Natural formulation is as effective as prescription 
NSAID against osteoarthritis of the knee 
By Edward R. Rosick, D.O., M.P.H.

One of the most common questions I get from patients doesn’t even concern their health: “What’s a D.O.?” The question is not that surprising, since only about 10% of U.S. doctors are osteopathic physicians; the other 90% are allopaths, or M.D.s. The short answer is that D.O.s are fully licensed physicians with all the medical privileges of their M.D. counterparts, but D.O.s are traditionally better versed in holistic, or “whole-person,” medicine. As part of this approach, they use whole-body manipulation techniques (not to be confused with the manipulations practiced by politicians!) to treat a variety of illnesses—especially those that affect the musculoskeletal system.

Osteoarthritis—NSAIDs Help, but at What Price?

One of the most common such illnesses is osteoarthritis (OA), a painful condition affecting mainly the middle-aged and elderly. It is estimated that at least 20 million Americans suffer from this often debilitating disease. Despite decades of research on OA, scientists are still not sure what causes it. Patients suffer progressive degeneration of all the joints in their bodies, but the ones most commonly afflicted are the hands and knees. In young and middle-aged people, OA of the knees is more often seen in men, but in older people, its incidence increases more rapidly in women. The joint degradation in severe cases is very painful and can cause significant loss of mobility.

When OA patients visit a doctor’s office, they can be pretty sure of getting a prescription for a nonsteroidal anti-inflammatory drug (NSAID). That’s because inflammation can be a significant factor in their pain, even though osteoarthritis is not primarily an inflammatory disease (rheumatoid arthritis, however, is). Although NSAIDs, both prescription and over-the-counter, are analgesics and are usually helpful in easing the pain and increasing mobility in OA patients, they do nothing to stop the progression of the disease. Furthermore, they can have serious and potentially life-threatening side effects, such as ulcers, gastrointestinal bleeding, and cardiovascular problems (see the sidebar “Hard Times for NSAIDs”). There is even some evidence that NSAIDs may actually worsen the progression of OA.1



Hard Times for NSAIDs

In April 2005, the U.S. Food and Drug Administration “asked” Pfizer, the manufacturer of the popular prescription NSAID valdecoxib (Bextra®) to withdraw the drug from the marketplace. The FDA had concluded that the overall risk/benefit ratio of Bextra was “unfavorable” owing to the following factors:

  • Insufficient data on cardiovascular safety with long-term use, in addition to a heart-health risk from even short-term use
  • Reports of potentially life-threatening skin reactions in both short-term and long-term users
  • A lack of any demonstrated advantages when compared with other NSAIDs

The FDA has also taken a second look at other NSAIDs, both prescription and over-the-counter (OTC). They’re asking the manufacturers of all prescription NSAIDs to revise their package inserts so as to highlight the potential for cardiovascular problems as well as other known adverse effects. And they’re asking the manufacturers of OTC NSAIDs to revise their labeling to include more specific warnings regarding potential gastrointestinal and cardiovascular risks.

The FDA has been concerned about the safety of both OTC and prescription NSAIDs for some time. In January 2004, they issued a safety paper on OTC NSAIDs and acetaminophen (which is an analgesic but not an anti-inflammatory).1 Later in 2004, they further refined their warnings regarding NSAIDs, announcing that long-term use of naproxen (Aleve®, Naprosyn®) and other OTC products might be associated with an increased cardiovascular risk compared to placebo. This warning emerged from a clinical trial—the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT)—that was being conducted to assess the potential role of anti-inflammatory drugs in preventing Alzheimer’s. The study was halted when initial data indicated an increase in cardiovascular and cerebrovascular events among those patients taking naproxen.

Also in late 2004, another clinical trial—this one using a prescription NSAID, celecoxib (Celebrex®)—was halted. The National Cancer Institute was investigating the potential of celecoxib for preventing adenomas. The researchers halted the study, however, when they discovered a 2.5-to-3.4-fold increase in fatal and nonfatal cardiac events in patients taking Celebrex, compared to those taking placebo.

