Adopted: 6/98 Revised: 2/05, 7/10 NSAIDs—Use of Over-the-Counter Nonsteroidal Anti-Inflammatory Drugs and Analgesics Over-the-counter (OTC) nonsteroidal anti-inflammatory drugs (NSAIDs) are used to control pain and inflammation in a variety of musculoskeletal conditions, including arthritis, low back pain and sports injuries. The main objective of this protocol is to review NSAIDs that are commonly used in clinical management of musculoskeletal conditions. Dosage, side effects, contraindications, and interactions with other medications are presented, as well as a strategy for decision-making. Although not an NSAID, the analgesic acetaminophen is also discussed. Because treatment with NSAIDs may mask or confuse the benefit of other therapies, it may be prudent to delay use of NSAIDs in some cases until the effectiveness of alternative therapy is determined. BACKGROUND Reducing Pain and Inflammation Limitations of Evidence Nonsteroidal anti-inflammatory drugs (NSAIDs) are Scientific evidence from drug trials may not commonly employed in the pharmacological apply to everyone taking a particular drug. For management of pain and inflammation. These example, minority groups, children, the drugs work by inhibiting enzymes called elderly, and persons at increased risk of cyclooxygenase 1 and 2 (COX 1-2). The COX 1-2 adverse events are often deliberately excluded enzymes are responsible for the production of from trials. Furthermore, therapeutic benefits prostaglandins, hormone-like substances involved of drugs and adverse reactions are not in inflammation and pain (Prisk 2003). NSAIDs have measured using comparable scales. Finally, been routinely used for the initial onset, drugs tend to be used for a wider range of continued relief, and re-injury or exacerbations of indications than those for which they are musculoskeletal pain. As such, they should be originally tested. Comprehensive databases recognized as potentially effective therapeutic linking prescriptions to hospital data and other adjuncts whose characteristics should be well health records are needed in order to assess understood by all clinicians. (See Table I. the relative benefits and harms of drug use in a Characteristics of Nonsteroidal Anti-Inflammatory wide variety of patients (Simons 1999). Drugs.) At the same time, clinicians must be aware of the dangers and limitations of this powerful class of drugs, particularly in patients suffering from chronic pain (PDR 2004 a, b, d, Donjon 1999). NSAIDs & Analgesics Page 1 of 32 NSAIDs and ANALGESICS OTHER THERAPIES There are three commonly used classes of 1. Herbal Therapy NSAIDs and analgesics available over the Currently there is increased interest in counter: aspirin, propionic acid derivatives, evidence-based complementary and alternative and acetaminophen. medicine for pain management in rheumatic disease and other musculoskeletal disorders 1. Aspirin (Gagnier 2004, van Tulder a 2004, Yokoyama et Aspirin is the prototype of NSAIDs and is effective al. 2004). Some of these therapies may also be in relieving pain, fever and inflammation. Aspirin appropriate for initial management of also reduces the blood’s ability to clot by affecting conditions such as osteoarthritis (Blumenthal platelets. This can significantly reduce risk of 2002, Little 2002). heart attack and some types of stroke but may The clinician and patient should weigh the increase risk of gastrointestinal bleeding and other evidence of likely effectiveness, potential side complications (Dalen 1992, Donjon 1999, Edwards effects, and the cost of botanicals compared et al. 2004, Eidelman 2003, PDR a, b 2004). with more traditional analgesics and NSAIDs. Clinical evidence supporting the efficacy of 2. Propionic Acid Derivatives herbal anti-inflammatory therapies is Over-the-counter (OTC) formulations are available increasing (Ernst 2000). for three propionic acid derivative NSAIDs: ibuprofen, ketoprofen and naproxen sodium. A 2006 Cochrane review reported on three oral These drugs have many of the same analgesic and herbal medications tested in ten randomized anti-inflammatory qualities of aspirin, but present controlled trials that included 1567 adults with a lower risk of gastrointestinal bleeding; however, non-specific acute or chronic low-back pain. NSAIDs are not recommended for long-term (Gagnier 2006) management of rheumatic conditions (Lanza 1998, PDR a 2004, Strom et al. 1997). o Devil’s Claw,(Harpagophytum Procumbens) in a standardized daily dose of 50 mg or 100 mg harpagoside, seemed to reduce pain more than WARNING: There is also clinical evidence that placebo; a standardized daily dose of 60 mg simultaneous use of aspirin and ibuprofen may reduced pain about the same as a daily dose of attenuate the antiplatelet effect of aspirin, 12.5 