Review paper Reumatologia 2018; 56, 3: 174–183 DOI: https://doi.org/10.5114/reum.2018.76816 Diclofenac in the treatment of pain in patients with rheumatic diseases Justyna Kołodziejska, Michał Kołodziejczyk Department of Pharmaceutical Technology, Chair of Applied Pharmacy, Medical University of Lodz, Poland Abstract Diclofenac, a phenylacetic acid derivative, is a drug demonstrating high efficacy after oral adminis- tration in the treatment of pain and physical disability in rheumatic diseases. In view of the adverse effects associated with using diclofenac, it is necessary to consider all known drug safety informa- tion before the drug is selected for therapy and the dosage regimen is set for individual patients. Selecting an oral dosage form with specific properties determined by excipients is a method to im- prove the availability of the drug substance and, at the same time, minimize adverse drug reactions. An alternative to tablet or capsule dosage forms is diclofenac application to the skin. The proven efficacy of this method is further improved through the use of transdermal penetration enhancers and vehicle ingredients which provide dosage forms with specific physical properties. Key words: diclofenac, efficacy, adverse effects, dosage form technology. Introduction on the market also exhibit technological differences (dosage form modifications). Intense pharmacological Diseases of the musculo-skeletal system affect 70% and formulation research is currently being conducted of the population over the age of 50 years. Pain caused to obtain more effective and safer products [2]. by rheumatic diseases decreases or resolves during re- NSAIDs are effective in multiple indications. In rheu- mission-inducing treatment. Drugs used in the therapy matology, they are used in the treatment of a range of of rheumatic diseases usually have a late onset of ac- diseases including rheumatoid arthritis, lupus erythe- tion. Consequently, in addition to the treatment of the matosus, psoriatic arthritis, ankylosing spondylitis, gout underlying disease analgesics are indicated as adjunct and rheumatic fever [3–5]. therapy. At all stages of pain treatment, analgesics can be used in combination with co-analgesics including sedatives, antidepressants and anti-epileptics which Efficacy of diclofenac after oral may contribute to a reduction in doses of analgesic administration drugs. Patients with chronic pain evaluated at a mini- In 2017 Costa et al. [6] published the findings of mum of 50% percent on the visual analogue scale (VAS: a study evaluating the efficacy of different drugs and 0–100 mm) are eligible for therapy with high-potency their doses in the treatment of pain secondary to os- opioids [1]. teoarthritis based on a search of the Cochrane Central Nonsteroidal anti-inflammatory drugs (NSAIDs) are Register of Controlled Trials. The researchers reviewed a pharmacokinetically and pharmacodynamically di- published studies from the period from January 1980 verse group of drug substances which have an effect to February 2015 in which the study group included at on different forms of cyclooxygenase (COX) and vary in least 100 patients. Overall, the review encompassed their mechanism of action, distribution to the inflamma- 8,973 publications based on studies conducted in a total tion site and half-life. Pharmaceutical products available of 58,451 patients. The results of efficacy comparisons Address for correspondence: Michał Kołodziejczyk, Department of Pharmaceutical Technology, Chair of Applied Pharmacy, Medical University of Lodz, 1 Muszyńskiego St., 90-151 Lodz, Poland, e-mail: [email protected] Submitted: 22.05.2018; Accepted: 21.06.2018 Reumatologia 2018; 56/3 Diclofenac in the treatment of pain in patients with rheumatic diseases 175 between paracetamol and NSAIDs (including naproxen, gesic efficacy achieved with the three products was per- ibuprofen, diclofenac, celecoxib, lumiracoxib, rofecoxib, formed by evaluating the level of pain on the VAS scale etoricoxib used at different therapeutic doses) were [9] on day 0 and then every week for 3 weeks in total. It analyzed in this cited review. The drugs were compared was found that lornoxicam, aceclofenac and diclofenac with each other and with placebo. The authors of the were equally effective as analgesic agents. The findings study concluded that diclofenac at a dose of 150 mg per are listed in Table I. day is currently the most effective drug in the treatment The drug substance which is most commonly com- of pain and physical disability caused by osteoarthritis pared with diclofenac is aceclofenac, which is related to (OA), and superior to widely used NSAIDs (including similarities in the structure and mechanism of action of ibuprofen, naproxen and celecoxib) at