Skip to main content
NCBI home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2026 Jul 11;30(6):e70334. doi: 10.1002/ejp.70334

Erdosteine Provides Effective Analgesia in Inflammatory Pain Without Impairing Pain Resolution: A Preclinical Comparison With Non‐Steroidal Anti‐Inflammatory Drugs

Lucas Vasconcelos Lima 1,2,✉, Mohamad Karaky 1,2, Grace Yu 2, Massimo Allegri 3, Nicoletta Marchesi 4, Stefano Govoni 4, Clive Page 5, Luda Diatchenko 1,2
PMCID: PMC13355304  PMID: 42434843

ABSTRACT

Background

Nonsteroidal anti‐inflammatory drugs (NSAIDs) provide effective analgesia but may paradoxically delay tissue recovery, pain resolution and contribute to chronic pain. Erdosteine, a thiol‐based prodrug with antioxidant and anti‐inflammatory properties, is a mucolytic used for treatment of respiratory diseases but has recently been suggested to possess analgesic potential.

Methods

We examined the analgesic efficacy of erdosteine and its metabolite, Met‐1, in experimental models of inflammatory and neuropathic pain and compared its effects with diclofenac and gabapentin. Male mice received complete Freund's adjuvant (CFA) or chronic constriction injury (CCI) to induce inflammatory or neuropathic pain, respectively. Erdosteine (100 or 300 mg/kg, per os), its metabolite MET‐1 (intravenous), diclofenac (per os), gabapentin (per os), or vehicle (per os or intravenous as appropriate) were administered for 7 days following CFA or CCI. In separate experiments, treatments were initiated prior to CFA. Mechanical allodynia was quantified by von Frey testing. Plasma levels of CXCL1, S100A8/S100A9, IL‐1Ra, and 8‐isoprostane were measured by ELISA.

Results

Erdosteine significantly reduced CFA‐induced allodynia, with efficacy comparable to diclofenac and gabapentin. Unlike diclofenac, erdosteine did not delay pain recovery in post‐CFA or pre‐CFA experimental settings and did not elevate plasma CXCL1 or 8‐isoprostane levels.

Conclusions

Erdosteine provides robust analgesia in an experimental model of inflammatory pain without disrupting inflammation‐resolution pathways or increasing oxidative stress, supporting its potential as a safe, non‐opioid analgesic. These findings support further investigation of erdosteine as a potential, non‐opioid analgesic drug that does not produce the adverse events associated with NSAIDs.

Perspective

Erdosteine produced NSAID‐comparable analgesia in inflammatory pain without delaying recovery or increasing oxidative and inflammatory markers. Given concerns that NSAIDs may prolong pain resolution, these findings identify erdosteine as a potential non‐opioid alternative that relieves inflammatory pain while preserving physiological healing processes.

Significance Statement

Effective and well‐tolerated treatments for chronic pain remain limited. Erdosteine is a clinically approved mucolytic with antioxidant and anti‐inflammatory properties whose analgesic potential is largely unexplored. We show that oral erdosteine reduces inflammatory pain and allodynia without delaying recovery, unlike the NSAID diclofenac, which increased systemic markers of inflammation and prolonged pain duration. These findings identify erdosteine as a promising candidate for drug repurposing and support further investigation of its potential utility in pain management.

Keywords: drug repurposing, Erdosteine, NSAIDs, oxidative stress, pain resolution

1. Introduction

Pain, both acute and chronic, remains a major clinical challenge. The development of novel analgesics is urgently needed, as opioids carry significant risks of dependence and overdose, while recent evidence suggests that commonly used non‐steroidal anti‐inflammatory (NSAIDs) drugs may paradoxically delay pain resolution (Parisien et al. 2022) and lead to prolonged use of opioids (Hussain et al. 2024). Erdosteine, a thiol‐based compound originally developed as a mucolytic agent for the treatment of respiratory diseases [34] with a placebo‐like safety profile (Dal Negro et al. 2015), has attracted growing interest for its potent antioxidant, anti‐inflammatory and cytoprotective properties, suggesting its potential use as an analgesic agent, possibly through modulation of novel pain pathways (Cazzola et al. 2019; Dal Negro et al. 2011; Marchesi et al. 2025).

Traditionally used in the management of chronic obstructive pulmonary disease (COPD) (Moretti 2007) and, more recently, COVID‐19 (Cazzola et al. 2021) due to its newly discovered antiviral property, erdosteine is a pro‐drug that exerts its effects through its active metabolite, Met‐1. Upon metabolic activation, Met‐1 releases a free thiol group capable of scavenging reactive oxygen species (ROS) and inhibiting key pro‐inflammatory pathways involved in oxidative tissue damage (Braga et al. 2006). Clinical studies have shown that erdosteine reduces systemic and airway oxidative stress markers—including ROS, 8‐isoprostane and inflammatory cytokines such as IL‐6 and IL‐8 (Dal Negro, Visconti, Micheletto, and Tognella 2008).

Recent research has expanded the therapeutic potential of erdosteine, in the potential regulation of both nociceptive and nociplastic pain pathways. A pivotal study by Marchesi et al. (2025) demonstrated that both erdosteine and Met‐1 inhibit activation of the TrkA receptor—a high‐affinity receptor for nerve growth factor (NGF) that plays a critical role in pain sensitization. Using in silico modelling and in vitro assays in human neuroblastoma cells, the study showed that erdosteine binds to the TrkA receptor pocket, disrupting NGF‐induced autophosphorylation and reducing receptor activation by up to 40% within 24 h (Marchesi et al. 2025). These findings suggest that erdosteine is as a novel NGF‐TrkA pathway antagonist—a validated target for non‐opioid analgesics in conditions such as osteoarthritis, low back pain and neuropathic pain (Barker et al. 2020).

Additionally, erdosteine has shown neuroprotective effects in vivo. In a rabbit model of spinal cord ischemia–reperfusion injury, pre‐treatment with erdosteine improved motor function and reduced both oxidative damage and neuronal loss (Ege et al. 2004). These results further support its role in modulating central pain pathways by mitigating oxidative stress and preserving neuronal integrity.

Collectively, these findings support a mechanistic basis for erdosteine's potential analgesic action in chronic inflammatory and neuropathic pain states. In the present study, we investigated the efficacy of erdosteine as an analgesic using established mouse assays of inflammatory and neuropathic pain.

2. Methods

2.1. Study Design

To investigate the potential analgesic effect of erdosteine and its metabolite MET‐1 as well as its effect on the duration of pain, we performed a series of mouse experiments using two well established experimental models. Two different dosages of erdosteine or MET‐1 were given to mice for 7 consecutive days following one of two pain models, the chronic inflammatory pain model induced by intraplantar injection of Complete Freund's Adjuvant (CFA) or the neuropathic pain assay of chronic constriction injury (CCI). Diclofenac and Gabapentin were given as positive controls; vehicle was used as a negative control. Mechanical pain sensitivity (paw‐withdrawal threshold) was measured at regular intervals for a total of 30 days using the von Frey method.