mg of Vioxx. making it less useful for cardioprotection (Patel 2004). o Willow Bark (Salix Alba), in a standardized daily dose of 120 mg and 240 mg of salicin Propionic acid derivative drugs cannot be reduced pain more than placebo; a standard- ized daily dose of 240 mg reduced pain about substituted for aspirin to provide cardiac the same as a daily dose of 12.5 mg of Vioxx. protection. o Cayenne (Capsicum frutescens) was tested in 3. Acetaminophen (Tylenol®) plaster form and reduced pain more than placebo and about the same as the Acetaminophen is not an NSAID since it has no homeopathic gel Spiroflor SLR. Adverse effects anti-inflammatory or blood thinning effects. It is were reported, but appeared to be primarily effective for mild to moderate pain. Unlike confined to mild, transient gastrointestinal NSAIDs, acetaminophen does not irritate the complaints. gastrointestinal tract and is considered the safest analgesic drug for geriatric patients (ACR 2000, Herbal formulations commonly used in the Cryer BL 2002, 2003). However, overdose of clinics for NSAID effect contain a combination acetaminophen can cause severe liver toxicity. of Indian Frankincense (Boswellia serrata), Tumeric (Curcuma longa), White Willow (Salix alba), Wild Yam (Dioscorea villosa), and Black Cohosh (Actaea racemosa). NSAIDs & Analgesics Page 2 of 32 2. Nutritional Supplementation Proteolytic enzymes (like bromelain) may be Topical NSAID patches and gels substituted for NSAIDs (with fewer side effects) for Since the early 1980s (Linn 2004) topical some types of acute trauma (Pizzorno 1999), but prescription of NSAID patches and gels have the effects will not be as rapid as over the counter been used in Europe. In the US they have been medications. used since 2007 (Altman 2009) (diclofenic). Multiple reviews have evaluated their clinical There is also evidence that micronutrients like effectiveness for both acute and chronic glucosamine sulfate, although slower acting, may musculoskeletal pain (Linn 2004, Altman 2009, aid in joint repair and relieve arthritic symptoms Stanos 2007, Rainsford 2008, Moore 1998, (Matheson 2003, McAlindo et al. 2000, Reginster et Mason 2004). al. 2001, Towheed TE 2003). No investigations They demonstrate that topical NSAIDs are have been done on potential applications such as significantly more effective than placebo for prevention of joint disease or broader treatment short term pain relief (2 weeks) and are of musculoskeletal trauma. See UWS protocol probably comparable to oral NSAIDs. For the “Glucosamine & Chondroitin Sulfate.” treatment of chronic pain from osteoarthritis, the results are mixed. Some trials have shown For more information on proteolytic enzymes and only short term pain relief (2 weeks) while micronutrients, see UWS protocol “Diet, others have shown longer lasting effects (12 Nutritional Supplements and Botanicals for weeks) (Stanos 2007). Musculoskeletal Conditions.” Topical application appears to reduce the risk 3. Prescription NSAIDs of serious systemic side effects (GI and renal) This protocol is restricted to discussion and that can occur with oral NSAIDs. recommendation of over-the-counter NSAIDs. Pharmacokinetic studies (Rainsford 2008, However, patients may be referred for Stanos 2007) have shown that plasma prescription drug therapy when appropriate. concentrations with topical NSAIDs are very low (less than 10%) compared to oral doses of the Many low-dose NSAIDs are available over the same agent. counter, but higher potency forms require a prescription. Co-management with a practitioner A 1998 meta-analysis (Moore 1998) pooled having access to prescription NSAIDs may be results from 86 randomized, placebo-controlled necessary for some patients, especially those with trials of topical NSAIDs for a mix of painful chronic osteoarthritis. conditions various painful diagnoses. Reports of COX-2 Inhibitors adverse events for the 10,160 patients treated At therapeutic doses these prescription drugs were mild and infrequent. These included local reduce inflammation by selectively inhibiting the skin irritation in 3.6% and less than 0.5% enzyme COX-2. COX-1 is not affected and is reporting any systemic side effects. available to protect the intestinal mucosa, A more recent (2004), meta-analysis (Mason reducing gastrointestinal side effects. Although 2004) of 26 double-blind, placebo-controlled more expensive than NSAIDs, COX-2 inhibitors have trials found a similar, low rate of side effects. fewer gastrointestinal side effects than traditional The rate of side effects for placebo and for NSAIDs (Bardell 2002, FitzGerald 2001, 2004, Husni topical NSAIDs was the same. 2002, 2004, Schnitzer 2002, Silverstein 2000). Clinical Warning: When treating a patient with Emerging information is creating