Osteoarthritis: Improving Treatment Plans

Osteoarthritis (OA) is the most common form of arthritis, affecting nearly 10% of men and 18% of women over the age of 60 years worldwide. Pain and joint tenderness associated with OA can lead to limitation in movement for 80% of patients, and 25% are unable to perform major activities of daily living. Considering this, it is not surprising that OA is considered one of the top 10 disabling diseases in developed countries.¹

No matter where you practice as a pharmacist, you are guaranteed to encounter patients suffering with OA who need improved treatment plans, education on their medications, and monitoring of their disease state.

The Disease

In the past, OA was considered to be part of the normal aging process, but now is thought to be a more complex process involving biomechanical forces, inflammatory processes, biochemical factors, and genetics. Ultimately, OA is a disease of the cartilage where there is an imbalance between cartilage formation and destruction.² This results in loss of articular cartilage and marginal and central bone formation.³ Although any joint can be affected, OA is primarily diagnosed in the knee, hip, and hands. Risk factors for OA include obesity, older age, female sex, genetics, joint injuries, and occupational/recreational activities.²

Treatment

Successful pain control will involve both non-pharmacologic and pharmacologic treatment. Guidelines are published by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) to guide therapy.^3-6 Non-pharmacologic treatment involves education, weight loss, exercise, physical and occupational therapy, and surgery for patients who fail conservative treatment.

Pharmacologic Treatment

Drug therapy focuses on relieving pain in order to improve functionality, prevent disability, and improve quality of life. Many patients may try self-treating OA with OTC medications and supplements. Pharmacists are well positioned to review medication histories, evaluate risks and benefits of therapy options, and follow up on symptoms. Since these medications are primarily used in the elderly and will be given long term, a conservative approach is appropriate. For patients with mild or moderate pain, acetaminophen may provide adequate relief. For more severe pain or inflammation, nonsteroidal anti-inflammatory drugs (NSAIDs) should be considered.

Acetaminophen

Acetaminophen is recommended by the ACR and EULAR as first-line oral drug therapy. Randomized controlled trials have indicated that acetaminophen is effective in treating OA and is safe when taken for long-term pain control. Compared with NSAIDs, efficacy data from trials is conflicting. While some trials support similar efficacy between NSAIDs and acetaminophen, others demonstrate superior pain control with NSAIDs. Considering the increased cardiovascular (CV), renal, and gastrointestinal (GI) adverse effects associated with NSAIDs, starting therapy with acetaminophen is a very reasonable option.^2-6

Patients may begin acetaminophen therapy by using 325 mg to 650 mg every 4 to 6 hours on an as-needed (PRN) basis. For patients who do not respond to a PRN strategy, it is recommended to change to a scheduled dose of up to 4 grams daily.² If patients are prescribed the maximum dosage, care must be taken to educate the patient on other products which could contain acetaminophen, such as OTC cold products and opioid combinations.⁶ For patients with heavy alcohol intake or liver disease, the dose should not exceed 2 grams daily.²

NSAIDs

If patients do not respond well to maximum-dose acetaminophen, then the ACR and EULAR recommend considering NSAIDs. NSAIDs as a class have similar efficacy, thus medication selection criteria include cost, frequency of administration, adverse effect profile, and the provider’s past experience. Patient response differs between NSAIDs, so patients may need to try different NSAIDs until they find adequate pain control. After titrating to the maximum tolerated dose, patients should be given 2 to 4 weeks for an adequate trial before consideration of another NSAID.^2-6

COX-2 selective and nonselective NSAIDs have shown similar efficacy for OA, but the toxicities of each agent will influence drug selection. GI adverse effects are well known to occur with nonselective NSAIDs. Endoscopically detected ulcers have occurred at a lower rate with celecoxib, but prevention of clinically significant ulcers has been conflicting in trials.^7-10 Risk factors for GI toxicity include age over 70 years, use of multiple NSAIDs including aspirin, anticoagulant therapy, corticosteroids, history of complicated ulcer, and high dose of NSAIDs.² The ACR has made specific recommendations on using NSAIDs in patients at high risk for GI complications.

If a provider decides to use NSAID therapy for a patient who experienced a symptomatic or complicated upper GI ulcer but did not have a GI bleed in the last year, then ACR recommends use of a COX-2 selective inhibitor or nonselective NSAID combined with a proton pump inhibitor (PPI). If a patient had an upper GI bleed and the provider still chooses to use an NSAID, then ACR recommends combining a COX-2 inhibitor with a PPI.⁶ If the risks of NSAID therapy are too great, it may be more prudent to use acetaminophen, topical agents, or steroid injection. ACR also cites a study by Latimer and colleagues which reported that combining a PPI with a nonselective or COX-2 selective NSAID is cost-effective for knee and hip OA; therefore, providers should consider adding a PPI to long-term NSAID therapy.^5,11

All NSAIDs carry a warning for increasing the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke. A meta-analysis published in The Lancet in 2013 sheds light on the magnitude of these risks. The risk of major vascular events (non-fatal myocardial infarction, non-fatal stroke, or death from vascular cause) was increased by about a third for patients taking a COX-2 selective inhibitor or diclofenac. Ibuprofen significantly increased the risk for major coronary events; however, high-dose naproxen was not associated with an increased risk for major vascular or coronary events.¹³ Rofecoxib was withdrawn from the market due to a clear increased risk for heart attack and stroke. Celecoxib, the only COX-2 selective NSAID on the US market, also increases risk for CV disease, but this risk may be similar to nonselective NSAIDs as stated above. If an NSAID must be used in a patient at higher risk for CV disease, consider using naproxen.

