Pain relief from pharmacologic interventions not only contributes to improved mobility, function, and quality of life but can also allow patients with OA to comfortably engage in physical activity, a key component of any disease management and prevention plan. Providers should carefully consider a patient’s comorbidities and other medications before recommending a therapeutic regimen.
Pharmacologic and Intraarticular Interventions
The pharmacologic options for osteoarthritis (OA) target the treatment of pain and other symptoms since no disease-modifying therapies have been developed to date. Simple over-the-counter (OTC) analgesics (e.g., acetaminophen, aspirin) as well as non-steroidal anti-inflammatory drugs (NSAIDs), and intraarticular injections are the mainstay of OA analgesia despite their modest efficacy. As research promotes the rise of evidence-based medicine and the re-evaluation of clinical treatment guidelines, it is important for all providers to remember that OA management should be individualized, and risks and benefits of therapeutic options carefully weighed. Refer to the Comorbidities and Co-Occurring Symptoms module for a table outlining contraindications for common OA meds.
Topical NSAIDs (e.g., diclofenac solution or 1% gel) are FDA-approved for the treatment of OA of the hand, hip, and knee. While they carry the same black box warning as the oral NSAIDs, given their minimal systemic absorption, they appear to be better tolerated in some patients (e.g., older adults and people with more comorbid conditions) and have fewer drug interactions. The ACR supports topical NSAID use in OA of the hand and knee, but not the hip (given likely minimal absorption at the deeper hip joint).1 Some patients may need counseling on appropriate use of topical NSAIDs; a dosing card comes inside the box with the tube and patients should be referred to these instructions. The Arthritis Foundation has published an article about Topical NSAIDs, which may be a useful tool for patients.
Topical capsaicin (available without a prescription) has demonstrated efficacy for the treatment of knee OA, and appears to have a relatively benign side effect profile.1 To help improve adherence, twice-daily application may be attempted while still achieving pain relief.4 A burning sensation is the most common side effect and patients should be cautioned to avoid contact with open skin and mucous membranes.
Although likely safe, other over-the-counter agents, such as topical salicylates5 and counterirritants (e.g., menthol) have not demonstrated benefits in studies to date.
Checklist for Recommending Oral NSAIDs for OA
- Non-pharmacologic therapies (e.g., weight loss, exercise, and education) have been implemented, but pain persists
- Consideration has been given to APAP
- Allergies have been reviewed and verified
- Patient has been assessed for their risk of GI, renal, CV and other side effects (as indicated)
- Potential drug interactions have been evaluated
- Patient has been counseled on proper NSAID use including dosing and interactions
- Gastrointestinal prophylaxis has been considered and implemented where indicated
Oral NSAIDs are recommended for hand, knee, and hip OA especially in the presence of appreciable inflammation.1 When taken only as needed, these drugs provide more analgesia than anti-inflammatory effects. Lower (OTC) doses of ibuprofen (< 1200 mg/day) are usually not enough to provide good anti-inflammatory activity. There is not enough data to recommend one NSAID over another; when one NSAID does not appear to work, consideration for the use of a different NSAID should be made when inflammation is noted.
NSAIDs pose a risk of gastrointestinal (GI) (e.g., ulceration and bleeding), renal (e.g., acute renal failure), and cardiovascular (e.g., hypertension, heart failure, stroke, myocardial infarction) side effects, and caution should be used when recommending and dispensing these agents to patients. The FDA has issued a black box warning on all NSAIDs regarding their potential cardiovascular side effects.7 Senior patients are most vulnerable to the adverse effects of NSAIDs; furthermore, seniors may also experience sedation, confusion, and/or falls when taking NSAIDs. NSAIDs should be used at the lowest effective dose for the shortest time possible in an effort to minimize these potentially serious side effects.
NSAIDs should be used at the lowest effective dose for the shortest time possible in an effort to minimize these potentially serious side effects.
