Pharmacologic Treatments for Osteoarthritis

Osteoarthritis (OA) is the leading cause of disability in the United States and is one of the most common reasons for ambulatory office visits.¹ Joint pain is not only distressing to the patient, but it also can result in a patient’s loss of function and independence and can impair his or her ability to perform activities of daily living. This can be particularly devastating for aging individuals. The management of OA involves a multidisciplinary approach, including physical therapy, patient education, and surgery. An article published in a previous issue of Clinical Geriatrics titled “Osteoarthritis: Eliminating Pain and Restoring Function—An Orthopedic Perspective”² addressed the management of this chronic disease from a surgical perspective. This article addresses the latest updates in the pharmacologic management of OA.

Treatments

Relieving symptoms and increasing functional ability remain the cornerstones of OA treatment. In most clinical trials, the effect size for pain relief is between 0.3 and 0.5,³ meaning that the amount of relief typically obtained is modest at best.

Acetaminophen 
The Osteoarthritis Research Society International guidelines⁴ recommend acetaminophen as the first line of treatment for OA in patients with mild to moderate pain. Although many people can tolerate doses of up to 4 g per day, there is increased concern for acetaminophen toxicity at this dosage. A lower maximum daily dosage has been recommended by advisors to the US Food and Drug Administration (FDA),⁵ and the FDA has requested that the maximum acetaminophen dosage unit be limited to 325 mg in prescription acetaminophen combination products.⁶ The liver injury that has been reported with acetaminophen products usually occurred in those who had consumed >4 g in a 24-hour period, in those who had used multiple acetaminophen-containing products simultaneously, and in those who had consumed alcohol while taking the drug.⁶ Acetaminophen should be administered on a regular basis (ie, daily) as opposed to “as needed” to obtain a steady state. Although acetaminophen is superior to placebo, it is less effective as an analgesic agent than nonsteroidal anti-inflammatory drugs (NSAIDs).^7,8 Acetaminophen is generally well tolerated, but hepatotoxicity can occur in patients with preexisting hepatic or renal impairment, even at therapeutic doses.⁹ Although rare, chronic interstitial nephritis and papillary necrosis have also been reported with chronic use of acetaminophen.¹⁰

Nonsteroidal Anti-inflammatory Drugs  
Mechanism of Action. In 1982, Sir John Robert Vane received the Nobel Prize in Physiology or Medicine for demonstrating that prostaglandin (PG) production is inhibited by NSAIDs.¹¹ This mechanism is mediated by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. Nonselective NSAIDs inhibit both COX enzymes, whereas COX-2 inhibitors inhibit only COX-2. COX-1 is constitutively expressed in most cells and stimulates PG synthesis, which regulates platelet aggregation while preserving renal and gastrointestinal (GI) mucosal integrity. The COX-2 enzyme is induced in response to inflammation and initiates pain. COX-2 inhibitors are more logical targets for pain relief, as theoretically they can decrease inflammation without causing GI irritation. Unfortunately, PGI2 is also decreased via this pathway and this may contribute to increased thrombosis.¹²

NSAIDs are the most effective agents for treating OA and should be used in patients who do not respond to acetaminophen. Given their potential toxicity, these drugs should be administered at the lowest dose for the shortest amount of time possible. NSAIDs should not be used for >10 days at a time without supervision from a healthcare provider.¹³ A 2006 meta-analysis of 15 randomized controlled trials reported that GI symptoms were more common with nonselective NSAIDs than with acetaminophen.⁸ Acetaminophen was less effective overall than NSAIDs in terms of pain reduction, global assessments, and improvements in functional status in the comparator-controlled randomized trials. Researchers found no significant difference overall between the safety of acetaminophen and NSAIDs; however, participants on traditional NSAIDs were more likely to have an adverse GI event (relative risk [RR], 1.47; 95% CI, 1.08-2.00). The risk of GI events with COX-2 selective drugs (celecoxib) was not significantly different than the risk with acetaminophen (RR, 0.98; 95% CI, 0.80-1.20).⁸

