Aspirin can delay childbirth and some data suggest that aspirin could cause premature closure of the ductus arteriosus on the fetus
• Aspirin can increase uricemia which leads to gout.
• Aspirin can also cause Reye’s Syndrome, which manifests as vomiting, lethargy, disorientation, and liver damage, and also secondary to taking aspirin and other salicylates
• It is more likely to occur in children and happens more often with viral infections, like the flu or chicken pox
• Effect on metabolism: larger doses cause hyperglycemia and glycosuria
• Toxic doses cause increased oxygen uptake and carbon dioxide production
• It can cause decreased lipogenesis and increased lipolysis
• Effect on the endocrine system: high doses of aspirin increases corticosteroid production and displace plasma thyroid hormones

Aspirin Pharmacokinetics

• Aspirin is highly bound to plasma proteins
• It reaches peak plasma concentration in 1-2 hours
• It has an elimination half life of 3-16 hours
• It is rapidly absorbed and metabolized and is Hydrolyzed to acetic acid and salicylate by esterase
• Aspirin has a serum half life of 15-20 mins, and it is glucuronic and undergoes glycine conjugation-salicyluric acid
• It is oxidized to gentisic acid and eliminated via the kidney
• Salicylate is metabolized with a half life of 4 hrs
• Elimination is greatly slowed down with high concentrations
• A higher urine pH enhances its excretion

Aspirin Adverse Effects

• Salicylism adverse effects occur from ingestion of more than 50mg/dL of aspirin
• Adverse effects: ringing in ears, visual problems, nausea, vomiting, sweating, thirst, headache, confusion, dizziness, and hyperventilation
• Toxicity from heavy overdose: severe metabolic acidosis with compensation for by respiratory alkalosis and respiratory depression Dehydration, fever, and hallucinations can appear, and can progress to convulsions, coma, cardiac collapse, and respiratory failure

Treatment for Aspirin Overdose

• Gastric lavage to minimize absorption and restore acid-base balance
• Also treat symptoms, perform hemodialysis if needed, make urine basic, and maintain vital signs

Aspirin Drug Interactions

• Many interactions that can lead to increased bleeding, especially with warfarin or heparin
• It displaces from plasma protein binding: methotrexate, sulfinpyrazone, tolbutamide, some NSAIDs
• It blocks the renal tubular secretion that inhibits the uricosuric effect of sulfinpyrazone and probenecid
• Aspirin increases toxicity of carbonic anhydrase inhibitors
• Blocks natriuretic effect of spironolactone

Aspirin preparations

• Buffered aspirin does not contain a sufficient buffer to be useful, but taking aspirin with water decreases irritation
• Enteric coated and timed released aspirin reduce stomach irritation and help to delay absorption/prolong action
• Some formulations are easier to swallow like, gelcaps or liquids
• Caffeine can be added to enhance efficacy

Acetaminophen

• Tylenol belongs to the drug class called acetaminophen
• Phenacetin is a prodrug metabolized into acetaminophen which is now considered too toxic
• Acetaminophen acts as an antipyretic and analgesic, more so than an anti-inflammatory
• Acetaminophen only alleviates protaglandin effects on the CNS
• Action is due to the inhibition of COX-3, does not cause GI erosion or hyperacidity
• Acetaminophen does not increase bleeding time and has no effect on the cardiovascular or respiratory system
• Moderate doses of acetaminophen may include a rash and anemia in very rare cases

Acetaminophen Toxicity

• Acetaminophen is relatively safe
• Occasional allergies, rashes, or fever may occur
• At higher doses, metabolites are toxic to the liver (>4 grams per day) and lead to hepatic necrosis and renal toxicity
• Overdoses are treated by emesis lavage and oral administration of N-acetylcysteine (NAC)
• Cimetidine can inhibit cytochrome P-450 and does not interfere with NAC; so it may be useful in acetaminophen overdoses
• Infants and alcoholics are more prone to overdose
• Infants are more prone due to less ability to glucuronidate
• Alcoholics are more prone due to glutathione depletion
• P450 inducing drugs can increase toxic metabolite formation
• High doses cause nephrotoxicity

Headaches

• 1 in 6 Americans have chronic headaches
• Half of those suffer from migraines
• 80% of migraine sufferers are women
• The average is 50-60 migraine attacks per year

Types of Headaches

• 98% of headaches are primary headaches
• Primary headaches are not secondary to another disease
• Three main forms of primary headaches: tension-type, neurovascular headaches, and cluster headaches
• Tension-type headache make up ~70% of headaches, Neurovascular headaches; Migraine 15% of headaches, and Cluster Headaches occur in 0.1% of headaches