The large multicenter PRECISION trial assessed over 24,000 patients with OA or rheumatoid arthritis taking celecoxib, naproxen, or ibuprofen over 2 years and found similar efficacy for all 3 NSAIDs. There was no significant difference among these 3 drugs for adverse cardiovascular events, although fewer gastrointestinal and renal events were seen in the celecoxib group.8
NSAIDs also pose the potential for drug interactions. NSAIDs should be avoided or used with extreme caution when used concomitantly with medications that increase the risk for bleeding (e.g., aspirin, warfarin, low-molecular weight heparin, anticoagulants, and glucocorticoids). Concurrent use of a diuretic, angiotensin converting enzyme (ACE)-inhibitor, angiotensin receptor blockers (ARB), or direct renin inhibitor (aliskiren) should also be carefully evaluated since concurrent use can significantly increase the risk of acute renal failure.
For many years, acetaminophen (APAP) was the drug of choice (over NSAIDs) for the initial management of mild OA pain. As an agent with no anti-inflammatory activity, APAP can provide adequate pain relief in some patients potentially fewer side effects compared with NSAIDs providing there is little to no inflammation present in the joint. The ACR 2019 guidelines conditionally recommend* acetaminophen for hand, knee and hip OA based on clinical research.1 Of note, the 2019 Osteoarthritis Research Society International (OARSI) guideline does not recommend use of APAP due to mounting evidence of minimal to no efficacy of this agent for OA pain and concerns for toxicity.6 The biggest caution with the use of APAP is the risk of potential overdose and liver toxicity which can occur when consumers do not recognize the APAP content of many OTC and prescription-based products or simultaneously consume other potentially hepatotoxic substances (e.g., alcohol). It is recommended that patients receive counseling from providers including physicians, physician assistants, nurse practitioners, and pharmacists to ensure safe doses and combinations of medication. Given the overall safety of APAP, doses of < 3 grams per day can be considered for the initial trial of mild OA pain unless there is a contraindication (e.g., reported allergy, known liver disease). Refer to the Comorbidities and Co-Occurring Symptoms module for a table outlining contraindications for common OA meds.
Duloxetine is a relative newcomer to the OA treatment armamentarium and is FDA-approved for chronic musculoskeletal pain, among other indications. It is a potent inhibitor of serotonin and norepinephrine reuptake and a centrally-acting analgesic, and can interact with other similar medications, including tramadol (discussed below). It has demonstrated a greater reduction in pain when compared to placebo.9,10 Although it is generally well-tolerated, frequently reported adverse effects include nausea, constipation, fatigue, diarrhea, and somnolence, potentially more severe in older individuals.11 Research has indicated that it may take four weeks before any significant OA pain relief with duloxetine may be seen. The most recent published treatment guidelines from the ACR conditionally recommend* duloxetine in OA of the knee, hand, and hip.1 Other centrally-acting agents (e.g., gabapentin, pregabalin) have not been adequately studied in OA but may prove to be useful.
Opioid narcotics should be reserved for patients who continue to have symptoms or who are not candidates for previously mentioned therapies. When used, opioids are frequently “add-on” therapy to acetaminophen or NSAIDs. In the context of the ongoing opioid epidemic, the use of these medications for non-cancer pain has come under increasing scrutiny.12 The 2019 ACR guidelines conditionally recommend against the use of non-tramadol opioids in hand, knee, and hip OA.
Tramadol, a “weak” opioid, has been recommended for refractory OA by a number of professional societies. However, it is still an opioid, and therefore a controlled substance with many potential adverse events including dependence, respiratory depression and death, among others. Additionally, as a norepinephrine and serotonin reuptake inhibitor, it has the potential for drug interactions with other serotonergic medications (similar to the drug interactions with duloxetine). Opioids are frequently associated with nausea, vomiting, constipation, sedation, and respiratory depression, which can be amplified in older adults or debilitated patients. When used in older patients, falls and altered mental status may also occur.
