Chronic dyspnoea represents a debilitating symptom affecting millions of individuals worldwide, particularly those suffering from advanced pulmonary and cardiac diseases (Mahler et al., 2012). This distressing sensation of breathlessness significantly impairs quality of life and functional capacity, often persisting despite optimal management of underlying conditions (Johnson et al., 2014). Traditional pharmacological interventions, including bronchodilators, corticosteroids, and oxygen therapy, may provide insufficient relief in refractory cases, leading clinicians to explore alternative therapeutic approaches (Currow et al., 2011). Opioids have emerged as a potential off-label treatment option for managing refractory chronic dyspnoea, with studies demonstrating their efficacy in reducing breathlessness intensity and improving exercise tolerance (Abernethy et al., 2003; Jennings et al., 2002). However, the long-term use of opioids for chronic conditions has raised significant concerns regarding their potential adverse effects on neurological and psychological functioning. Growing evidence suggests that chronic opioid exposure may lead to substantial cognitive and psychiatric complications (Schiltenwolf et al., 2014; Vowles et al., 2015). Cognitive domains such as memory, attention, and executive function appear particularly vulnerable to the effects of prolonged opioid therapy (Moriarty et al., 2011). Studies have documented impairments in working memory, processing speed, and decision-making abilities among chronic opioid users (Kurita et al., 2012). Furthermore, opioid use has been associated with an increased risk of developing anxiety and depressive disorders, potentially through disruption of neurotransmitter systems and alterations in brain reward pathways (Kosten et al., 2002). Despite the growing global use of opioids for chronic dyspnoea management, there remains a paucity of research examining their long-term cognitive and psychiatric effects, particularly in the Indian healthcare context. The unique demographic, genetic, and environmental factors prevalent in the Indian subcontinent may influence both the efficacy and adverse effect profile of opioid therapy (Sharma et al., 2018). Additionally, cultural attitudes toward mental health and pain management may affect the recognition and reporting of cognitive and psychiatric symptoms in this population. Given the increasing prevalence of chronic respiratory and cardiovascular diseases in India and the potential for expanded opioid use in managing associated dyspnoea, it is crucial to understand the long-term neuropsychiatric implications of such therapy. Therefore, this cross-sectional study aimed to investigate the effects of long-term opioid use for chronic dyspnoea on cognitive function and psychiatric disorders among patients in Telangana, India, with the goal of informing evidence-based clinical decision-making and optimizing patient care in this vulnerable population.

Study Design and Setting A cross-sectional observational study was conducted at the Government Medical College, Sangareddy, Telangana, India. The study spanned six months, from January to June 2024. The research protocol was reviewed and approved, and written informed consent was obtained from all participants prior to enrolment. The study adhered to the principles of the Declaration of Helsinki for biomedical research on human participants. Study Population and Recruitment A total of 400 adult participants (aged 40–80 years) with a clinical diagnosis of chronic dyspnoea, secondary to advanced pulmonary or cardiac conditions, were recruited from the Medicine and Respiratory Medicine outpatient clinics. • Opioid User Group (n=193): Patients prescribed opioids for the management of chronic dyspnoea for ≥6 months, irrespective of underlying pulmonary or cardiac etiology. Morphine was the most commonly prescribed opioid, administered either orally or parenterally in titrated doses as per clinical requirement. • Control Group (n=207): Age- and sex-matched patients with chronic dyspnoea managed without opioids. Inclusion Criteria • Adults between 40–80 years of age. • Diagnosed with chronic dyspnoea (>3 months duration). • Able to communicate adequately and complete cognitive and psychiatric assessments. Exclusion Criteria • Acute exacerbation of underlying disease within the past 4 weeks. • History of severe psychiatric illness (e.g., schizophrenia, bipolar disorder). • Current or past non-medical substance abuse (excluding prescribed opioids). • Severe cognitive deficits preventing participation in testing (MMSE < 15). • Presence of terminal illness with expected survival <6 months. Sample Size Determination The sample size was calculated using a two-group comparison formula for proportions, based on pilot observations and previous literature reporting a 30–40% prevalence of opioid-related cognitive impairment (Schiltenwolf et al., 2014). At a 95% confidence interval, power of 80%, and effect size of 0.3, the minimum required sample was 180 per group. To account for potential dropouts, 193 opioid users and 207 controls were enrolled, totaling 400 participants. Assessment Tools 1. Cognitive Function • Montreal Cognitive Assessment (MoCA): A 30-point global cognitive screener, sensitive to mild cognitive impairment across domains (Nasreddine et al., 2005). A cut-off score <26 indicated cognitive impairment. • Mini-Mental State Examination (MMSE): Widely used for screening global cognitive decline (Folstein et al., 1975). A cut-off <24 suggested significant impairment. • Trail Making Test (TMT-A and TMT-B): Measures attention, processing speed, and executive function; longer completion times suggested cognitive deficits (Reitan, 1992). 2. Psychiatric Assessment • Hospital Anxiety and Depression Scale (HADS): Evaluates anxiety and depressive symptoms in patients with chronic medical illness (Zigmond & Snaith, 1983). • Beck Depression Inventory-II (BDI-II): Measures severity of depressive symptoms with higher scores indicating greater severity (Beck et al., 1996). • Generalized Anxiety Disorder Scale (GAD-7): Assesses frequency and severity of anxiety symptoms (Spitzer et al., 2006). Data Collection Procedure • Sociodemographic and clinical details (age, sex, education, socioeconomic status, diagnosis, smoking history, comorbidities, opioid type and dose) were obtained through structured interviews and case records. • Cognitive and psychiatric tests were administered by trained research assistants under supervision of faculty specialists to minimize interviewer bias. • Standardized conditions (quiet room, uniform sequence of tests, rest intervals) were maintained to avoid fatigue bias. • For opioid users, duration and cumulative dose of opioid exposure were documented. Outcome Measures • Primary Outcome: Cognitive impairment as defined by standardized cutoffs in MoCA, MMSE, and TMT. • Secondary Outcome: Prevalence and severity of anxiety and depression symptoms (HADS, BDI-II, GAD-7). Statistical Analysis • Data were analyzed using SPSS version 26 (IBM Corp., Chicago, IL, USA). • Continuous variables were expressed as mean ± standard deviation (SD), while categorical variables were presented as percentages. • Differences between opioid users and controls were assessed using independent-sample t-tests (continuous data) and Chi-square tests (categorical data). • Logistic regression was performed to assess the association of opioid use with cognitive impairment and psychiatric disorders after adjusting for potential confounders such as age, sex, and education. • Statistical significance was set at a p-value < 0.05.

