Current concept updates in NSAID's

Alberto Rivera Sanchez MD FAAPMR, ABPM, ABDAPain Management Sub SpecialistAmerican Board of Pain Medicine

Member of the American Academy of Pain Management

Overview• NSAID’s are the most preferred drug and

prescribed drug for chronic pain (Rasu et al J Pain, 2013)

• Annually 98 million prescriptions filled (Wilcox, J Rheumatol, 2005)

• 23 million people in the US take them OTC (Wilcox, J Rheumatol, 2005)

Overview• Anti pyretic action• Anti-inflammatory action • Analgesic properties• Indicated for mild to moderate pain• Preferred to opiates due to effectiveness

and limited potential for abuse (Atchison W, et al JCMP Nov. 2013)

Overview• All of them inhibit COX• Cox 1 is in the stomach and kidney• Cox 2 is in the joints• Steroids also work on Cox• Once Cox is inhibited the cascade shifts to

LOX

• To tea or not to tea

Overview• All NSAID’s inhibit the prodution of PG by

inhibiting the activity of PGG/H synthase, a.k.a. COX

(Crofford LJ. J Rheumatol Suppl. 1997;49:15-19)

Overview

• LOX produces leukotrienes (LT)• LTE4 elevation in urine is linked to ASA

induced asthma. TH Lee, Thorax, Dec 1993

• LT are linked smooth muscle inflammation and increase vascular permeability

Overview• Dyspepsia and nephrotoxocity is due to

Cox-1 inhibition• Metabolized thru p450 the cyp substrate

varies with medication not just subtype• Follow up labs are essential• Always measure risks over benefits

Overview

• All are lipid soluble and highly bound to plasma protein

• Renal and hepatic failure affect the kinetics and elimination of NSAID’s

• The amount of drug in the synovial fluid is dependent on the level of albumin in the joint

Am J Med 2009;122:836-842

• Users of COX-2 inhibitors (n=40) had decreased knee cartilage defect development in the medial tibiofemoral compartment (OR 0.4), whereas users of conventional NSAIDs (n=21) had increased knee cartilage defect development in both medial (OR 3.1) and lateral (OR 2.6,) tibiofemoral compartments according to an MRI study

Aspirin

Excretion80-100% in urine

SalivaSweat Liver

- Inhibits COX- Inhibits platelet aggre-

gation by blocking PG mediated

Degranulation- Inhibits platelet COX-1 thereby preventing TxA2

Aspirin• Pain dose is 300mg QID up to 1000mg QID• Max dose 4000mg• It is rarely used for pain• The effect on the platelets lasts for 10 days

which is the lifespan of the platelet• PUD related to ASA are due to systemic

rather than local

Aspirin Contraindications- Bleeding disorders (VII and/or IX)- Asthma- Sensitivity to NSAID’s- Tartrazine dye (yellow food and drug coloring)- PUD- Uncontrolled HTN- Pt using NSAID’s- Children less than 16y/o with Varicella or Flu-like syndromes

Aspirin• PPI’s are the consensus as the mainstay of Tx and

prevention of GI ulcers and bleeding in patients on antiplatelet therapy who are at increased risk of bleeding

• AHA, ACC & ACG expert consensus document (Circulation 2008)

• PPI’s may interfere with ASA antiplatelet action (BMJ 2011)

• Aspirin-Phosphatidylcholine resulted in fewer ulcer and erosions in industry sponsored clinical trials (Am J Gastroenterology 2008)

Naproxen• 500mg BID or TID• 275mg-550mg BID or TID• Onset of action for analgesia is 1 hour• Onset of action for anti-inflammatory effect is 2

weeks • Duration is 7 hours• NSAID of choice in the high CV risk patient (Ann

Rheum Disease 2007)

Naproxen in ADAPT

• Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) showed an increase in the risk of cardiovascular events in patients given naproxen but not in those given celecoxib; the trial was halted

ADAPT trial- NSAIDs may protect subjects carrying

one or more ε4 allele of the apolipoprotein E against the onset of Alzheimer's disease

- 4-year follow-up revealed that subjects previously exposed to naproxen 440mg/day were protected from the onset of AD by 67% compared to placebo

Ibuprofen• Its elimination does not appear to be affected

in liver disease. (Menkes CJ. Scand J Rheumatol Suppl. 1989)

• Inhibits both COX-1 and Cox-2

• Onset of analgesia is 30 minutes

• Durarion 4-6 hours

• Use should not exceed 10 days nor 3,200mg/day

Ibuprofen• OA or RA 1200mg-3200mg/day• Dysmenorrhea 400mg every 4 hours• Mild to moderate pain 400mg every 4-6

hours as needed• Increase CV risk in elderly (Arthritis Care Res

2008)

• High rate of CV events in pt with prior MI

Nabumetone• 500mg-1000mg with meals• 750mg BID with meals• Max dose: 1500mg-2000mg/day• Has low incidence of GI upset, no

interference with platelets • Elevates LFT’s in 1-5%, transitory

Nabumetone Side Effects per time of use

• At <1 month: dyspnea, pain, pruritus, rash, edema, CHF, low plt, urticaria, myalgia

