Arthritis is one of the most common chronic medical conditions encountered with older age, and osteoarthritis (OA) is the most common type of arthritis, and a major cause of disability. OA of the knee is more common than any other joint. Symptoms include pain, stiffness, and decreased range of motion. Subjects often become limited in their activities and quality of life, due to pain.
To manage the symptoms of OA, subjects and healthcare providers often resort to multiple approaches, which include lifestyle modifications, medications, exercise or surgery. Non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay medications used to manage osteoarthritis pain. NSAIDs prevent inflammation and control pain by blocking cyclooxygenase (COX-1 and COX-2 enzymes) but their side effect profile is not always acceptable, particularly among the elderly. Each year more than 100,000 subjects are hospitalized for gastrointestinal complications of NSAIDs, and of those approximately 15% die from these complications [1
Newer NSAIDs, known as COX-2-inhibitors such as valdecoxib (Bextra), celecoxib (Celebrex), and rofecoxib (Vioxx), were introduced recently as providing similar anti-inflammatory activity and pain relief but fewer gastrointestinal side effects, including a reduced risk of GI erosion and bleeding. However, recent evidence does not always support these claims, and a few studies have suggested a possible increased risk of heart disease [2
]. In addition, subjects often lose the benefit from these medications once they are discontinued; however, OA is a progressive disease and as such requires continuous management.
Over the last decade many dietary supplements were introduced to the public for the management of a variety of conditions including arthritis. Advertisement and information about supplements targeting people with arthritis can be found everywhere. Acupuncture, massage, magnet therapy, and dietary supplements have been promoted for the management of arthritis.
Given the limitations of the established osteoarthritis medications/treatments, and the recent explosion of information and interest in complementary and alternative medicine (CAM), the public has turned their attention to CAM and is exploring safer alternatives to manage their symptoms. The recent American College of Rheumatology (ACR) guidelines for treating OA included dietary supplements, such as glucosamine sulfate, chondroitin sulfate, and antioxidants, as well as acupuncture and magnets as therapies under investigation [3
]. While their final judgment of their effectiveness is yet to be scientifically proven, these therapies do seem to have the advantage of showing, possible benefit with fewer side effects. S-Adenosylmethionine (SAMe) is one of the dietary supplements that gained popularity, and was recently reported to be effective in the management of depression, liver disease and arthritis.
SAMe was first discovered in Italy in 1952 [4
]. Soon after, it became popular in Europe and more recently in the U.S. SAMe is an important physiologic compound that is distributed throughout the body tissues and fluids. It is produced endogenously from methionine and adenosine triphosphate (ATP). It is an important methyl group donor playing an essential role in many biochemical reactions involving enzymatic transmethylation. Those play an important role in the biosynthesis of phospholipids that are important for the integrity of cell membranes. Despite our basic understanding of its role, the exact mechanism of action in different disease conditions is not well established. Oral SAMe achieves peak plasma concentrations (0.5 – 1 mg/L) 3 to 5 hours after ingestion of an enteric-coated tablet (400 – 1000 mg). The half-life is about 100 minutes, and it is excreted in urine and feces [5
Biochemically, SAMe is involved in three main metabolic pathways: 1) methylation, as the principal source of methyl groups in the body; 2) transsulfuration, SAMe forms S-Adenosylhomocysteine (SAH) and then converted to homocysteine (Hcy) which can be converted to cystathionine then to cysteine and the sulfate (SO4
) donated to other metabolic intermediates; and 3) aminopropylation, as SAMe plays an important role in the synthesis of polyamines which can eventually form and recycle methionine [6
The exact mechanism of SAMe in reducing pain of OA is not known, but evidence suggests that it may play a role in reducing inflammation, increasing proteoglycan synthesis or having an analgesic effect. Whether SAMe is a COX-2 inhibitor is also not known. In vitro studies using human articular chondrocytes have shown SAMe-induced increases in proteoglycan synthesis [7
] and proliferation rates in rabbits [8
]. SAMe may reduce inflammatory mediators thus reducing pain. This was noted in other studies with the reduction of Tumor Necrosis Factor (TNF)-alpha and fibronectin RNA expression using cultured rabbit synovial cells [9
Initial studies with SAMe used the parenteral route exclusively due to the instability of the oral form. As additional work allowed the development of a stable oral form of SAMe, further studies tested the effectiveness of the oral form in the management of several medical conditions including osteoarthritis. The length of treatment differed in each study ranging from 7 to 84 days for testing oral preparations, 5 days for intravenous and 7 days for intramuscular preparations. Study designs usually implemented a parallel group design and two studies used a cross-over design [10
]. Only one cross-over study used an oral preparation with a 5-day washout period [10
]. The majority of studies compared SAMe to NSAIDs. Most studies used either 600 mg or 1200 mg of SAMe per day. No specific explanations were provided to justify the dose used. The overall conclusions of these studies pointed toward an effect size in favor of SAMe compared to placebo and equivalent to NSAIDs in reducing pain and improving functioning.
Three reviews analyzed available studies to date [12
]. One is a meta-analysis [13
], the other two provide a general overview of the articles. All three reviews reach similar conclusions that the results of available studies are heterogeneous and do not allow for a firm conclusion about the effectiveness of SAMe in the management of OA. However, despite this limitation the consensus is that SAMe appears to be of equivalent effectiveness to NSAIDs in reducing pain and improving functional limitations, with fewer side effects. Di Padova (1987) [15
]concluded that SAMe had a slower onset of action than NSAIDs, with equivalent results at 4 weeks.
Studies were frequently limited though, in quality of design and implementation. Most studies were done during the 1980's, with one study [16
] in 1994. Since at that time the majority of the studies compared SAMe to placebo or NSAIDs, there are presently no studies available that evaluate the effectiveness or safety of SAMe versus the new class of drugs used for OA, COX-2 inhibitors. The objective of the present study is to assess the therapeutic effectiveness of oral SAMe (S-adenosylmethionine), in comparison to celecoxib (Celebrex®
), to relieve pain and improve function in adults with OA of the knee.