Table 1: Demographic Characteristics Variable Opioid Users (n=193) Controls (n=207) Age (years, mean ± SD) 58.2 ± 8.7 57.6 ± 9.1 Gender (M/F) 99/94 107/100 Education: Primary (%) 34.2 31.4 Education: Graduate (%) 18.1 20.3 Hindu (%) 64.8 65.2 Muslim (%) 28.5 29.9 Participant Characteristics A total of 400 participants were included, comprising 193 chronic opioid users and 207 non-opioid controls. The mean age of opioid users was 58.2 ± 8.7 years, comparable to 57.6 ± 9.1 years in the control group. Gender distribution (52% vs. 51% males), religion, and educational status were also similar between groups (Table 1). These findings confirm adequate comparability of the two groups with respect to key sociodemographic variables. Table 2: Cognitive Function Scores Measure Opioid Users (Mean ± SD) Controls (Mean ± SD) p-value MoCA 22.40 ± 3.66 25.74 ± 2.60 <0.001 MMSE 24.09 ± 3.10 27.08 ± 1.93 <0.001 TMT-A (sec) 51.60 ± 16.25 41.75 ± 13.00 <0.001 TMT-B (sec) 128.35 ± 36.91 98.23 ± 27.28 <0.001 Cognitive Function Outcomes Opioid users demonstrated significantly poorer cognitive performance across all three assessment tools. • Global cognition (MoCA): Mean scores were 22.4 ± 3.7 among opioid users compared to 25.7 ± 2.6 in controls (p < 0.001). The prevalence of cognitive impairment (MoCA < 26) was markedly higher in opioid users (78.8%) than controls (43.5%) (Figure 1). • Mini-Mental State Examination (MMSE): Opioid users scored 24.1 ± 3.1 versus 27.1 ± 1.9 in controls (p < 0.001). Moderate impairment (MMSE < 24) was observed in 41.9% of opioid users compared to 12.6% of controls. • Executive function (Trail Making Test): Mean completion times were significantly prolonged in opioid users—TMT-A: 51.6 ± 16.3 sec vs. 41.8 ± 13.0 sec (p < 0.001); TMT-B: 128.3 ± 36.9 sec vs. 98.2 ± 27.3 sec (p < 0.001). This indicates greater deficits in processing speed and task-switching ability. Taken together, these results confirm a strong association between chronic opioid use and impaired global, attentional, and executive functions. Table 3: Psychiatric Symptom Scores Measure Opioid Users (Mean ± SD) Controls (Mean ± SD) p-value HADS Anxiety 9.81 ± 4.13 6.05 ± 2.94 <0.001 HADS Depression 8.20 ± 4.73 5.31 ± 3.06 <0.001 BDI-II 18.19 ± 8.16 10.88 ± 6.47 <0.001 GAD-7 10.99 ± 5.13 7.29 ± 3.89 <0.001 Group MoCA < 26 (%) Opioid users 78.8 Controls 43.5 Group HADS-A ≥11 (%) Opioid users 41.5 Controls 7.2 Psychiatric Outcomes Psychiatric symptoms were significantly higher among the opioid group across all measures (Table 2). • HADS-Anxiety (HADS-A): Mean scores were 9.8 ± 4.1 vs. 6.1 ± 2.9 in non-users (p < 0.001). Prevalence of clinically significant anxiety (HADS-A ≥11) was 41.5% in opioid users compared with only 7.2% in controls(Figure 2). • HADS-Depression (HADS-D): Mean scores were 8.2 ± 4.7 vs. 5.3 ± 3.1 (p < 0.001). • BDI-II: Opioid users reported higher depressive symptom burden (18.2 ± 8.2) compared with controls (10.9 ± 6.5, p < 0.001). Notably, 32% of opioid users met criteria for moderate-to-severe depression compared to 11% of controls. • GAD-7: Mean scores were 11.0 ± 5.1 vs. 7.3 ± 3.9 (p < 0.001), with 29% of opioid users meeting cut-off for moderate-to-severe generalized anxiety compared to only 10% of controls. Additional Observations • Duration of Opioid Therapy: Cognitive and psychiatric impairments were evident even with moderate opioid exposure (>6 months) and did not show a consistent linear trend with duration of therapy, suggesting susceptibility may occur early in treatment. • Educational Level: Patients with lower educational attainment exhibited more pronounced cognitive deficits, especially in MoCA and TMT performance, independent of opioid use. • Comorbidity Influence: While comorbid conditions such as diabetes and hypertension were common, subgroup analyses suggested opioid exposure remained an independent predictor of cognitive and psychiatric impairment after adjusting for these variables. Summary of Key Findings 1. Chronic opioid use was associated with substantially higher rates of cognitive impairment (up to 80% vs. 44% in controls). 2. Opioid users exhibited a 3–4 fold higher prevalence of anxiety and depression, with clinically significant symptoms in >40% of opioid patients. 3. Deficits spanned multiple cognitive domains, particularly executive function and working memory. 4. The associations persisted even after adjusting for sociodemographic and clinical variables, supporting an opioid-specific effect.

