The association of pain with suicidal ideation and suicide attempts with depressive symptoms among adults aged ≥50 years from low‐ and middle‐income countries

We aimed to examine the relationship of pain with suicidal ideation and suicide attempts with depressive symptoms among adults aged ≥50 years from six low‐ and middle‐income countries (LMICs) (China, Ghana, India, Mexico, Russia, and South Africa).


| INTRODUCTION
Suicide is defined as death caused by self-directed injurious behavior with intent to die, as a result of the behavior. 1 Approximately 700,000 people die by suicide each year, of which 77% occur in lowand middle-income countries (LMICs). Suicidal ideation (defined as thinking about, considering, or planning suicide) 1 typically precedes a suicide attempt (defined as a non-fatal, self-directed, potentially injurious behavior with intent to die as a result of the behavior), 1 and a prior suicide attempt is the most important risk factor for completed suicides in the general population. 2 In addition, suicide attempts are associated with a plethora of negative outcomes including injury, hospitalization, and loss of independence, as well as imposing a significant financial burden on society. 3 Although suicide attempts are more frequent among adolescents and young adults, older men and women show the highest suicide rate in almost all countries. 4,5 Moreover, the rate of suicide increases with age among people older than 60 years. 6 Given this, it is important to develop targeted interventions to prevent suicidal ideation and suicide attempts among older adults, especially in the context of LMICs.
One understudied but potentially important risk factor for suicidality among older people in LMICs is pain. Pain may increase risk for suicidal ideation and suicide attempt by, for example, causing mental defeat, which is a thought process involving a loss of emotional autonomy and a sense of feeling broken. 7 Importantly, mental defeat has been identified as a key indicator for heightened suicide risk. 8 Moreover, pain can lead to insomnia and problemsolving deficits, 9 and these conditions may increase risk for suicidality. 10,11 Pain may be an important risk factor for suicidality especially in older adults in LMICs as studies have shown a trend toward increasing prevalence of pain with increasing age with the highest prevalence being observed among older adults, [12][13][14] while the prevalence of chronic pain has been reported to be particularly high in LMICs. 15 Cancer pain, acute pain, and chronic non-cancer pain all contribute to a large burden of pain in LMICs, which is frequently underdiagnosed and undertreated. 16 While there is a scarcity of literature on the prevalence of untreated pain globally, the World Health Organization (WHO) estimates that 5.5 billion people (more than 80% of the global population) do not have access to treatments for moderate to severe pain, and states that most of these people are living in LMICs. 17 Indeed, in many LMICs, the range of analgesic medications is very limited, and the supply of medications may be intermittent or non-existent. 16 One recent systematic review focusing on pain as a risk factor for suicidal behavior in older adults (defined as people aged ≥60 years) included 38 original research articles, and suggested the existence of a relationship between pain and suicidal behavior in older adults. However, none of the studies were from LMICs. 18 In fact, there is just one previous study on pain and suicidal thoughts and behavior among older people from LMICs. Specifically, in this study including a sample of 251 Ghanian women aged ≥50 years, mild and moderate pain, when compared to severe or extreme pain, was associated with a lower risk of suicidal ideation. 19 It is clear that more research is needed to investigate the association between pain and suicidal thoughts or behavior among older adults from LMICs given that findings from high-income countries may not be applicable to LMICs due to different disease profiles that may lead to pain and the limited availability of treatment for pain in this setting. 20 Moreover, multi-country studies are needed as these studies allow for the comparison of standardized estimates across different settings and can thus better inform targeted intervention and policy.
Given this background, the aim of the present study was to examine the relationship between pain with suicidal ideation and suicide attempts among adults aged ≥50 years from six LMICs (China, Ghana, India, Mexico, Russia, and South Africa).  21 Briefly, in order to obtain nationally representative samples, a multistage clustered sampling design method was used. The sample consisted of adults aged ≥18 years with oversampling of those aged ≥50 years. Trained interviewers conducted face-to-face interviews using a standard questionnaire.

| METHODS
Standard translation procedures were undertaken to ensure comparability between countries. The survey response rates were: China 93%; Ghana 81%; India 68%; Mexico 53%; Russia 83%; and South Africa 75%. Sampling weights were constructed to adjust for the population structure as reported by the United Nations Statistical Division. Ethical approval was obtained from the WHO Ethical Review Committee and local ethics research review boards. Written informed consent was obtained from all participants.

