Introduction

Opioid use disorder [1] (OUD), is a chronic relapsing disease with significant morbidity, including chronic viral infections, overdose, traumatic injuries and premature mortality [2-5]. However, the widespread of preventive public health interventions, especially opioid agonist therapy, has improved the health-related quality of life and survival of people with substance use disorders [6-8]. Among benefits of opioid agonist therapy are included  its efficacy in retaining subjects in treatment, decreasing opioid use, risk behaviors related to the hepatitis and HIV infectious diseases, criminal behavior linked to drug consumption and fatal overdose [9,10]. The resulting increase in life expectancy of people with OUD has been accompanied by progressive aging and a growing concern of interest in the study of age-related comorbidity [11-14].

In this sense, frailty is an aging-related syndrome characterized by a decline in the physiological capacity of multiple organ systems, leading to increased vulnerability to stressors events resulting in an increased risk of falls, fractures, hospitalization, institutionalization, impaired quality of life and mortality [15]. Prevalence of frailty among the community-dwelling population aged 65 years and older is about 10% depending on which frailty definitions are used [16]. Frailty may initially be overlooked or incorrectly identified as part of the normal aging process because of the variable nature of the presentation and diagnosis [15-17]. Symptoms include generalized weakness, exhaustion, slow gait, poor balance, decreased physical activity, cognitive impairment, and weight loss [15-17], but the individual’s frailty level can be improved through multi-component training exercises [17-19]. There is no current recommendation for frailty routine screening. Frailty is not diagnosed by a single patient-reported symptom or physical examination finding [15], and there are no specific laboratory tests or imaging studies for frailty [20]. Rather, a comprehensive geriatric assessment can identify risk factors and symptoms suggestive of frailty. Suspected clinical frailty should be evaluated using validated frailty diagnosis scale, which classify patients as robust, prefrail, or frail [21].

Frailty is not only consequence of aging, female sex, unhealthy lifestyle, multiple comorbidities, polypharmacy and lower economic status has also been identified as additional risk factors [15-17]. In contrast to the general population, data on frailty are scarce for people with OUD. However, they share several risk factors associated to an accelerating aging, which may suggest a higher prevalence of frailty in this population.

Substance use, especially cocaine and heroin, contributes to aging through multiple pathways, including alterations in oxidative stress, excitotoxicity, mitochondrial dysfunction and telomere length reduction,  which ultimately leading to cell degeneration and apoptosis [22-26]. By contrast, studies have shown reversed association with frailty risk, probably   due to reverse causality, residual confounding or survival bias [27-28].

Moreover, people with OUD have a high prevalence of chronic medical conditions [29-31], which are contributing factor to frailty in the general population [31-34]. Age-related diseases and frailty share common risk factors and have a bidirectional relationship with each other. Chronic diseases can contribute as a causal or precipitating factor to the fragile syndrome, while it can lead to greater vulnerability and complications in older adults who suffer from underlying chronic diseases [32,33]. In addition, chronic viral infections, which are more prevalent in people with OUD than general population, have harmful effects on the individual’s immune system, exacerbating aging. However, antiretroviral therapy initiation reverses partially the biological aging process and additionally can have some toxicities that influence aging [34].

Understanding potentially modifiable factors that influence the risk of frailty and its progression is a key concern for the management of this urgent contemporary public health challenge. So, it is necessary to carry out studies in people with OUD to promote a healthy aging and improve quality of care. Thus, the aim of this study was to determine the prevalence of frailty and clinical characteristics in a sample of people with opioid use disorder, who received integrated clinical, including medical and psychosocial support, in an outpatient drug addiction center.

Methods

A cross sectional study was conducted in a sample of people with OUD. The former were selected from three outpatient drug treatment centers (CAS: Centro de Attention y Seguimiento a las drogodependencias: Drug Addiction Attention and Follow up Centre) located in or adjoining Barcelona, Spain: CAS Barceloneta, CAS Forum Sent Marti and CAS Santa Coloma. The centers belonged to the public health system and received individuals from two different districts of Barcelona and from the metropolitan area, respectively. Functioning of the centers has been published elsewhere [35].

All those aged >50 years with OUD diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Text Revision V criteria, and who had received integrated clinical care, including medical and psychosocial support,  at the three drug addiction outpatient centers in 2022 were invited to participate during their routine clinical visits. Participants gave written informed consent.