Despite frequent patient perception that opioids provide strong analgesia, many patients report only modest improvements in their pain and the effects are usually short-term resulting in the need for multiple daily dosing. A large network meta-analysis showed similar pain reduction for NSAIDs, weak, and potent opioids, with greater adverse events for the opioid medications.13 Therefore, more potent opioids (e.g., oxycodone) or long-acting opioids should generally be avoided if possible, given their poor benefit to risk ratio for chronic OA pain.
More potent opioids or long-acting opioids should generally be avoided given their poor benefit to risk ratio for chronic OA pain.
COMPLEMENTARY & INTEGRATIVE TREATMENTS
More than 30% of American adults use treatments that are not typically considered mainstream. These may include natural products and mind and body practices, many of which were developed outside traditional Western practice.14 Pharmacologic complementary and integrative health treatments for OA include natural products such as herbs, vitamins and minerals, probiotics, and cannabis derivatives.
In light of the paucity of effective treatments for the management of OA and the enormous direct-to-consumer advertising for “all natural” treatments reporting to be “safe and effective” in patients with OA, the use of complementary and alternative medicines is a billion-dollar industry. While most herbal supplements have few side effects in the majority of users, the science behind their claims is often unsubstantiated and the placebo effect cannot be discounted; these products are also unregulated and therefore may not contain the ingredients advertised or may have contaminants. Based on either inconsistent data or lack of scientific evidence, neither ACR nor the AAOS recommends the use of herbal supplements (e.g., glucosamine, chondroitin, turmeric, ginger, copper, omega-3) for the treatment or prevention of OA.
Similarly, while cannabidiol (CBD) derivatives have demonstrated potential utility in animal models,16 no studies have shown efficacy in humans, and the compounds available to consumers are unregulated and have unknown safety profiles, such that these should not be recommended for use in OA.
Intraarticular injections are used primarily as alternative therapies to acetaminophen and NSAIDs for OA and their efficacy has been associated with a placebo effect.17 Intraarticular corticosteroids are backed by the most evidence and are conditionally recommended* by the ACR for the treatment of hand OA and strongly recommended for hip and knee OA.1 However, due to their potential systemic and local adverse effects combined with their short duration of action (4-6 weeks) and lack of consistent efficacy, they are most often used as second line agents or when local inflammation within a particular joint is appreciated.18
Other intraarticular therapies are more controversial in the OA literature, with some disagreement among guidelines. In general, the evidence for intraarticular hyaluronic acid is mixed, and their use is not widely supported by guidelines, although they may be useful for selected patients. Similarly, the evidence base for intraarticular platelet-rich plasma or mesenchymal stem cells is still evolving, and until more robust efficacy, safety, and optimal dosing data are available, these treatments are not generally recommended.
On the Horizon
There are as yet no disease modifying drugs for osteoarthritis (DMOADs), although many clinical trials are ongoing. Agents in development include those targeted toward subchondral bone, cartilage damage, and synovial inflammation, among others.19
While it has proven challenging to affect structural progression in OA, novel symptomatic therapies have shown promise. In particular, humanized monoclonal antibodies against nerve growth factor (anti-NGF) therapies have demonstrated efficacy in reducing OA pain in clinical trials. NGF is a neurotrophin with increased expression in OA and other painful states which has nociceptive sensitizing effects; its blockade is therefore an interesting target for pain reduction.20 Initially studied at high doses and often in combination with NSAIDs, there were signals for increased joint damage, leading to a hold on further studies. Since 2015, studies have resumed with risk mitigation strategies including lower doses, avoiding combination therapy with NSAIDs, and extensive radiographic screening and monitoring. Anti-NGF agents are likely to be available for clinical use in the near future but will require careful patient selection and vigilance for potential adverse events.
