NSAIDs are the most effective pain relievers available.  Over-the-counter ibuprofen and naproxen are quite effective.  However, NSAIDs are considerably overused, especially at higher dosages for long periods of time, which may result in peptic ulcers, kidney damage, hypertension, and heart disease.  Their long-term usage can be minimized by positive strategies such as glucosamine/chondroitin for cartilage and tendon damage and vitamin K and bisphosphonates for bone damage.

Habituation and rebound pain can occur.  Treatment should be started at the lowest dosage, since side-effects are dosage related.  Doctors often jump to high doses prematurely.  Doses over 1600 mg/day of ibuprofen are associated with increased rates of kidney damage.  Still, hypertension is minor with NSAIDs and bleeding ulcers are primarily a problem for the elderly.  Individuals with risk factors for ulcer bleeding should take Prilosec ($22/month) as use other preventive strategies.  Melatonin, taurine, and misoprostol are also very protective with the first two very inexpensive over-the-counter.

Death from peptic ulcer disease due to all cause were reported as 4,604 deaths in the USA in 1999 (NVSR Sep 2001); The CDC gives 6,500 deaths per year as the correct figure. H. pylori is the main causative factor, followed by tobacco, advanced age (over 59 and especially over 75). NSAIDs cause at most 50% of deaths or up to 3,250 per year and probably many fewer.  While it is popular to quote the figure of 15,000 to 20,000 deaths per year as being due to NSAID induced GI bleeds, this is a grossly inflated figure.  The deaths that occur are mainly in the elderly over age 75.  Also, NSAIDs may reduce deaths from other factors. Prilosec ($22) reduced the risk of GI bleeds by 75% and H2 blockers may also help. Misoprostol 200 mg twice a day is quite effective, but somewhat more expensive ($60/month).

Clinical factors associated with an increased risk of complicated NSAID ulcer disease include age older than 75 years, history of PUD, history of gastrointestinal bleeding, corticosteroid use, and cardiac disease. In a large study of patients with rheumatoid arthritis taking chronic NSAIDs, ulcer complications occurred in only 0.4 percent of patients with none of these risk factors, in one percent when one factor was present, and in nine percent when all four factors were present. It is these high-risk patients who should be placed on preventive therapy, e.g. Prilosec.

For non-medication interventions, animal research suggests that melatonin and taurine may considerably lower the risk.  They also have numerous other health benefits, especially melatonin, which is my current favorite at 12 mg/night for $5 per month.  Many other herbal remedies have single studies in animals in the past year including Cuachalalate methanol extract, Asparagus racemosus Willd (Shatawari) and Withania somnifera Dunal (Ashwagandha) root extract, Pterocarpus santalinus, Usnea longissima, essential oil from Casearia sylvestris leaves, Desmodium gangeticum (available from iherb.com 38 mg with olive leaf for hypertension, but omeprazole did better and the dose in the study was much larger than 38 mg.), Mammea americana L., Aronia melanocarpa fruit juice, astaxanthin (available on iherb.com but human equivalency unclear), and Justicia prostrata.  However, none has more than a small amount of research and absolutely no human research to date.

NSAID Deaths Vastly Overrated: Guess and coworkers conducted the largest epidemiologic cohort (follow-up) study on the subject until now in a defined population of 1 million residents. Among 111,478 users of NSAIDs younger than 75 years, the authors identified only 1 case of NSAID use associated with a fatal peptic ulcer complication. Guess HA, West R, Strand LM. et al. Fatal upper gastrointestinal hemorrhage or perforation among users and nonusers of nonsteroidal anti-inflammatory drugs in Saskatchewan, Canada 1983. J Clin Epidemiol 1988;41:35–45. Clinical studies indicate that male sex, prior peptic ulcer disease, advanced age, high NSAID dose, and combination of NSAIDs with corticosteroids or anticoagulants are high risk factors for NSAID-related ulcer complications, such as bleeding or perforation.

Delayed Bone Healing esp with Cox-2 Inhibitors, but Not Other NSAIDs or Acetaminophen: University of New Jersey 253 young rats with a splinted broken leg either Vioxx, Celebrex, indomethacin or no drug. A second study from the UMDNJ-New Jersey Medical School with rats found that celecoxib, but not acetaminophen slowed bone healing. J Orthop Trauma 2005 Nov-Dec;19(10):717-23.

Large Prospective Study Finds Low Risk of GI Bleeds and Relief by Proton Pump Inhibitors: In a nested case-control study of 367 UK general practices of all patients aged 25 or more with a first ever diagnosis of an adverse upper gastrointestinal event (peptic ulcer or haematemesis) and up to 10 controls per case, the incidence of adverse upper gastrointestinal events was 1.36 per 1000 person years. Using 9,407 incident cases and 88,867 matched controls, increased risks of adverse gastrointestinal events were associated with current use of cyclo-oxygenase-2 inhibitors and with conventional non-steroidal anti-inflammatory drugs. Risks were reduced after adjustment for confounders but remained significantly 112% increased for naproxen, 96% for diclofenac, and 56% for rofecoxib but not for current use of celecoxib (11%). Researchers found clinically important interactions with current use of ulcer healing drugs that removed the increased risks for adverse gastrointestinal events for all groups of non-steroidal anti-inflammatory drugs except diclofenac, which still had a 49% increased odds ratio. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. Hippisley-Cox J, et al. University of Nottingham, UK. . BMJ 2005 Dec 3;331(7528):1310-6.

