Research ArticleClinical Studies
Open Access

The Effect of Concomitant Usage of Analgesics on Immune Checkpoint Inhibitor-related Interstitial Lung Disease

TAKAYUKI MANABE, KUNINORI IWAYAMA, MASAYUKI CHUMA, YOSHIKAZU TASAKI and SEIJI MATSUMOTO
In Vivo May 2023, 37 (3) 1260-1265; DOI: https://doi.org/10.21873/invivo.13203

Abstract

Background/Aim: Interstitial lung disease (ILD) is a serious adverse event (AE) associated with the use of immune checkpoint inhibitors (ICIs). However, the risk factors for developing ICI-related ILD remain poorly understood. Therefore, this study investigated the effect of concomitant analgesics on developing ICI-related ILD using the Japanese Adverse Drug Event Report (JADER) database. Patients and Methods: All the reported AE data were downloaded from the Pharmaceuticals and Medical Devices Agency website, and the JADER data between January 2014 and March 2021 were analysed. The relationship between ICI-related ILD and concomitant use of analgesics was assessed using reporting odds ratio (ROR) and 95% confidence interval. We investigated whether the effect of developing ILD varied according to the type of analgesics used during ICI treatment. Results: Positive signals for ICI-related ILD development were detected for the concomitant use of the narcotic analgesics codeine, fentanyl and oxycodone, but not with morphine. In contrast, there were no positive signals for the concomitant use of the non-narcotic analgesics celecoxib, acetaminophen, loxoprofen and tramadol. An increased ROR for ICI-related ILD in cases with concomitant use of narcotic analgesics was observed in a multivariate logistic analysis adjusted by sex and age. Conclusion: These results suggest that the concomitant use of narcotic analgesics is involved in the development of ICI-related ILD.

Key Words:

Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is involved in immunosuppression (1). The inhibition of CTLA-4 leads to the activation of host immunity and exerts an antitumour effect. These effects have been demonstrated in recent clinical trials and approved for several types of advanced cancer (2, 3).

Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs), such as interstitial lung disease (ILD), acute kidney injury, dermatitis, cardiovascular toxicities, type 1 diabetes, and hypophysitis (4-8). irAEs developing in patients treated with ICIs exhibit phenotypes different from those caused by cytotoxic anticancer agents (9). Among irAEs, risk factors for the development of ICI-related acute kidney injury include increased combination ICI therapy and lower baseline estimated glomerular filtration rate (10). In addition, the concomitant use of proton pump inhibitors, non-steroidal anti-inflammatory drugs, and fluindione as drugs with ICIs is also a risk factor for the development of acute kidney injury (11). An analysis of the Japanese Adverse Drug Event Report (JADER) database reported that the concomitant use of proton pump inhibitors and ICIs increased the development of nephritis (12).

ILD is a clinically serious and fatal condition that can also result from therapy. Therefore, early detection and treatment of ICI-related ILD are important for patient safety (13). Risk factors for the development of ICI-related ILD include pre-existing lung disease, prior thoracic radiotherapy, and increased combination ICI therapy (14-16). In contrast, the development of ICI-related ILD according to concomitant medications of the patient is not well understood. Previous studies have reported the use of non-steroidal anti-inflammatory drugs as a risk for the development of ILD (17). Analgesics are actively used to control pain during cancer, as it is important for treatment continuation and improving the quality of life of the patient. Therefore, we focused on the concomitant use of analgesics with ICI and investigated whether the type of analgesic influences the effect of developing ICI-related ILD.

The JADER is a database of voluntary AE reports published by the Japan Pharmaceuticals and Medical Devices Agency and is particularly useful for analysing AE reports with a small number of occurrences (18-20). This study focused on the use of analgesics to relieve cancer pain and used JADER to examine the association between analgesic use and the development of ICI-related ILD.

Patients and Methods

Data source. All AE report data were downloaded from the Pharmaceuticals and Medical Devices Agency website (https://www.pmda.go.jp), and the JADER data collected between January 2014 and March 2021 were analysed. The JADER open-access database consists of anonymized patient information in four datasets: Patient demographic information, drug information, adverse events, and medical history. Therefore, no review or approval by the Ethics Committee was required. In addition, informed consent was not required because individual patients could not be identified.

Target of analysis. The AE identified for extraction was ILD as described in the Medical Dictionary for Regulatory Activities/Japanese Ver. 24.1 J (https://www.jmo.pmrj.jp/), and we used the following Preferred Term for ILD: Interstitial lung disease (code: 10022611). The drugs analysed were nivolumab, atezolizumab, durvalumab, ipilimumab, pembrolizumab and avelumab, and only reports in which these drugs were described as the ‘suspected drug’ were extracted. Concomitant drugs were extracted from ‘concomitant or interacting drug’. When the actual drug, such as a placebo or administration, was unclear, it was excluded. Concomitant drugs investigated were celecoxib, acetaminophen, loxoprofen, tramadol, codeine, fentanyl, oxycodone and morphine, which are frequently used to treat cancer pain. Codeine was excluded because 1% codeine phosphate and cherry bark extract codeine were used as antitussives.

Method of analysis. The JADER database was created using Microsoft Access 2019® (Microsoft, Redmond, WA, USA) and JMP® Pro 16 (SAS Institute Inc., Cary, NC, USA). Overlapping data for the same outcome from drugs with the same identification numbers were excluded. The reporting odds ratio (ROR) was used as the signal detecting the development of ILD and was calculated using a 2×2 contingency table classified based on the use or non-use of a drug and ILD occurrence (21). Additionally, signal detection by ROR was stratified according to sex and age. The ROR was considered a positive signal when the lower limit of the 95% confidence interval (CI) was >1 (21). The ROR for ICI-related ILD in cases of concomitant narcotic analgesics was evaluated in a multivariate analysis adjusted for sex and age. Values of p<0.05 were considered statistically significant. All data analyses were performed by two Authors independently, and all statistical analyses were conducted using EZR and JMP® Pro 16 (22).