NSAIDs are also known to cause renal problems and should be avoided in patients with chronic kidney disease (CKD) stage IV or V (CrCl below 30 mL/min). For those with CKD stage III (CrCl 30-60 ml/min), risks and benefits must be considered with each patient individually. If an NSAID is selected, close monitoring of serum creatinine is warranted.^2,5

Topical Agents

Topical agents can be used as monotherapy or combined with oral agents. Capsaicin, which is isolated from hot chili peppers, works by releasing substance P and then depleting it from nociceptive nerve fibers. It is available over the counter with labeling instructions 4 times daily, although patients may get adequate pain relief with once- or twice-daily administration. Patients should be counseled that it may take 2 weeks to be effective and can cause local irritation. Care should be taken to counsel patients to wash their hands thoroughly after application.²

Topical NSAIDs are especially useful for patients who are unable to tolerate oral NSAIDs or if their use is contraindicated. The ACR strongly recommends the use of topical NSAIDs over oral NSAIDs in patients older than 75 years. Diclofenac is available as a 1% gel and a patch. The 1% gel is approved for OA and is dosed 4 times daily to the upper (2 grams per application) or lower extremities (4 grams per application). A dosing card is provided with the prescription, which allows patients to measure the dose. The total daily dose should not exceed 32 grams.¹³ A patch is also available, but is approved for acute pain due to minor strains, sprains, and contusions, and thus may not be approved by a patient’s insurance for treatment of OA.¹⁴

Glucosamine and Chondroitin

The role of these nutritional supplements has been controversial. They are both substances which naturally occur in cartilage and are widely used by patients. When these supplements entered wide use around 1996 they showed promise for improving OA; however, in 2006 a landmark study funded by the NIH involving more than 1500 patients found that the supplements did not provide significant pain relief. The ACR does not recommend the use of these supplements; however, they are well tolerated with few side effects, so it is not unreasonable for patients to undergo a trial if desired.¹⁵

Intrarticular Corticosteroid Injections

Intrarticular corticosteroid injections are a reasonable option if a patient does not achieve adequate relief with acetaminophen and NSAIDs. Pain relief can start within 24 to 72 hours. Although the effects may last 4 to 8 weeks, the maximal effects typically start to wane 2 weeks after an injection. Patients generally receive 3 to 4 injections per year.^2,3

Opioids and Tramadol

Opioids are recommended by ACR for patients with knee or hip OA that have not responded to non-pharmacologic and preferred pharmacologic agents and are unable or unwilling to undergo joint replacement. Opioids may also be useful for patients with renal failure unable to take NSAIDs.

Tramadol has demonstrated a modest benefit in OA compared with placebo. The ACR recommends considering tramadol for patients who do not achieve adequate relief with acetaminophen and are unable to take NSAIDs.⁵

Caroline Howard, PharmD, BCACP, CPP, is a graduate of the UNC Eshelman School of Pharmacy in Chapel Hill and is board certified in ambulatory care. After completing a pharmacy practice residency at the Durham Veterans Affairs Hospital, she practiced in the primary care clinics at the Asheville VA Medical Center with a focus on diabetes, high blood pressure, high cholesterol, and anticoagulation.

References:

• World Health Organization: chronic rheumatic conditions. www.who.int/chp/topics/rheumatic/en/. Accessed November 22, 2013.
• Buys LM, Elliot ME. Osteoarthritis. In: DiPiro JT, Talbert RL, Yee GC, editors. Pharmacotherapy: a pathophysiologic approach. New York: McGraw-Hill; 2008:1519-1537.
• Jordan KM, Arden NK, Doherty M, et al. EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a task force of the standing committee for international clinical studies including therapeutic trials (ESCISIT). Ann Rheum Dis. 2003;62(12):1145-1155.
• Zhang W, Doherty M, Arden N, et al. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2005;64(5):669-681.
• Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):465-474.
• Zhang W, Doherty M, Leeb BF, et al. EULAR evidence based recommendations for the management of hand osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2007;66(3):377-388.
• Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA. 1999;282:1921.
• Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet. 1999;354:2106.
• Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial: Celecoxib long-term arthritis safety study. JAMA. 2000;284:1247.
• Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med. 2006;119:255.
• Latimer N, Lord J, Grant RL, et al. Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton pump inhibitor for people with osteoarthritis. BMJ. 2009;339:b2538.
• Coxib and traditional NSAID Trialists’ (CNT) Collaboration; Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382:769.
• Voltaren gel [package insert]. Parsippany, NJ: Novartis Consumer Health, Inc; 2009.
• Flector patch [package insert]. Bristol, TN: King Pharmaceuticals, Inc; 2011.