A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Comparative Study to Evaluate the Efficacy and Safety of Newly Developed Diclofenac Patches in Patients With Cancer Pain

Shigeki Yamaguchi; Takaaki Terahara; Koji Okawa; Hiroshi Inakura


Pain. 2022;163(7):1303-1312. 

In This Article

Abstract and Introduction


This phase III multicenter randomized double-blind placebo-controlled comparative study evaluated the efficacy and safety of diclofenac sodium patches for the treatment of cancer pain. The study consisted of a 2-week to 4-week open-label dose-titration phase and a 4-week double-blind phase. In the double-blind phase, patients who were expected to continue treatment of cancer pain with nonopioid analgesics alone were randomized to the diclofenac sodium patch or placebo group. Once-daily diclofenac sodium patches were started at 150 mg/day (2 patches) and could be increased up to 225 mg/day (3 patches). The primary efficacy endpoint was the time to insufficient analgesic response. Statistical analysis of the double-blind phase included data from 120 patients of the diclofenac sodium patch group and 118 patients of the placebo group. Time to insufficient analgesic response was significantly longer with diclofenac sodium patches than with placebo (P = 0.0016). The hazard ratio for insufficient response for diclofenac sodium patch vs placebo was 0.459 (95% confidence interval, 0.275–0.768). Regarding sleep quality during the double-blind phase, the proportion of patients with "very good sleep" or "good sleep" in the diclofenac sodium patch and placebo groups was 90.8% and 88.1% at the start of the double-blind phase and 81.4% and 78.6% at the final assessment, respectively. The incidence of adverse events was 60.8% (73/120) in the diclofenac sodium patch group and 60.2% (71/118) in the placebo group. Once-daily diclofenac sodium patches are effective in treating cancer pain and are well tolerated.


Medical treatments for cancer pain include nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol, and opioid analgesics, such as codeine, morphine, oxycodone, and fentanyl.[18] World Health Organization (WHO) guidelines recommend administering NSAIDs, paracetamol, and opioids as monotherapy or combination therapy from the start of cancer pain management, depending on pain intensity.[18] However, cancer patients may have difficulties taking oral medicines because of symptoms such as nausea, vomiting, dysphagia, and gastrointestinal obstruction, and nausea and vomiting may occur as adverse reactions to anticancer therapy.[18] As an alternative to oral administration, opioid analgesics can be administered by a transdermal drug delivery system containing fentanyl, which is useful for cancer patients who have difficulty taking orally administered drugs.[13,19] As regards nonopioid analgesics, the WHO guideline includes only oral and injectable formulations and suppositories and no transdermal drug delivery system.[18]

Diclofenac sodium is an NSAID that exerts analgesic and anti-inflammatory effects by inhibiting cyclooxygenase.[6] It is indicated for pain relief of osteoarthritis and rheumatoid arthritis and is expected to be effective for cancer pain.[2,10,11,16] A systematic review published in 2019 suggested that NSAIDs were more effective than placebo in 7 randomized controlled trials in cancer patients with mild pain who were not receiving analgesics.[9] However, all of the NSAIDs evaluated in these randomized controlled trials were single-dose, immediate-release oral or injectable formulations. To the best of our knowledge, no studies have evaluated the efficacy and safety of either long-acting NSAIDs or continuous administration of NSAIDs for the treatment of cancer pain.

Recently, a new systemic transdermal delivery system of diclofenac sodium, a diclofenac sodium patch, was developed in Japan specifically for the management of cancer pain. In Japan, a 70 cm2 (7 cm × 10 cm) patch containing 15 mg of diclofenac sodium is broadly used for local pain;[12] however, treatment of cancer pain requires stable blood concentrations and a systemic effect. The new diclofenac sodium patch is the same size as the topical patch but contains 5 times the amount of active pharmaceutical ingredient (75 mg). Furthermore, the new patch is a matrix-type patch with an improved preparation composition that enhances transdermal absorption of the active pharmaceutical ingredient. A pharmacokinetic study demonstrated that the relative bioavailability of repeated application of diclofenac sodium patch 225 mg (corresponding to 3 patches) was approximately 76% that of repeated dosing of oral diclofenac 100 mg/day (the maximum daily dose in Japan) and estimated that the Cmax was lower than that of oral diclofenac 25 mg.[15] Because once-daily application of diclofenac sodium patch can achieve a stable blood concentration, this new formulation is expected to be useful for achieving long-term, sustained systemic effects. Therefore, we performed a randomized double-blind placebo-controlled study to evaluate the efficacy and safety of diclofenac sodium patches administered once daily at a dose of 150 mg/day (2 patches) or 225 mg/day (3 patches).