Additionally, we performed an experiment where erdosteine (and controls) treatment started prior to CFA assay (perioperative). We have also collected plasma samples of mice after 3 days of treatment following CFA to run a battery of ELISAs to quantify plasma levels of pro‐inflammatory (CXCL1, S100A8/9), anti‐inflammatory (IL‐1Ra) and oxidative stress (8‐isoprostane) markers. These markers were selected based on previous evidence identifying CXCL1 and S100A8/S100A9 as neutrophil‐linked inflammatory mediators (Cao et al. 2014; Shabani et al. 2018), IL‐1Ra as a marker of anti‐inflammatory activity (Arend 2003) and 8‐isoprostane as a gold‐standard plasma biomarker of NSAID‐related oxidative stress and lipid peroxidation (Chan et al. 2002; Montuschi et al. 2004).

The experimental unit was an individual mouse. Animals were randomly assigned to experimental groups at the level of the individual mouse (not by cage) using a random allocation procedure, resulting in treatment groups being distributed across cages. No formal a priori sample size calculation was performed; sample sizes were determined based on previous experience with similar experiments and group sizes commonly used in the literature while aiming to minimize animal use. The experimenter conducting the experiments and performing outcome assessments was blinded to group allocation. Data were excluded only in cases of clear technical issues or obvious technical outliers (three datapoints). A small number of animals died during the course of the experiments (four in the diclofenac group and one in the gabapentin group); data collected prior to death were retained and included in the analyses, except for analyses requiring complete follow‐up (e.g., day‐to‐return analysis). Potential confounders were minimized by maintaining standardized housing and experimental conditions, processing animals from different experimental groups in parallel and collecting measurements at the same time of day.

2.2. Mice

CD‐1 male mice, aged between 8 and 12 weeks (ICR:Crl, Charles River Laboratories, St. Constant, QC) were used in these experiments (n = 6–8 per group). Only male mice were included to reduce variability associated with estrous cycle–dependent fluctuations in inflammatory pain sensitivity and analgesic responses. Mice were housed in standard shoebox cages with 2–4 animals per cage in a light (14:10 h, lights on at 07:00 h), temperature (20°C ± 1°C) and humidity‐controlled (30%–70%) environment with ad libitum access to food (Harlan Teklad 8604) and tap water. Cages contained environmental enrichment in the form of enviro‐dry and nestlets. Mice were acclimatized to the vivarium for 7 days post‐arrival and before experimentation. Each mouse was used in a single experiment. All animal procedures were approved by the McGill University Animal Care Committee and conducted in accordance with the guidelines of the Canadian Council on Animal Care.

2.3. Drugs

All drugs were administered daily for 7 consecutive days following induction of pain. Each drug was tested using two routes of administration (separate experiments): intravenous (I.V., tail vein) injection and oral (gavage). Erdosteine and Met‐1 were provided by Edmond Pharma (Paderno Dugnano MI, Italy) and administered at two different doses (100 mg/kg, 300 mg/kg). Diclofenac (25 mg/kg/day) and gabapentin (50 mg/kg/day) were purchased from MiliporeSigma Canada. 5% DMSO in saline was used as vehicle. Formulations were prepared at room temperature. For oral administration, the doses were given using a syringe with an attached gavage tube.

For tail vein injection, mice were immobilized in a restraining tube with their tail exposed. The tail was heated with a 50‐W heat lamp until the lateral tail vein was dilated, and a volume of 0.2 mL was injected via an insulin syringe. Doses for diclofenac and gabapentin were chosen based on established rodent pain literature demonstrating analgesic efficacy within these dose ranges (Brings et al. 2025; Parisien et al. 2022). The timing and duration of treatment were based on our previous studies with diclofenac, which demonstrated robust analgesic efficacy during treatment but delayed pain recovery during the resolution phase. Thus, this drug's regimen allowed us to assess both acute analgesic effects and potential impacts on long‐term recovery (Karaky et al. 2025; Parisien et al. 2022).

2.4. Pain Assays

To induce inflammatory pain, complete Freud's adjuvant (50% CFA, 20 μL volume) was injected into the plantar surface of the left hind paw of mice. This model is known to produce mechanical hypersensitivity (allodynia) lasting an average of 10–15 days before resolving (Stein et al. 1988).

To induce neuropathic pain, chronic constriction injury (CCI) was used (Austin et al. 2012). The procedure is performed under isoflurane anaesthesia and consists of an incision made below the mouse's left hip bone followed by exposure of the sciatic nerve and the application of three ligatures with 4/0 silk thread loosely tied around the sciatic nerve proximal to its trifurcation. The incision was then closed in layers.

2.5. Experimental Groups

Different routes of administration were used for Erdosteine and Met‐1, oral and intravenous, respectively, with each drug being tested in a different experiment. Controls (vehicle, diclofenac, gabapentin) were also delivered via the respective appropriate route of administration. Thus, for each Pain model (CFA, CCI) the experimental groups were as follows:

For erdosteine experiments (oral gavage):

  1. Vehicle

  2. Diclofenac (25 mg/kg/day)

  3. Gabapentin (50 mg/kg/day)

  4. Erdosteine (100 mg/kg/day)

  5. Erdosteine (300 mg/kg/day)

For Met‐1 (Intravenous, tail vein):

  1. Vehicle

  2. Diclofenac (25 mg/kg/day)

  3. Gabapentin (50 mg/kg/day)

  4. Met‐1 (100 mg/kg/day)

  5. Met‐1 (300 mg/kg/day)

2.6. Mechanical Paw Withdrawal Threshold

To assess the effects of erdosteine on pain behaviour following injury, mechanical paw‐withdrawal threshold (PWT) was measured with von Frey filaments using the up‐down staircase method of Dixon (Chaplan et al. 1994). Mice were habituated for 1 h prior to testing in plexiglass cubicles placed on top of a wire mesh platform. PWT was measured at baseline (Day 1, prior to CFA/CCI), the day following injury (Day 0) and at Days 1, 2, 4, 6, 8, 10, 15, 20 and 30 post injury. Testing occurring during the treatment period was performed 1 h after treatment (Days 1, 2, 4 and 6).

2.7. Enzyme‐Linked Immunosorbent Assay (ELISA)

Plasma concentrations of chemokine (C‐X‐C motif) ligand 1 (CXCL1), S100A8/S100A9 heterodimer, interleukin‐1 receptor antagonist (IL‐1Ra), and 8‐Isoprostane were quantified using ELISAs according to the manufacturers' instructions. CXCL1 and S100A8/S100A9 were measured using DuoSet ELISA kits (R&D Systems, Minneapolis, MN, USA), IL‐1Ra was quantified using a Quantikine ELISA kit (R&D Systems, Minneapolis, MN, USA), and 8‐Isoprostane levels were measured using a competitive ELISA kit (Biomatik, Wilmington, DE, USA).

Briefly, high‐binding 96‐well plates were coated overnight at 4°C with the capture antibody diluted in carbonate–bicarbonate coating buffer (0.05 M, pH 9.6). Plates were washed three times with phosphate‐buffered saline containing 0.05% Tween‐20 (PBS‐T) and blocked with 1% bovine serum albumin (BSA) in PBS for 1 h at room temperature. Plasma samples were thawed on ice and diluted as recommended for each analyte before loading. Recombinant standards provided with each kit were serially diluted to generate standard curves. Samples and standards were added in duplicate and incubated for 2 h at room temperature.

