Efficacy of Switching from Prior Nonsteroidal Anti-inflammatory Drugs to Transdermal Diclofenac in Cancer Pain Management

Authors: YUSUKE IIKURA, TAKASHI YOKOKAWA, WATARU HARASHIMA, KAZUYOSHI KAWAKAMI, YUTARO MAE, TAIZO ISHIGURO, AKIKO HASEGAWA, RYOTA FURUTANI, MIZUKI OCHI, HISANORI SHIMIZU, MASAKAZU YAMAGUCHI

Abstract

Background/Aim

Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended for mild cancer pain and can be combined with opioids for moderate-to-severe pain. The efficacy of switching from prior NSAIDs to transdermal diclofenac in patients with cancer has not been fully evaluated, however.

Patients and Methods

We conducted a retrospective observational study at the Cancer Institute Hospital, Ariake, Japan, from May 21, 2021, to May 20, 2023. Hospitalized of patients with cancer who were switched from prior NSAIDs to transdermal diclofenac were included. Patients were excluded if they never applied the patch, could not continue treatment for ≥7 days, or had dementia/delirium precluding pain assessment. The primary endpoint was change in numerical rating scale (NRS) score from baseline (Day 0) to Day 8. Statistical analyses were performed using the Wilcoxon signed-rank test, with p<0.05 considered indicative of statistically significant differences.

Results

A total of 72 patients were included. The median age was 67 years, and 46 were female. Prior NSAIDs included loxoprofen, flurbiprofen, naproxen, and celecoxib. Concomitant opioids were used in 55 patients. Mean NRS score decreased from 3.8 to 2.4 by Day 8 (p<0.001). Forty-six patients (64%) showed reduced NRS scores. Rescue medication use decreased in 13 patients (18%), remained unchanged in 39 (54%), and increased in 20 (28%). One patient reported mild pruritus; no treatment discontinuation occurred.

Conclusion

Switching to transdermal diclofenac effectively reduced pain in patients with cancer and may serve as a useful alternative when oral or prior NSAID therapy is difficult to continue.

Introduction

Diclofenac sodium is a phenylacetic acid-derived nonsteroidal anti-inflammatory drug (NSAID) that exerts analgesic and anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity (1-5). Compared with other NSAIDs, diclofenac demonstrates higher COX-2 inhibitory activity, which is primarily induced at sites of inflammation (1, 6-9). NSAIDs are recommended as first-line agents for mild cancer pain. However, in cases of moderate-to-severe cancer pain in which adequate analgesia is not achieved with opioids, or opioid dose escalation is limited by adverse effects, combination therapy with NSAIDs and opioids is advised (10). Until recently, non-opioid analgesics approved for cancer pain in Japan were available only as oral or injectable formulations.

Transdermal diclofenac tape, approved in May 2021, represents the first transdermal preparation for cancer pain in Japan (11). A once-daily application provides stable plasma concentrations for 24 h, allowing sustained pain relief. This formulation is also suitable for patients with difficulties taking oral medications due to gastrointestinal obstruction, increased intracranial pressure, chemotherapy-related side effects, or cachexia-associated nausea, vomiting, and dysphagia. Moreover, transdermal application allows visual confirmation by caregivers, improving adherence, and is not limited by meal timing (12, 13). Recent reports also suggest that transdermal diclofenac causes fewer gastrointestinal adverse events than oral formulations (14-16). Pharmacologically, repeated transdermal administration of diclofenac maintains COX-2 inhibition above the 80% inhibitory concentration (IC80) while keeping COX-1 inhibition below the IC80, which may explain the balance between analgesic efficacy and reduced frequency of adverse events (10).

Previous clinical trials in patients with cancer (Phase II/III HP-3150-JP-03) showed mean visual analog scale (VAS) score reductions of ≥15 mm from baseline by Day 4 of dose titration. A study of long-term administration (HP-3150-JP-04) also demonstrated a decrease in VAS score, from 27.1 mm at baseline to 16.3 mm by Day 21. A phase III trial (HP-3150-JP-06) showed similar results (17). However, these trials excluded patients with prior NSAID or opioid use and did not evaluate changes in pain following a switch from another NSAID. The present study retrospectively evaluated pain in patients with cancer who switched from other NSAIDs to transdermal diclofenac. The optimal timing and role of transdermal diclofenac in clinical practice was also examined.