Nonselective Nonsteroidal Anti-inflammatory Drugs. Over-the-counter nonselective NSAIDs include naproxen and ibuprofen, both of which have been shown to be more effective than placebo and acetaminophen.¹³ There are many nonselective agents that are fairly similar in both efficacy and safety. The Beers List of potentially inappropriate medications in older adults specifically indicates that indomethacin is a medication to avoid in this population, given its more significant side effects in older adults.¹⁴ The choice among other agents in this class remains empirical due to the immense variability in response and toxicity between patients.^13,14

Cyclooxygenase-2 Inhibitors. Major GI side effects have been shown to be reduced with the use of COX-2 inhibitors such as celecoxib when compared with nonselective NSAIDs. The CLASS (Celecoxib Long-term Arthritis Safety Study)¹⁵ demonstrated a 50% reduction in GI events with celecoxib use when compared with naproxen use in patients with OA. This gastroprotection was afforded to those who were not taking aspirin. When low-dose aspirin was included, there was no significant difference in complicated GI end points (eg, perforations, ulcers, bleeds). Since there is a potential risk of greater cardiovascular toxicity with the use of COX-2 inhibitors, these agents should be avoided in individuals with cardiac risk factors. Both rofecoxib and valdecoxib were taken off the market due to increased cardiovascular toxicity.

COX-2 inhibitors should be used in patients with OA who cannot tolerate acetaminophen and in whom the GI risk is high and the cardiovascular risks are low (Table¹⁶). Traditionally, in a high-risk patient, either an NSAID plus a proton-pump inhibitor (PPI) or a COX-2 inhibitor alone are employed to improve GI safety. A recent study suggested that a COX-2 inhibitor (celecoxib) may be safer than a traditional NSAID (diclofenac) plus a PPI (omeprazole).¹⁷ This study used a novel end point looking at anemia as a surrogate of GI toxicity throughout the entire upper and lower GI tract.

Topical Nonsteroidal Anti-inflammatory Drugs. Although not widely used, topical NSAIDs are gaining in popularity due to their lack of systemic side effects. A recent analysis of 47 studies revealed that these agents are superior to placebo at reducing pain in patients with OA.¹⁸ Unfortunately, most of the studies that are available were of short duration and compare topical agents with placebo and not an oral NSAID. The systemic side effects of topical NSAIDs are very minimal, but the FDA still requires that they carry the same black box warning as other NSAIDs.¹⁹ This black box warning relates to an increase in cardiovascular and GI side effects.²⁰ Diclofenac is also available in patch form, which has similar efficacy and tolerability to the gel formulation.

Nonacetylated Salicylates. Unlike aspirin, nonacetylated salicylates have fewer inhibitory effects on platelet aggregation. Consequently, they are less likely to cause bleeding as a side effect and are safer from a GI standpoint. When compared with regular NSAIDs, drugs such as magnesium trisalicylate 500 mg to 750 mg two or three times daily are effective therapies for many patients, and they provide a cheaper alternative to COX-2 inhibitors.²¹ If a patient needs cardioprotection, he or she will need to take concomitant antiplatelet agents.

Side Effects of Nonsteroidal Anti-inflammatory Drugs. All NSAIDs have potential side effects, which can limit their effectiveness in the treatment of OA. The most common side effects include confusion; GI upset and bleeding; and impairment of hepatic, renal, and bone marrow function. Rarely, a hypersensitivity reaction can occur. Unfortunately, these effects are difficult to predict for specific individuals. Although age has always been considered a risk factor for toxicity, a 1997 analysis of NSAID toxicity suggested that comorbidities, comedications, and medical history might be better predictors.²² All NSAIDs, including COX-2 inhibitors, have the potential to elevate blood pressure and increase cardiovascular risk. When prescribing for high-risk patients, a careful analysis should be made to ensure that the clinical benefit outweighs the cardiovascular risk.²³

 Opiates   
Opiates should be considered for patients who are unable to tolerate NSAIDs or for whom acetaminophen is not effective. Although short-term use is preferred, long-term use may be required for patients with OA who are not surgical candidates or for whom the pain is so severe that it impedes their ability to function. Nüesch et al²⁴ stated that for older adults with OA, the risks of long-term opioid use outweigh potential benefits.

