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Publication Briefs

Prescription Use of Codeine Associated with Greater Risk of New Onset Depression among Veterans

Evidence supports the conclusion that chronic (>90 day) and sub-chronic (>30 day) prescription opioid analgesic use increases the risk of new onset depression as compared to use for <30 days; however, it is not known whether specific opioid analgesics differ in contributing to this risk. This large, retrospective cohort study sought to determine whether the hazard of new depression diagnosis differs among VA patients prescribed only codeine, only hydrocodone, or only oxycodone. Using VA data, investigators identified 11,462 Veterans who used VA healthcare between 2000 and 2012 and were started and remained on only codeine (n=2,622), only hydrocodone (n=7,225), or only oxycodone (n=1,615) for more than 30 days. The observation period was 2002 to 2012. Depression was defined by two or more outpatient diagnoses within the same 12-month period, or at least one inpatient diagnosis for depression. All patients were free of diagnosed depression for two years prior to baseline, and were free of opioids at baseline. Investigators also measured comorbidities (i.e., PTSD, substance use disorder, diabetes, pain diagnoses and pain scores) and demographics. Access to VA healthcare only vs. VA plus other coverage served as proxy for income.


  • Veterans prescribed only codeine for 30 days or longer had a 29% increased risk of a new diagnosis of depression compared to Veterans prescribed only hydrocodone for 30 days or longer. Those prescribed only oxycodone for 30 days or longer were not significantly more likely to develop a new depression diagnosis compared to patients prescribed hydrocodone only.
  • Opioid use of 30-90 days was most common among oxycodone users, and opioid use of more than 90 days was most common among hydrocodone users.
  • The distribution of individual comorbid conditions did not significantly differ across the three types of opioids. However, PTSD and substance use disorder, including nicotine dependence, were significantly more common among Veterans receiving oxycodone.
  • Significant differences in the distribution of co-variates by type of opioid were removed following weighting and use of propensity scores.

    • Patients and clinicians should consider the elevated risk of new onset depression in all chronic opioid use and might consider additional risk associated with the use of codeine for more than 30 days. Also, patients using any of the three opioids examined in this study should be routinely screened for depression at the start and during the course of opioid therapy.


    • There was a lack of data on adherence, thus investigators were unable to confirm whether opioids were taken as prescribed.
    • Higher than national average prevalence of PTSD and other psychopathology among Veterans likely increases risk of depression, which may reduce the ability to detect the association between opioid use and depression. Thus, the estimate of risk of depression may be conservative.

    Dr. Scherrer is a former HSR&D Career Development Awardee; he and Ms. Salas are part of the Harry S. Truman Memorial VA Hospital in Columbia, MO. Dr. Copeland is part of the Central Texas Veterans Health Care System.

    PubMed Logo Scherrer J, Salas J, Bucholz K, et al. New Depression Diagnosis Following Prescription of Codeine, Hydrocodone or Oxycodone. Pharmacoepidemiology and Drug Safety. March 22, 2016;e-pub ahead of print.

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What are HSR Publication Briefs?

HSR requires notification by HSR-funded investigators about all articles accepted for publication. These journal articles are reviewed by HSR and publication briefs or summaries are written for a select number of articles that are then forwarded to VHA Central Office leadership to keep them informed about important findings or information. Articles to be summarized are selected by HSR based on timeliness of the findings, interest of leadership, or potential impact on the organization. Publication briefs are written for only a small number of HSR published articles. Visit the HSR citations database for a complete listing of HSR articles and presentations.

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