Among people with polypharmacy, five high-risk medication patterns—a RAAS inhibitors cluster, a mental health drugs cluster, a CNS drugs cluster, a RAAS inhibitors and antithrombotics cluster, and an antithrombotics cluster—were identified using an agglomerative hierarchical clustering method. Over the 6-year follow-up, the mental health drugs cluster showed increased risk of all-cause mortality (HR = 1.55) and CVD mortality (SHR = 2.11) compared with the CNS drugs cluster, while none of the other medication patterns (single or combined use of RAAS inhibitors and antithrombotics) showed differences in mortality. Apart from medications for mental illness and CVD, the mental health drugs cluster also had a higher prevalence of opioids (33.2% versus 18.6%) and muscle relaxants (21.5% versus 4.4%) than the CNS drugs cluster. These findings suggest that older adults with polypharmacy who take medication for mental disorders (primarily antidepressants), opioids, and muscle relaxants have added risks of all-cause and CVD mortality when their polypharmacy status is positively associated with mortality. The robustness of the main findings was largely confirmed by the sensitivity analyses; the reliability of the significant associations could be assured by the estimated adequate power.
The mechanisms that account for the increased risk of mortality with mental health drugs, opioids, and muscle relaxants among people with polypharmacy may potentially involve drug-drug interactions or comorbidities. Antidepressants that include tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin and norepinephrine reuptake inhibitors have shown many pharmacokinetic and pharmacodynamic interactions with other medications, and some of these are of clinical significance, such as serotonin syndrome . For example, antidepressants in combination with fentanyl (long-acting opioids) or lithium (antimanic agents) are likely to promote serotonin syndrome. Older people on antidepressants have also been confirmed to have a higher number of comorbidities; therefore, a higher proportion of people have at least one potential treatment conflict between other conditions (e.g. CVD and arthritis or pain management) and antidepressants .
Similarly, major potential drug-drug interactions between opioids and other medications have been reported where opioids are frequently prescribed with antifungal agents, antibiotics, CCBs, antiarrhythmics, SSRIs, or anticonvulsants for chronic pain opioid users . In the mental health drugs cluster, 33.2% were opioid users, and such interactions could have had a major clinical influence. Opioid prescription at discharge from hospital has also been found to be related to the greater illness burden (i.e. higher multimorbidity severity) among hospitalised older people . In addition, a study of breast cancer survivors provided a link between mental disorders and opioid use, implying that this association might be present among older adults as well .
There are also concerns about drug-drug interactions with muscle relaxants, including quinine, diazepam, and baclofen . However, there has been no systematic discussion of the drug-drug interactions of muscle relaxants because they include diverse drug classes. Both opioids and muscle relaxants are commonly prescribed for pain management, and they both simultaneously showed the highest prevalence in the mental health drugs cluster. To summarise, the use of antidepressants and opioids may lead to clinically important drug-drug interactions and treatment conflicts with conditions. This situation is likely to be more complicated and unpredictable for older adults with polypharmacy and may account for the increased mortality in the mental health drugs cluster.
Although exclusively long-term medications were considered to define polypharmacy, the medications were taken not only for conditions (e.g. antihyperglycemic agents) but also for symptoms (e.g. pain relief), including over-the-counter medications, as shown in Additional file 1: Table S1. The purpose of this study was to reflect the concurrent medications used in a real-life manner instead of limiting them to prescribed medications, and to identify the patterns of high-risk medications that would affect the risk of mortality. Given the complexity of polypharmacy, medication adherence is another concern because the omission of essential medications may influence subsequent health outcomes (i.e. mortality). Polypharmacy has been found to negatively affect medication adherence among older adults [48, 49], with various barriers to adherence reported that include patient-related factors (e.g. health literacy), drug-related factors (e.g. adverse effects), the patient-provider relationship, difficulties of obtaining medications, and the use of non-prescription medications [48, 50].
Comparison with existing literature
To our knowledge, this was the first study to investigate the association between high-risk medication patterns and mortality among older adults with polypharmacy; thus, direct comparisons with previous studies are difficult to make.
