2) Ocular Analgesics and Pain Management

What are the characteristics of acute ocular pain?

→ involves recent trauma or surgery

• limited duration

• resolves when the source of pain is detected and treated

• responds effectively to pharmacologic intervention

What are nociceptors? Give their common locations.

→ nerve endings where pain signals are initiated

• Viscera

• Musculoskeletal system

• Structures making up the eye and orbit

What are the stimuli and chemicals activating nociceptors?

Stimuli - strong mechanical stimulation (trauma)

Chemical - serotonin, bradykinin & histamine (released in response to injury)

What is the role of prostaglandins and leukotrienes in pain?

→ DON’T directly stimulate nociceptors

• sensitize nociceptors to inflammatory mediators (bradykinin or histamine) which then interact with substance P to stimulate nerve ending

Give the pathway of conduction of ocular pain.

1. Pain signals originate at ocular nociceptors

2. Conveyed via trigeminal nerve (CN5) → brainstem

3. Impinge on cells of the sensory and spinal nuclei of the trigeminal nerve

4. Sent to the somatosensory cortical areas of the brai

   • this is where the degree and location of pain are perceived

How is arachidonic acid formed? What are the 2 enzymes acting on arachidonic acid and their respective end products?

Trauma triggers conversion of membrane phospholipids → arachidonic acid via Phospholipase A₂ (inhibited by corticosteroids)

1. COX converts arachidonic acid → endoperoxides → Thromboxane A₂, Prostaglandins (PGE₂, PGF₂ₐ, PGD₂), Prostacyclin (PGI₂)

   • (inhibited by NSAIDs)

2. Lipoxygenase converts arachidonic acid → hydroperoxides → Leukotrienes

What are the main targets of peripherally acting agents, anesthetic agents, and centrally acting agents? Give their role.

Peripherally acting agents: Target peripheral pain receptors (nociceptors) to prevent sensitization and discharge

• e.g., NSAIDs/aspirin block prostaglandin synthesis at the COX pathway

Anesthetic agents: Target and interrupt the nociceptive signal b/w its peripheral source and central target (in brain or spinal cord)

Centrally acting agents: Target specific CNS receptors to interrupt the pain message +emotional responses (e.g., opioid analgesics)

How does aspirin relieve pain? What is its influence on cyclooxygenase?

→ inhibits prostaglandin E₂ synthesis

• causes irreversible acetylation & inactivation of cyclooxygenase

How does the activity of Aspirin change based on dose?

Low doses = analgesic

Higher doses = anti-inflammatory (3 to 4 g daily)

What are the advantages of adding antacids to aspirin formulation?

• ↓ GI irritation

• ↑ dissolution and absorption rate of aspirin

What are the advantages of nonacetylated salicylates over aspirin (acetylsalicylic acid)?

• Minimal antiplatelet properties

• Less inflammatory

• Fewer GI side effects

  • useful for pt who can’t tolerate aspirin or other NSAIDs

What is the adult dose of aspirin?

325 to 650 mg every 4 hours (not to exceed 4 g/day)

Give some major side effects of salicylates.

• GI disturbances (dyspepsia, gastric irritation, GI bleeding, gastric ulceration/erosion)

• Prolonged bleeding time (12–15 days)

• HA, tinnitus, dizziness, deafness

• Confusion in elderly pt (>70 yrs)

• Reduced renal function

• Acute systemic HTN

• Congestive HF

• Displacement of other drugs from plasma proteins

• Reye's syndrome in children/teenagers with viral infections

What are the 2 ways by which aspirin hypersensitivity can occur?

1. Respiratory reaction - seen in rhinitis, asthma, or nasal polyps pt

2. Type I hypersensitivity reaction - urticaria, wheals, angioedema, itching, rash, bronchospasm, laryngeal edema, hypotension, shock, or syncope

What are the 4 classic signs of salicylism?

1. HA

2. Tinnitus

3. Dizziness

4. Deafness

What are the major contraindications to Aspirin and nonsalicylate NSAIDs?

• Active upper GI disease

• Hx of heavy alcohol use

• Hx of bronchial asthma, nasal polyps, or aspirin hypersensitivity

• Bleeding disorders, anticoagulant therapy, or vitamin K deficiency

• Pre-/postop cataract or other invasive surgery

• Chronic renal or hepatic disease

• HTN or congestive HF

• Pregnancy

• Children or teenagers with flu-like (viral) sx

Give the mechanism of action of nonsalicylate NSAIDs.

→ Inhibit cyclooxygenase in injured or inflamed tissues

• ↓ or eliminating sensitizers (like PGE₂) for peripheral nociceptors

Compare the analgesic efficacy of ketoprofen, ketorolac tromethamine, and Ibuprofen to that of aspirin.

Ibuprofen: Superior

Ketoprofen: Superior

Ketorolac tromethamine: Superior

Give the clinical uses of Systemic NSAIDs.

Treat mild to moderate pain assoc with:

• inflammation

• postoperative pain

• posttraumatic pain

Give the clinical uses of Topical NSAIDs.

1. Corneal abrasions

2. Pre/post Betadine 5% treatment for EKC

3. Post FB removal

4. Post anterior stromal puncture

5. Post PKP or laser procedures

6. Post-cataract surgery care

7. Treating/preventing cystoid macular edema

8. Adapting to punctal plugs

9. Allergic conjunctivitis

10. Photophobia

11. Scleritis (adjunct)

12. Inflamed pterygia/pingueculae

What are the main clinical indications for Bromsite formulation? What is the vehicle used in the formulation and its specific advantage?

