Wk 12 - Analgesic Intro / NSAIDs

Question 1

Local anesthetic agents

Answer 1

• Proparacaine
• Lidocaine
• Benoxinate
• Lidocaine/Prilocaine (EMLA)

Question 2

EMLA cream / patch

Answer 2

Lidocraine / prilocaine mixture
Uses:
-Pre-­‐op for removing skin lesions
-Post-­‐herpetic neuralgia

Question 3

Local anesthetic MOA

Answer 3

Sodium channel blockers

-Block Na channels on nociceptor axons to block the transmission of the pain signal

Question 4

Local anesthetic Adverse Effects

Answer 4

Long term use slows wound healing and can degrade the cornea, so we never Rx these
-Use in-office only

Question 5

Peripherally Acting Analgesics

Answer 5

• NSAIDs

- Aspirin

Question 6

NSAID & Aspirin MOA

Answer 6

COX inhibitors
-Inhibit the enzyme cyclooxygenase to prevent the production of prostaglandins from arachidonic acid
Prostaglandins sensitize nociceptors, so preventing their production helps to prevent pain signal
-NO EFFECT on leukotriene production
-DO NOT prevent the formation of subepithelial infiltrates in the cornea since white blood cell migration is controlled by leukotrienes
- comparison: Remember that steroids inhibit phospholipase to prevent the production of arachidonic acid, prostaglandins, and leukotrienes

Question 7

Centrally Acting Analgesics

Answer 7

• Opiods

- Acetaminophen

Question 8

Opiod & Acetaminophen MOA

Answer 8

Block pain signal to the brain (opioid mu agonists, SNRIs, etc.)

Question 9

Clinical uses of Topical NSAIDs

Answer 9

• Anterior segment
  GOOD:
  o Pain control
  • Abrasions, peri-operative (esp cataract surgery), betadine treatment for EKC
  • Topicals are better than oral NSAIDs for A-Seg pain
  POOR:
  o Anti-inflammatory effects are poorer than oral NSAIDs or topical steroids
  o Limited value in treatment of allergy

-Posterior segment
o Treatment of cystoid macular edema
• Caused by inflammation in the retina
• Topical NSAIDs penetrate to the retina well to inhibit prostaglandin synthesis

Question 10

Adverse effects of Topical NSAIDs

Answer 10

1) May allow formation of subepithelial infiltrates after corneal surgery
2) May delay wound healing
o Not as much as steroids
o Reported more with long term use
3) Corneal melt syndrome
o May cause extreme corneal damage
o More likely in unhealthy eyes and with overdosing
o Generic diclofenac is most likely drug to cause CMS
o Watch patients carefully and stick to FDA recommended dosing
4) Burning, stinging, SPK, and conjunctival hyperemia
o More common with the classic/older NSAIDs
5) Contraindicated in soft CL wearers
o Corneal toxicity and decreased immunity can leave patient more susceptible to bacterial infections

Question 11

Diclofenac 0.1% (Voltaren)

Answer 11

Topical NSAID

•Older formulation, rarely used today

Indications:

• Post-op inflammation after cataract extraction
• Pain and photophobia in patients undergoing corneal refractive surgery

Dosing: 1 gt qid

Question 12

Ketorolac 0.5% (Acular)

Answer 12

Topical NSAID

-Ketorolac is an older NSAID, used occasionally today.

Indications:
• Ocular itching due to SAC
• Post-op inflammation after cataract extraction

Dosing: 1 gt qid

Question 13

Ketorolac 0.4% (Acular LS)

Answer 13

Topical NSAID

Slightly lower concentration reduces stinging

Indication: reduction of pain following refractive surgery

Dosing: 1 gt qid

Question 14

Ketorolac 0.45% (Acuvail)

Answer 14

Topical NSAID

Preservative free

Indication: treatment of pain and inflammation after cataract extraction

Dosing: 1 gt bid

Question 15

Bromfenac 0.7% (Prolensa)

Answer 15

Topical NSAID

Newer formulation used commonly.
Comfortable and well tolerated.
Earlier 0.9% formulations (Xibrom and Bromday) have been discontinued.

Indication: Treatment of post-op inflammation and reduction of ocular pain in patients who have undergone cataract surgery

Dosage: 1 gt qday
= 1 gt the day before surgery, 1 gt the day of survery, and 1 gt qday for 14 days after surgery

Question 16

Nepafenac 0.1% suspension (Nevanac)

Answer 16

Nepafenac is a newer formulation used commonly.

