Tramadol (Conzip, Ryzolt, Ultram) is a narcoticlike medication that can provide stronger pain relief than other agents. Narcotic analgesics are useful alternatives for patients in whom NSAIDs are contraindicated, ineffective, and/or poorly tolerated. Codeine, oxycodone (Oxecta, Oxycontin, Roxicodone) and propoxyphene (recently taken off the market) are narcotic analgesics used in severe OA. However, long-term use may cause drug dependency and tolerance that can necessitate an increase in dose over time to maintain pain relief. Side effects should be reviewed with the patient, as these could be detrimental to overall health. Dizziness is common and could cause falls in patients with unstable hip or knee joints. Constipation is a common complaint, so patients should be advised to use such measures as OTC stool softeners or to drink prune juice as alternatives to offset this problem. 


Topical formulations of NSAIDs, methyl salicylate creams (e.g., Biofreeze), and capsaicin have been shown to be helpful adjuncts to symptom management. These agents come in various forms, such as gels, patches, rubs or sprays, that are applied on the skin over a painful joint. They contain combinations of salicylates, skin irritants, and local anesthetics. Note that using these topical agents with heat therapy can cause burns and serious injury, especially in diabetic patients. The newest addition to the pain armamentarium is a nasal formulation of toradol (Sprix) that can be used in patients who are unable to tolerate oral medications.


Other pharmacologic options


Such COX-2 inhibitors as celecoxib (Celebrex) tend to be less toxic to the GI tract than other agents. Celecoxib is currently undergoing structural changes in order to reduce its adverse effects — primarily cardiovascular in nature, such as strokes and MIs. The efficacy of this class of drugs has been compared with that of traditional NSAIDs, including ibuprofen, naproxen and diclofenac (Cambia, Cataflam, Voltaren, Zipsor). All NSAIDs can cause occasional decline in renal function. 


Cyclooxygenase-inhibiting nitric oxide donators (CINOIDs), a new class of agents, increase vascular tone and mucosal blood flow.28 In addition, CINOIDs have the advantage of causing fewer adverse effects than NSAIDs, including renal injury and GI and liver effects, as well as hypertension. CINOIDs are similar in efficacy to naproxen but superior to placebo


Combination drugs are common in treating hypertension and dyslipidemia, but have not yet been used for OA. One combination now available for OA is Vimovo. This drug combines naproxen and a proton pump inhibitor (PPI), which helps to reduce GI toxicity. Vivomo has similar efficacy and tolerability to celecoxib but is associated with a greater number of heartburn-free days. Another combination drug recently approved by the FDA is Duexis, which combines 800 mg of ibuprofen with 26.6 mg of famotidine (proton pump inhibitor). 


Hyaluronic acid therapy involves injecting the knee joint directly with hyaluronans, a substance found naturally in joint fluid that helps provide lubrication and cushioning. Viscosupplementation utilizing hyaluronans seems to have a large placebo effect, as demonstrated in a systematic review and other studies.29,30 Intra-articular steroids may help with acute exacerbations of pain in patients who have signs of local inflammation with joint effusion but are of limited benefit (less than a week) for pain and function.31

Surgical options 


The need for surgery is best determined by an orthopedic surgeon with a specialty in the involved joint. The most common orthopedic interventions for OA are arthroscopic debridement and lavage (cleaning and vacuuming of the joint), osteotomy (corrects misalignment by cutting and resetting bone), cartilage transplant (from stem cells or patient’s own cells), arthroplasty (rebuilding of a joint) and joint replacement. The incomplete, temporary improvement seen with arthroscopic knee surgery is a placebo effect.32

Indications for total joint replacement


Night pain that is unresponsive to anti-inflammatory agents, major inability or difficulty to perform ADLs, or unacceptable reduction in the ability to walk or work are indications for total joint replacement. With proper patient selection, good to excellent results can be achieved in 95% of joint replacement procedures; the expected 15-year survival rate of the implant is also 95%.33

In a May 2011 report on joint replacements, research showed that younger people are more commonly having joint replacement. Knee replacement surgeries have doubled over the past decade and more than tripled in the 45- to 64-year-old age-group. Hips are trending that way too. According to Nicholas Di Nubile, MD, spokesperson for the AAOS, “The baby boomers are the first generation trying to stay active in droves on an aging frame. They are less willing to use a cane or put up with pain or stiffness, as their grandparents did.”34

Acupuncture and OA


Acupuncture is the use of fine needles inserted into the skin at precise points. Stimulation of these points can help block pain. There is some evidence that acupuncture may be useful to ease the pain of OA, but the data are generally equivocal.35 Additional clinical studies are under way to determine if acupuncture is an effective treatment for OA of the knee. 


Evidenced-based research


While biologic therapy has been available to treat rheumatoid arthritis for more than 10 years, such therapy has not been available for OA. Tanezumab, a new monoclonal antibody, may be a treatment option for OA knee pain.

