Pain is the most common presenting symptom in rheumatologic diseases. Pain is what brings patients to seek medical attention. It interferes with their mental and physical wellness as well as their quality of life.

A study of the U.S. adult population estimated the prevalence of “self-reported doctors-diagnosed arthritis” to be at 21% (46.4 million persons). Among those, 27 million were estimated to have osteoarthritis, 3 million to have gout, and 1.3 million to have rheumatoid arthritis.^1,2

There are certain principles that will help guide clinicians in the general management of arthritis pain:

1. 
   

   Diagnose correctly the underlying etiology of the pain such as rheumatoid arthritis (RA) versus osteoarthritis (OA), and distinguish rheumatic diseases from nonmusculoskeletal sources of pain such as neuropathies or somatic etiologies. Recognize that there could be an overlap among different disorders at times, and pain could be of multifactorial etiology. This will influence which approaches to choose to treat the underlying diseases and the ensuing pain.

   
   
2. 
   

   Almost always treat the underlying disease first and consider consulting a rheumatologist. For example, starting a disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis will alleviate the inflammation and, thus, the pain.

   
   
3. 
   

   When the underlying disease is amenable to treatment with other long-term measures, employ pain management as a bridge therapy until achieving long-term disease control (i.e., controlling the activity of RA with DMARDs or preventing gout attacks with uric acid–lowering agents).

   
   
4. 
   

   Consider nonpharmacological interventions such as physical therapy; orthotics, if indicated; and safe, potentially effective, alternative therapies, and address other comorbidities such as obesity.^3–7

   
   
5. 
   

   Keep in mind the potential treatment side effects, consider the individual risk factors, and thrive to prevent those side effects.

   
   
6. 
   

   Pay more attention to potential treatment-related complications in the elderly population.⁸ Always ask the question, “Do the benefits really outweigh the risks?”

   
   
7. 
   

   Consider starting with milder agents and low doses initially, as patients respond differently to medications. (See Table 41-1.)

While this chapter will focus on the management of pain in OA and RA, the same concepts apply for joint pain in other rheumatic diseases. The administration and management for narcotics and treatment of pain in fibromyalgia are beyond the scope of this chapter and are covered elsewhere in this textbook.

Nonpharmacologic approaches depend on the site of OA and include patient education, self-management and exercise programs, physical and occupational therapy, quadriceps-strengthening exercises,^9,10 knee braces, correct footwear, lateral wedged insole (for medial knee OA), and patellar bracing or taping for patellofemoral pain and knee OA. Proper use of a cane in the contralateral hand to the affected hip or knee can also reduce pain and improve function.^3,7,11 Nonpharmacological therapies such as education and occupational physical therapy and joint protection techniques have a role in RA as well.

Glucosamine and chondroitin sulfate (GCS) are dietary supplements commonly used in knee OA. However, their use is considered controversial; while certain guidelines recommend GCS, others recommend against them.^3,7 As dietary supplements, GCS products are not controlled by the Food and Drug Administration (FDA). The largest randomized placebo-controlled study of chondroitin sulfate and glucosamine did not reduce pain in knee OA.¹² A meta-analysis from 2010 also did not show clinically significant reduction in pain or progression of joint space narrowing in knee OA.¹³ The updated Osteoarthritis Research Society International (OARSI) 2010 guidelines also revised downward the effect size of GCS on pain in knee OA compared to its 2008 guidelines.¹⁴ Potential explanations of the heterogeneity and variability among the studies could be related to a different brand or regimen of glucosamine used (i.e., glucosamine sulfate), industry bias, and failed concealment of allocation during the randomization process of the trials subjects.¹⁵

If patients inquire about the use of GCS for knee OA, it is reasonable if they wish to try them for a period of 3 to 6 months to see if they gain any benefit—assuming they recognize the evidence of the lack of effectiveness of CGS, their cost, and the lack of monitoring or control of those supplements by a governmental agency.

Acupuncture may benefit some patients, but it is operator dependent; a meta-analysis suggested benefits compared to sham acupuncture. It is a reasonable option considering its safety profiles in expert hands.^3,7,16,17 Financial constraints are a limiting factor because most insurers do not reimburse for acupuncture.