Patients and Methods

Study design and patients. This retrospective observational study was conducted at the Cancer Institute Hospital, Ariake, Japan, between May 21, 2021, and May 20, 2023. Eligible subjects were hospitalized patients with cancer who were switched from NSAIDs to transdermal diclofenac. Exclusion criteria were as never applied the prescribed diclofenac patch, inability to continue treatment for ≥7 days, or dementia/delirium precluding pain assessment.

Endpoints. The primary endpoint was the change in NRS score from baseline (Day 0) to Day 8. Secondary endpoints included rescue medication use and NRS score changes stratified by application site and prior NSAID. When multiple daily NRS score assessments were recorded, the mean daily value was used.

Statistical analyses. Statistical analyses were performed using the Wilcoxon signed-rank test, with p<0.05 considered statistically significant.

*Ethics.*The study protocol was approved by the Ethics Committee of the Cancer Institute Hospital (approval no. 2023-GB-150). As the study used only existing clinical data with no new sample collection, informed consent was not required; patients were provided an opt-out opportunity, however.

Data collection. Collected data included demographic information (age, sex, primary cancer type, performance status, comorbidities); 24-h average NRS score; prior NSAID, acetaminophen, and opioid use; rescue medication usage; diclofenac dose; application site; and skin-related adverse events.

Results

Patient characteristics. A total of 72 patients met the inclusion criteria. The baseline characteristics of enrolled patients are summarized in Table I. The median age was 67 years (range=24-89 years), with 46 females and 26 males. Primary cancers included pancreatic (n=19) and lung (n=10). Prior NSAIDs included loxoprofen (n=40), flurbiprofen (n=20), naproxen (n=8), and celecoxib (n=4). Opioids were co-administered in 55 patients (76.4%), and acetaminophen was co-administered in 19 patients (26.4%). The most frequently used patch application sites were the abdomen (n=34), chest (n=11), and upper arm (n=10). Reasons for switching included difficulty with oral administration (n=28, 38.9%), reduction of caregiver burden (n=24, 33.3%), and insufficient efficacy of prior NSAIDs (n=13, 18.1%). Oral intake remained possible in 37 patients (51.4%).

Table II shows the distribution of concomitant opioid use among 55 patients treated with diclofenac sodium transdermal patches and changes in opioid dosage during the treatment period. Oxycodone formulations were the most frequently used, and opioid dose escalation occurred in 34.5% of patients during the treatment period.

*Changes in NRS score. *A significant reduction in NRS scores was observed from Day 0 to Day 8. The median NRS score decreased from 3 to 2 (p<0.001), and the mean score decreased from 3.8 to 2.4 (Figure 1). On Day 0, the first and third quartiles were 1.875 and 6, respectively [interquartile range (IQR)=4.125], whereas at Day 8 they were 0 and 4, respectively (IQR=4). No outliers were identified according to the 1.5 × IQR criterion. Overall, decreased scores were observed in 46 patients (64%), whereas scores remained unchanged in 14 patients (19%) and increased in 12 patients (17%).

Changes in rescue medication use. Rescue medication use decreased in 13 patients (18%), remained unchanged in 39 patients (54%), and increased in 20 patients (28%). The most commonly used rescue medications were oxycodone (injection), hydromorphone (injection or oral), and morphine (injection or oral). Twenty-nine patients (40.3%) did not require any rescue medication (Table III). From Day 0 (median=2) to Day 8 (median=3) after initiation of diclofenac sodium transdermal patches, the overall frequency of rescue medication use showed no significant change (p=0.517).

Changes in NRSscore by application site. **The changes in NRS score varied according to application site (Figure 2). In patients using abdominal application, the score decreased from 3.9 to 2.6 (decreased in 24, did not change in five, and increased in five patients). In patients who applied patches to the chest, the NRS score decreased from 2.5 to 1.6 (decreased in six, did not change in three, and increased in two patients). Among patients who applied patches to the upper arm, the NRS score decreased from 2.8 to 1.5 (decreased in eight patients and did not change in two). In patients who applied patches to the back, the NRS score decreased from 5.9 to 2.8, with all patients showing improvement. For thigh application, the NRS score decreased from 3.2 to 2.8 (decreased in one patient and did not change in two). For waist application, the NRS score increased from 6.1 to 6.3 (increased in one patient). For patients who used shoulder application, the NRS score decreased from 8.0 to 1.0 (decreased in one patient). Eight patients with unknown application sites were excluded from the analysis. Due to an imbalance in the number of patients among groups, no statistical comparison was performed.

