Efficacy and safety of topical diclofenac containing... : PAIN (original) (raw)
1. Introduction
When non-pharmacological measures are not sufficient to control the symptoms of osteoarthritis, current evidence-based guidelines support pharmacological treatment with acetaminophen or oral nonsteroidal anti-inflammatory drugs (NSAIDs) [3,39,56,57]. Acetaminophen has been linked with an increased risk of hepatic, hypertensive and cardiovascular adverse effects [14,19,20,42,52]. NSAIDs are more effective [49] and carry more well-known gastrointestinal and cardiovascular risk [4,14,28,37]. The attempt to minimize their risk of both morbidity and potential mortality by prescribing COX-2 selective NSAIDs (‘coxibs’) has not achieved the goal [32,34].
Topical NSAIDs present a safer potential alternative [18,27] to oral therapy, with decreased systemic exposure to the active NSAID molecule. While previous reviews [36] had suggested that topical NSAIDs are effective for osteoarthritis, Lin et al. [33] in their meta-analysis of the same studies stressed that the various products showed symptom relief at 1 or 2weeks but loss of benefit at 4weeks, and rejected them as sufficient evidence to justify a recommendation of long-term use.
Subsequently published randomized controlled studies have described a penetrating topical diclofenac solution (TDiclo) in a dimethyl sulfoxide (DMSO)-containing vehicle as efficacious and safe in relieving the symptoms of primary osteoarthritis of the knee over 4-, 6-, and 12-week treatment periods [5,12,43,50]. Recent topical NSAID reviews and meta-analyses [6,7,11,25,38,41,48,55] have evaluated the data from these TDiclo studies, and subsequently published national guidelines [15,39,47,56,57] have cited these studies as evidence for the use of topical NSAIDs as first line therapy for osteoarthritis.
The efficacy of topical NSAIDs, such as TDiclo, is thought to be due to local action of the active NSAID molecule following its penetration through the skin to the tissue sites of inflammation and pain. Diclofenac sodium is a member of the arylacanoic acid group of NSAIDs with lipophilic properties that limit its percutaneous penetration [40]. The biological property of DMSO to enhance skin penetration of both hydrophilic and lipophilic molecules is well known [53], with recent research focusing on the mechanism of enhancement [24]. The percutaneous absorption of diclofenac following a multidose regimen of TDiclo (in DMSO-containing vehicle) was significantly enhanced compared with an aqueous diclofenac formulation without DMSO [26]. Within the extensive literature on DMSO are unsubstantiated claims of therapeutic efficacy in the treatment of osteoarthritis; but no efficacy of DMSO vehicle was shown in a previous, 4-week randomized controlled study of TDiclo [12]. High dose exposure of non-primate species to DMSO has demonstrated some ocular abnormalities [44]; however no such changes have been observed in humans [13,23,46].
We describe here the safety and efficacy results of a confirmatory 12-week, 5-arm randomized controlled study of TDiclo, including a placebo arm to establish its efficacy, a DMSO vehicle arm to address DMSO claims of efficacy, an oral diclofenac arm to compare with TDiclo and a combination of TDiclo plus ODiclo to assess combined treatment.
2. Methods
2.1. Study subjects
This randomized, double-blind, double-dummy, placebo-, vehicle- and active-controlled study was conducted at 40 outpatient centers in Canada and at 21 centers in the United States, from February 2004 to October 2005, following approval by the appropriate institutional review boards. Eligible subjects, after written informed consent, included men and non-pregnant women aged 40–85 with primary OA of the knee based on (i) standard radiological criteria for OA [2] on a recent (within 3months) examination, (ii) pain, with regular use of a NSAID or other analgesic medication (at least 3days a week in the previous month) and (iii) a flare of pain and minimum Likert pain score of 8 (40 on a scale normalized to 0–100; see below, Efficacy Measures) at baseline, following washout of that medication. [A flare was defined as an increase in total Likert pain score of 25% and at least 2, and a score of at least moderate on one or more of the five items/questions of the WOMAC LK3.1 pain subscale.] All knee films were reviewed by a single radiologist and each compartment was scored (none=1, mild=2, moderate=3, severe=4). Only one knee was treated; where both knees met all entry criteria, the more painful knee (or dominant knee if they scored the same) was selected. Standard exclusion criteria were employed, as described previously [43].