Nonsteroidal anti-inflammatory drugs (NSAIDs) include the traditional, nonselective NSAIDs such as naproxen and ibuprofen and the selective NSAIDs, which are the cyclooxygenase-2 (cox-2) inhibitors. Only celecoxib is available in the U.S. market; the other two—rofecoxib and valdecoxib—were withdrawn from the market due to the association with increased cardiovascular risks.¹⁸

EFFICACY

There is evidence that selective and nonselective NSAIDs are modestly effective in reducing pain in osteoarthritis and rheumatoid arthritis. There is no evidence from clinical trials that either selective or nonselective NSAIDs are more effective than each other,^19–21 or that a particular NSAID is more potent than others, although the individual response to one agent versus the other does vary.^22–24 On the other hand, analysis of multiple studies suggested that nonselective NSAIDs might be more effective, compared with selective NSAIDs, in severe OA.¹⁸

NSAIDs in RA are almost always used in combination with DMARDs and are often used with corticosteroids. This complicates interpreting the effects of NSAIDs on pain in subjects with RA. In any case, the goal of treatment in RA is to reduce the disease activity to enable discontinuing pain medications, including NSAIDs, when feasible.

CARDIOVASCULAR RISKS

Most nonselective and selective NSAIDs seem to be associated with a small to moderate increased risk of cardiovascular diseases (CVDs). However, several patients’ characteristics may be associated with increased CVD risk when using NSAIDs, such as patient age over 80, history of cardiovascular disease, RA, chronic obstructive pulmonary disease (COPD), renal disease, and hypertension.²⁵ There is no evidence, though, from placebo-controlled trials that nonselective NSAIDs are associated with cardiovascular risk; otherwise, this could be due to the relatively short duration of those trials. A meta-analysis suggested that rofecoxib, diclofenac, and ibuprofen were associated with increased cardiovascular risk, while naproxen and celecoxib were not.²⁶ This could be explained by the cox-2 selectivity of diclofenac and the relatively weak cox-2 selectivity of celecoxib as compared with rofecoxib. Ibuprofen may interfere with the protective role of low-dose aspirin; hence, it might be associated with increased cardiovascular risks.^27,28 There are no adequate data regarding other NSAIDs, but one study suggested a similar role to naproxen in blocking the effect of aspirin.²⁹ (See Table 41-2.)

GASTROINTESTINAL RISKS AND PREVENTIVE STRATEGIES

NSAIDs are associated with gastrointestinal (GI) side effects including gastritis, ulcers, and their complications such as perforation, bleeding, and obstruction. Nonselective NSAIDs are associated with a 2.7- to 5.4-fold increase in GI side effects.^30–32 The relationship between endoscopic ulcers and clinically significant GI events is not well established.³³ Thus, studies looking at peptic ulcer–related complications might be more clinically relevant.

There is a higher risk of GI complications in subjects with RA; other risk factors for NSAIDs and related GI complications include patient age over 75, previous history of GI bleed, female gender, concomitant corticosteroid use or anticoagulants, and cardiovascular disease.^{30–32,34,35}

Nonacetylated salicylate seems to be associated with a better GI safety profile, but it is less effective compared with other NSAIDs.^18,36

Lumiracoxib and rofecoxib, both selective NSAIDs and not available in the United States, were associated with decreased GI serious complications compared with naproxen and ibuprofen.^37,38 Although the decrease in the GI-related complications disappeared in aspirin users in the lumiracoxib study,³⁷ being on low-dose aspirin seems to wipe out the benefit from cox-2 inhibitors in regard to GI-related complications. High-dose celecoxib (400 mg twice daily) did not decrease the risk of serious ulcers compared with ibuprofen or diclofenac at 6 and 12 months.^19,39 For the secondary outcomes of symptomatic ulcers, high-dose celecoxib was better than ibuprofen but not diclofenac. However, there was no significant difference with celecoxib in aspirin users compared with nonselective NSAIDs.¹⁹

Other strategies for GI protection are proton pump inhibitors (PPIs) and misoprostol, which are more effective than the regular dosing of antihistamine-2 in preventing peptic ulcer disease in patients on NSAIDs.^40–43