Results

Analysis of ILD development in patients under ICI treatment. We identified 590,596 reports of AEs, including 38,773 that included use of one of the six different ICIs (nivolumab, atezolizumab, durvalumab, ipilimumab, pembrolizumab or avelumab) using JADER.

Positive signals for ILD were detected for nivolumab, pembrolizumab, ipilimumab, durvalumab, and atezolizumab (Table I) but not for avelumab (Table I). Next, we examined the ROR for the development of ICI-related ILD stratified according to sex and age. As shown in Table II, a positive signal for ICI-related ILD was detected in men and in patients over 70 years of age.

View this table:
Table I.

Univariate analysis of the development of interstitial lung disease (ILD) during treatment with immune checkpoint inhibitor (ICI).

View this table:
Table II.

Univariate analysis of the effect of sex and age on the development of immune checkpoint inhibitor-related interstitial lung disease (ILD).

Effect of concomitant use of analgesics on the development of ICI-related ILD. We investigated the effect of using analgesics for cancer pain during ICI therapy on the development of ILD. Non-narcotic analgesics celecoxib, acetaminophen, loxoprofen and tramadol did not produce a positive signal for developing ICI-related ILD. Conversely, positive signals were detected for the narcotic analgesics codeine, fentanyl and oxycodone for developing ICI-related ILD (Table III). However, morphine did not produce a positive signal for ICI-related ILD development (Table III). Narcotic analgesics (codeine, oxycodone, fentanyl, and morphine) were also investigated for the development of ILD as suspected drugs. No positive signals for the development of ILD were detected for any of these analgesics (codeine, fentanyl, oxycodone, and morphine ROR (Table IV). Furthermore, multivariate logistic analysis using concomitant narcotic analgesics, male sex, and age ≥70 years gave a positive signal for the occurrence of ICI-related ILD with concomitant use of narcotic analgesics (Table V).

View this table:
Table III.

Univariate analysis of the effect of concomitant use of analgesics on the development of immune checkpoint inhibitor (ICI)-related interstitial lung disease (ILD).

View this table:
Table IV.

Univariate analysis of the effect of developing interstitial lung disease (ILD) with narcotic analgesic treatment.

View this table:
Table V.

Multivariate logistic analysis of the development immune checkpoint inhibitor-related interstitial lung disease.

Discussion

In this study, JADER database analysis demonstrated that concomitant use of narcotic analgesics was associated with the development of ICI-related ILD.

Positive signals for developing ICI-related ILD was detected for five ICIs, namely nivolumab, pembrolizumab, ipilimumab, durvalumab and atezolizumab, but not avelumab (Table I). Owing to the short time since the approval of avelumab, there may be inadequate reporting regarding associated AEs. These results suggest that ILD is a relatively frequent AE associated with ICI use, consistent with findings of a previous study (13).

AEs of ICI have been well investigated (4-8). However, there are not many reports of concomitant drugs for ICI affect the occurrence of AEs (11, 12). On the other hand, there were no findings regarding concomitant drugs affecting the development of ICI-related ILD. In this study, we show for the first time that narcotic analgesics (codeine, oxycodone, fentanyl and morphine) affect the development of ICI-related ILD. The finding that analgesics affect the development of ICI-related ILD provides important information for the selection of analgesics for pain management. Although further clinical studies are needed, the results of this study are promising for continued drug treatment with ICIs.

Therefore, careful monitoring for the development of ILD in patients being treated with an ICI is considered important. To detect ILD (especially pneumonia) early on, it is important to manage risk by monitoring the biomarkers Krebs von den Lungen-6, surfactant proteins D and A, C-reactive protein, lactate dehydrogenase and oxygen saturation of a peripheral artery, together with computed tomography or radiography (23, 24).

This study had several limitations. Firstly, the JADER database is based on self-reporting, and not all AEs are reported. Therefore, there is bias due to under- or over-reporting and confounding factors such as complications (21, 25). Moreover, the JADER database has missing data, and there is a lack of a common denominator for incidence estimation. Secondly, no conclusive evidence was obtained to prove a causal relationship between the concomitant use of narcotic analgesics and the occurrence of ICI-related ILD. Therefore, the relationship suggested in this study should be interpreted with caution.

The association between the development of ICI-related ILD and narcotic analgesics should be investigated in prospective clinical studies. We expect that the results of this study will contribute to increasingly effective ICI treatment.

Acknowledgements

The Authors thank Editage (https://www.editage.com/) for English review of this article.

Footnotes

  • Authors’ Contributions

    TM and KI designed this study. TM and KI carried out the survey of the JADER database. TM and KI performed the statistical analyses. TM and KI drafted the article. All Authors contributed to data interpretation and intellectual content. All Authors approved the final article.

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received February 11, 2023.
  • Revision received February 25, 2023.
  • Accepted March 2, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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The Effect of Concomitant Usage of Analgesics on Immune Checkpoint Inhibitor-related Interstitial Lung Disease
TAKAYUKI MANABE, KUNINORI IWAYAMA, MASAYUKI CHUMA, YOSHIKAZU TASAKI, SEIJI MATSUMOTO
In Vivo May 2023, 37 (3) 1260-1265; DOI: 10.21873/invivo.13203
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