• Comfortable and well tolerated.
• Minimized potential for toxicity
• Pentrates vitreous much better than older NSAIDs like ketorolac

Indication: treatment of pain and inflammation after cataract surgery

Major Off-label use:
Prevention of cystoid macular edema

Dosing: 1 gt tid

Question 17

Nepafenac 0.4% suspension (Ilevro)

Answer 17

Nepafenac is a newer formulation used commonly.

• Comfortable and well tolerated.
• Minimized potential for toxicity
• Pentrates vitreous much better than older NSAIDs like ketorolac

•Similar performance compared to Nevanac
Indication: post-op cataract surgery

Major Off-label use:
prophylactic for CME

Dosing: 1 gt qday

Question 18

General info on Topical NSAIDs

Answer 18

-Diclofenac is FDA Category D ; All the rest are Category C

Dosing:
Diclo and Ketoro (older) = QID
Brom and Ilevro (newer) = Qday
Nevanac (low concentration) = TID

Minimum Age:
Ketoro = 3
Nepa = 10
Brom = 18

Question 19

Oral NSAIDs MOA

Answer 19

Inhibit COX-1 and -2 enzymes to prevent the production of prostaglandins, which sensitize nociceptors

Notes:
1) Ceiling effect
o Beyond a certain dose there is no further analgesic effect
o No ceiling effect in opioids

2) No risk of tolerance or addiction with repeated or chronic use.
o Not the case with opioids

3) Patients vary in response to different NSAIDs.
o If max dose is not effective, switch to an alternate

Question 20

Oral NSAID Side Effects and Possible Complications

Answer 20

1) Renal and liver excretion
o Use caution in patients with history of renal or liver problems, diabetes, or significant use of diuretics
2) Highly protein bound
o Can cause interactions by displacing other drugs from plasma proteins
3) GI upset, ulcers, etc.
o COX-2 is involved in production of prostaglandins that cause pain
o COX-1 produces prostaglandins that have a protective function in the stomach
o Most NSAIDs are COX nonspecific, so they inhibit the production of good prostaglandins in the stomach
4) Bleeding disorders
o Effects on platelets causes blood thinning
o Can worsen bleeding/clotting disorders
o Increased risk of re-bleed in problems like hyphema and vitreous heme
5) CAUTION IN:
o Asthma, aspirin hypersensitivity, after invasive surgery, 3rd trimester pregnancy

Question 21

Aspirin

Answer 21

Oral NSAID

Prototype NSAID
o Analgesic, anti-inflammatory, anti-pyretic, and anti-platelet effects

Clinical uses
o Corneal abrasion
o Conjunctival discomfort from viral infection
o Can be combined with Tylenol, codeine, or other narcotics for an additive pain relieving effect

Toxic reaction
o Tinnitus – ringing in the ears

Formulations
o Buffered aspirin has increased dissolution rate
o Enteric coating can reduce GI problems
o **Avoid either of these in acute pain

Contraindication:
children under 18
o Can cause Reyes syndrome

Question 22

Dosing for Aspirin

Answer 22

Anti-inflammatory dosing
o 3-4 grams/day or 8-16 OTC tabs/day

Adult dose for ocular pain
o Two 325 mg or one 650 mg tab q4h
o Do not exceed 4 gm/day

Question 23

Ibuprofen (Motrin, Advil, Nuprin, Medipren)

Answer 23

Oral NSAID
non-selective COX inhibitor

More effective analgesic than aspirin. 
Half-life is 2 hours. 
Peak levels reached in 1-2 hours.  
Formulations
o	200 mg tabs OTC
o	300-800 mg tabs Rx

Dosing
Adult analgesic dose = 400 mg q4h
2400 mg is anti-inflammatory level
3200 mg is max daily dose

Question 24

Naproxen (Anaprox, Naprosyn, Aleve)

Answer 24

Oral NSAID
non-selective COX inhibitor

May be the safest NSAID
For relief of mild to moderate pain

Adult Rx dose
- 550 mg initially followed by 275 mg q6-8h
OTC dose
- 220 mg q8-12h

Question 25

Ketoprofen (Orudis, Oruvail)