2.2. Study design
Eligible subjects were stratified by the investigator at baseline into stratum 1 (no pain and normal radiological examination in the non-study knee) or stratum 2 (pain and/or abnormal radiological examination in the non-study knee), and were then randomized into the trial on receiving the next numbered study kit at that clinic for that stratum. Each study kit contained topical solution and oral tablets for one of the five treatment regimens: (i) ‘TDiclo’; topical diclofenac solution plus oral placebo tablets (topical diclofenac solution is 1.5% w/w diclofenac sodium in a vehicle solution containing 45.5% w/w DMSO and other excipients [Pennsaid® Topical Solution, Nuvo Research Inc.]), (ii) ‘DMSO vehicle’; vehicle solution plus oral placebo tablets (vehicle solution was the complete carrier, including 45.5% DMSO and other excipients, with no diclofenac), (iii) ‘placebo’; placebo solution plus oral placebo tablets (placebo solution was a modified vehicle solution with only 2.3% DMSO, for blinding purposes, and no diclofenac), (iv) ‘ODiclo’; placebo solution plus oral diclofenac tablets (100mg slow release), or (v) ‘TDiclo+ODiclo’; topical diclofenac solution plus oral diclofenac tablets. Subjects applied 40 drops of solution (approximately 1.2mL) around the entire circumference of the study knee, without massage, four times daily, and took one study tablet daily for up to 12weeks.
Concomitant analgesic and anti-inflammatory medications, including over-the-counter NSAIDs and other analgesics, were prohibited. Continuation of stable treatment with glucosamine, chondroitin, anti-depressants or a proton pump inhibitor (previous 90days), or low-dose (≤325mg/day) acetylsalicylic acid (previous 30days) was permitted. Acetaminophen was provided, and permitted (up to four 325-mg caplets per day) except during the 3days before each efficacy assessment. Other topical products on the knee, including skin emollients, were prohibited. A patient with a gastrointestinal adverse event was allowed to start a proton pump inhibitor. Compliance with the treatment regimen was assessed by weighing the solution bottles and counting study tablets at each clinic visit.
All study solutions appeared as identical clear, colorless liquids. It was expected that some subjects applying TDiclo or DMSO vehicle would report a garlic taste or odor from exhaling dimethyl sulfide, a volatile DMSO metabolite; therefore, a token amount of DMSO (2.3%) was included in the placebo solution. Previous trials with TDiclo confirmed the success of this blinding procedure as the incidence of ‘taste perversion’ adverse events was no different with placebo solution from TDiclo. Oral diclofenac and placebo tablets appeared identical (Novopharm® Inc.). Each study kit was assembled according to a computer-generated randomization schedule created by an external statistician for each stratum using a block size of 5. The randomization sequence was concealed from investigators, subjects and the sponsor’s clinical research personnel until after data lock.
2.3. Efficacy measures
Each subject completed a full efficacy assessment questionnaire after randomization at baseline and at 4, 8 and 12weeks, or at drop out. The co-primary efficacy variables [10] were defined a priori as WOMAC pain and physical function, measured by the 5-point Likert scale [9], and patient overall health assessment (POHA). The POHA (see Section 4) asked the question, “Considering all the ways your osteoarthritic (study) knee and its treatment affect you, including both positive and negative effects, how would you rate your overall state of health in the past 48 hours?”. Secondary efficacy variables were WOMAC stiffness and patient global assessment (PGA) of knee osteoarthritis. The PGA asked the question, “How has the osteoarthritis in your study joint been over the last 48 hours?”. The POHA and PGA were scored on a 5-point Likert scale. There was no assessment of the non-treated knee.
2.4. Safety measures
At all visits, vital signs were measured, dermatological evaluation of the study knee was done according to a standard numerical (0–4) scale [35] and adverse events were solicited using open-ended questions. Adverse events were categorized according to Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) [51]. Blood and urine samples were obtained for routine laboratory analysis at baseline, 4 and 12weeks. Ocular examination (visual acuity test, slit lamp examination and lens assessment) was conducted at the baseline and final visit.
2.5. Statistical analysis plan
All planned analyses were specified a priori. Analysis of the Likert efficacy data was by modified intent to treat (mITT), excluding only those subjects who had no baseline data or did not administer at least one dose of both study solution and tablets [31]. Statistical tests were two sided at the 5% level of significance. All efficacy analyses were done by analysis of covariance of the change in score from baseline to landmark final assessment, with baseline score as the covariate. Subjects in both randomization strata were combined for all analyses.