Because of these problems, the FDA issued an “FDA Talk Paper” in December 2004 that detailed multiple public health concerns regarding NSAIDs.2 The paper stated that “FDA is issuing an advisory because of recently released data from controlled clinical trials showing that the COX-2 selective agents (Vioxx®, Celebrex, and Bextra) may be associated with an increased risk of serious cardiovascular events (heart attack and stroke) …”

All these warnings serve as a reminder that NSAIDs should generally be used only for short periods (2 weeks or less) unless specifically recommended by a physician. For long-term use, there are safe, natural supplements that can help ease the pain of arthritis.


  1. Safety concerns associated with over-the-counter drug products containing analgesic/antipyretic active ingredients for internal use. January 22, 2004.
  2. FDA issues public health advisory recommending limited use of COX-2 inhibitors. December 23, 2004.


Nonpharmacological Treatment Is Key

So if a patient can’t tolerate the side effects of NSAIDs, what else can a doctor do to help? Not a lot, but a lot more than prescribing drugs. The real cornerstone of OA therapy consists of nonpharmacological measures, such as therapeutic exercises for pain relief and restoration of function, and cognitive-behavioral therapy for developing coping skills and building self-confidence. In addition, osteopathic manipulation by a D.O. can help regain some lost mobility, and surgery is sometimes used to replace joints that have been severely degraded. As with NSAIDs, unfortunately, none of these measures can do anything to affect the progression of the disease—they provide symptomatic relief only.

The only agents that can affect the progress of the disease are two nutritional supplements, glucosamine and chondroitin, which are a boon for osteoarthritis sufferers.* This article, however, is about certain other safe, natural supplements—two enzymes and a flavonoid—that can help ease the pain and increase the mobility of people with OA.


Anti-Inflammatory Enzymes and Flavonoids Can Help

Some preliminary studies have shown that certain enzymes, such as bromelain, can be useful as anti-inflammatory agents for the treatment of both osteoarthritis and rheumatoid arthritis. In an open-label (non-placebo-controlled) study on mild knee pain of unspecified origin in otherwise healthy, young-to-middle-aged adults, researchers tested the effects of 200 and 400 mg daily of oral bromelain over a 1-month period.2 The results were favorable, showing significant reductions in knee pain as well as subjective improvements in general well-being. The effects were dose-dependent, i.e., the 400-mg dose was substantially more effective than the 200-mg dose.

Flavonoids are compounds that give many flowers, fruits, and vegetables their bright colors. Many are antioxidants, and they have a wide variety of biological activities, including antimicrobial, antiviral, and antineoplastic effects. In addition, certain flavonoids have potent anti-inflammatory activity. A recent study examined three flavonoids—rutin, quercetin, and morin—in animal models of both acute and chronic inflammation.3 Although all three compounds showed anti-inflammatory activity for chronic inflammation, rutin (which is also known as rutoside) was by far the most effective. That’s curious, because rutin, which is just quercetin with a sugar molecule called rutinose attached to it, is fully metabolized to quercetin and rutinose in the intestines, and it’s the quercetin that then enters the bloodstream.

The primary sources of bromelain, trypsin, and rutin.
Bromelain/Trypsin/Rutin Mixture Is Compared with Prescription NSAID

Researchers in Pakistan have published a study examining the efficacy of an enzyme-flavonoid mixture in a head-to-head trial with diclofenac (Voltaren®), a prescription NSAID.4 The enzymes used were bromelain and trypsin, which are proteolytic enzymes, i.e., they catalyze the breakdown of proteins to amino acids. Bromelain is found in pineapple stems and is used as a meat tenderizer. Trypsin is a human pancreatic enzyme that aids in the digestion of our food. The flavonoid used was rutin,which is found in many plants, notably buckwheat, black tea, and apple skins. These three agents were used in the form of a commercial, enteric-coated tablet (to prevent the enzymes from being destroyed by stomach acid.) containing 90 mg of bromelain, 48 mg of trypsin, and 100 mg of rutin.