Indications

1. Preventing ocular pain in cataract surgery pt

2. Tx postoperative inflammation

Vehicle: DuraSite delivery vehicle

Advantage: Extends the drug's residence time on the ocular surface

Compare the effects of COX-1 and COX-2 isoforms of cyclooxygenase.

COX-1: COX-1 products are cytoprotective in the kidney and gastric mucosa

COX-2: makes prostaglandins in inflammatory rxns

Why is Acetaminophen not a drug of choice for inflammation?

• weak inhibitor of prostaglandin synthesis

• little or no anti-inflammatory properties

What are the clinical uses of Acetaminophen?

• Analgesic for mild to moderate pain when aspirin/NSAIDs are contraindicated

• Pt w/ upper GI disease (ulcers, gastritis), bleeding disorders (hemophilia), post-cataract surgery, pregnancy, or lactation

• Adjunct to narcotics for severe pain

Who is Acetaminophen contraindicated in?

• Chronic alcoholism

• Preexisting liver impairment (due to risk of liver toxicity and severe liver failure)

What is the benefit of including caffeine and belladonna alkaloids in nonnarcotic combinations?

Caffeine - helps tx certain vascular HA syndromes

Belladonna Alkaloids - antispasmodic properties

What are opiates and opioids?

Opiates - agents derived from opium

Opioids - synthetic or natural compounds having morphine-like analgesic properties

How do opioid analgesics work?

produce analgesia by binding to opioid receptors in the brain, brainstem, and spinal cord → alter physical pain sensation + suffering

How are narcotic analgesics classified?

→ based on their activity at opioid receptors:

1. Agonists

2. Partial agonists

3. Mixed agonist–antagonists

Give the 5 major opioid receptors. What are the receptors at which the agonists mainly act?

1. mu (μ)

2. kappa (κ)

3. sigma (σ)

4. delta (δ)

5. epsilon (ε)

   
   

Main Agonist Targets: Most clinically useful opioid agonists act primarily at mu (μ) and kappa (κ) receptors

How do the opioids differ from nonnarcotic analgesics?

DON’T have a ceiling effect (↑ doses = ↑ analgesia)

• Note: pt can develop tolerance to their analgesic effects

Where is codeine metabolized and into what compound?

metabolized in Liver into morphine via the cytochrome P-450 system

What are the main drawbacks of codeine use?

• ↑ sedation

• ↑ GI side effects

• Ceiling effect

Compare the potency and side effects of hydrocodone and oxycodone to that of codeine.

Oxycodone

• 10-12x potent than codeine

• produces more euphoria

• lower incidence of side effects

• has abuse potential

Hydrocodone

• 6x potent than codeine

• less sedation

• less constipation

Give the mechanism of action and application of Tramadol.

→ Centrally acting codeine analogue that binds to mu opioid receptors

• inhibits NE & serotonin reuptake

Application: Tx moderate to moderately severe pain

Identify an opioid analgesic that has MAX efficacy for analgesia and ability to produce euphoria.

Oxycodone

Give major side effects of opioid analgesics on CNS, GIT, respiratory system and the eye.

CNS: Sedation, lightheadedness, confusion, dizziness, drowsiness, disorientation, euphoria, HA

GIT: Anorexia, nausea, vomiting, constipation, dry mouth

Resp System: Bronchospasm, cough suppression, respiratory depression, breathing difficulty/shortness of breath

Eye: Blurred vision, miosis, diplopia

Name the common analgesics (opioids and nonopioids) prescribed for Children.

Nonopioids

• Acetaminophen

• Ibuprofen

• Naproxen

• Tolmetin

Opioids

• Codeine

Name the common analgesics (opioids and nonopioids) prescribed for Elderly.

Nonopioids

• Acetaminophen

• Ibuprofen

• Diclofenac

• Diflunisal

• Fenoprofen

• Naproxen sodium

• COX-2 inhibitors

Opioids

• Codeine + acetaminophen

• Oxycodone + acetaminophen

Identify the drug name + drug concentration associated with the following trade names:

• Motrin

• Aleve

• Celebrex

• Tylenol

• Excedrin migraine tablets

• Anacin

• Lortab

• Vicodin

Motrin: Ibuprofen

Aleve: Naproxen sodium

Celebrex: Celecoxib

Tylenol: Acetaminophen

Excedrin migraine tablets: Acetaminophen (250 mg) + Aspirin (250 mg) + Caffeine (65 mg)

Anacin: Aspirin (400 mg) + Caffeine (32 mg)

Lortab: Hydrocodone + Acetaminophen

Vicodin: Hydrocodone + Acetaminophen

Identify the drug name + drug concentration associated with the following trade names:

• Percocet

• Darvocet

• Ultram

• Ultracet

Percocet: Oxycodone (5 mg) + Acetaminophen (325 mg)

Darvocet: Propoxyphene napsylate + Acetaminophen

Ultram: Tramadol (50 mg)

Ultracet: Tramadol (37.5 mg) + Acetaminophen (325 mg)

Identify the drug name + drug concentration associated with the following trade names:

• Voltaren

• Acular LS

• Acuvail

• Ilevro

• Prolensa

• Bromsite

• Nevanac

Voltaren: Diclofenac sodium 0.1%

Acular LS: Ketorolac tromethamine 0.4%

Acuvail: Ketorolac tromethamine 0.45%

Ilevro: Nepafenac 0.3%

Prolensa: Bromfenac 0.07%

Bromsite: Bromfenac 0.075%

Nevanac: Nepafenac 0.1%