Triple threat combination drugs prove dangerous and costly

High-risk triple threat combination related to higher cost of care

November 30, 2017

What was the study about?

To combat today’s opioid epidemic, we wanted to learn more about members taking the dangerous and increasingly common drug combination known as the triple threat. Triple threat occurs when a member has overlapping prescriptions of:

  • Opioids
  • Benzodiazepines or non-benzodiazepine sedative/hypnotics, and
  • Muscle relaxants

When combined, the synergistic side effects of taking these drugs can cause respiratory depression and may result in death.1

This study looked at the relationship between the number of consecutive triple threat overlapping days and health care utilization and total cost of care.

What did we learn?

Of the 15 million members in the study, 4 per 1,000 had at least one day of triple threat overlap. Nearly 40 percent of that group had eight to 20 days of overlap. The triple threat was associated with increased health care utilization and costs:

  • 32.3 percent had one or more emergency room visits
  • 1.5 percent had one or more hospitalizations
  • 39.7 percent used four or more prescribers

As the number of overlapping days increased, the total cost of care increased.


The study used integrated medical and pharmacy claims data from 13 health plans and 15 million commercially insured members across the United States. Members were enrolled for all of 2013 and 2014. For this study, we did not exclude members with cancer. Members were identified with at least one day of overlapping prescriptions (triple threat) in 2013; the members were then followed throughout 2014.


Members with more than 21 days of concurrent use of all three drugs had a significantly higher total cost of care than members with less than 20 days of concurrent triple threat drug use. Annual mean per member adjusted total cost of care was $3,175 higher for members with more than 31 days compared to less than or equal to 30 days.


The study found at least one day of triple threat overlap for four of 1,000 commercially insured members who were continuously enrolled for two years. Analysis showed higher use of emergency rooms and more hospitalizations for these members.

Kaiser’s annual Survey of Employer-Sponsored Health Benefits supports this research. According to Kaiser, average annual premiums for single coverage for employer-sponsored health insurance are $6,690.2 Less than a week of triple threat overlap can more than triple an individual’s annual cost of care.

What does this mean for you?

Decreasing triple threat overlap impacts the safety, health outcomes and cost of care of commercial members.

Prime’s Controlled Substance Management Program can help plan sponsors identify members on any combination of controlled substance drugs. Programs like the following can assist with interventions:

  • GuidedHealth®
  • Concurrent drug utilization review (DUR)
  • Medication Therapy Management
  • Commercial Medication Therapy Management

Read the study: Controlled Substances Triple Threat Overlapping Days: Relationship with Healthcare Utilization and Costs. April 2016.


1. “The Perfect Storm: Opioid Risks and the Holy Trinity,” by Jeffrey Fudin. Pharmacy Times. September 24, 2014. Pharmacy & Healthcare Communications, LLC. Accessed at:

2. “Employer Health Benefits: 2017 Summary of Findings.” Kaiser/HERT Survey of Employer-Sponsored Health Benefits, 2017. Sept 19, 2017. Kaiser Family Foundation and Health Research and Education Trust. Accessed at:

Controlled Substances Triple Threat Overlapping Days: Relationship with Healthcare Utilization and Costs. April 2016.

Related news


April 19, 2024

AMCP 2024: Behind the Research with Prerak Parikh

Parikh, director of medical pharmacy strategy at Prime/MRx, shares the latest on interchangeable biosimilars


April 19, 2024

LISTEN NOW: Live at AMCP Annual 2024 – Digging into managed care pharmacy insights | Pharmacy Friends podcast

In this episode, Prime/MRx clinicians — along with special guests — discuss the hottest topics covered at the Academy of Managed Care Pharmacy (AMCP)'s 2024 Annual Meeting in New Orleans


April 17, 2024

AMCP 2024: Behind the research with YuQian Liu

Ahead of her session with Andy Killpack, Liu — senior director of specialty clinical solutions at Prime/MRx — shares current care management strategies for cell and gene therapy and the future of this exciting frontier