The primary efficacy comparison was TDiclo vs. placebo for the primary efficacy variables, with no correction for analysis of multiple primary variables (regulatory design required superiority for each primary variable). The sample size required to show the superiority of TDiclo over placebo was 142 subjects per arm, based on an estimate from previous trials [5,12,43] of the difference (standard deviation) between groups for the change in the score of 1.5 (4.5) for pain, 5.0 (15) for physical function and 0.4 (1.2) for PGA, power of 80% and Type I error rate of _α_=0.052-tailed. A post hoc sensitivity analysis of the primary efficacy data was performed by imputing no improvement (i.e., baseline score was carried forward and imputed as final score [BOCF]) to non-completers by reason of an adverse event or lack of effect and for subjects excluded from mITT.
Secondary comparisons included TDiclo vs. placebo for the secondary variables, and TDiclo vs. DMSO vehicle and DMSO vehicle vs. placebo for all variables. A post hoc efficacy analysis compared TDiclo vs. ODiclo and TDiclo+ODiclo vs. ODiclo. For a missing final score, last observation was carried forward.
Safety analyses were performed on all subjects who received even one dose of either study medication. There was no imputation of missing safety data.
3. Results
3.1. Study subjects
Of 1396 subjects screened, 775 were randomized to one of the five treatment arms and 527 subjects completed treatment (Fig. 1). Over 95% of patients had bilateral disease (pain or abnormal radiological examination also in non-study knee) with pain in the contralateral knee in 90%. A total of 88% subjects met the modified [29] American College of Rheumatology (ACR) criteria [1] for osteoarthritis, pain and osteophytes, and the remaining had pain with either joint space narrowing or subchondral sclerosis. Subjects in each treatment arm had similar demographic and baseline characteristics (Table 1), duration of exposure and compliance (>89% of expected use for topical solution and oral tablets). Withdrawals for an adverse event were similar among treatment groups. Withdrawals for lack of effect were similar among TDiclo, placebo and DMSO vehicle arms, but fewer with the oral diclofenac arms (Fig. 1).
Flow of subjects through the trial. ∗‘Other’ reason for withdrawal was primarily a scheduling conflict. ∗∗Included in efficacy analysis of pain variable. Additional subjects were excluded from the analysis of the variables physical function and patient overall health assessment due to missing baseline data (see Section 3).
Demographic and baseline characteristics.a
There were 772 subjects included in the mITT group. Three subjects were excluded who did not take at least one dose of both topical and oral medication, or had no data (Fig. 1). Individual subjects who omitted baseline assessment for a specific efficacy variable were excluded from that analysis.
3.2. Efficacy
The primary efficacy analyses, as shown in Table 2, show the superiority of TDiclo over placebo for the three co-primary variables – pain (_P_=0.015), physical function (_P_=0.034), and POHA (P<0.0001). Superiority was observed also for the secondary variable PGA (_P_=0.016), but not for stiffness. There was greater improvement with TDiclo (P<0.05) than with DMSO vehicle for all five variables (Table 2). A post hoc BOCF sensitivity analysis of the primary efficacy data of all 775 patients did not change any of the conclusions regarding the superiority of TDiclo over placebo (pain, _P_=0.031; physical function, _P_=0.041; POHA, _P_=0.0001).
Efficacy variable scoresa.
No significant efficacy advantage of the DMSO vehicle over placebo was observed for the primary or secondary variables, except for the POHA (Table 2). A comparison of ODiclo vs. TDiclo found no statistical difference for any of the five efficacy variables (Table 2). The combination of TDiclo+ODiclo was no better than ODiclo alone for all variables (pain, _P_=0.30; physical function, _P_=0.33; POHA, _P_=0.43; stiffness, _P_=0.16; PGA, _P_=0.50).
Mean [SD] acetaminophen use with TDiclo (0.64 [0.83] caplets per day) was lower than that with placebo (0.95 [1.14], _P_=0.005) and DMSO vehicle (0.99 [1.11], _P_=0.002), and was not different from that with ODiclo (0.55 [0.82], _P_=0.41) or TDiclo+ODiclo (0.46 [0.70]; _P_=0.10).
3.3. Safety
Skin adverse events predominated with TDiclo, most being dry skin (Table 3). The overall incidence of skin adverse events was similar in TDiclo+ODiclo, and lower in placebo, and ODiclo arms. The rate with DMSO vehicle was intermediate between TDiclo and placebo. Only five (3.2%) subjects in TDiclo withdrew due to an application site reaction.