| Suicidal ideation and suicide attempts
Information on suicidal ideation and suicide attempt were assessed in the same way as in previous SAGE publications, [22][23][24] using an adapted version of the depression module of the WHO Composite International Diagnostic Interview. 25 Those who screened positive in the depression module were further asked about suicidal thoughts and behavior. A positive screen referred to having at least one of the three following conditions for more than 2 weeks in the past 12 months: sadness, loss of interest, or low energy. Suicidal ideation was assessed by the question "Did you think of death, or wish you were dead?" and suicide attempts by the question "During this period, did you ever try to end your life?" with "yes" and "no" answer options. 22,23

| Pain
Pain was assessed with the question "Overall in the last 30 days, how much of bodily aches or pain did you have?" With answer options "none" (unweighted n = 13,059), "mild" (n = 10,729), "moderate" (n = 6579), "severe" (n = 3095) and "extreme" (n = 221). In the analysis, "severe" and "extreme" were collapsed into one category as there were very few people who answered "extreme". Furthermore, a dichotomized variable of severe/extreme pain (yes/no) was also created and used in some analyses. A followup question on difficulty in daily life due to pain ("Overall in the last 30 days, how much difficulty did you have in your daily life because of your pain?") was asked to those who answered "mild" to "extreme" to the above-mentioned question on pain. Answer options were the same as above and those who answered "severe" and "extreme" were categorized together as very few people answered "extreme".

| Control variables
The control variables were selected based on past literature, 26 and included age, sex, education (under secondary, secondary or higher), wealth quintiles based on income, alcohol consumption in the past 30 days, and chronic physical conditions. Information on 10 chronic physical diseases (angina, arthritis, asthma, chronic lung disease, diabetes, edentulism, hearing problem, hypertension, stroke, visual impairment) were obtained. The details on the diagnosis of these conditions are provided in Table S1 (Appendix A). The number of chronic conditions were summed and categorized as 0, 1, and ≥2.

| Statistical analysis
The statistical analysis was conducted with Stata 14.2 (Stata Corp LP). The analysis was restricted to people aged ≥50 years. The difference in sample characteristics by severe/extreme pain was tested by Chi-squared tests and Student's t-tests for categorical and continuous variables, respectively. Multivariable logistic regression analysis was conducted to examine the association between severity of pain or difficulty in daily life due to pain (four-category variable with values "none", "mild", "moderate", "severe/extreme"; exposures) and suicidal ideation or suicide attempt (outcomes). The analysis on difficulty in daily life excluded those who did not report pain. We also conducted test of trend to assess whether increasing severity of pain was dose-dependently associated with higher odds for suicidal ideation or suicide attempt. This was done by including the variables on severity of pain or difficulty in daily life due to pain as a continuous variable rather than a categorical variable in the model. The analysis on severity of pain was also stratified by age group (50-64 years [middle-aged adults] and ≥65 years [older adults]) and sex.
Furthermore, to examine the between country-heterogeneity in the association between severe/extreme pain and suicidal ideation, we conducted country-wise analysis and calculated the Higgin's I 2 , which represents the degree of heterogeneity that is not explained by sampling error with values of 25%, 50%, and 75% often being considered as low, moderate, and high levels of heterogeneity. 27 Overall estimates were obtained based on country-wise estimates by meta-analysis with random effects. Country-wise analysis with suicide attempts as the outcome could not be conducted because stable estimates were unobtainable due to the small number of suicide attempts in each country.
All regression analyses were adjusted for age, sex, education, wealth, alcohol consumption, number of chronic conditions, and country, except for the sex-and country-stratified analyses which were not adjusted for sex and country, respectively. Adjustment for country was done by including dummy variables for each country in the model as in previous SAGE publications. 28 Table 1. Those with severe/ extreme pain were more likely to be older, be females, have lower levels of education and wealth, and were less likely to consume alcohol, while they had more chronic conditions. Country-wise sample characteristics are provided in Table S2 of the Appendix A. The prevalence of females and ≥ secondary education was particularly high in Russia. The prevalence of suicidal ideation and suicide attempt increased linearly with increasing severity of pain (Figure 1).
For example, the prevalence of suicidal ideation was only 0.6% among those without pain but this increased to 14.8% among those with severe/extreme pain. In the overall sample, after adjustment for potential confounders, compared to no pain, mild, moderate, and severe/extreme pain were associated with 2.83 (95% CI = 1.51-5.28), 4.01 (95% CI = 2.38-6.76), and 12.26 (95% CI = 6.44-23.36) times higher odds for suicidal ideation ( Table 2). Results were similar for middle-aged and older adults. For suicide attempt, only severe/ extreme pain was associated with significantly increased odds (OR = 4.68; 95% CI = 1.67-13.08). Among those who had pain, increasing severity of difficulty in daily life due to pain was dosedependently associated with higher odds for suicidal ideation and suicide attempt (Table 3). For example, severe/extreme difficulty in daily life due to pain (vs. no difficulty) was associated with 7.50 (95% CI = 2.98-18.88) and 24.63 (95% CI = 6.52-93.00) times higher odds for suicidal ideation and suicide attempt, respectively. Test for trend was significant for all analyses on severity of pain or difficulty in daily life due to pain, suggesting dose-dependent associations. Finally, country-wise analysis showed that severe/extreme pain was significantly associated with suicidal ideation in all countries, except Mexico, with a moderate level of between-country heterogeneity (I 2 = 60.2%) (Figure 2).