Codeine and oxycodone are effective at managing OA pain, but attention should be paid to potential side effects in the elderly, including confusion, constipation, and sedation. Tramadol alone or tramadol with acetaminophen has been shown to be effective in OA and works as a partial mu receptor agonist²⁵; theoretically, this makes it less addictive than other opiates. Nevertheless, serious addiction is a possibility with all opiates, including tramadol. When discontinuing treatment with opiates in a patient, it is important to taper slowly to avoid withdrawal.²⁶ Other unique side effects of tramadol include the lowering of the seizure threshold when combined with selective serotonin reuptake inhibitors or antiseizure medications, or when used in patients with epilepsy.²⁷ Opiates have recently been linked to an increased risk of fractures in older adults.²⁸

Intra-articular Corticosteroids 
When a patient with OA presents with a monoarticular flare that has not responded to an oral agent, an intra-articular injection of a corticosteroid should be considered. This is also useful in patients who cannot tolerate NSAIDs. Although this type of treatment can be safely administered, its effects may be short-lived, with pain relief lasting from days to months.²⁹ Studies examining the efficacy of intra-articular corticosteroid injections at the hip and carpometacarpal joint have been of short duration and had high placebo response; therefore, the efficacy is less certain in these areas.³⁰ Repeated intra-articular corticosteroid injections appear to be safe for up to 2 years without causing narrowing of the joint space.³¹ Most rheumatologists recommend that patients receive up to three injections annually, although data about the optimal number of injections are lacking.

The choice of corticosteroid is empirical, but the solubility of the steroid preparation is important. The more insoluble the preparation, the longer it lasts and the more likely it is to have cutaneous adverse effects. The available corticosteroid preparations arranged from least soluble to most soluble are as follows: triamcinolone hexacetonide < triamcinolone acetonide < methylprednisolone < betamethasone. Rare side effects of intra-articular corticosteroid injections include facial flushing, postinjection flare, and transient hyperglycemia. If an injection is given in a superficial area, postinjection atrophy and depigmentation can occur, especially if a long-acting, less-soluble agent is used.³²

Viscosupplementation 
Viscosupplementation is an intra-articular method of restoring the homeostatic balance to the knee by injecting a high-molecular-weight hyaluronan.³³ Its therapeutic goal is to restore the viscoelasticity of synovial hyaluronan, thereby decreasing pain, improving mobility, and restoring the natural protective functions of hyaluronan in the joint. Viscosupplementation’s short-term mode of action is thought to be based on the pain-relieving effect of the elastoviscous fluid in the affected joint. In the long-term, the restoration of joint mobility due to relief of pain triggers a sequence of events, which restores the transsynovial flow and, subsequently, the metabolic and rheological homeostasis of the joint.

Current commercially available preparations in the United States include sodium hyaluronate and hylan G-F 20. Although they are of different molecular weights, these agents appear to be of equivalent efficacy.³⁴ Viscosupplementation was approved by the FDA as a procedure for treating OA in humans in 1997. Recommended dosing is three to five weekly injections, with each course costing, on average, $543.³⁵ The cost does not include the physician visits during which the injections are administered.

A 2003 meta-analysis of 22 trials of hyaluronic acid (HA) versus placebo for the treatment of knee OA included several different formulations of HA.³⁶ Seventeen of these trials were industry-sponsored, and the study population varied in size from 24 to 108 patients. Based on the findings of this meta-analysis, intra-articular HA has—at best—modest efficacy in the treatment of knee OA. This effect is equivalent to the effect of NSAIDs over that of acetaminophen. From a safety standpoint, the major adverse events include postinjection flare, which occurs in <5% of injected knees.³⁷ The American College of Rheumatology has recommended intra-articular HA for the treatment of OA in patients at increased risk for GI tract adverse events, as an alternative to oral agents.⁷ Currently, there are inadequate placebo-controlled data to support the use of viscosupplementation in areas other than the knee.³⁸