*Changes in NRS score by prior NSAID.*Changes in NRS score also varied according to prior NSAID (Figure 3). In patients previously treated with loxoprofen (n=40), the NRS score decreased from 4.6 to 3.0 (decreased in 29, did not change in five, and increased in six patients). In patients previously treated with flurbiprofen (n=20), the NRS score decreased from 2.7 to 2.0 (decreased in 10, did not change in five, and increased in five patients). In the naproxen prior NSAID group (n=8), the NRS score decreased from 2.6 to 1.4 (decreased in five, did not change in two, and increased in one patient). In the celecoxib prior NSAID group (n=4), the NRS score decreased from 1.2 to 0.7 (decreased in two patients, remained unchanged in two patients, and did not increase in any patient). Due to an imbalance in the number of patients among groups, no statistical comparison was performed.

*Skin adverse events.*One patient reported mild pruritus; however, treatment with transdermal patches was continued.

Discussion

This study is the first to evaluate analgesic efficacy in patients with cancer who switched from a prior NSAID to transdermal diclofenac. We found a significant reduction in NRS score following the switch, suggesting clinical utility, especially for patients who have difficulty with oral intake or have adherence challenges. Although use of rescue medication resulted in a non-significant decrease, this could be attributable to therapeutic recovery due to concomitant treatments such as chemotherapy or radiotherapy. Approximately 30% of patients in this study required opioid dose adjustments during the observation period, which may have contributed to the decrease in NRS score and simultaneously masked potential changes in rescue medication usage.

Previous domestic trials excluded patients with prior NSAID use, leaving the effects of switching largely unexamined (17). The results of our study complement these previous findings by demonstrating that transdermal diclofenac provides meaningful analgesia even in patients previously treated with other NSAIDs. Although no direct head-to-head clinical trials have compared the efficacy of different NSAIDs in alleviating cancer pain, other reports suggest that diclofenac may be particularly effective for cancer pain management relative to other NSAIDs (18). The consistent NRS score reductions across prior NSAID groups in our study support this observation and suggest that diclofenac retains efficacy regardless of prior NSAID exposure. Analysis of the site of patch application revealed NRS score decreases across all application sites, indicating that analgesic efficacy can be expected regardless of administration site. The absence of a reduction in NRS score in patients who applied patches at the waist appears to be due to random variation rather than a consistent site effect.

Our findings have important clinical implications. Transdermal diclofenac offers a practical alternative when continuation of prior NSAIDs is difficult, particularly for patients with swallowing difficulties, gastrointestinal risks, or poor adherence. The once-daily application of transdermal diclofenac ensures stable plasma concentrations and facilitates caregiver monitoring, potentially improving treatment compliance. Moreover, the favorable safety profile compared with oral NSAID use supports its application in multimodal cancer pain management.

Future prospective, multicenter studies are warranted to confirm our findings and directly compare diclofenac with other NSAIDs in treating cancer pain. Further studies could also explore optimal switching strategies and application site considerations.

Study limitations. Pain evaluations were based on nurses’ records, which may have missed peak pain episodes. Concomitant opioid therapy could not be fully controlled, and dose adjustments may have confounded the observed analgesic effects. In addition, the retrospective, single-center design limits generalizability, and subgroup analyses were constrained by small sample sizes.

Conclusion

Switching to transdermal diclofenac is a valuable option to reduce pain in cancer patients when continuation of prior NSAIDs is difficult. Transdermal diclofenac is particularly useful for patients with swallowing difficulties, gastrointestinal risks, or poor adherence, and thus may contribute to improved compliance and safety in multimodal cancer pain management.

Conflicts of Interest

The Authors declare no conflicts of interest related to this study.

Authors’ Contributions

Yusuke Iikura: conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, visualization, writing –original draft, and writing – review and editing. Takashi Yokokawa: conceptualization, data curation, investigation, methodology, project administration, and writing – review and editing. Wataru Harashima: methodology, data curation, investigation, and writing – review and editing. Kazuyoshi Kawakami: data curation, investigation, and writing – review and editing. Yutaro Mae, Taizo Ishiguro, Akiko Hasegawa, Ryouta Furutani, Mizuki Ochi: investigation, writing – review and editing. Hisanori Shimizu: writing – review and editing. Masakazu Yamaguchi: project administration, supervision, and writing – review and editing.

Acknowledgements

The Authors thank the medical and nursing staff of the Cancer Institute Hospital, Ariake, Japan, for their support in patient care and data collection.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Artificial Intelligence (AI) Disclosure

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.