This study provides compelling evidence for significant associations between chronic opioid use for dyspnoea management and both cognitive impairment and psychiatric symptoms in an Indian population. The findings align with emerging research from Western populations while providing important insights into these effects in a diverse demographic setting, Our findings align with previous studies showing opioid-associated cognitive and psychiatric impairment (Schiltenwolf et al., 2014; Moriarty et al., 2011)[4][6]. The high prevalence of cognitive impairment and psychiatric symptoms among opioid users highlights the need for routine monitoring (Vowles et al., 2015)[5]. The lack of strong correlation with opioid duration suggests that even moderate exposure may increase risk (Kosten et al., 2002)[7]. Limitations Several limitations should be acknowledged. The cross-sectional design precludes causal inferences, and the possibility of reverse causation cannot be excluded. Participants with pre-existing cognitive or psychiatric conditions may have been more likely to receive opioid therapy. The study did not control for all potential confounders, including specific medical conditions, concomitant medications, or genetic factors that might influence opioid responses. Additionally, the convenience sampling method may limit generalizability, and the lack of standardized opioid dosing information represents a limitation in understanding dose-response relationships. Future longitudinal studies with larger, more diverse populations are needed to establish causal relationships and identify risk factors for these adverse effects. Future Directions These findings highlight the need for prospective studies examining the temporal relationship between opioid initiation and cognitive/psychiatric changes. Research into alternative therapies for refractory dyspnoea, including non-pharmacological interventions and novel medications with better safety profiles, is urgently needed. Investigation of genetic and demographic factors that may predispose certain populations to opioid-related cognitive and psychiatric effects could inform personalized treatment approaches. Additionally, studies examining the reversibility of these effects following opioid discontinuation would provide valuable clinical guidance.

Chronic opioid use for dyspnoea in patients is associated with significant cognitive and psychiatric morbidity. Regular assessment and careful risk-benefit consideration are warranted. Acknowledgments We thank the participants who contributed to this study and the staff at Government Medical College, Sangareddy, for their support during data collection.

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