Clinical trial data in support of changing guidelines in osteoarthritis treatment

Figures & data

Table 1 Topical nonsteroidal anti-inflammatory drug formulations currently approved for use by prescription in the USA

Molecular salt	Formulation	Main penetration enhancer(s)	Dosage	Peak plasma concentration
Diclofenac sodium	1% gel	Isopropyl alcohol, propylene glycol, water	2 g (elbow, wrist, hand) or 4 g (knee, ankle, foot), 4× daily	15.0±7.3 ng/mL (4 g, 4× daily, 7 d) 53.8±32.0 ng/mL (12 g, 4× daily, 7 d)
Diclofenac sodium	1.5% w/w topical solution	45.5% w/w dimethyl sulfoxide	40 drops, 4× daily	8.1±5.9 ng/mL (80 drops, 1×) 19.4±9.3 ng/mL (80 drops, 4× daily, 7 d)
Diclofenac epolamine	Patch	Nonea	One 180 mg patch, 2× daily	1.3–8.8 ng/mL (1 patch, 2× daily, 5 d)

Notes:

a Diclofenac epolamine, in contrast to diclofenac sodium, is sufficiently lipophilic to not require a penetration enhancer.⁵¹ This table is based on data provided in Barkin,³⁶ with additional data from Herndon⁵¹ and the prescribing information for each product.^48–50

Abbreviations: d, days; w/w, weight per weight.

Table 2 Systemic adverse events among randomized controlled trials

Adverse effect	Treatment group/drug administrationa (range, %)
	Topical	Oral	Vehicleb	Placebo
Upper GI NOS	10.3	8.5	–	–
GI NOS	2.6–4.8	0.8–13.4	–	7.3
Abdominal pain	1.4–12.0	3.0–22.0	0.9–3.1	0.6–2.4
Dyspepsia	0.7–15.0	3.0–26.0	0.9–5.0	0.8–6.0
Gastritis	0.9–2.2	0.0	0.0	0.0–2.4
Nausea	0.0–8.0	2.0–13.0	0.6–5.6	0.0
Diarrhea	0.0–9.0	1.5–17.0	0.0–2.0	0.0–4.0
Constipation	0.9–8.0	0.0–10.0	0.6–1.0	1.0
GI bleedc	0.0–1.0	0.0–2.0	0.0–1.2	0.0
Halitosis	0.0–5.0	0.3	0.0–1.2	0.0
Liver function abnormality	0.0–6.9	7.9–19.6	1.3–5.3	0.6–4.2
Renal abnormalityd	0.0–7.6	7.2–10.0	6.0	0.0–5.7
Change in hemoglobin	0.0–2.1	5.8–10.0	3.3	4.9
Respiratory disordere	0.0–3.2	2.0–5.3	0.5–2.5	3.8
CNS NOS	6.0–9.5	6.8–7.3	–	4.9
Dizziness	0.6–1.2	4.0	0.0	–
Vertigo	0.0–1.0	–	–	–
Headache	5.0–17.5	6.0–17.2	4.3–13.0	11.5

Notes:

a The studies from which these numbers were retrieved were heterogeneous and were included as part of a review of the literature rather than a meta-analysis;⁵⁹

b vehicle contains dimethyl sulfoxide and pluronic lecithin organogel base, or isopropyl alcohol, propylene glycol, cocoyl caprylocaprate, mineral oil, ammonia solution, perfume cream 45/3, Carbomer^® 980, polyoxyl 20 cetostearyl ether, and purified water;

c GI bleed includes melena and rectal hemorrhage;

d percentage of patients changing from normal to abnormal creatinine clearance (mL/min);

e respiratory disorder includes asthma, cough, and dyspnea.

Copyright © 2010. The Journal of Rheumatology. Reproduced with permission of Makris UE, Kohler MJ, Fraenkel L. Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review. J Rheumatol. 2010;37(6):1236–1243.⁵⁹

Abbreviations: CNS, central nervous system; GI, gastrointestinal; NOS, not otherwise specified.

Table 3 Recommendations for topical analgesics in OA treatment guidelines

Guideline	Recommendation(s)
AAOS	Knee OA: strong recommendation to use oral or topical NSAIDs or tramadol
ACR	Hand OA: topical capsaicin, topical NSAIDs (including trolamine salicylate), oral NSAIDs (including COX-2 inhibitors), or tramadol should be considered Knee OA: acetaminophen, oral or topical NSAIDs, tramadol, or intra-articular corticosteroid injections should be considered Hand or knee OA: for patients aged 75 years or older, topical NSAIDs, rather than oral NSAIDs, are recommended
AGS	Localized, non-neuropathic, persistent pain: all patients may be candidates for topical NSAIDs
EULAR	Hand OA: topical treatments are preferred over systemic treatments, especially for mild to moderate pain and when only a few joints are affected Knee OA: topical NSAIDs and capsaicin have clinical efficacy and are safe
NICE	Knee or hand OA: topical NSAIDs should be considered for pain relief in addition to core treatment. Topical NSAIDs and/or acetaminophen should be considered ahead of oral NSAIDs, COX-2 inhibitors, or opioids
OARSI	Knee OA: topical NSAIDs and capsaicin may be considered as adjunctives or alternatives to oral analgesics or anti-inflammatory agents

Note: Copyright © 2011. Springer Healthcare. Adapted with permission of Altman RD, Barthel HR. Topical therapies for osteoarthritis. Drugs. 2011;71(10):1259–1279.⁶⁵ Additional data from Hochberg et al and AAOS.^66–67

Abbreviations: AAOS, American Association of Orthopaedic Surgeons; ACR, American College of Rheumatology; AGS, American Geriatric Society; COX, cyclooxygenase; EULAR, European League Against Rheumatism; NICE, National Institute for Health and Clinical Excellence; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; OARSI, Osteoarthritis Research Society International.

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