Following incubation, plates were washed with PBS‐T and incubated with the respective biotinylated detection antibody for 1 h at room temperature, followed by horseradish peroxidase (HRP)‐conjugated streptavidin for 30 min. After the final wash, tetramethylbenzidine (TMB) substrate was added, and colour development was stopped with 2 N sulphuric acid. Absorbance was measured at 450 nm using a microplate reader (BioTek Synergy HT, Winooski, VT, USA). Concentrations were calculated from standard curves generated using a four‐parameter logistic (4‐PL) regression model. All samples were assayed in duplicate, and results were averaged from at least two independent experiments.

2.8. Data Analysis

Time course data of averaged von Frey PWTs in all experiments are shown graphically. To quantify the acute effects of treatments on mechanical thresholds during the treatment period (average PWT from Days 1, 2, 4 and 6), the percentage of maximum possible allodynia was quantified as: % allodynia = [(baseline threshold−average during treatment)/baseline threshold] × 100. A reduction of % allodynia thus represents an acute analgesic and/or anti‐inflammatory action of the treatment.

To quantify the effect of treatment on the duration of the entire CFA or CCI‐induced allodynia, the post‐treatment mechanical thresholds of individual mice were considered. A modification of a previously used (Parisien et al. 2022) calculation consisting of the first of two consecutive days that an individual subject's PWT had returned to within one standard deviation (calculated separately for each experiment) of its baseline PWT was interpreted as the number of days it took for each mouse to return to its baseline (Days to Return; i.e., how long it took for full recovery from pain to be achieved). The arbitrary value of “40” was given to subjects which did not return to its baseline PWT by Day 30 assessment. Statistical analyses were performed using GraphPad Prism (Version 10.6, GraphPad software). Data distributions were assessed for normality using the Shapiro–Wilk test. Unpaired t‐tests or two‐way ANOVA were used as appropriate, and α = 0.05 was considered as statistically significant. Post hoc comparisons were made using Tukey's test. ELISA data were analysed using one‐way analysis of variance (ANOVA) followed by appropriate post hoc comparisons where applicable. Results are presented as mean ± standard error of the mean (SEM), and statistical significance was defined as p < 0.05.

3. Results

3.1. Oral Erdosteine Inducted an Anti‐Allodynic Effect in the CFA‐Induced Inflammatory Pain Model

We first tested the analgesic properties of erdosteine in the inflammatory pain model induced by CFA. Mice were randomly assigned to receive vehicle, erdosteine (100 or 300 mg/kg), diclofenac (25 mg/kg), or gabapentin (50 mg/kg) (see Figure 1a). Diclofenac, a NSAID, was included as a reference compound having peripheral anti‐inflammatory and analgesic efficacy, while gabapentin served as a centrally acting positive control. These treatments allowed comparison of erdosteine's potential analgesic activity with established analgesics targeting distinct mechanisms of action. Twenty‐four hours after CFA injection, all mice showed a significant decrease in paw mechanical thresholds (Figure 1b, Day 0), compared to baseline (p < 0.001, two‐way ANOVA). Both doses of orally administered erdosteine (100, 300 mg/kg), diclofenac and gabapentin treatments induced significant increases in mechanical thresholds (i.e., reduced % allodynia) during the treatment phase 1 day after injury (Figure 1c, p < 0.05, compared to vehicle). There was no significant difference in % of allodynia between treatments. In the days to return analysis, erdosteine and gabapentin both reduced the duration of pain, unlike diclofenac, which showed a significant increase in the duration of pain, as all mice in that group had not returned to baseline by Day 30 (Figure 1d, p < 0.05, compared to vehicle). No significant difference was observed between the other treatment groups.

FIGURE 1.

FIGURE 1

Open in a new tab

Analgesic effects of oral erdosteine, diclofenac and gabapentin in the CFA model of inflammatory pain. (a) Experimental timeline for behavioural and treatment protocol. Mice received an intraplantar injection of complete Freund's adjuvant (CFA, red arrow) on Day 1 to induce inflammatory pain. Treatments were administered orally once daily for seven consecutive days (blue arrows), beginning 24 h after CFA injection and included erdosteine (100 or 300 mg/kg), diclofenac (25 mg/kg), gabapentin (50 mg/kg), or vehicle. (b) Time course of mechanical pain sensitivity, measured via withdrawal thresholds (g) to von Frey fibre application, before and at various time points after CFA injection. Blue shading indicates the treatment period. (c) Percentage of allodynia during treatment period (mean % allodynia of Days 1,2,4 and 6). (d) Days required to return to pre‐ CFA baseline thresholds; Mice that had not returned to baseline by Day 30 were assigned a value of 40 days. For all panels, n = 8 mice per group. Symbols and bars represent mean ± SEM. #p < 0.05 versus baseline; *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 versus vehicle‐treated mice. CFA, Complete Freund's Adjuvant injection; VF, Von Frey testing.

3.2. Diclofenac, but Not Erdosteine, Prolongs the Duration of Allodynia in the Pre‐Injury Treatment of CFA‐Induced Inflammation

To further investigate the potential of erdosteine for long‐term pain prolongation as previously reported for NSAIDs and dexamethasone (Parisien et al. 2022), we modified the drug administration regimen in our CFA‐induced inflammatory pain model. We initiated the delivery of both diclofenac and erdosteine 1 day prior to CFA injection and included a group where diclofenac was given intraperitoneally (i.p.) (Figure 2a), since this regimen was previously shown to produce a more robust long‐term pain phenotype compared with post‐injury administration. Pre‐treatment with diclofenac (both routes) and erdosteine (both doses) equally prevented the CFA‐induced reduction in paw mechanical thresholds measured 1 day after injection (Figure 2b, Day 1; p < 0.001, two‐way ANOVA), compared to vehicle‐treated controls. The percentage of allodynia remained significantly lower in all treatment groups throughout the treatment phase (Figure 2c; p < 0.05 vs. vehicle), demonstrating robust analgesic efficacy during the inflammatory period.

FIGURE 2.

FIGURE 2

Open in a new tab

Pre‐treatment with erdosteine, diclofenac and gabapentin in the CFA model of inflammatory pain. (A) Experimental timeline for behavioural and treatment protocol. To test the effect of perioperative administration, treatments were given once daily for seven consecutive days beginning 1 day prior (Day 1) to CFA injection (Day 0, red arrow). (B) Time course of mechanical pain sensitivity, measured via withdrawal thresholds (g) to von Frey fibre application, before and at various time points after injection of complete Freund's adjuvant (CFA) into the hind paw of mice. In the period indicated by blue shading, mice received daily oral (or I.P.) administrations of their respective treatment group. (C) Percentage of allodynia during treatment period (mean % allodynia of Days 1,2,4 and 6). (D) Days required to return to pre‐CFA baseline thresholds; Mice that had not returned to baseline by Day 30 were assigned a value of 40 days. For all panels n = 7–8 mice per group Symbols and bars represent mean ± SEM. < 0.05 versus baseline; *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 versus vehicle‐treated mice. CFA, Complete Freund's Adjuvant injection; VF, Von Frey testing.