Proton-Pump Inhibitors Markedly Reduced Ulcers: In two DB PC studies, VENUS (United States) and PLUTO (multinational), a total of 844 and 585 patients requiring daily NSAIDs, including COX-2 inhibitors were randomized to receive esomeprazole (20 or 40 mg) or placebo, daily for 6 months. In the VENUS study, patients who developed ulcers over 6 months were 20.4% on placebo, 5.3% on esomeprazole 20 mg (p < 0.001), and 4.7% on esomeprazole 40 mg (p < 0.0001). In the PLUTO, the values were 12.3% on placebo, 5.2% with esomeprazole 20 mg (p= 0.018), and 4.4% with esomeprazole 40 mg (p= 0.007). Significant reductions were observed for users of both non-selective NSAIDs and COX-2 inhibitors. Pooled ulcer rates for patients using COX-2 inhibitors (n = 400) were 16.5% on placebo, 0.9% on esomeprazole 20 mg (p < 0.001) and 4.1% on esomeprazole 40 mg (p= 0.002).

Misoprostol Reduced Hospitalization for Peptic Ulcer Disease: In a study of 1 million people in Saskatchewan, Canada, entitled to drug plan benefits, patients who filled a prescription for one of the 4 study NSAID (18,424 individuals) were then followed for 6 months to determine outcomes. Compared to Arthrotec (diclofenac plus misoprostol 200 mg) the adjusted odds of hospitalization for PUD for participants taking nabumetone was 2.6, diclo+coRx 6.8, and naproxen 7.9. No significant differences were noted in terms of admissions for GI hemorrhage. Risk of hospitalization with peptic ulcer disease or gastrointestinal hemorrhage associated with nabumetone, Arthrotec, diclofenac, and naproxen in a population based cohort study. Ashworth NL, et al. University of Alberta, Canada. . J Rheumatol 2005 Nov;32(11):2212-7.

Netherlands Study Find GI NSAID Bleeds Disease of the Elderly: In 2000, data of all 361 patients presenting with peptic ulcer bleeding were prospectively collected in a defined geographical area, including 14 hospitals, and serving a catch area of 1.68 million persons. The overall incidence was 21.5 cases per 100,000 persons. Mean age was 71, and 41% had severe or life-threatening comorbidity. NSAIDs were used by 52%, and in only 17% concomitant acid suppressive therapy was given. Of the patients tested for H pylori, 43% were positive. Mortality during initial admission was 14%. During follow-up mortality was high, 29%. Almost a quarter of the ulcers were associated with neither H pylori infection nor NSAID use. Mortality, both during hospitalization and follow-up, was substantial. Outcome of peptic ulcer bleeding, nonsteroidal anti-inflammatory drug use, and Helicobacter pylori infection. Ramsoekh D, et al. Amsterdam, The Netherlands. Clin Gastroenterol Hepatol 2005 Sep;3(9):859-64. Ed: In this elderly and very sick population, assuming that 100% of the NSAID associated immediate deaths were due to the NSAID, this rate would equal 4,300 for a population the size of the U.S.  In fact, most of the patients dying were already seriously ill due to other diseases. An average of one death per year was linked to an NSAID ulcer bleed in a large Dallas VA hospital in primarily elderly males in poor health. Am J Surg 2005 Nov;190(5):775-9.

Heliobacter Elimination Helps, But Proton Pump Inhibitor Better: In a meta-analysis for 5 randomized trials (939 patients) comparing H. pylori eradication vs. non-eradication or eradication vs. a proton pump inhibitor in patients receiving a non-steroidal anti-inflammatory drug, 34 of 459 (7.4%) patients developed a peptic ulcer in the eradicated group vs. 64 of 480 (13.3%) in the control group. Sub-analyses showed a significant reduction of risk for non-steroidal anti-inflammatory drug-naive (odds ratio = 0.26; 95% confidence interval: 0.14-0.49) but not for previously treated patients (odds ratio = 0.95, 95% confidence interval: 0.53-1.72). Two studies with a total of 385 patients compared eradication vs. a proton pump inhibitor; five of 196 (2.6%) developed a peptic ulcer in the eradicated group vs. zero of 189 (0%) in the proton pump inhibitor group. Meta-analysis: role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users. Vergara M, et al. Universitat Autonoma de Barcelona, Spain. Aliment Pharmacol Ther 2005 Jun 15;21(12):1411-8.