One trial compared celecoxib 200 mg twice daily with and without esmoprazole in high-risk subjects who had recent peptic ulcer disease. The study found that the combination with a PPI was more effective in reducing the risk of recurrent ulcers. There was no control arm with nonselective NSAIDs and PPIs.⁴⁴

Looking at serious lower and upper GI side effects, 4484 subjects were randomly allocated to receive celecoxib 200 mg twice daily versus diclofenac 75 mg twice daily with omeprazole 20 mg daily. In this trial, 0.9% in the celecoxib group versus 3.8% in the diclofenac plus omeprazole group developed a serious lower or upper GI event (hazard ratio 4.3, 95% CI 2.6–7.0; p < 0.0001).⁴⁵

When used in patients with a high risk for GI complications, NSAIDs should be combined with misoprostol or a PPI. Celecoxib might have a modest decrease in GI side effects compared with nonselective NSAIDs but not in patients who are on low-dose aspirin. In those patients, using nonselective NSAIDs with PPIs or misoprostol is probably more cost effective. In patients with a previous history of serious GI complications, NSAIDs should be avoided completely; however, if they have to be on NSAIDs, then selective NSAIDs combined with PPI might provide better protection. More data are needed to evaluate the safety of nonselective NSAIDs combined with PPI for that population. (See Table 41-3.)

In the choice of NSAIDs, balancing the GI and cardiovascular risks and patient’s response, should be considered on an individual basis. In addition, NSAIDs should be used with caution in subjects with mild renal insufficiency (glomerular filtration rate [GFR] 60–90 ml/min), and they should be, preferably, avoided altogether in moderate to severe renal insufficiency (GFR <60).

Topical NSAIDs and capsaicin are recommended for hand and knee OA in existing guidelines.^3,7,14 Topical NSAIDs have a modest effect in reducing pain in OA based on a meta-analysis of 13 trials.⁴⁶ There is evidence, though, of publication bias, which might overestimate the effect of NSAIDs. Topical diclofenac was effective in reducing pain and improving function in knee OA.^47–49 Topical NSAIDs seem overall to be as effective and safer than oral NSAIDs; they are well tolerated overall but have more local skin reactions, such as itching or redness.^49–51 Nonetheless, topical NSAIDs could have systemic side effects; an FDA warning recommended checking liver function tests for topical and oral diclofenac due to reported cases of liver toxicity, including failure.⁵²

Capsaicin cream is extracted from chili peppers; it activates and sensitizes peripheral c-nocireceptors.³ There is evidence based on a meta-analysis that capsaicin 0.025% cream when applied four times a day on painful joints has a mild to modest effect on pain in knee and hand OA.⁵³ It is important to point out, though, that blinding in randomized controlled trials is not possible with capsaicin because it causes skin burning, which is a common side effect.

Acetaminophen is an alternative to NSAIDs for mild to moderate OA.^3,7 It has a better safety profile, especially regarding the GI tract and renal function. If it is used in high doses (more than 4 grams daily), it is associated with liver toxicity. The long-term use of high doses of acetaminophen could be associated with GI and liver toxicity, especially in the elderly.^54,55 Hence, it is necessary to keep the daily dose of acetaminophen lower than 4 grams—and probably at 3 grams or lower in the elderly.

Acetaminophen is less potent than NSAIDs, based on multiple trials and a Cochrane review.^56,57 In addition, acetaminophen seems to be less effective than NSAIDs in inflammatory arthritis such as RA.⁵⁸

Prednisone, even in small doses for RA, such as 5 to 10 mg, is effective in reducing pain. It is often used initially in RA as a bridge therapy in conjunction with DMARDs until they take effect. The corticosteroid side effects preclude their use for a prolonged period of time; those side effects in a smaller dose of 5 mg or less are minimal. A small study of 31 subjects with RA showed that 1 to 4 mg of prednisone was effective; more subjects withdrew in the placebo arm compared to the prednisone-treated ones.⁵⁹

Tramadol is another alternative to NSAIDs for the treatment of osteoarthritis. Tramadol is a mild opioid but has a distinct effect on serotonin and norepinephrine as well.