In the recovery analysis, neither dose of erdosteine prolonged the duration of allodynia, indicating that erdosteine's preventive analgesic action did not interfere with the normal course of recovery following CFA‐induced inflammation. In contrast, diclofenac, regardless of route of administration, produced a significant delay in the return to baseline mechanical thresholds compared to vehicle (Figure 2d; p < 0.05), consistent with its previously reported effect. The effect of the observed diclofenac‐dependent allodynia was more substantial than in the post‐CFA drug delivery experiments (Figure 1b).

3.3. Diclofenac, but Not Erdosteine, Increases Plasma CXCL1 and 8‐Isoprostane After CFA‐Induced Inflammation

Finally, we measured the inflammatory and oxidative stress markers post administration of oral erdosteine or diclofenac. ELISA analyses performed 3 days after CFA injection and following three consecutive days of treatment (Figure 3a) revealed significant group differences in CXCL1 and 8‐isoprostane plasma concentrations. Diclofenac‐treated mice exhibited significantly higher plasma levels of CXCL1 (Figure 3b; p < 0.05) and 8‐isoprostane (Figure 3c; p < 0.05) compared to both the saline and erdosteine (100 mg/kg) treated groups. No significant difference was observed between the saline and erdosteine (100 mg/kg) treated groups for either analyte. In contrast, plasma levels of IL‐1Ra and S100A8/S100A9 heterodimer did not differ significantly among treatment groups (Figure 3d,e; p > 0.05 for all comparisons). These results indicate that diclofenac treatment selectively elevated circulating CXCL1 and 8‐isoprostane levels 3 days after CFA‐induced inflammation, whereas erdosteine did not alter the plasma concentrations of any of the measured inflammatory and oxidative stress markers.

FIGURE 3.

FIGURE 3

Open in a new tab

Quantification of inflammatory and oxidative stress markers after treatment with erdosteine or diclofenac in the CFA model of inflammatory pain. (A) Experiment timeline. Mice received CFA on Day 0 and were administered oral erdosteine (100 mg/kg/day), diclofenac (25 mg/kg/day) or vehicle once daily for three consecutive days Plasma was collected 1 h after the final dose on Day 3. Enzyme‐linked immunosorbent assays (ELISAs) were performed to measure concentrations of (B) CXCL1, (C) 8‐Isoprostane, (D) IL‐1RA and (E) S100A8/9 heterodimer in plasma samples collected from experimental animals. For all panels n = 4–6 mice per group. Bars represent mean ± SEM. *p < 0.05, **p < 0.01. CFA, Complete Freund's adjuvant injection; ELISA, enzyme‐linked immunosorbent assay.

3.4. Intravenous Injection of Met‐1 Had no Significant Effect on Allodynia in the CFA Model

We next investigated the analgesic efficacy of Met‐1 to determine whether direct administration of this compound could reproduce the analgesic effects observed with oral erdosteine. Met‐1 was administered intravenously at two doses (e.g., 100 or 300 mg/kg/day), alongside vehicle, diclofenac and gabapentin treatment groups for comparison (Figure 4a).

FIGURE 4.

FIGURE 4

Open in a new tab

Analgesic effects of I.V. MET‐1, diclofenac and gabapentin in the CFA model of inflammatory pain. (a) Experimental timeline for behavioural and treatment protocol. Mice received an intraplantar injection of complete Freund's adjuvant (CFA, red arrow) on Day 1 to induce inflammatory pain. Treatments were administered intravenously once daily for seven consecutive days (blue arrows) beginning 24 h after CFA injection and included MET‐1 (100 or 300 mg/kg), diclofenac (25 mg/kg), gabapentin (50 mg/kg), or vehicle. (b) Time course of mechanical pain sensitivity, measured via withdrawal thresholds (g) to von Frey fibre application, before and at various time points after injection of complete Freund's adjuvant (CFA) into the hind paw of mice. Blue shading indicates the treatment period. (c) Percentage of allodynia during treatment period (mean % allodynia of Days 1,2,4 and 6). (d) Days required to return to pre‐CFA baseline thresholds Mice that had not returned to baseline by Day 30 were assigned a value of 40 days. For all panels, n = 8 mice per group. Symbols and bars represent mean ± SEM. #p < 0.05, versus baseline, *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 versus vehicle‐treated mice. CFA , Complete Freund's Adjuvant injection; VF, Von Frey testing.

Twenty‐four hours after CFA injection, mice from all 5 groups showed significant decreases in paw mechanical thresholds (Figure 4b, Day 0), compared to baseline (p < 0.001, two‐way ANOVA). Both diclofenac and gabapentin induced a significant reduction in allodynia when administered during the treatment period (Figure 4c, p < 0.05, compared to vehicle). In contrast, neither of the two tested doses of Met‐1 produced significant analgesic effects relative to vehicle. In the recovery analysis, only the diclofenac‐treated group showed a statistically significant increase in the number of days required to return to baseline thresholds (Figure 4d; p < 0.05 vs. vehicle). No significant differences in recovery time were observed among the Met‐1, gabapentin and vehicle groups.

3.5. Neither Erdosteine nor Met‐1 Had a Significant Effect on Allodynia in the CCI Model

We next evaluated the effects of erdosteine, its active metabolite Met‐1 and reference analgesics in the CCI model of neuropathic pain (Figures 5a and 6a). Twenty‐four hours after CCI surgery, all mice exhibited a significant reduction in paw mechanical thresholds compared to baseline values (Figures 5b and 6b, Day 0; p < 0.001, two‐way ANOVA), confirming the successful induction of neuropathic allodynia. During the treatment phase, gabapentin significantly reduced allodynia, as reflected by increased mechanical thresholds compared to the vehicle group (Figures 5c and 6c; p < 0.05). In contrast, neither diclofenac nor either dose of erdosteine (100 or 300 mg/kg), or intravenously administered Met‐1 produced any significant analgesic effects relative to vehicle treated mice. In the recovery analysis, no significant differences were observed among any treatment groups in the number of days required to return to baseline thresholds (Figures 5d and 6d; p > 0.05).

FIGURE 5.

FIGURE 5

Open in a new tab

Analgesic effects of oral erdosteine, diclofenac and gabapentin in the CCI model of neuropathic pain. (a) Experimental timeline for behavioural and treatment protocol. Chronic constriction injury (CCI, green arrow) was performed on Day 1 to induce neuropathic pain Treatments were administered orally once daily for seven consecutive days (blue arrows) beginning 24 h after CCI injection and included erdosteine (100 or 300 mg/kg), diclofenac (25 mg/kg), gabapentin (50 mg/kg), or vehicle. (b) Time course of mechanical pain sensitivity, measured via withdrawal thresholds (g) to von Frey fibre application, before and at various time points after CCI. Blue shading indicates the treatment period. (c) Percentage of allodynia during treatment period (mean % allodynia of Days 1,2,4 and 6). (d) Days required to return to pre‐CCI baseline thresholds; Mice that had not returned to baseline by Day 30 were assigned a value of 40 days. For all panels, n = 7–8 mice per group. Symbols and bars represent mean ± SEM. #p < 0.05 versus baseline; *p < 0.05, **p < 0.01, and ****p < 0.0001 versus vehicle‐treated mice. CCI, chronic constriction injury; VF, Von Frey testing.