In the literature, only all-cause mortality has been widely explored, rather than cause-specific mortality. The finding concerning the relationship between mental health drugs and mortality is supported by the literature [16, 51, 52], although some studies have focused on exposure to antipsychotics in schizophrenia patients  or older adults with dementia . The finding that opioids are associated with higher mortality is also in line with previous literature [16, 17, 53], including samples of people with chronic non-cancer pain [16, 53] or at least one hospitalisation during the study period . However, some differences between this study and the previous literature can be observed. The use of muscle relaxants was linked to increased mortality in this study, while previous studies have shown a lower risk . Also, this study did not find an association between anticholinergics and mortality as Sevilla-Sanchez et al.’s research , whereas the use of anticholinergics has shown a higher risk of mortality in previous studies [13,14,15]. The difference in the medication classifications used may explain the lack of association in this study. This study adopted 14 high-risk medication categories based on their pharmacological mechanisms (e.g. antidepressants and the remaining anticholinergics), whereas the anticholinergic cognitive burden scale in the literature has included wide-ranging drug classes such as paroxetine (an antidepressant), fentanyl (an opioid), and nifedipine (a CCB) .
Strengths and limitations
This study had several strengths. First, the medication profiles were collected by nurses rather than self-reported by participants, and they were used to verify the self-reported health conditions. This verification and collection process helped to reduce reporting bias. Second, a rigorous definition of polypharmacy was chosen that included medications in long-term use and excluded the temporary use of painkillers. Third, over-the-counter medications for long-term conditions were also included, since some interactions between over-the-counter and prescribed medications might be a concern. Fourth, the study employed a nationally representative sample followed up for 6 years, for whom comprehensive characteristics were available ranging from socio-demographic characteristics to health status. Fifth, a wider range of potential confounders was adjusted for statistically than in previous research, including cognitive function, mobility impairment, lifestyle factors, and depressive symptoms. Lastly, this study used advanced statistical techniques—cluster analysis and survival analysis—to investigate the association between high-risk medications and mortality. The adoption of cluster analysis allows researchers to take concurrent medications into account, which is different from traditional analyses using separate models for each drug class. Concurrent medications are complicated among older adults with polypharmacy and may interact with other medications and further influence mortality. Competing-risks analysis was used for cause-specific mortality to take account of the event of interest and competing events simultaneously, and thus, the estimates should be more accurate .
Some limitations of this study should also be acknowledged. Information was collected during the nurse visits on medication type but not on duration, dose, or frequency. These factors are likely to be important in determining whether polypharmacy has adverse effects. For example, specific medications at high doses may impact mortality markedly, as in the case of opioids that have been identified as particularly problematic in the polypharmacy guidance from the Scottish government . Furthermore, the collection of medication information was made at a single time point, and the medicines may have changed over the follow-up period. Although this study employed a rigorous definition of long-term medications and broad medication categories that included one or more drug classes to minimise the bias caused by the change in the medications, unmeasured time bias could not be avoided . Also, the effectiveness of the medications could not be assessed due to the nature of one-time collection and a lack of information. Moreover, the exclusion (i.e. cancer patients) and attrition of the study sample might have limited the representativeness of this study, even though the supplementary analysis suggested this was not the case. Lastly, the lack of a significant association between cause-specific mortality and the medication patterns might be due to low statistical power, attributable to the small number of deaths.
Implications for clinical practice
NHS England’s medication review service is in transition at the moment, moving away from the medicines use reviews (MURs) commissioned from community pharmacies and towards enhanced ‘structured medication reviews’ carried out by clinical pharmacists . In addition to people with polypharmacy and heightened polypharmacy who are advised to have medication reviews according to NICE , and NHS England  and Scottish government guidance , respectively, this study provides more information on high-risk medications that contribute to increased mortality among older people with polypharmacy. The results of this study somewhat confirm the effectiveness of MURs that were introduced in 2005 and ended in the 2020–2021 financial year . One of the target groups for MURs is patients who take high-risk medicines, including NSAIDs, anticoagulants, antiplatelets, and diuretics , and none of them showed an association with increased mortality in this study. Furthermore, some medication use has been highlighted in the polypharmacy guidance issued by the NHS England and NHS Scotland. The service model of structured medication reviews proposed by the NHS England includes addictive pain management drugs (e.g., opioids) , while the Scottish government has set up a long list of high-risk medications . In the list of high-risk medications, no mental health drugs or muscle relaxants are discussed except for lithium, but opioids at high doses and in long-term use are emphasised. This study supports the inclusion of opioids in the current guidance, but it also suggests that older adults with polypharmacy who take mental illness medications and muscle relaxants are prone to suffer from adverse outcomes and therefore may need more attention. These results are expected to provide more evidence to improve the service model of structured medication reviews, contributing to early intervention for older adults with polypharmacy and on specific medications. Early intervention in medication use, such as the close monitoring of specific medications and regular medication reviews, would ensure treatment appropriateness and medication optimisation, reduce polypharmacy-related problems such as adverse effects, drug-drug interactions, and redundant medications, and potentially bring clinical benefits to older people with polypharmacy.