maximum doses. both drug substances [10]. In their studies, Hinz et al. Etoricoxib at a maximum dose of 60 mg per day exhibits [11] assessed whether the biotransformation of ace- comparable efficacy to diclofenac at a dose of 150 mg clofenac to metabolites including 4′-hydroxyaceclofenac, per day in the therapy of pain, but its effect on the treat- diclofenac and 4′-hydroxydiclofenac contributes to the in- ment of physical disability is undetermined. The authors hibitory effect on cyclooxygenase isoenzymesin vitro and of the review assert that in view of the diclofenac safety ex vivo. Short-term in vitro tests based on human whole profile all available information should be considered blood and monocytes showed that neither aceclofenac when diclofenac treatment is selected and its dose is nor 4′-hydroxyaceclofenac affected COX-1 and COX-2, determined for individual patients [6]. whereas diclofenac and 4′-hydroxydiclofenac were found Pavelka [7] presented randomized well-controlled to inhibit both isoforms. In long-term in vitro tests both clinical trials, excluding reviews, meta-analyses and aceclofenac and 4′-hydroxyaceclofenac inhibited both n = 1 trials. A number of databases were searched in- isoforms of COX, but the inhibition occurred in parallel cluding Embase, Ovid Medline, and Ovid Medline In-Pro- to the conversion to diclofenac and 4′-hydroxydiclofenac, cess & Other Non Indexed Citations. The review encom- respectively. Comparative studies of aceclofenac and di- passed a total of 263 articles published after 1999. The clofenac found the maximum plasma concentration of studies focused on comparing the therapeutic efficacy diclofenac after application of both aceclofenac and di- of diclofenac with other drugs including etoricoxib, ce- clofenac (0.39 μmol/l and 1.28 μmol/l, respectively). The lecoxib, lumiracoxib, rofecoxib, aceclofenac, dexketo- obtained concentrations were recognized as sufficient to profen, etodolac, lornoxicam, meloxicam, nabumetone, achieve over 97% inhibition of COX-2 (50% inhibitory con- nimesulide, acetaminophen, tramadol, diacerein and centration: 0.024 μmol/l). Studies show unambiguously oxaceprol. The authors found that in the majority of that the inhibition of COX isoenzymes by aceclofenac studies diclofenac at therapeutic doses exhibited similar requires its conversion to diclofenac. Table II shows the efficacy to the other drugs listed above. Thus, diclofenac potency of the inhibitory effect produced by the studied confirmed its status as the reference drug of choice in drugs and their metabolites on cyclooxygenases both in the therapy of OA. Based on the studies, the efficacy of short- and long-term tests [11]. diclofenac is not inferior to newer analgesic medications Yamazaki et al. [12] also studied the mechanisms used in the treatment of OA [7]. underlying the effect of aceclofenac in primary cultured Patnaik et al. [8] published the findings of a study synovial cells obtained from 10 patients with rheuma- comparing the efficacy of lornoxicam and aceclofenac toid arthritis. The research showed that aceclofenac and and diclofenac in patients with musculoskeletal disor- 4′-hydroxyaceclofenac, the main chemical compounds ders. The subjects were randomized into three groups of found in human blood, have no inhibitory effect on the 50. The patients in the three groups were treated with activity of cyclooxygenase (COX) or the expression of lornoxicam (dose 4 mg), aceclofenac (dose 100 mg) and COX in rheumatoid synovial cells. It was also observed diclofenac (dose 50 mg). The drugs were applied twice that aceclofenac and 4′-hydroxyaceclofenac were hy- a day after meals. A comparative assessment of anal- drolyzed in rheumatoid synovial cells to COX inhibitors Table I. Comparison of analgesic efficacy of lornoxicam, aceclofenac and diclofenac [9] Treatment Mean VAS ±SD n Baseline value n First week n Second week Percentage reduction Lornoxicam 50 4.16 ±1.63 50 2.15 ±1.46 41 1.42 ±1.25 48 Aceclofenac 50 4.34 ±1.67 50 1.91 ±1.24 39 1.03 ±0.94 56 Diclofenac 50 4.48 ±1.35 50 2.07 ±1.14 38 1.03 ±0.97 62 Reumatologia 2018; 56/3 176 Justyna Kołodziejska, Michał Kołodziejczyk Table II. Potency of inhibitory effect of aceclofenac, 4′-hydroxyaceclofenac, diclofenac and 4′-hydroxydiclofenac on COX-1 and COX-2 in short- and long-term in vitro tests [11] Substance Short-term test Long-term test or metabolite COX-1 IC50 COX-2 IC50 COX-1 IC50 COX-2 IC50 (µmol/l) (µmol/l) (µmol/l) (µmol/l) Aceclofenac no inhibition* no inhibition* 3.59 ±0.54 1.65 ±0.46 4′-hydroxyaceclofenac no inhibition* no inhibition* 12.73 ±3.53 25.35 ±7.98 Diclofenac 0.43 ±0.13 0.0054 ±0.0028 0.16 ±0.03 0.024 ±0.007 4′-hydroxydiclofenac 8.28 ±0.93 0.72 ±0.40 1.63 ±0.56 0.76 ±0.03 IC50 – 50% inhibitory concentration;