FIGURE 6.

FIGURE 6

Open in a new tab

Analgesic effects of I.V. MET‐1, diclofenac and gabapentin in the CCI model of neuropathic pain. (a) Experimental timeline for behavioural and treatment protocol Chronic constriction injury (CCI, green arrow) was performed on Day 1 to induce neuropathic pain Treatments were administered orally once daily for seven consecutive days (blue arrows) beginning 24 h after CCI injection and included MET‐1 (100 or 300 mg/kg), diclofenac (25 mg/kg), gabapentin (50 mg/kg), or vehicle. (b) Time course of mechanical pain sensitivity, measured via withdrawal thresholds (g) to von Frey fibre application, before and at various time points after CCI Blue shading indicates the treatment period. (c) Percentage of allodynia during treatment period (mean % allodynia of Days 1,2,4 and 6). (d) Days required to return to pre‐CCI baseline thresholds; Mice that had not returned to baseline by Day 30 were assigned a value of 40 days. For all panels, n = 8 mice per group. Symbols and bars represent mean ± SEM. #p < 0.05 versus baseline; *p < 0.05, **p < 0.01, and ****p < 0.0001 versus vehicle‐treated mice. CCI, chronic constriction injury; VF, Von Frey testing.

4. Discussion

Erdosteine produced robust analgesic effects in the CFA assay of inflammatory pain comparable to diclofenac and gabapentin. Unlike diclofenac, erdosteine did not delay recovery from inflammation‐induced allodynia and did not elevate systemic inflammatory or oxidative stress markers. These findings suggest that erdosteine provides effective non‐opioid analgesia while preserving the natural resolution of inflammation.

The analgesic efficacy of erdosteine may involve multiple mechanisms reported in previous studies, including antioxidant and anti‐inflammatory actions, as well as potential modulation of TrkA signalling. (Braga et al. 2000; Dal Negro, Visconti, Micheletto, and Tognella 2008; Marchesi et al. 2025; Moretti and Marchioni 2007; Negro 2008). Several clinical studies have supported the antioxidant capacity of erdosteine in patients with COPD (Dal Negro, Visconti, Trevisan, et al. 2008; Dal Negro et al. 2015; Dal Negro and Visconti 2016). In addition, previous reports show that erdosteine inhibits lipopolysaccharide (LPS)‐induced NF‐κB activation in macrophages, reduces the production of pro‐inflammatory mediators such as TNF‐α, IL‐1β, IL‐5 and IL‐8 and increases IL‐10 levels in vivo (Demiralay et al. 2006; Fraňová et al. 2019; Hayashi et al. 2000; Jang et al. 2003; Negro 2008; Park et al. 2016). Although we did not detect reductions in oxidative stress or inflammatory markers at the assessed time points in our study—levels were similar to those in vehicle‐treated mice—we propose that these effects of erdosteine are more evident under active inflammatory conditions or during longer‐term disease processes. Importantly, unlike diclofenac, erdosteine did not increase CXCL1 or 8‐isoprostane levels following treatment (Figure 3), further supporting its more favourable profile in terms of circulating inflammatory markers during the period of treatment.

Notably, erdosteine‐induced analgesia may also be related to inhibition of the NGF–TrkA signalling axis, a key pathway in the development and maintenance of inflammatory pain, although the contribution of this mechanism to the observed analgesia was not directly assessed in the present study. Inhibition of TrkA signalling reduces peripheral and central sensitization (Hirose et al. 2016). In silico analysis has shown that erdosteine exhibits very good binding affinity to the TrkA receptor, promoting a specific rearrangement of the receptor and preventing its autophosphorylation (Marchesi et al. 2025). Although TrkA signalling was not directly assessed in the present study, these observations raise the possibility that modulation of the NGF–TrkA pathway may contribute to the analgesic effects of erdosteine observed in the CFA model. Future studies directly examining TrkA activation and downstream signalling in vivo will be required to establish the contribution of this pathway to erdosteine‐induced analgesia. Erdosteine is converted via hepatic first‐pass metabolism to the active metabolite Met‐1, which has been proposed as the primary mediator of erdosteine's mucolytic and antioxidant effects. Furthermore, Met‐1 has been identified as a biologically active compound in both clinical and cellular studies (Braga et al. 2006; Cazzola et al. 2020; Miyake et al. 1999). Met‐1 contains a free sulfhydryl group that neutralizes reactive oxygen species and limits lipid peroxidation. In vitro, Met‐1 significantly inhibited PMA (Phorbol Myristate Acetate)‐stimulated reactive oxygen species production in neutrophils and eosinophils from both rodents and humans (Miyake et al. 1999). A notable finding of this study is that direct intravenous administration of Met‐1 failed to reproduce the analgesic effects observed with oral erdosteine. Although Met‐1 is widely considered the primary active metabolite responsible for the antioxidant and anti‐inflammatory properties of erdosteine, several factors may explain this apparent discrepancy between in vitro activity and in vivo analgesic efficacy. First, oral erdosteine undergoes first‐pass hepatic metabolism, resulting in a sustained and regulated production of Met‐1 over time (Miyake et al. 1999), whereas intravenous delivery likely produces transient peak concentrations followed by rapid clearance, potentially limiting effective exposure at target tissues. Second, differences in tissue distribution may play an important role, as locally generated Met‐1 may achieve higher or more sustained concentrations at sites of inflammation and nociceptor activation compared to systemically administered Met‐1. Third, the free thiol group of Met‐1, while central to its antioxidant properties, may also confer high chemical reactivity, leading to rapid oxidation or binding to circulating proteins, thereby reducing its bioavailability under physiological conditions. In addition, emerging evidence suggests that erdosteine and Met‐1 may differ in their interactions with the TrkA receptor, with erdosteine exhibiting stronger and more stable binding within the NGF‐binding pocket, which may contribute to differences in NGF–TrkA pathway modulation in vivo (Marchesi et al. 2025). Furthermore, the sequence and relative contribution of the pharmacological events underlying erdosteine‐induced analgesia remain unknown. Previous in vitro studies suggest that erdosteine and Met‐1 may differ in the onset of their biological effects, with erdosteine requiring longer incubation times than Met‐1 to achieve maximal activity. It is therefore possible that differences in the temporal profile of target engagement contribute to the divergent analgesic effects observed in vivo. Another possibility is that the doses of intravenously administered Met‐1 used in the present study, although based on previously published work (Muramatsu et al. 1998), may not have been optimal for revealing analgesic activity in this model. Importantly, the dissociation between the reported biological activity of Met‐1 and its lack of analgesic efficacy in vivo raises the possibility that the analgesic effects of erdosteine are not exclusively mediated by Met‐1, but instead reflect a combination of parent‐compound activity, metabolite contribution and/or site‐specific metabolic activation. Together, these considerations highlight the importance of pharmacokinetic and tissue‐specific mechanisms in determining analgesic efficacy. In contrast, erdosteine and Met‐1 both failed to reduce allodynia in the CCI model of neuropathic pain, whereas gabapentin was effective. These findings suggest that erdosteine acts primarily through mechanisms more relevant to inflammatory nociceptive pain and nociplastic processes rather than neuropathic pain. These findings may reflect fundamental mechanistic differences between these two pain pathways. One possibility relates to TrkA signalling that could be modulated by erdosteine based on previous studies' reports (Marchesi et al. 2025). TrkA signalling is implicated in inflammatory pain (Ugolini et al. 2007), while neuropathic pain involves complex processes associated with nerve injury and neuronal dysfunction and is less dependent on TrkA signalling (Costigan et al. 2009). Finally, although the recovery analysis did not reach statistical significance, erdosteine‐treated mice showed a trend towards faster recovery compared with vehicle treated controls. As the CCI model typically produces long‐lasting mechanical allodynia, with most vehicle‐treated mice still hypersensitive at Day 30, the observation period may have been insufficient to reveal potential recovery differences. Extending the follow‐up period could clarify whether erdosteine facilitates the resolution of neuropathic pain over longer time courses.