*In the 2019 ACR guidelines, “A conditional recommendation for using a modality was determined when the quality of the evidence proved low or very low and/or the balance of benefits versus harms and burdens was sufficiently close that shared decision‐making between the patient and the clinician would be particularly important; a strong recommendation was determined when there was compelling evidence of efficacy and benefits clearly outweighed harms.”1
Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393(10182):1745-1759.
Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020;72:220-233.
Movement Is Life Shared Decision Making Tool for the treatment of knee OA– pre-recorded Lunch & Learn, featuring Charla Johnson, DNP, RN, ONC
Overview of the 2019 ACR Guidelines– pre-recorded Lunch & Learn, featuring Amanda Nelson, MD, MSCR, RhMSUS
CLINICAL TAKE-HOME POINTS
- Pharmacologic therapy should always be used in conjunction with non-pharmacologic approaches.
- Topical agents are often as effective as and generally safer than oral agents.
- Consideration of comorbidities and potential risks should be carefully weighed for each patient.
- Oral NSAIDs should be used at the lowest dose and for the shortest time possible.
- Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020;72:220-233.
- Guedes V, Castro JP, Brito I. Topical capsaicin for pain in osteoarthritis: A literature review. Reumatol Clin. 2018;14(1):40-45.
- Schnitzer T, Morton C, Coker S. Topical capsaicin therapy for OA pain: achieving a maintenance regimen. Semin Arthritis Rheum. 1994;23(Suppl 3):34-40.
- Henrich WL, Agodoa LE, Barrett B, et al. Analgesics and the kidney: summary and recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the National Kidney Foundation. Am J Kidney Dis. 1996;27(1):162-165.
- Derry S, Matthews PR, Wiffen PJ, Moore RA. Salicylate-containing rubefacients for acute and chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2014(11):CD007403.
- Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis and Cartilage. doi:10.1016/j.joca.2019.06.011.
- U.S. Food & Drug Administration. FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Drug Safety and Availability. 2015. Available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warning-non-aspirin-nonsteroidal-anti-inflammatory. Accessed May 23, 2019.
- Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med. 2016;375(26):2519-2529.
- Brown JP, Boulay LJ. Clinical experience with duloxetine in the management of chronic musculoskeletal pain. A focus on osteoarthritis of the knee. Ther Adv Musculoskelet Dis. 2013;5(6):291-304.
- Wang ZY, Shi SY, Li SJ, et al. Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain: A Meta-Analysis of Randomized Controlled Trials. Pain Med. 2015;16(7):1373-1385.
- Cymbalta (duloxetine) [package insert]. In. Indianapolis, IN: Eli Lilly and Company; 2017.
- Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49.
- Smith SR, Deshpande BR, Collins JE, Katz JN, Losina E. Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review. Osteoarthritis Cartilage. 2016;24(6):962-972.
- National Center for Complementary and Integrative Health. Complementary, Alternative, or Integrative Health: What’s in a Name? 2018. Available at https://nccih.nih.gov/health/integrative-health. Accessed May 22, 2019.
- Liu X, Eyles J, McLachlan AJ, Mobasheri A. Which supplements can I recommend to my osteoarthritis patients? Rheumatology (Oxford). 2018;57(suppl_4):iv75-iv87.
- Philpott HT, O’Brien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain. 2017;158(12):2442-2451.
- McAlindon TE, LaValley MP, Harvey WF, et al. Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA. 2017;317(19):1967-1975.
- Kroon FP, Rubio R, Schoones JW, Kloppenburg M. Intra-Articular Therapies in the Treatment of Hand Osteoarthritis: A Systematic Literature Review. Drugs Aging. 2016;33(2):119-133.
- Oo WM, Yu SP, Daniel MS, Hunter DJ. Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics. Expert Opin Emerg Drugs. 2018;23(4):331-347.
- Miller RE, Block JA, Malfait AM. What is new in pain modification in osteoarthritis? Rheumatology (Oxford). 2018;57(suppl_4):iv99-iv107.