For the 6-week trial, the researchers recruited 103 middle-aged patients who had painful OA of the knee with a disease flare in one knee joint. In a randomized, double-blind protocol, half the patients received the bromelain/trypsin/rutin mixture thrice daily, while the other half received diclofenac (50 mg) twice daily (no placebo was used as a control). The efficacy of the two treatments, recorded at 2-week intervals, was gauged by means of Lequesne’s Algofunctional Index, a self-reported scale measuring pain, maximum distance walked, and ability to perform activities of daily living, as well as a “complaint index” that included the reporting of pain at rest and during motion, as well as restricted function.

The Enzyme-Flavonoid Mixture Is Equally Effective

The results showed that, in virtually all respects, diclofenac and the bromelain/trypsin/rutin mixture were about equally effective in relieving the patients’ pain and improving their mobility, with no serious adverse events in either case. Using the acronym ERC for enzyme-rutin combination,” the authors concluded,

. . . ERC is equally effective as NSAIDs in the treatment of painful OA with a disease flare. Onset of efficacy may be slower, but the patients may profit from its well known superior safety and tolerability profile. Thus ERC emerges as an alternative in the standard of care for OA, allowing more patients to be treated for longer periods without the inherent toxicities of NSAIDs.

Don’t Overlook Manipulation—or Supplements

It appears that the days of NSAIDs for the control of arthritis pain may be numbered, thanks to the advent of safe and effective alternatives. And for you osteoarthritis patients who may be looking for other nonpharmacological treatments as well, don’t overlook your local D.O.s and their manipulation skills. Chances are, in addition to therapeutic manipulation, supplements such as enzymes and flavonoids may be just what the (osteopathic) doctor ordered.


  1. McAlindon T. Glucosamine for osteoarthritis: dawn of a new era? Lancet 2001 Jan 27;357:247-8.
  2. Walker AF, Bundy R, Hicks SM, Middleton RW. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomed 2002;9(8):681-6.
  3. Rotelli AE, Guardia T, Juarez AO, et al. Comparative study of flavonoids in experimental models of inflammation. Pharm Res 2003;48:601-6.
  4. Akhtar NM, Naseer R, Farooqi AZ, et al. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee—a double-blind prospective randomized study. Clin Rheumatol 2004;23:410-5.



Inflammation Can Be a Killer

Unlike osteoarthritis, rheumatoid arthritis (RA) is a true inflammatory disease, and the inflammation can have serious systemic consequences beyond those of the disease itself. A recent study has indicated a significantly increased risk for cardiac death in RA patients, even after accounting for the many traditional risk factors for cardiovascular disease (smoking, family history, hypertension, obesity, diabetes, etc.) as well as for other illnesses the patients had.1

Researchers at the Mayo Clinic in Rochester, Minnesota, examined medical data on 603 RA patients (73% of them women) whose average age was 58. During the 15-year (on average) follow-up period, 354 of the patients died, and heart disease was ascertained as the primary cause of death in 176 of them (50%); in 38 other cases (11%), heart disease was listed as a contributory cause of death.

These data indicate an increased risk of death from heart disease in patients with RA, and the researchers found that three specific markers of inflammation that are associated with RA were independently correlated with the increased risk. It must be noted, however, that inflammation was only one of five possible reasons discussed by the authors for the higher incidence of cardiac death in RA patients.


  1. Maradit-Kremers H, Nicola PJ, Crowson CS, et al. Cardiovascular death in rheumatoid arthritis. Arth Rheum 2005;52(3):722-32.



Dr. Rosick is an attending physician and clinical assistant professor of medicine at Pennsylvania State University, where he specializes in preventive and alternative medicine. He also holds a master’s degree in healthcare administration.