We focused on whether erdosteine prolongs pain after injury. In our previous study, pre‐treatment with diclofenac or dexamethasone administered intraperitoneally for seven consecutive days, beginning 1 day before CFA injection, resulted in a robust paradoxical prolongation of pain behaviour during the recovery phase (Parisien et al. 2022). Given that erdosteine has been reported to possess also anti‐inflammatory and anti‐oxidant activity (Negro 2008; Xi et al. 2020), we evaluated whether it could produce a similar effect. In our initial post‐CFA treatment experiments, pain prolongation was observed with diclofenac but not with other drugs, including erdosteine, although this effect was modest but significant (Figure 1d). To further explore this phenomenon, we performed pre‐treatment experiments in the CFA model comparing the effects of erdosteine and diclofenac. We found pronounced pain prolongation and allodynia at Day 30 in mice pre‐treated with diclofenac, administered orally or intraperitoneally, but not with either dose of oral erdosteine (Figure 2a–d). These results further support the view that erdosteine may represent a safer alternative to NSAIDs with respect to the risk of pain prolongation and indicate that the analgesic efficacy of erdosteine likely involves mechanisms beyond its antioxidant and anti‐inflammatory properties. Prolonged use of NSAIDs has been shown to interfere with the resolution phase of inflammation (Bittermann et al. 2018; Bryant et al. 2017; Sisignano and Geisslinger 2023; Thai et al. 2023) and to predispose individuals to persistent pain states (Parisien et al. 2022), effects that have been linked to impaired tissue repair and paradoxical increases in pro‐inflammatory cytokines and oxidative stress (Bryant et al. 2017; Thai et al. 2023). Consistent with these findings, diclofenac‐treated mice in our study exhibited delayed pain recovery and significant increases in plasma CXCL1 and 8‐isoprostane concentrations, indicating sustained inflammatory and oxidative activity. CXCL1 is a pro‐inflammatory chemokine that recruits and activates neutrophils, amplifying local inflammation and contributing to nociceptor sensitization (Capucetti et al. 2020; Silva et al. 2017), whereas 8‐isoprostane is a stable biomarker of lipid peroxidation reflecting systemic oxidative stress (Janicka et al. 2010; Montuschi et al. 2004). The elevation of these markers in diclofenac‐treated mice suggests prolonged activation of inflammatory and oxidative pathways during the resolution phase. In contrast, erdosteine did not produce these changes, indicating that its analgesic effects occur without triggering the pro‐inflammatory or pro‐oxidative responses observed with diclofenac. By limiting oxidative stress and cytokine signalling while sparing resolution pathways, erdosteine may produce analgesia without compromising recovery.

The oral doses of erdosteine used (100–300 mg/kg) correspond to human‐equivalent doses within or slightly above the therapeutic range used in COPD (Dal Negro, Visconti, Micheletto, and Tognella 2008) suggesting clinical feasibility. The lack of dose–response suggests maximal efficacy at lower doses, consistent with erdosteine's saturable pharmacokinetics and favourable safety profile (Dal Negro et al. 2015). The overall excellent safety profile of erdosteine, supported by decades of clinical use with minimal adverse effects (Rogliani et al. 2019; Zatloukal et al. 2025), suggests that this drug should be further investigated for its suitability as a treatment of pain.

This study has several limitations. First, experiments were conducted exclusively in male mice; therefore, the generalizability of these findings to females remains to be established, particularly given known sex differences in pain mechanisms and analgesic responses. Second, although previous studies suggest that erdosteine can modulate NGF–TrkA signalling, TrkA activation was not directly assessed in the present study, and the contribution of this pathway to the observed analgesic effects remains uncertain. Finally, the lack of efficacy of intravenously administered Met‐1 was unexpected and the underlying reasons remain unclear. Future studies incorporating pharmacokinetic analyses, tissue distribution measurements, and direct assessment of TrkA signalling will be necessary to clarify the mechanisms responsible for the differential effects of erdosteine and Met‐1.

5. Conclusion

Our findings suggest that erdosteine may be a promising non‐opioid analgesic that provides robust relief of inflammatory pain without delaying recovery. In contrast to diclofenac, which increased systemic markers of inflammation and oxidative stress and prolonged pain duration, erdosteine preserved the natural resolution of inflammation while reducing allodynia. Its antioxidant and anti‐inflammatory actions, associated with the potential inhibition of the NGF–TrkA pathway, suggest a unique mechanism distinct from classical NSAIDs. Given its established safety and clinical availability, erdosteine represents a promising candidate for repurposing as a non‐opioid analgesic capable of alleviating inflammatory pain while supporting physiological recovery.

Author Contributions

L.V.L. contributed to conceptualization, methodology, data acquisition, formal analysis and writing of the manuscript. M.K. and G.Y. performed and analysed the ELISA experiments. M.A., N.M., S.G. and C.P. contributed to methodological design and to writing and reviewing the manuscript. L.D. supervised the project, contributed to study design and reviewed and edited the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by research funds from Edmond Pharma and the Alan Edwards Centre for Research on Pain (AECRP) at McGill University.

Conflicts of Interest

This work was supported by research funds from Edmond Pharma. S.G., N.M. and M.A. are co‐inventors of the patent N. WO2024028157A1, owned by Edmond Pharma S.p.A. C.P. is a consultant to Edmond Pharma S.p.A. The authors declare no further conflicts of interest.

Acknowledgements

This work was supported by research funds from Edmond Pharma and the Alan Edwards Centre for Research on Pain (AECRP) at McGill University. The Authors thank both organizations for their financial support and commitment to advancing pain research. This work includes unlabeled/investigational use of the drug erdosteine, which is currently approved for treatment of respiratory disease. During the preparation of this work the authors used ChatGPT to assist with grammar and sentence flow. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article. S.G., N.M. and M.A. are co‐inventors of the patent N. WO2024028157A1, owned by Edmond Pharma S.p.A. C.P. is a consultant to Edmond Pharma S.p.A.

Data Availability Statement

The datasets generated during the current study are available from the corresponding author upon request.