General characteristics and medical history of the participants were obtained from the medical records. Severity of the comorbidity was assessed trough an adapted version of the Cumulative Illness Rating Scale for its use in older patients (CIRS-G) [36]. The CIRS-G contemplated 14 groups of diseases or categories, evaluating its severity from 0 (no impairment) to 4 (highest possible impairment),      giving a final score (score) which was the sum of these evaluations (between 0-56).  Low comorbidity was considered for scores 0-2, moderate for 3-8 and high for 9 according to CIRS-G [36]. The FRAIL questionnaire [21] was used to determine frailty and was applied by the center’s physician during routine clinical visits. The FRAIL scale included 5 components: Asthenia, Resistance, Ambulation, Illness, and Loss of weight, Frail scale scores ranged from 0–5 (i.e., 1 point for each component; 0=best to 5=worst) and represented frail (3–5), pre-frail (1–2), and robust (0) health status [21]. For this study, Asthenia was measured by asking respondents how much time during the past 4 weeks they felt tired with responses of “all of the time “or “ most of the time” scored 1 point. Resistance was assessed by asking participants if they had any difficulty walking up 10 steps alone without resting and without aids, and Ambulation by asking if they had any difficulty walking several hundred yards alone and without aids; “yes” responses were each scored as 1 point. Illness was scored 1 for respondents who reported 5 or more chronic diseases, excluding psychiatric disorders. Loss of weight was scored 1 for respondents with a weight decline of 5% or greater within the past 12 months.

The primary outcome of the study was the prevalence of frailty among participants. Secondary outcomes were the variables associated with frailty and the prevalence and severity of comorbidity.

Descriptive statistics were expressed as median and interquartile range for the quantitative variables, and percentages for the qualitative variables. Means of quantitative variables were compared with the Wilcoxon test. The χ² test was used to compare categorical variable proportions.

Logistic regression models were employed to examine the association of clinical variables with  FRAIL scores classified as frail or pre-frail vs. robust. Variables included in the analyses were: age, gender, substance use disorder, dual disorders, intravenous use of substances, HIV infection, CIRS-G scoring, time on opioid agonist therapy and total number of medical drug prescriptions. A p value < 0.05 was considered significant. Statistical analyses were performed using the free statistical R (3.5.2 version).2.7.

The study was approved by the local ethics committee (2019/8870 CEIC Parc de Salut Mar, Barcelona). All procedures performed in the study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

Results

All of 169 adults aged >50 years with OUD who were monitored at the three centers agreed to participate in the study. 

Clinical and social characteristics of the participants are shown in (Table 1).  Most of the participants were male, middle age Spanish, living at home, unemployed and one third had criminal records.

Table 1: Social and clinical characteristics of the 169 individuals with opioid use disorder.

One quarter had dual disorders and all the individuals had heroin as the main opioid consumed before seeking treatment. The main mode of substance administration was intravenous and 151(89.2%) had other substance use disorders mainly cocaine, alcohol and cannabis. Women had more intravenous substance and cannabis use compared to men. All the subjects had been on opioid agonist therapy for nearly thirty years and one third remained abstinent. One quarter of the individuals had HIV infection with a median of 483[interquartile range 118-743] cells/mm3 and all had suppressed RNA HIV-1. Three quarters of persons had positive hepatitis C antibodies (immunoglobulin G) but all were on sustained viral response.

One or more chronic medical conditions were determined in more than a half of individuals: chronic respiratory diseases in 61(35.1%), hypertension in 52(30.2%), diabetes in 25(14.8%), chronic liver disease in 24(14.2%), vascular diseases 23(13.6%), cancer 15(8.8%), hypothyroidism 6(3.55) and dementia 3 (1.8%). Half of the participants had moderate or high comorbidity according to CIRSG and they were taken a median of 4 drugs including opioid agonist therapy.

Frail status was diagnosed in 28 (16.6%; CI95%: 11.0-22.2%) subjects and pre-frailty in 41(24.2%) according to the Frail Scale. Women had a non-significant tendency to higher frail and pre-frail status.  Asthenia in 58(33.2%) individuals, low resistance in 39(25.4%), loss of DE ambulation in 39(22.8%), loss of weight in 16(9.4%) and more than 4 chronic diseases in 7 (4.1%) were the most clinical symptoms of frailty. Factors associated with the frailty and pre-frailty are shown in (Table 2). Only age and CIRS-G were associated to frailty in the multivariate analyses.

Table 2: Multivariate analysis of clinical factors associated to frailty and pre-frailty among 169 individuals with opioid use disorder