Incidence of adverse events.a
The incidence of adverse events of the digestive system with TDiclo was no greater than that with placebo and was much lower than with ODiclo and TDiclo+ODiclo. Withdrawal due to an adverse event of the digestive system was higher in ODiclo (11 [7.3%]) vs. TDiclo (4 [2.6%]) and placebo (3 [1.9%]). The combination of TDiclo+ODiclo did not increase the incidence of events of the digestive system over ODiclo alone (Table 3).
No difference between treatment groups was observed for cardiovascular events, which were <2% in each treatment group. The incidence of hypertension was similar for all groups (1.3% for TDiclo, ODiclo and TDiclo+ODiclo; 1.2% for DMSO vehicle; 0.6% for placebo). There was no difference among the groups for reports of an abnormal taste sensation or odor, confirming the success of the blinding procedure for DMSO.
There was no serious adverse event in the TDiclo arm, four in placebo (one anemia, one cerebrovascular accident, one fractured hip, one dislocated prosthetic hip), one in DMSO vehicle (acute enteritis), one in ODiclo (post-polypectomy lower gastrointestinal bleed, 8days after withdrawal of study medication) and three in TDiclo+ODiclo (one leg cellulitis, one unstable angina, one transient ischemic attack).
Changes in key NSAID-related laboratory parameters are shown in Table 4. Overall, the mean change in the laboratory value and the number of subjects developing an abnormality showed no difference between TDiclo and placebo or DMSO vehicle, but a greater mean change and higher incidence of abnormality occurred with the ODiclo arms. With ODiclo compared with TDiclo, there was a greater mean change in hemoglobin, alanine aminotransferase, gamma-glutamyl transpeptidase, creatinine and creatinine clearance, and a greater number of subjects developing an abnormality for these parameters (Table 4). Development of abnormal laboratory parameters was generally below clinically relevant levels. No subject developed a clinically significant change in hemoglobin or creatinine. An increase in any liver enzyme to three times the upper limit of normal occurred in one subject with placebo, one with DMSO vehicle, two with ODiclo and three with TDiclo+ODiclo, but none with TDiclo.
Analysis of changea in laboratory parameters.
Ocular examination at baseline and final revealed no change in visual acuity (data not shown) and no difference in the development of lens abnormality (cataract) with placebo (4 [2.6%]) vs. TDiclo (2 [1.3%]) or DMSO vehicle (6 [3.8%]).
4. Discussion
The results of this study clearly show the effectiveness of TDiclo, a solution of diclofenac in a DMSO vehicle, applied topically to treat the symptoms of osteoarthritis of the knee. TDiclo was superior to both topical comparator groups (placebo and DMSO vehicle) for all three primary efficacy variables, pain, function and patient overall health. Efficacy was confirmed by a conservative BOCF sensitivity analysis. This study followed a typical 12-week oral NSAID trial design – primary osteoarthritis of the knee with pain and abnormal radiological findings. Although most subjects had bilateral osteoarthritis, only one painful knee was treated with topical solution. Inasmuch as outcome measures of physical function and overall patient health assessment are likely to be negatively influenced by symptoms in the non-treated knee, this trial design biased against TDiclo. In any oral NSAID trial, and in this study’s ODiclo arms, subjects automatically treat both knees, avoiding these factors. The inclusion of oral therapy for all groups added a second placebo effect to the topical comparator arms, imposing a yet higher burden to prove the efficacy of TDiclo over placebo. Despite these elements in trial design the efficacy of TDiclo was robustly established.
The response of patients in the ODiclo group in this study (40–48% improvement in variable score) was the same as seen in other oral NSAID trials [8,54], providing a powerful external audit on the validity of the trial design and conduct, and further confirmation of the sustained efficacy of TDiclo. TDiclo was found to be as effective as ODiclo at relieving the symptoms of knee osteoarthritis with less NSAID-related systemic toxicity than ODiclo. These observations support the safety and efficacy results of a previous equivalence study of this TDiclo vs. ODiclo [50]. The cumulative data with TDiclo sustain the recent recommendations advocating the use of topical NSAIDs as first-line therapy for the treatment of osteoarthritis [15,39,47,56,57].
