Prevalence of Central Nervous System Polypharmacy and Associations with Overdose and Suicide-Related Behaviors in Iraq and Afghanistan War Veterans in VA Care 2010–2011

Polypharmacy and CNS polypharmacy specifically has been examined in older individuals and has been identified as a risk factor for adverse drug events [26, 27]. This has not been examined broadly in younger adults, possibly because they generally receive fewer medications, have adequate hepatic metabolism and renal clearance, and are less sensitive to CNS-acting medications such as opioids, benzodiazepines, and antipsychotics [9, 28‐31]. Our findings of relatively high polypharmacy are surprising given the young age of this cohort. However, evaluation of the co-morbidity profiles suggest that multimorbidity may explain the high rates of polypharmacy in IAVs, who have been identified as a patient population with a high prevalence of TBI, PTSD, and pain (also known as the polytrauma clinical triad (PCT) [14, 32, 33]. Recent studies have found that depression and headaches are also highly prevalent and co-morbid with PTSD and TBI in IAVs [34‐36]. Pharmacotherapy for these conditions and associated symptoms typically consists of CNS-acting medications as recommended by the VA/DoD treatment guidelines [17‐20]. Since treatment guidelines are usually aimed at treating specific conditions, multimorbid patients are more likely to receive multiple CNS-acting medications, each indicated by a separate guideline. Each medication is appropriate in isolation but in combination CNS drugs may increase the risk for adverse drug effects and events. Management of the chronic conditions examined in this study relies heavily on evidence-based therapies [37]; however, multimorbidity may challenge the determination of a best practice approach. Additional research is needed to better understand how CNS polypharmacy may be the result of interplay between guidelines for co-morbid conditions and problems with coordination of care.

Recent public attention has focused on improving treatment for IAVs with psychiatric, pain, and SUD, particularly related to reducing risk for substance abuse, medication burden, and drug overdose [38]. Bohnert et al. [39] found accidental overdose to be associated with both psychiatric and SUDs. SUDs, and specifically opioid use disorders, carry the highest risk of accidental overdose. Recent work by Finley et al. [15] demonstrated that Veterans with SUD or combinations of PCT conditions (especially co-morbid PTSD + depression) were more likely to have diagnoses for SRB. However, to our knowledge, this is the first systematic study to examine the association of adverse outcomes among IAVs receiving multiple CNS-acting medications. Our work shows that even after controlling for all other diagnosed co-morbidities, CNS polypharmacy was independently associated with drug/alcohol overdose and SRB. This may be due to pharmacodynamic drug interactions, concomitant use of these medications with other substances such as alcohol, or merely an artifact of treating patients with multimorbidity. If the latter, the significant association may be an indicator of disease severity that can be used clinically to identify at-risk individuals and refer them to interdisciplinary specialty care.

Given the multimorbidity of this population, vigilance and organization of care is vital to avoid harmful drug interactions and to improve patient outcomes [29]. In a study examining poly-sedative prescribing among Veterans over 8 years, 78 % of the dual opioid-benzodiazepine prescriptions were written by separate providers [10], suggesting that suboptimal coordination of care in conjunction with multiple guidelines for care may lead to suboptimal prescribing, including high severity drug interactions and possible unintentional drug overdose [39].

The unprecedented rise of unintentional drug overdose in the US population [5] coupled with our findings related to CNS polypharmacy highlights the need for applicable evidence-based strategies that healthcare providers can use to effectively manage potential risks associated with CNS polypharmacy in Veterans and the general population. Our study uses five or more dispensed CNS medications in assessing risk of adverse events. It is possible that this, or potentially less rigorous criteria, could be used as a guideline for healthcare providers when evaluating patients with multiple CNS-acting medications. Further research is needed to determine if CNS polypharmacy could be used as an effective screening tool to identify patients whose treatment plan may need refinement in order to prevent overdose, SRB, and other adverse events and outcomes.

Our study has several limitations. First, our definition of CNS polypharmacy (five or more prescribed CNS medications) may be considered conservative compared to studies in elderly adults using two or more CNS drugs [16], and Bernardy et al.’s [10] criteria of three or more sedative classes. However, given that nearly 9 % of the cohort met our CNS polypharmacy measure, we believe this is a clinically relevant threshold that may be used to identify individuals at risk of adverse outcomes. Our data did not examine the simultaneous use of medications, dosing, adherence, or whether medications were scheduled or used as needed. More detailed analysis including attention to concomitant drug use, specific co-prescribed medications, and dose is needed to determine if particular classes of medications are more closely associated with these adverse events.

In addition, ICD-9 codes were used to identify suicidal ideation and attempts, which results in a conservative assessment of SRB as data on completed suicides were not available. Information on severity of ideation or the lethality of any suicide attempt was not available. Our analysis also does not take into account severity of associated co-morbidities so we do not know how the severity of a condition affects CNS polypharmacy, overdose, or suicide-related behavior in our cohort. This may be relevant for some conditions such as TBI where studies with more clinically rich data indicate that TBI severity may play a role in suicide risk [9, 40]. Lastly, the study examined associations in cross-sectional data. An examination of the timing of each CNS medication and the adverse outcomes was too complex for this ‘signal finding’ study; therefore, causality and directionality of identified correlates cannot be determined. However, these findings indicate that a more complex assessment of CNS polypharmacy is needed; these studies would include: different definitions of CNS polypharmacy; determination of whether specific CNS medications are more important than others when considering this problem; and timing between CNS polypharmacy and outcomes.