The usual purpose of NSAIDs is to reduce inflammation and associated pain
by inhibiting the COX-2 enzyme, which would otherwise
produce mostly inflammation-promoting prostanoids
from omega-6
arachidonic acid (AA) fatty acidsresiding
in cell membranes. Prostanoids are a subgroup of eiconsonoids(all produced
from the essential omega-3 and omega-6
polyunsaturated fats), which predominately have the effect
of promoting inflammation with its associated
pain, blood-clotting and cell proliferation. Eicosonoids act as hormones in
local areas of trauma / infection, ALL vitally involved in mediation of:
The traditional NSAIDs, such as Beyer®Motrin®, Advil®and Aleve® inhibit
both of these enzymes, preventing both the inflammatory
and anti-inflammatory
functions of eicosanoids.
Effects maintained throughout the 10-day life of the platelet.
Use of Cox-1 inhibitor NSAIDs significantly increases risk of death
COX-1 inhibitors include aspirin, Aleve, Advil and Motrin
Unfortunately, when NSAIDs block the COX-1
enzyme the body loses some important functions provided by this enzyme.
Including:
-
Maintaining the integrity of mucosal cells lining the stomach and
intestines. Thereby promoting stomach and dudenal ulcers
-
Helping maintain kidney function.
-
Promoting blood clotting. Low dose aspirin
is largely used as a prevention for CVD and heart attacks. However,
there is some evidence that concurrent use with other NSAIDS, which generally
do not have this CVD prevention benefit, may inhibit aspirin's antiplatelet
effect.
The loss of such protective functions easily explains the unwanted side-effects
of using COX-1 inhibiting NSAIDs. In fact, extended use of COX-1
inhibiting NSAIDS can cause GI discomfort and stomach ulcers leading to internal
bleeding. A 2000 analysis including data of 250,000 patients from 15 randomized
clinical trials, found that, on average, one of 1220 patients who take NSAIDs
for at least two months will die as a result of gastroduodenal complications.
This presents a pretty significant risk of dying! --- In perspective, it is 1000
times more perilous than taking a single flight.
Number Needed To Kill Individual Drug Risk with NSAIDs, 2000
And to hammer home this alarming risk ---
comparing data published from pre-1997 to that from 1997-2008, mortality in patients
suffering from an upper gastrointestinal bleed or perforation has fallen from
1 in 9 to 1 in 13 overall,
but has actually increased from about
1 in 7 to 1 in 5 in those exposed to NSAIDs!
Straube et
al, 2009
Selective COX-2 inhibiting NSAIDs
In light of problems caused by inhibiting COX-1, some newer NSAIDS selectively
block only the COX-2 enzyme.
- Celecoxib (Celebrex®)
- Obscenely expensive Rofecoxib (Vioxx®, recalled in 2004)
was an attempt at suppressing COX-2, whilst
preserving COX-1. It FAILED,
causing an estimated 60,000 deaths due to heart attack or stroke.
However, selective COX-2 inhibitors
ONLY HALVE the incidence of serious gastrointestinal events seen with
COX-1 inhibitors. This may partially reflect
their impact on epithelial COX-2-dependent
prostaglandins and thromboxane that accelerate ulcer healing in the stomach and
intestinal duodenum.
NOTE: unlike aspirin, COX-2 inhibitors
are not effective for preventing strokes or heart-attacks in individuals at high
risk for such.
Alternative anti-inflammatory treatments
Salicylates - promising anti-inflammatory drugs
(also lower blood sugar)
Do not affect the Cox enzymes at all, but instead
inhibit the master factor in inflammation called NF-kB.
This is activated in response to stress, cytokines [E.g. TNF, IL-1b], free
radicals, UV radiation, ionizing radiation, oxidized LDL, bacterial / viral infections,
cocaiine);
Generic form called salsalate is better tolerated than sodium salicylate
Salicylates not only reduce inflammation, they also lower blood glucose.
In 2013, researchers published results of stage 2 of a clinical trial called
TINSAL-T2D (Targeting Inflammation using Salsalate in Type 2 Diabetes), which involved
286 participants who could not adequately control their blood sugar levels with
medication. 48 weeks of treatment lowered HbA1C by 37% more than placebo group.
Goldfine
et al, 2010
NATURAL, SELECTIVE COX-2 Inhibitors
Many
phytonutrients contain selective
COX-2 inhibitors - including, amongst many others:
-
Polyphenols (anthocyanins) in cherries
-
Curcumin in curries and yellow mustard (not brown or Dijon)
Phytonutrients - Anti-inflammatory, Anti-oxidant and/or Anticancer
Acetaminophen (E.g. Tylenol®) is a pain-killer, not an anti-inflammatory drug
Acetaminophen, although not an NSAID, also inhibits prostaglandin synthesis,
but is less likely than NSAIDs to increase blood pressure or cause stomach pain
/ bleeding, However, it may cause liver damage / failure, especially
at high doses. Addtionally, It can increase the anti-blood-clotting effect of the
blood-thinner warfarin.
Anti-inflammatory tactics
How to moderate eicosonoid/prostanoid effects
How to treat CHRONIC
Inflammation
How to treat ACUTE
(Short-lived) Inflammation
References
Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts
H, Taubert KA. (2007) Use of nonsteroidal anti-inflamatory drugs: an update for
clinicians: a scientific statement from the American Heart Association. Circulation
2007; 115 (12): 1634-42.
Circulation
Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA,
Shoelson SE (2010 Mar 16) The effects of salsalate on glycemic control in patients
with type 2 diabetes: a
randomized trial Ann Intern Med 152(6):346-57
PubMed
S.Straube et al (2009 Jun 5) Mortality with upper gastrointestinal
bleeding and perforation: effects of time and NSAID use. ;BMC Gastroenterol. 9:41.
PubMed
Number Needed To Kill Individual Drug Risk with NSAIDs
Tramèr MR, Moore RA, Reynolds DJM, McQuay HJ (2000) Quantitative estimation of rare
adverse events which follow a biological progression - a new model applied to chronicNSAID
use. Pain 85:169-182
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