Claims of therapeutic efficacy for DMSO in osteoarthritis were discounted in an earlier, 4-week trial with TDiclo [12] and are further disproven by this 12-week study. The DMSO-containing vehicle likely retains a role in TDiclo by facilitating percutaneous penetration of the active diclofenac sodium [26]. As such, generalization of the results with TDiclo to other topicals is cautioned. The various NSAID formulations differ not only in their active medication but also in the components of the vehicle, the nature of the formulation (lotion, gel, solution, patch, etc.) and the presence of penetration enhancers [21,22,45]. Lin et al. in their critical meta-analysis of topical NSAIDs observed also that efficacy might be drug specific [33].
The patient overall health assessment (POHA) was chosen as a primary variable and the more common patient global assessment (PGA) as a secondary variable, at the request of the FDA. The POHA is a more holistic question which affords the subject the opportunity to intuitively integrate the overall efficacy of the treatment (as assessed also by the PGA) with the adverse effects it causes (or is perceived to cause). The PGA question was the same as that used in the previous trials of TDiclo [5,12,43,50]. It is interesting to note that the improvement was greater for PGA than for POHA for both TDiclo (−1.36 vs. −0.95) and ODiclo (−1.42 vs. −0.88), perhaps reflecting a penalty for adverse effects imposed by the subject on efficacy. Whereas ODiclo scored a slightly higher improvement on PGA, TDiclo scored slightly higher on POHA perhaps reflecting a greater penalty for the adverse effects of ODiclo.
The commonest adverse events with TDiclo therapy were application site skin reactions and the majority entailed only skin dryness. The incidence was similar for DMSO vehicle suggesting that it is due primarily to the vehicle. DMSO may dissolve surface lipids, leaving the skin dry. To detect the maximum potential skin adverse event profile, subjects were not allowed to apply any skin emollient to counter the anticipated drying effect of the vehicle carrier. There was no apparent difference between TDiclo and placebo in NSAID-associated gastrointestinal adverse events (the incidence was actually lower with TDiclo). There is a potential for bias if investigators or subjects presume that diclofenac applied topically will not cause gastrointestinal or other systemic events and ignore such adverse events. Inclusion of the oral placebo countered this possibility but likely contributed inordinately to the adverse events of the digestive system reported in even 9.6% of subjects using placebo (Table 3).
Previous reports in non-primate species (dogs, rabbits, pigs) identified ocular abnormalities with prolonged high dose exposure to DMSO [44]. Clinical studies in humans where DMSO was applied directly to the eye or to the skin at extremely high doses (greater than 25 times daily dose of DMSO as in TDiclo application), showed no deleterious ocular changes [13,23,46]. In this study, no eye lens abnormalities were observed with DMSO vehicle or TDiclo treatment.
The combination of TDiclo+ODiclo showed no increase in adverse events relative to TDiclo or ODiclo alone. The blood level of diclofenac following topical application as TDiclo is only about 12ng/mL [30] and the incremental increase with the combination would be negligible compared with the predicted level of 1500ng/mL that is reported with oral diclofenac [17]. Although combined treatment with TDiclo+ODiclo did not provide a statistical advantage over ODiclo alone, this regimen could be a reasonable treatment paradigm in an individual with persistent or breakthrough knee pain despite an oral NSAID.
In conclusion, we have shown in this study that this formulation of TDiclo provides durable improvement in the symptoms of osteoarthritis of the knee, and that relief is not contributed by the DMSO carrier. Efficacy of TDiclo was comparable to that achieved with ODiclo. Dry skin was frequent but systemic NSAID class-related clinical and laboratory adverse events occurred less frequently than with ODiclo. For the patient initiating pharmacological therapy for relief of symptoms associated with osteoarthritis of the knee based on current treatment guidelines, this TDiclo formulation is a viable, evidence-based treatment option.
Acknowledgements
The authors acknowledge the commitment of all study investigators and support staff, without whom the present study would not have been possible. The sponsor, Nuvo Research Inc., provided medication and funding for this study, and managed and analyzed the data. All study authors contributed to interpretation of data and critical review of the manuscript, and agreed upon the final version independently of the sponsor. Dr. Simon is a consultant and Dr. Bookman has chaired advisory boards for the sponsor. Dr. Grierson, Mr. Naseer and Dr. Shainhouse own stock in and are employees of Nuvo Research Inc.
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Keywords:
Topical diclofenac; NSAID; Osteoarthritis; Knee pain
© 2009 Lippincott Williams & Wilkins, Inc.