Glucosamine and Chondroitin Sulfate 
The presumed mechanism of action of glucosamine and chondroitin sulfate proposes that they are partially ingested in the intestinal tract and may ultimately reach the joint, having some reparative effect.³⁹ Global sales of glucosamine supplements reached $2 billion in 2008, and the demand for cartilage constituents is increasing.⁴⁰ Despite these impressive numbers, the data showing any benefit in the treatment of OA are weak and the data on efficacy have been conflicting. Trials that have shown benefit are hampered by small sample size and poor study quality, whereas larger and more robust studies, such as the GAIT (Glucosamine/Chondroitin Arthritis Intervention Trial),⁴¹ have shown minimal or no benefit when compared with placebo. A recent meta-analysis evaluating 10 trials with >3800 patients concluded that when compared with placebo, glucosamine, chondroitin, and the combination of glucosamine and chondroitin do not reduce joint pain or have an impact on radiographic improvement.⁴² Despite these findings, many patients are convinced that these preparations are beneficial and can alleviate their pain, as demonstrated by their high global sales. Given the lack of toxicity with the use of these agents, it is not unreasonable to continue them in individuals who have failed to respond to conventional medications.

Future Agents

Due to the limitations of current therapies, a great deal of research is being done to elicit more efficacious and safe options for OA. As our understanding of the underlying mechanisms improve, hopefully we will be able to retard or ultimately prevent disease.

Tanezumab
Nerve growth factor (NGF) is a neurotrophin that plays an important role in the mediation of pain and is upregulated in injured or inflamed tissue. Tanezumab is a humanized immunoglobin G2 monoclonal antibody directed against NGF that blocks receptor interaction.⁴³ A recent study examined 450 patients with knee OA who received varying doses of tanezumab or placebo.⁴⁴ In this study, two injections of tanezumab given 8 weeks apart resulted in a clinically significant decrease in joint pain, stiffness, and limitation of physical function in patients with moderate to severe knee OA. The side effects of the infusion were mild, and paresthesia occurred in 7% of patients.⁴⁴ Unfortunately, further studies of tanezumab have been halted due to a worsening of OA in some patients.⁴⁵

Nitric Oxide Inhibitors/Donors
Nitric oxide (NO) can function as both an inflammatory and protective mediator in OA. This dual role is complex but has proven to be an attractive target for relieving inflammation and improving safety. In humans, one form of NO—inducible NO synthase (iNOS)—is upregulated and may be responsible for the pain state and cartilage degradation associated with OA. A 2-year, phase 2 study in obese patients with knee OA is under way to assess the effect of iNOS inhibitor SD-6010 on radiographic narrowing.⁴⁶

Paradoxically, NO may also have a beneficial effect on OA due to the maintenance of GI integrity and protective cardiovascular benefits experienced with its use.⁴⁷ Due to this protective effect, a new class of drugs called COX-inhibiting nitric oxide donors have emerged and are currently undergoing safety and efficacy trials. These drugs are NSAIDs that have had a covalently linked NO group attached. Once absorbed in the gut, the NO is cleaved and liberated to counteract the deleterious side effects of the NSAID. Although the data for these agents thus far reveal an improved blood pressure profile compared with regular NSAIDs,⁴⁸ their application for approval was rejected by the FDA, which requested more robust cardiovascular safety data.⁴⁹

Conclusion

The pharmacologic management of OA requires an individualized plan that should be adjusted as the disease progresses and comorbidities develop. Nonpharmacologic therapy should be instituted and maximized prior to the addition of medications. The first line of therapy should be acetaminophen followed by NSAIDs, including nonselective NSAIDs or COX-2 inhibitors. NSAIDs are to be used for the shortest amount of time possible, and COX-2 inhibitors should be reserved for high-risk patients. NSAIDs should be avoided in combination with anticoagulants, corticosteroids, or aspirin. For patients with chronic, nonresponsive, and severe pain, opioid therapy should be used with appropriate screening and monitoring for side effects and falls. Intra-articular therapies and topical NSAIDs or patches can be considered for short-term relief. Newer agents are being developed, although long-term data on safety and efficacy are lacking, and more robust clinical trials are needed.

The author reports no relevant financial relationships.

Dr. Ali is Assistant Professor of Medicine and Rheumatology, Mount Sinai School of Medicine, New York, NY.

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