Answer 25

Oral NSAID • 2 hour half life • 50 mg q4h may be as effective as Tylenol+Codeine for analgesia Adult dose o Orudis: 50 or 75 mg q6-8h o Oruvail: 200 mg q?h (Sustained release, Rx only)

Question 26

Ketorolac

Answer 26

Oral NSAID Very potent with a much higher risk of side effects. Used short term only – 5 day max Dosing: 10 mg q4-6h, max 40 mg/day

Question 27

Indomethacin

Answer 27

Oral NSAID Very cheap Dosing: 25-50 mg bid-tid

Question 28

Meloxicam (Mobic)

Answer 28

Oral NSAID • We don’t Rx this much, but common to see patients taking it in clinic • Easier on stomach Dosing: 7.5-15 mg qd

Question 29

Celecoxib (Celebrex)

Answer 29

Oral NSAID MOA: COX-2 selective inhibitor o Fewer gastric side effects Adverse effects: Increased risk of heart attack and stroke Dosing: 100 or 200 mg qday-bid

Question 30

Acetaminophen (Tylenol)

Answer 30

MOA: Centrally acting COX inhibitor o Exact MOA not fully understood o Analgesic and antipyretic o NOT anti-inflammatory or anti-platelet Use: For mild-moderate pain o Often combined with narcotic analgesics Adverse Effects: o Risk of liver, renal tubule, and myocardium toxicity • Contraindicated with liver impairment • Acetaminophen OD is #1 cause of liver failure o Limit of 325 mg added to narcotic agents or other meds to prevent overdose o Known for its safety, except in the case of overdose Comparison to aspirin: o Less GI upset o Greater safety during breastfeeding o Does not affect platelet clotting factors (No bleeding risk)

Question 31

Dosing for Acetaminophen (Tylenol)

Answer 31

Adult dose: 325-1000 mg q4h | Max = 4000 mg/day

Question 32

Synergistic Analgesic Combinations and Adjuvants

Answer 32

Alternate central acting acetaminophen + peripheral acting ibuprofen o Analgesic effect approximates Tylenol #3 (Tylenol+Codeine) in dental and post-op pain studies o 650-1000 mg acetaminophen q4h and 400 mg ibuprofen q4h • Ex. acetaminophen at noon, ibuprofen at 2 pm, acetaminophen at 4 pm, ibupofen at 6 pm Adujvants o Added substances like caffeine can enhance the effect of NSAIDs or narcotic agents

Question 33

NSAID Safety Overview

Answer 33

-Aspirin, Ibuprofen, Meloxicam are all FDA Category D ; Celebrex is C early / D late ; All the rest are Category C. ``` Minimum Age: Ibuprofen = 2 mos Naprox, Melox, Indometh, Aceta = 2 yr Ketoro = 17 yr Aspirin, Ketopro = 18 yr ``` ``` Max Dose Per Day Meloxicam has lowest at 15 mg. Ketorolac is just behind at 40 mg. Indomethacin next at 150-200 mg. Ketoprofen at 300 mg. Celebrex at 400 mg. Naproxen at 1000 mg. Ibuprofen at 3200 mg. Aspirin and Acetaminophen are highest at 4000 mg. ```

Question 34

Points To Remember

Answer 34

Ocular pain is usually acute and short lived, best treated with an opioid + NSAID, aspirin, or acetaminophen Schedule III is usually a safe bet and can be Rx’d by ODs in most states Avoid combining aspirin and codeine with barbiturates o Watch out for polypharmacy! ``` Children o Note dosage recommendations, stick to FDA guidelines, and consult with patient’s pediatrician o Avoid aspirin combinations – Reye’s syndrome o Good choices • Acetaminophen 10-15 mg/kg q4h • Ibuprofen 4-10 mg/kg q6h • Naproxen 5-7 mg/kg q8h • Codeine 0.5-1 mg/kg q4-6h ``` Elderly patients o Usually have poorer renal/liver clearance o Increased risk of side effects • Sedation, constipation, CNS effects o More likely to be on multiple drugs • Interactions, polypharmacy • Opioid allergies are rare o If present, use tramadol or an NSAID as an alternative • Use precautions when writing an Rx to avoid tampering Remember that just because a pain med contains an opioid, it isn’t necessarily the best pain killer • Ibuprofen 400 mg was shown in this study to give better ocular pain relief than Tylenol #4