Efficacy and Safety of Topical Diclofenac
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PAINÒ 143 (2009) 238–245 www.elsevier.com/locate/pain Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis Lee S. Simon a, Lisa M. Grierson b, Zahid Naseer b, Arthur A.M. Bookman c, J. Zev Shainhouse b,* a SDG LLC Consulting, 124 Mt. Auburn Street, Cambridge, MA, USA b Nuvo Research Inc., 7560 Airport Road, Mississauga, ON, Canada L4T 4H4 c Division of Rheumatology, University Health Network, Western Division, University of Toronto, Toronto, ON, Canada article info abstract Article history: While topical non-steroidal anti-inflammatory drugs are considered safe, their long-term efficacy for Received 1 October 2008 osteoarthritis has been suspect. We conducted a 12-week, double-blind, double-dummy, randomized Received in revised form 21 January 2009 controlled trial of topical diclofenac (TDiclo) in a vehicle solution containing dimethyl sulfoxide (DMSO) Accepted 9 March 2009 in 775 subjects with radiologically confirmed, symptomatic primary osteoarthritis of the knee. This 5- arm study compared TDiclo with a placebo solution, the DMSO vehicle, oral diclofenac (ODiclo) and Keywords: the combination of TDiclo + ODiclo for relieving the signs and symptoms of knee osteoarthritis. Subjects Topical diclofenac applied study solution, 40 drops four times daily, and took one study tablet daily for 12 weeks. Co-pri- NSAID mary efficacy variables were WOMAC pain and physical function and a patient overall health assessment. Osteoarthritis Secondary variables were WOMAC stiffness and patient global assessment (PGA) of the knee osteoarthri- Knee pain tis. TDiclo was superior to placebo for pain (À6.0 vs. À4.7, P = 0.015), physical function (À15.8 vs. À12.3, P = 0.034), overall health (À0.95 vs. À0.37, P < 0.0001), and PGA (À1.36 vs. À1.01, P = 0.016), and was superior to DMSO vehicle for all efficacy variables. No significant difference was observed between DMSO vehicle and placebo or between TDiclo and ODiclo. The commonest adverse event associated with TDiclo was dry skin (18.2%). Fewer digestive system and laboratory abnormalities were observed with TDiclo than with ODiclo. Addition of TDiclo to ODiclo did not increase the incidence of systemic adverse events. TDiclo in DMSO vehicle is an effective treatment option for knee osteoarthritis with efficacy similar to, but tolerability better than ODiclo. DMSO vehicle was no more efficacious than placebo. Ó 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. 1. Introduction meta-analysis of the same studies stressed that the various prod- ucts showed symptom relief at 1 or 2 weeks but loss of benefit at When non-pharmacological measures are not sufficient to con- 4 weeks, and rejected them as sufficient evidence to justify a rec- trol the symptoms of osteoarthritis, current evidence-based guide- ommendation of long-term use. lines support pharmacological treatment with acetaminophen or Subsequently published randomized controlled studies have oral nonsteroidal anti-inflammatory drugs (NSAIDs) [3,39,56,57]. described a penetrating topical diclofenac solution (TDiclo) in a di- Acetaminophen has been linked with an increased risk of hepatic, methyl sulfoxide (DMSO)-containing vehicle as efficacious and safe hypertensive and cardiovascular adverse effects [14,19,20,42,52]. in relieving the symptoms of primary osteoarthritis of the knee NSAIDs are more effective [49] and carry more well-known gastro- over 4-, 6-, and 12-week treatment periods [5,12,43,50]. Recent intestinal and cardiovascular risk [4,14,28,37]. The attempt to min- topical NSAID reviews and meta-analyses [6,7,11,25,38,41,48,55] imize their risk of both morbidity and potential mortality by have evaluated the data from these TDiclo studies, and subse- prescribing COX-2 selective NSAIDs (‘coxibs’) has not achieved quently published national guidelines [15,39,47,56,57] have cited the goal [32,34]. these studies as evidence for the use of topical NSAIDs as first line Topical NSAIDs present a safer potential alternative [18,27] to therapy for osteoarthritis. oral therapy, with decreased systemic exposure to the active The efficacy of topical NSAIDs, such as TDiclo, is thought to be NSAID molecule. While previous reviews [36] had suggested that due to local action of the active NSAID molecule following its pen- topical NSAIDs are effective for osteoarthritis, Lin et al. [33] in their etration through the skin to the tissue sites of inflammation and pain. Diclofenac sodium is a member of the arylacanoic acid group * Corresponding author. Tel.: +1 905 673 6980. of NSAIDs with lipophilic properties that limit its percutaneous E-mail address: [email protected] (J.Z. Shainhouse). penetration [40]. The biological property of DMSO to enhance skin 0304-3959/$36.00 Ó 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2009.03.008 L.S. Simon