Tension Headaches

• Tension headaches are due to tension, stress or muscle contraction
• 70% of males and 80% in females experience tension headaches
• Mild to moderate intensity pain that doesn’t last more than 30 minutes
• Episodic headache is considered to occur less than 15 days/month, while chronic headache is greater than 15 days/month for 6 months
• Pain is bilateral and nausea may occur along with chronic headaches
• Feeling of pressure and tightness in neck muscles

Treatment of Tension Headaches

• Simple analgesics like acetaminophen and over the counter NSAIDs such as aspirin, naproxen, and ibuprofen, may be used
• For severe or persistent headaches, consider anti-migraine medicines or more aggressive NSAIDs therapy

Cluster Headaches

• Extremely severe unilateral headache that produces pain in the areas around and above eyes
• Symptoms that are associated: redness of the eye, lacrimation, nasal congestion, forehead and facial sweating, contraction of the pupil, and puffy eyelid
• The attack lasts for 15 minutes to 3 hours in series and is found predominantly in men

Treatment of Cluster Headaches

• Oxygen inhalation
• Sumatriptan (imitrex) injections or nasal spray
• Dihydroergotamine (migranal) injection or nasal spray
• Lidocaine (xylocaine) nasal drops
• Oral aspirin, naproxen, ibuprofen, and other NSAIDs are not effective

Migraine Headaches

• Migraine headaches are unilateral and throbbing
• They last from 4-72 hours (3-4 attacks per month)
• Signs and symptoms include nausea, vomiting, photophobia, phonophobia, and sweating
• Often stimulus triggers the attack: smoke, fear, pressure, and certain foods
• Physical activity aggravates the pain and it is often seen along generations
• Classical Migraines occur 25% of the time, where an aura precedes the attack, visual disturbances, hallucinations of light or sounds, and loss of vision.
• Common Migraines occur 75% of the time, with no aura being present

Causes of Migraines

• Cerebral vessels undergo vasoconstriction followed by vasodilation
• Swelling activates pain receptors along the trigeminal nerve
• Serotonin promotes vasoconstriction and interferes with pain transmission
• Agonists can be used to treat migraines: 5HT1b and 1D agonists are most effective

Migraine as a Seizure-like Attack

• A migraine can be treated as a siezure
• Other seizures have auras
• Anti-seizure medications are being studied for migraine prophylaxis

Treatment of Migraines

• Treatment is based on severity
• Mild migraine: basic analgesics (NSAIDs; aspirin, ibuprofen) and nausea: dimenhydrinate or metoclopramide
• Moderate migraine: combination of caffeine with acetaminophen and aspirin (excedrin migraine); ergotamine, triptans
• Severe migraine: triptans first, analgesics

Serotonin Agonists

• Non-selective serotonin agonists can be taken, such as ergotamine
• Dihydroergotamine has more potent actions, but greater side effects, such as nausea, peripheral vasoconstriction, and rises in blood pressure
• Triptans: 5HT-1D and 1B agonists

Triptans

• Triptans are remedies for moderate to severe migraine headaches
• Sumatriptan has 14% bioavailability; SC (quick) or nasal spray (slow) routes of administration are used; a short half life
• Rizatriptan, naratriptan, zolmitritan are more bioavailable
• Zolmitriptan is the most potent
• Naratriptan is long acting (6 hours) and has less side effects

Triptans Side Effects

• High BP/cerebrovascular hemorrhage
• Coronary vasospasm
• Pain in jaw and neck
• Light headiness, fatigue, and pressure sensations
• Contraindicated in uncontrolled hypertension, prone to coronary artery disease, and pregnant women.
• Do not combine with ergots, MAOI or SSRIs

Preventing Migraines

• Beta blockers like propranolol: but this is contraindicated in diabetics, asthmatics, heart block or failure, and pregnant women
• Calcium channel blockers such as verapamil can be used but are contraindicated in hypotension, CHF, pregnancy, and arrhythmias
• Other options include antidepressants such as amitriptyline and anticonvulsants such as valproic acid
• Anti-serotonergics, such as methysergide can also be used
• Side effects of anti-serotonergics: extreme nausea, cramps, insomnia, weight gain, hypertension, and pulmonary fibrosis

Novel Migraine Therapeutics

• Antiepileptics have shown some effectiveness in treatment
• Valproic acid is effective as a prophylactic in 255% of patients
• Topirimate is also effective as prophylactic
• Botulinum toxin injections and surgery at trigger points may also be used