References

  1. Arend, W. P. 2003. “The Role of Interleukin‐1 Receptor Antagonist in the Prevention and Treatment of Disease.” Modern Rheumatology 13: 1–6. [DOI] [PubMed] [Google Scholar]
  2. Austin, P. J. , Wu A., and Moalem‐Taylor G.. 2012. “Chronic Constriction of the Sciatic Nerve and Pain Hypersensitivity Testing in Rats.” Journal of Visualized Experiments: JoVE 61: 3393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barker, P. A. , Mantyh P., Arendt‐Nielsen L., Viktrup L., and Tive L.. 2020. “Nerve Growth Factor Signaling and Its Contribution to Pain.” Journal of Pain Research 13: 1223–1241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bittermann, A. , Gao S., Rezvani S., et al. 2018. “Oral Ibuprofen Interferes With Cellular Healing Responses in a Murine Model of Achilles Tendinopathy.” Journal of Musculoskeletal Disorders and Treatment 4: 049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Braga, P. C. , Dal Sasso M., Culici M., Verducci P., Lo Verso R., and Marabini L.. 2006. “Effect of Metabolite I of Erdosteine on the Release of Human Neutrophil Elastase.” Pharmacology 77: 150–154. [DOI] [PubMed] [Google Scholar]
  6. Braga, P. C. , Dal Sasso M., and Zuccotti T.. 2000. “Assessment of the Antioxidant Activity of the SH Metabolite I of Erdosteine on Human Neutrophil Oxidative Bursts.” Arzneimittel‐Forschung 50: 739–746. [DOI] [PubMed] [Google Scholar]
  7. Brings, V. , Woller S., Sharma S., Conrad C., Kempegowda D., and Iyengar S.. 2025. “In Vivo Profiling of Diazepam and Gabapentin in Rats in the NIH HEAL Initiative Preclinical Screening Platform for Pain Program.” Journal of Pain 29: 104997. [Google Scholar]
  8. Bryant, A. E. , Aldape M. J., Bayer C. R., et al. 2017. “Effects of Delayed NSAID Administration After Experimental Eccentric Contraction Injury–A Cellular and Proteomics Study.” PLoS One 12: e0172486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cao, D.‐L. , Zhang Z.‐J., Xie R.‐G., Jiang B.‐C., Ji R.‐R., and Gao Y.‐J.. 2014. “Chemokine CXCL1 Enhances Inflammatory Pain and Increases NMDA Receptor Activity and COX‐2 Expression in Spinal Cord Neurons via Activation of CXCR2.” Experimental Neurology 261: 328–336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Capucetti, A. , Albano F., and Bonecchi R.. 2020. “Multiple Roles for Chemokines in Neutrophil Biology.” Frontiers in Immunology 11: 1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cazzola, M. , Calzetta L., Page C., Rogliani P., and Matera M. G.. 2019. “Thiol‐Based Drugs in Pulmonary Medicine: Much More Than Mucolytics.” Trends in Pharmacological Sciences 40: 452–463. [DOI] [PubMed] [Google Scholar]
  12. Cazzola, M. , Page C., Rogliani P., Calzetta L., and Matera M. G.. 2020. “Multifaceted Beneficial Effects of Erdosteine: More Than a Mucolytic Agent.” Drugs 80: 1799–1809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cazzola, M. , Rogliani P., Salvi S. S., Ora J., and Matera M. G.. 2021. “Use of Thiols in the Treatment of COVID‐19: Current Evidence.” Lung 199: 335–343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chan, L. Y.‐S. , Chiu P. Y., Siu N. S., Wang C. C., and Lau T. K.. 2002. “Diclofenac‐Induced Embryotoxicity Is Associated With Increased Embryonic 8‐Isoprostaglandin F2α Level in Rat Whole Embryo Culture.” Reproductive Toxicology 16: 841–844. [DOI] [PubMed] [Google Scholar]
  15. Chaplan, S. R. , Bach F. W., Pogrel J. W., Chung J. M., and Yaksh T. L.. 1994. “Quantitative Assessment of Tactile Allodynia Evoked by Unilateral Ligation of the Fifth and Sixth Lumbar Nerves in the Rat.” Journal of Neuroscience Methods 53: 55–63. [DOI] [PubMed] [Google Scholar]
  16. Costigan, M. , Scholz J., and Woolf C. J.. 2009. “Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage.” Annual Review of Neuroscience 32: 1–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dal Negro, R. , Visconti M., Micheletto C., and Tognella S.. 2008. “Changes in Blood ROS, e‐NO, and Some Pro‐Inflammatory Mediators in Bronchial Secretions Following Erdosteine or Placebo: A Controlled Study in Current Smokers With Mild COPD.” Pulmonary Pharmacology & Therapeutics 21: 304–308. [DOI] [PubMed] [Google Scholar]
  18. Dal Negro, R. , Visconti M., Tognella S., and Micheletto C.. 2011. “Erdosteine Affects Eicosanoid Production in COPD.” International Journal of Clinical Pharmacology and Therapeutics 49: 41–45. [DOI] [PubMed] [Google Scholar]
  19. Dal Negro, R. , Visconti M., Trevisan F., Bertacco S., Micheletto C., and Tognella S.. 2008. “Erdosteine Enhances Airway Response to Salbutamol in Patients With Mild‐To‐Moderate COPD.” Therapeutic Advances in Respiratory Disease 2: 271–277. [DOI] [PubMed] [Google Scholar]
  20. Dal Negro, R. , Visconti M., and Turco P.. 2015. “Efficacy of Erdosteine 900 Versus 600 mg/Day in Reducing Oxidative Stress in Patients With COPD Exacerbations: Results of a Double Blind, Placebo‐Controlled Trial.” Pulmonary Pharmacology & Therapeutics 33: 47–51. [DOI] [PubMed] [Google Scholar]
  21. Dal Negro, R. W. , and Visconti M.. 2016. “Erdosteine Reduces the Exercise‐Induced Oxidative Stress in Patients With Severe COPD: Results of a Placebo‐Controlled Trial.” Pulmonary Pharmacology & Therapeutics 41: 48–51. [DOI] [PubMed] [Google Scholar]
  22. Demiralay, R. , Gürsan N., and Erdem H.. 2006. “Regulation of Sepsis‐Induced Apoptosis of Pulmonary Cells by Posttreatment of Erdosteine and N‐Aceylcysteine.” Toxicology 228: 151–161. [DOI] [PubMed] [Google Scholar]
  23. Ege, E. , Ilhan A., Gurel A., Akyol O., and Ozen S.. 2004. “Erdosteine Ameliorates Neurological Outcome and Oxidative Stress due to Ischemia/Reperfusion Injury in Rabbit Spinal Cord.” European Journal of Vascular and Endovascular Surgery 28: 379–386. [DOI] [PubMed] [Google Scholar]
  24. Fraňová, S. , Kazimierová I., Pappová L., Molitorisová M., Jošková M., and Šutovská M.. 2019. “The Effect of Erdosteine on Airway Defence Mechanisms and Inflammatory Cytokines in the Settings of Allergic Inflammation.” Pulmonary Pharmacology & Therapeutics 54: 60–67. [DOI] [PubMed] [Google Scholar]