• 1-6 months: AMI 4.5% (N=196), ARF 1.74% (n=76), diarrhea 7.41% (n=323)

• Total of 4,358 pts reporting in ehealthme.com

• May cause photosensitivity

Meloxicam• NSAID with dose dependent COX 2

selectivity• 7.5mg is more COX 2 selective than 15mg• Short term 7.5mg daily is less likely than

naproxen or diclofenac to be associated serious GI complications

• Elevates liver function tests in 15%

Sulindac• Onset of action: 1 hour• Half life of active metabolite is 18 hours• Excretion 50% in urine, 25% feces• Metabolism: Liver• Maximum therapeutic response is seen at 3

weeks

Sulindac• 150mg-200mg BID with meals• Max dose 400mg/d• Associated with lethal hypersensitivity• High rate of GI bleeding• Less likely to inhibit renal PG synthesis and

affect renal function than the other NSAID’s

Sulindac Interactions• ACE inhibitors• Anticoagulant

s• Angiotensin II

antagonists• Antiplatelet

drugs• Cyclosporine

Non pharmacologic Tx:- Ethanol

- Red clover- Horse chestnut

- Ginger- Gingko biloba

- Primrose- Feverfew- Cat’s claw- Green tea- Ginseng

• Lithium

• Loop diuretics

• Thiazide diuretics

• Warfarin

• Hydralazine

Celecoxib• Celecoxib must be used when other

NSAID’s have failed (Circulation 2006)

• Associated with high cardiac risk and lower GI AE’s

• It is not the most selective Cox-2 inhibitor• Preffered to regular NSAID’s in pt with high

risk CV already on low dose ASA (Lancet 2007)

Black Box Warning on all NSAID’s

GI events• Do not mix any NSAID or COX 2 inhibitor

with Warfarin, high risk of GI hemorrhage (Arch Int Med 2005)

• There is a protocol for COX 2 and Warfarin• Beware as protocol does not prevent

hemorrhage• Use celecoxib with PPI in patients with high

GI risk

GI events• Pts treated with conventional NSAIDs are 5X

more likely to be hospitalized with GI problems ( Drug Safety 2004)

• Ulcer complications occur less often with COX2 inhibitors (Lancet 2004)

• COX2 therapy does not reduce the use of PPI (ACR 2004)

• Previous bleeding ulcers will recur even on celecoxib or diclofenac/omeprazole (Gastroenterology 2006)

Oral vs Topical

• A meta-analysis evaluating 34 studies from 7,688 adults with chronic musculoskeletal pain found that topical NSAID’s provided adequate pain relief, equivalent to oral NSAID’s for hand and knee OA ( Derry S. et el Chocrane Database Syst Rev. 2013;4:Cd008040)

Cardiac events• Significant increase in the rate ratio for

myocardial infarction with COX-2 inhibitors compared with placebo. (Kearney et al. BMJ 2006)

• 8 placebo controlled, randomized trials, showed that NSAID’s posed a cardiovascular hazard, similar in magnitude to that resulting from being a smoker or a diabetic (G Fitzgerald, Penn Medicine May 2012)

Cardiac events• Heart healthy patients taking NSAIDs for

prolonged periods might be gradually increasing their risk of heart attacks and strokes by progressively hardening their arteries U Penn Medicine 2012

• In a cohort study of 565,451 US veterans NSAID’s increase risk of CV events but decrease mortality in both non-CAD and CAD (Am J Med 2007)

Cardiac events• Diclofenac has the same CV risk as

Rofecoxib (Danish National Database June 2010)

• Even short term NSAID use (selective and non selective) was associated w/ CV events according to 83,000 pt registry data (Circulation 2011)

• A fib risk increases with both selective and non selective in new users BMJ 2011

Adverse Events

• Endoscopic studies have demonstrated that gastric or duodenal ulcers develop in 15% to 30% of patients who regularly take NSAIDs (Laine, Gastrointest Endosc Clin N Am1996)

AnalgesicPercent with at least

50% relief Number needed to treat

Ketorolac 60 56 1.8

Ibuprofen 800 100 1.6

Diclofenac 100 67 1.9

Naproxen 550 46 3.0

Tramadol 150 48 2.9

Tramadol 100 30 4.8

Tramadol 50 19 8.3

Codeine 60 15 16.7

Oxycodone 5/325 24 5.5

Morphine 10mg IM 50 2.9

Placebo 18 N/A

Oxford League Table (Most frequently used)

Conclusions• NSAID’s should be used in the lowest possible dose for the

shortest time necessary• Use celecoxib or COX 2 inhibitors cautiously• Alert patients of the cardiac risks• Look for alternative medicine options• Dietary changes, PRP, prolotherapy, Stem Cell Tx and

herbal supplements are more appealing than lawsuits• Explore the option of Radiofrequency Lesioning, SCS