Tanezumab has been shown to be efficacious when taken for 24 weeks in both phase 2 and phase 3 clinical trials. The antibody acts differently depending on the tissue. In OA and other diseases, the target is nerve growth factor. One key trial was halted when patients’ OA damage worsened, although their pain was lessened. Some trial participants had to have hip replacement surgery.36

Future of OA


The years 2002-2012 were declared to be the International Bone and Joint Decade, the intent of which was to increase awareness of OA. As a result of data concerning the staggering costs of this disease, NIH has provided support for outstanding, investigator-initiated research in the form of additional grant dollars. NIH initiated and participated in natural history studies of OA. It has lent its support and participated in meetings and processes to reach consensus with regard to diagnostic criteria, acceptable outcome measures, and recommendations for treatments. 


Backing from NIH led to the creation of the Osteoarthritis Initiative (OAI), which has as its goal the design, development, and support of a research project to identify, test, and validate biomarkers as surrogate end points for clinical trials in OA. The OAI is a public-private partnership that includes funding from the pharmaceutical industry and several of the National Institutes, including NIAMS. OAI comprises a public data set of clinical, functional, and imaging data on 4,800 subjects, aged 45 to 79 years, with eight years of follow-up. It is a unique resource for investigators, many of whom use the data source to explore research questions. For example, bone marrow lesions (BMLs), defined as increased signal areas on MRI, have been shown occur less frequently in patients treated with bisphosphonates, the class of drugs most often used to treat osteoporosis. Additional associations with cartilage loss and joint space loss in OA have also been reported. Evidence that OA is not just a “wear-and-tear” disease has been demonstrated through the OAI.


A similar research grant provided support for the Multicenter Osteoarthritis Study (MOST) involving 3,000 subjects, aged 45 to 79 years, with risk factors for OA and six years of follow-up as of 2011. The Health, Aging, and Body Composition Study (Health ABC) included 3,075 subjects, aged 70 to 79 years at the start of the study, with more than six years of follow-up. Results indicated that genetics plus additive risk factors puts larger joints at higher risk of OA than smaller joints.37

Stem cell research has been quite controversial across the globe. In OA, stem cells have been injected into joints to grow new cartilage and bone. Autologous supplementation involves the removal of cartilage cells from the patient. These cells are then grown in culture and reinjected into the joint several weeks later. In the future, mesenchymal cells, progenitors of new growth in cartilage, may become injectable.


Research is being conducted in the area of genetics and the impact it has on OA. According to emerging data from evidenced-based research, the impact of genetics is likely greater than previously thought. One study done by the ACR looked at possible therapeutic approaches to activating particular gene pathways in order to reduce the progression of OA.38

Public research is being conducted with the help of the Arthritis Foundation Innovative Research Grant. One study has revealed a strong connection between key regulatory proteins referred to as “nuclear factors of activated T cells (NFATs)” and severe OA symptoms. Researchers found that a lack of certain NFAT proteins results in serious joint degradation. Additional studies should also reveal more details about how an enzyme called HtrA1 degrades proteins in joint cartilage.39


At the 2011 European League Against Rheumatism (EULAR) Annual Congress, two posters discussed randomized controlled trials with therapy supporting efficacy in knee OA. The first poster, by Abou-Raya and colleague, was a two-arm study of 188 outpatients, aged 65 years and older, who had symptomatic and radiographic OA and took the antidepressant duloxetine 60 mg or placebo for 16 weeks. The outcome measure was reduction in knee pain and stiffness. Results in this study supported efficacy of duloxetine in knee OA.40

The second poster, by Laslett and colleagues, was a randomized controlled trial of the bisphosphonate zoledronic acid (5 mg/mL) versus placebo in 59 patients ranging in age from 50 to 80 years who had knee pain from OA and BMLs on MRI. Pain and radiographic data were assessed at baseline, 6 months, and 12 months with pain scales and T2-weighted MRI images. This study asked the question: Can patients with knee OA be treated with bisphosphonates and reduce the symptom of pain? Validation of this treatment will require repetition of the study using a larger number of subjects.41

Chondrocytes may be the most exciting area of research to date. Data have suggested that chondrocytes act as sensors, and the possibility exists that these cells could serve as novel targets for disease-modifying OA drugs. 


Inhibition of cartilage degradation and stimulation of cartilage growth and repair are the two additional areas of research to date. More insight is being gained as various targets are revealed through scientific research. 


In addition, the etiology of pain is still poorly understood. What local structural factor is most responsible for pain and functional impairment in OA? Much remains to be done in this complex area. 


Conclusion


The direction of current and future treatment of OA is to modify the disease itself, instead of just treating the symptoms. Clinicians should be cognizant of the availability of emerging research, so that they can help be part of the solution to decreasing the public burden of this disease.

Linda Davis, MHS, PA-C, is a physician assistant with the Texas Health Physicians Group, Fort Worth.



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