  25. Hayashi, K.‐I. , Hosoe H., Raise T., and Ohmori K.. 2000. “Protective Effect of Erdosteine Against Hypochlorous Acid‐Induced Acute Lung Injury and Lipopolysaccharide‐Induced Neutrophilic Lung Inflammation in Mice.” Journal of Pharmacy and Pharmacology 52: 1411–1416. [DOI] [PubMed] [Google Scholar]
  26. Hirose, M. , Kuroda Y., and Murata E.. 2016. “NGF/TrkA Signaling as a Therapeutic Target for Pain.” Pain Practice 16: 175–182. [DOI] [PubMed] [Google Scholar]
  27. Hussain, N. , Brull R., Gilron I., et al. 2024. “Association of Peri‐Operative Prescription of Non‐Steroidal Anti‐Inflammatory Drugs With Continued Prescription of Opioids After Total Knee Arthroplasty: A Retrospective Claims‐Based Cohort Study.” Anaesthesia 79: 725–734. [DOI] [PubMed] [Google Scholar]
  28. Jang, Y. Y. , Song J. H., Shin Y. K., Han E. S., and Lee C. S.. 2003. “Depressant Effects of Ambroxol and Erdosteine on Cytokine Synthesis, Granule Enzyme Release, and Free Radical Production in Rat Alveolar Macrophages Activated by Lipopolysaccharide.” Pharmacology & Toxicology 92: 173–179. [DOI] [PubMed] [Google Scholar]
  29. Janicka, M. , Kot‐Wasik A., Kot J., and Namieśnik J.. 2010. “Isoprostanes‐Biomarkers of Lipid Peroxidation: Their Utility in Evaluating Oxidative Stress and Analysis.” International Journal of Molecular Sciences 11: 4631–4659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Karaky, M. , Lima L. V., Oveisi A., Montagna F., Mogil J. S., and Diatchenko L.. 2025. “Prostaglandins Prevent Long‐Lasting Pain in a Mouse Model of Chronic Postsurgical Pain.” British Journal of Anaesthesia 136, no. 2: 641–652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Marchesi, N. , Govoni S., Page C. P., et al. 2025. “Interaction of Erdosteine With TrkA Signaling Pathways: Implications for Analgesia.” International Journal of Molecular Sciences 26: 4079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Miyake, K. , Kaise T., Hosoe H., Akuta K., Manabe H., and Ohmori K.. 1999. “The Effect of Erdosteine and Its Active Metabolite on Reactive Oxygen Species Production by Inflammatory Cells.” Inflammation Research 48: 205–209. [DOI] [PubMed] [Google Scholar]
  33. Montuschi, P. , Barnes P. J., and Roberts L. J.. 2004. “Isoprostanes: Markers and Mediators of Oxidative Stress.” FASEB Journal 18: 1791–1800. [DOI] [PubMed] [Google Scholar]
  34. Moretti, M. 2007. “Pharmacology and Clinical Efficacy of Erdosteine in Chronic Obstructive Pulmonary Disease.” Expert Review of Respiratory Medicine 1: 307–316. [DOI] [PubMed] [Google Scholar]
  35. Moretti, M. , and Marchioni C. F.. 2007. “An Overview of Erdosteine Antioxidant Activity in Experimental Research.” Pharmacological Research 55: 249–254. [DOI] [PubMed] [Google Scholar]
  36. Muramatsu, N. , Toyo'oka T., Yamaguchi K., and Kobayashi S.. 1998. “High‐Performance Liquid Chromatographic Determination of Erdosteine and Its Optical Active Metabolite Utilizing a Fluorescent Chiral Tagging Reagent, R‐(−)‐4‐(N, N‐Dimethylaminosulfonyl)‐7‐(3‐Aminopyrrolidin‐1‐Yl)‐2, 1, 3‐Benzoxadiazole.” Journal of Chromatography B: Biomedical Sciences and Applications 719: 177–189. [DOI] [PubMed] [Google Scholar]
  37. Negro, R. W. D. 2008. “Erdosteine: Antitussive and Anti‐Inflammatory Effects.” Lung 186: 70–73. [DOI] [PubMed] [Google Scholar]
  38. Parisien, M. , Lima L. V., Dagostino C., et al. 2022. “Acute Inflammatory Response via Neutrophil Activation Protects Against Pain Chronification.” Science Translational Medicine 14: eabj9954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Park, J. S. , Park M.‐Y., Cho Y.‐J., et al. 2016. “Anti‐Inflammatory Effect of Erdosteine in Lipopolysaccharide‐Stimulated RAW 264.7 Cells.” Inflammation 39: 1573–1581. [DOI] [PubMed] [Google Scholar]
  40. Rogliani, P. , Matera M. G., Page C., Puxeddu E., Cazzola M., and Calzetta L.. 2019. “Efficacy and Safety Profile of Mucolytic/Antioxidant Agents in Chronic Obstructive Pulmonary Disease: A Comparative Analysis Across Erdosteine, Carbocysteine, and N‐Acetylcysteine.” Respiratory Research 20: 104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Shabani, F. , Farasat A., Mahdavi M., and Gheibi N.. 2018. “Calprotectin (S100A8/S100A9): A Key Protein Between Inflammation and Cancer.” Inflammation Research 67: 801–812. [DOI] [PubMed] [Google Scholar]
  42. Silva, R. L. , Lopes A. H., Guimarães R. M., and Cunha T. M.. 2017. “CXCL1/CXCR2 Signaling in Pathological Pain: Role in Peripheral and Central Sensitization.” Neurobiology of Disease 105: 109–116. [DOI] [PubMed] [Google Scholar]
  43. Sisignano, M. , and Geisslinger G.. 2023. “Rethinking the Use of NSAIDs in Early Acute Pain.” Trends in Pharmacological Sciences 44: 193–195. [DOI] [PubMed] [Google Scholar]
  44. Stein, C. , Millan M., and Herz A.. 1988. “Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds.” Pharmacology Biochemistry and Behavior 31: 445–451. [DOI] [PubMed] [Google Scholar]
  45. Thai, P. N. , Ren L., Xu W., et al. 2023. “Chronic Diclofenac Exposure Increases Mitochondrial Oxidative Stress, Inflammatory Mediators, and Cardiac Dysfunction.” Cardiovascular Drugs and Therapy 37: 25–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ugolini, G. , Marinelli S., Covaceuszach S., Cattaneo A., and Pavone F.. 2007. “The Function Neutralizing Anti‐TrkA Antibody MNAC13 Reduces Inflammatory and Neuropathic Pain.” Proceedings of the National Academy of Sciences 104: 2985–2990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Xi, Y. , Huang X., Tan G., et al. 2020. “Protective Effects of Erdosteine on Interleukin‐1β‐Stimulated Inflammation via Inhibiting the Activation of MAPK, NF‐κB, and Wnt/β‐Catenin Signaling Pathways in Rat Osteoarthritis.” European Journal of Pharmacology 873: 172925. [DOI] [PubMed] [Google Scholar]
  48. Zatloukal, J. , Page C., Brat K., et al. 2025. “Effect of Treatment With Mucoactive Drugs on COPD Exacerbations During 5 Years of Follow‐Up in The Czech Republic: A Real‐World Study.” Lung 203: 61. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated during the current study are available from the corresponding author upon request.

Articles from European Journal of Pain (London, England) are provided here courtesy of Wiley

RESOURCES