Cox II Inhibitors Vioxx and Celebrex May be Bad to the Bone: Indomethacin rats took a week longer to heal than untreated rats; the resulting bone was as strong. Rats given Vioxx or Celebrex hadn't fully healed after two months and what new bone formed sometimes was only a weakened shell, J. Patrick O'Connor J Bone and Mineral Research 5/02. Brit research found applies to human bone healing, too.  Indomethacin is an inexpensive prescription NSAID

Acetaminophen, NSAID Deaths: BMJ brief claims 450 US deaths per year due to liver damage from acetaminophen overdoses and 16,000 deaths from GI bleeds due to NSAIDs! Ed: I simply don’t believe the latter figure. This is 3 times the total number of deaths from peptic ulcer bleeding of all causes for the United States.  BMJ 9/28/02.

Change in BP Meds Uncommon: Study of 5000 osteoarthritis on rofecoxib, ibuprofen 800 TID, diclofenac in phase II/III study found HBP due to meds rare. Only one renal failure and due to ibuprofen. Curr Med Res Opin 2002;18(2):82-91;

No Impact on ACE Rx: Study of ibuprofen and two others for 30 days each with 24 HBP pt on ACE Inhib and diuretic found no change in BP. East Afr Med J 2001 Oct;78(10):507-9; Similar lack of change in DB of 167 Rx verapamil. Arch Intern Med 1995 May 22;155(10):1049-54

Slight Incr BP with HCTZ: BD study patients started on HCTZ for BP and ibuprofen 800 TID or naproxen added found 2 mmHg incr BP at 4 weeks. J Clin Pharmacol 1993 Oct;33(10):971-8

BP Impact of Ibuprofen Minimal: Arch Intern Med 1993 Feb 22;153(4):477-84. Fifty-four studies with 123 NSAID treatment arms met inclusion criteria. The mean age of subjects was 46 years. Of the 1324 participants, 1213 subjects (92%) were hypertensive. Impact only on hypertensive patients and mean arterial BP incr with ibuprofen less than 1 mmHg.

No Diff Cox-2: No differential incr CV deaths or HBP in DB randomized long-term study of 8000 with cox-2 or ibuprofen or diclofenac. Am J Cardiol 2002 Feb 15;89(4):425-30. Adding ASA didn’t affect rate of MI.

Rofecoxib Worse Renal: Review of databases found celecoxib and traditional NSAID better in renal function, renal failure, HBP, heart failure. : Clin Ther 2001 Sep;23(9):1478-91

Small BP Incr in Elderly: In DB study of 22 on HCTZ, ibuprofen 1800/d for 4 weeks incr systolic BP 4 mmHg. J Gerontol A Biol Sci Med Sci 1996 Mar;51(2):M74-9

Taurine: Ulcers: Misoprostol and taurine each very protective against monochloramine ulcerogenesis in rats. Spasov AA, et al. Volgograd State Medical University. Bull 2006 Mar;141(3):334-6.

Taurine: Alendronate Damage Prevented: Alendronate (ALD) causes serious gastrointestinal adverse effects. Chronic oral administration to rats of ALD induced significant gastric damage, increasing lipid peroxidation, MPO activity and collagen content, as well as decreasing tissue GSH levels. Treatment with taurine prevented the damage and also the changes in biochemical parameters. ALD induces oxidative gastric damage by a local irritant effect, and that taurine ameliorates this damage by its antioxidant and/or membrane-stabilizing effects. Sener G, et al. Marmara University, Istanbul, Turkey. Fundam Clin Pharmacol. 2005 Feb;19(1):93-100.

Ulcers: Proton Pump Inhibitor Decreases NSAID Induced Ulcers: Esomeprazole (Nexium) prevented ulcers among 573 long-term painkiller users and produced few side effects. James Scheiman, University of Michigan, Baltimore meeting of the American College of Gastroenterology 10/14/03. Everyone in the study was at an increased risk of developing ulcers because of their regular painkiller use combined with a history of previous ulcers (about 26 percent), an age over 60 years (about 64 percent), or both (about 10 percent). Those on placebo instead of esomeprazole, 12.3 percent developed either a gastric ulcer or duodenal ulcer in the six months of the study. But the ulcer rate was 5.2 and 4.4 percent, respectively, for non-Cox II inhibitor NSAID users who received either 20 milligrams or 40 milligrams of esomeprazole daily. In the small subgroup of patients who were using Cox II inhibitors, 17 percent taking placebo pills developed ulcers. (Ed: Prilosec and generic omeprazole (Prilosec) are available over-the-counter. Nexium costs $5 a pill while generic while generic omeprazole is available online for as little as 23 cents.)

Ganoderma Helped NSAID Ulcers in Rats: The water-soluble PS fractions from Ganoderma lucidum (Reishi mushroom) have been shown to inhibit indomethacin-induced gastric mucosal lesions in rats. Oral administration of G. lucidum PS at 0.5 and 1.0 g/kg for 2 weeks caused a significant acceleration of acetic acid-induced ulcer healing by 40% and 56% in rats. J Med Food 2004 Winter;7(4):417-21.