et al. / PAINÒ 143 (2009) 238–245 239 penetration of both hydrophilic and lipophilic molecules is well oral diclofenac tablets. Subjects applied 40 drops of solution known [53], with recent research focusing on the mechanism of (approximately 1.2 mL) around the entire circumference of the enhancement [24]. The percutaneous absorption of diclofenac fol- study knee, without massage, four times daily, and took one study lowing a multidose regimen of TDiclo (in DMSO-containing vehi- tablet daily for up to 12 weeks. cle) was significantly enhanced compared with an aqueous Concomitant analgesic and anti-inflammatory medications, diclofenac formulation without DMSO [26]. Within the extensive including over-the-counter NSAIDs and other analgesics, were pro- literature on DMSO are unsubstantiated claims of therapeutic effi- hibited. Continuation of stable treatment with glucosamine, chon- cacy in the treatment of osteoarthritis; but no efficacy of DMSO droitin, anti-depressants or a proton pump inhibitor (previous vehicle was shown in a previous, 4-week randomized controlled 90 days), or low-dose (6325 mg/day) acetylsalicylic acid (previous study of TDiclo [12]. High dose exposure of non-primate species 30 days) was permitted. Acetaminophen was provided, and per- to DMSO has demonstrated some ocular abnormalities [44]; how- mitted (up to four 325-mg caplets per day) except during the ever no such changes have been observed in humans [13,23,46]. 3 days before each efficacy assessment. Other topical products on We describe here the safety and efficacy results of a confirma- the knee, including skin emollients, were prohibited. A patient tory 12-week, 5-arm randomized controlled study of TDiclo, with a gastrointestinal adverse event was allowed to start a proton including a placebo arm to establish its efficacy, a DMSO vehicle pump inhibitor. Compliance with the treatment regimen was as- arm to address DMSO claims of efficacy, an oral diclofenac arm sessed by weighing the solution bottles and counting study tablets to compare with TDiclo and a combination of TDiclo plus ODiclo at each clinic visit. to assess combined treatment. All study solutions appeared as identical clear, colorless liquids. It was expected that some subjects applying TDiclo or DMSO vehi- cle would report a garlic taste or odor from exhaling dimethyl sul- 2. Methods fide, a volatile DMSO metabolite; therefore, a token amount of DMSO (2.3%) was included in the placebo solution. Previous trials 2.1. Study subjects with TDiclo confirmed the success of this blinding procedure as the incidence of ‘taste perversion’ adverse events was no different This randomized, double-blind, double-dummy, placebo-, vehi- with placebo solution from TDiclo. Oral diclofenac and placebo tab- cle- and active-controlled study was conducted at 40 outpatient lets appeared identical (NovopharmÒ Inc.). Each study kit was centers in Canada and at 21 centers in the United States, from Feb- assembled according to a computer-generated randomization ruary 2004 to October 2005, following approval by the appropriate schedule created by an external statistician for each stratum using institutional review boards. Eligible subjects, after written in- a block size of 5. The randomization sequence was concealed from formed consent, included men and non-pregnant women aged investigators, subjects and the sponsor’s clinical research person- 40–85 with primary OA of the knee based on (i) standard radiolog- nel until after data lock. ical criteria for OA [2] on a recent (within 3 months) examination, (ii) pain, with regular use of a NSAID or other analgesic medication 2.3. Efficacy measures (at least 3 days a week in the previous month) and (iii) a flare of pain and minimum Likert pain score of 8 (40 on a scale normalized Each subject completed a full efficacy assessment questionnaire to 0–100; see below, Efficacy Measures) at baseline, following after randomization at baseline and at 4, 8 and 12 weeks, or at drop washout of that medication. [A flare was defined as an increase out. The co-primary efficacy variables [10] were defined a priori as in total Likert pain score of 25% and at least 2, and a score of at least WOMAC pain and physical function, measured by the 5-point Lik- moderate on one or more of the five items/questions of the WO- ert scale [9], and patient overall health assessment (POHA). The MAC LK3.1 pain subscale.] All knee films were reviewed by a single POHA (see Section 4) asked the question, ‘‘Considering all the ways radiologist and each compartment was scored (none = 1, mild = 2, your osteoarthritic (study) knee and its treatment affect you, moderate = 3, severe = 4). Only one knee was treated; where both including both positive and negative effects, how would you rate knees met all entry criteria, the more painful knee (or dominant your overall state of health in the past 48 hours?”.