| Main findings
In the present large sample of older adults from six LMICs, it was observed that increasing severity of pain is dose-dependently associated with higher odds for suicidal ideation and suicide attempts. For  Note: Models are adjusted for age, sex, education, wealth, alcohol consumption, number of chronic physical conditions, and country, except for the sex-stratified analysis which was not adjusted for sex. Significant test for trend for all models (p < 0.05).

| Interpretation of findings
Findings from the present study support previous literature that has observed a positive association between pain and suicidality in multiple high-income countries, 18,30 and pain and suicidal ideation in a sample of Ghanaian women. 19 Our findings add to this literature through confirming that such an association holds in a very large sample of older adults from multiple LMICs.
There are several plausible pathways that likely explain the association between pain and suicidal thoughts and behavior. First, as previously discussed, pain can cause mental defeat, which is a key indicator for heightened suicide risk. 8 Mental defeat likely heightens suicide risk via worse functioning, and a breakdown in selfmanagement. Moreover, defeat is aversive and the resultant urge when defeat is perceived is to escape, which thus likely leads to suicidal behaviors. 8 The relationship between pain and suicidal thoughts and behavior may also be partly explained by depression, which is a key risk factor for suicidality. 31 For example, depression increases the susceptibility for pain, and non-specific pain may be expressions of late-life depression. Moreover, chronic pain might result in dependence on others, loss of dignity and fear of institutionalization, contributing to depression and subsequently suicidal behaviors. 18 Finally, literature has shown that pain is associated with sleep complications potentially owing to pain-induced alterations in dopamine signaling that may influence the raphe nuclei modulation of sleep and wake. 32 Importantly, sleep complications have been associated with suicide behavior 33 potentially due to decreased ability of self-regulation. 34 Interestingly, the present study found that increasing severity of difficulty in daily life due to pain was dose-dependently associated with higher odds for suicidal thoughts and behavior. It may be hypothesized that an increase in difficulty in daily life heightens feelings of mental defeat and depression, for example, through loss of independence and feelings of being a burden, subsequently increasing risk of suicidality.
Finally, there was a moderate level of between-country heterogeneity in the association between severe/extreme pain and suicidal ideation, with this association being non-significant in Mexico. Abbreviations: CI, confidence interval; OR, odds ratio.

F I G U R E 2
Country-wise association between severe/extreme pain and suicidal ideation (outcome) estimated by multivariable logistic regression. Abbreviations: CI, confidence interval; OR, odds ratio. Models are adjusted for age, sex, education, wealth, alcohol consumption, and number of chronic physical conditions. Overall estimate was obtained by meta-analysis with random effects. The sample size of the regression analysis for each country were as follows: China n = 12,341; India n = 6508; Ghana n = 4209; Mexico n = 2200; Russia n = 3819.
by nurses, social workers, psychologists and diverse specialists. 35 Alternatively, it is also possible that questions on suicidal ideation and suicide attempts were interpreted differently across different cultures. Clearly, further studies are necessary to understand the reasons for the between-country heterogeneity observed.

| Strengths and limitations
The use of a large nationally representative dataset of older adults residing in multiple LMICs is a clear strength of the present study.
However, findings must be interpreted in light of the study limitations. First, the study is cross-sectional in nature, and it is thus not known whether pain leads to suicidality or vice versa. For example, it may be hypothesized that injury sustained from a suicide attempt may result in chronic pain. Second, the majority of variables were self-reported, potentially introducing social desirability and recall bias into the findings. Third, the current measure of suicidal ideation was related with wish to die, which has been differentiated from active suicidal ideation. However, a wish to die has been reported to be equally important clinically as the presence of active suicidal ideation. 22 Fourth, suicidal ideation and suicide attempts were only examined in people who endorsed depressive symptoms (i.e., sadness, loss of interest or low energy). This may have resulted in an underestimation of suicidal ideation and suicide attempts, but it is worth noting that depressive symptoms are very frequently observed in suicidal thoughts and behavior. 39 Furthermore, due to this, it was not possible to assess the role of depression or depression severity in the association between pain and suicidal ideation or suicide attempts.

| Conclusion
In this large sample of older adults from multiple LMICs, pain was associated with substantially increased odds for suicidal ideation and suicide attempts, dose-dependently. Future longitudinal or intervention studies that assess the impact of pain management in older adults in LMICs on suicidality are now needed.

This paper uses data from WHO's Study on Global Ageing and Adult
Health (SAGE). SAGE is supported by the U.S. National Institute on Aging through Interagency Agreements OGHA 04034785, YA1323-08-CN-0020, Y1-AG-1005-01 and through research grants R01-AG034479 and R21-AG034263. Dr. Guillermo F. López Sánchez is funded by the European Union -Next Generation EU.