Clinical Context

Long-term opioid therapy has a potential risk for opioid misuse. One form of misuse is taking the medication for a condition other than that for which it is prescribed, according to the National Institute on Drug Abuse. Another form of misuse is aberrant behavior of giving opioids to others or getting opioids from others, as reported by Smith and colleagues in the November-December 2010 issue of the American Journal on Addictions. In the November-December 2009 issue of Family Medicine, Braker and colleagues described misuse as nonadherence by taking more medication than prescribed or asking for early refills.

Mental health disorders can be a risk factor for opioid misuse, as reported by Sullivan and colleagues in the August 2010 issue of Pain. Substance use disorders are also a predictor of long-term opioid use and misuse, according to Sullivan and colleagues in the October 23, 2006, issue of the Archives of Internal Medicine.

This study by Grattan and colleagues assesses whether depression is associated with opioid misuse in adults receiving long-term opioid therapy who have no history of substance abuse.

Study Synopsis and Perspective

Depressive symptoms appear to raise the risk for opioid misuse in patients with no history of substance use disorders who are receiving long-term opioid therapy, new research suggests.

In a large study, investigators at the University of Washington School of Medicine in Seattle found that depression in the absence of substance abuse is significantly associated with the use of opioids for stress or sleep and with the use of more opioids than prescribed.

"Our study suggests that if depressed patients are not in full remission, they remain at increased risk of opioid misuse," the authors, led by Alicia Grattan, MD, write.

The study is published in the July/August issue of Annals of Family Medicine.

Tackling Opioid Abuse

This article is 1 of a series in the same issue of the journal that investigated opioid use for the management of chronic pain and the rising levels of misuse, overdose, and addiction associated with opioid pain medications.

Although depression may be a risk factor for opioid misuse, "it has been difficult to tease out the contribution of co-occurring substance abuse," Dr. Grattan and colleagues write.

To investigate, they interviewed 1334 patients at 2 of the largest health plans in the United States — Group Health Cooperative (GHC) and Kaiser Permanente of Northern California (KPNC). All of the participants were receiving long-term opioid therapy for noncancer pain, and none had a history of substance abuse.

The patients were asked about 3 forms of inappropriate opioid use: self-medicating for symptoms other than pain; self-increasing their dose; and giving to or getting opioids from other people. Depressive symptoms were evaluated using the 8-item Patient Health Questionnaire (PHQ-8).

For nonpain symptoms, 36.9% of patients without depression (PHQ-8 score, 0 - 4) misused opioids, compared with 40.2% of patients with mild depression (PHQ-8 score, 5 - 9), 47.2% of those with moderate depression (PHQ-8 score, 10 - 14), and 51.8% of those with severe depression (PHQ-8 score, 15 or higher).

Patients with moderate and severe depression were 1.75 (P = .031) and 2.42 (P = .001) times more likely, respectively, to misuse their opioid medications for nonpain symptoms than were nondepressed patients.

Patients with mild, moderate, and severe depression were 1.93 (P < .001), 2.89 (P < .001), and 3.13 (P < .001) times more likely, respectively, to use more opioids than prescribed compared with nondepressed patients.

There was no statistically significant association between depressive symptoms and either giving opioids to others or getting them from others.

These results "begin to clarify the types of opioid misuse associated with depression among patients without SUDs [substance use disorders]," the investigators note.

Self-Medicating for Nonpain Symptoms

Reached for comment, Amanda L. Divin, PhD, assistant professor, Department of Health Sciences, Western Illinois University in Macomb, told Medscape Medical News that the findings "are in line with the idea of patients self-medicating their non-pain symptoms with opioids."

As reported previously by Medscape Medical News, Dr. Divin and her colleagues found evidence that college students may abuse opioid painkillers, sedatives, and other prescription drugs to inappropriately self-medicate for psychological distress.

"The pharmacological properties of opioids make it such that opioids are used for a variety of reasons, such as inducing euphoria (why people may use if depressed), reducing tension, anxiety, and aggression, and inducing a general calming effect (why people may use for depression, anxiety, sleep disturbances, or stress)," said Dr. Divin.

She said a "huge strength" of the new study is that researchers excluded participants with known substance use disorders.

"People with SUDs are known to have higher rates of depression, opioid misuse, nonadherence, and aberrant behaviors. To find these results in a sample of subjects with no known SUDs, to me, strengthens the argument that no one is immune from the potentially dangerous mood-impacting side effects of opioids," Dr. Divin said.

Practical Implications

Echoing Dr. Divin's thoughts, Dr. Grattan and colleagues acknowledge in their article that it is hard to tease out a causal relationship between opioid misuse and depression.

They point out that, historically, opioids have been used to treat psychological distress (mania and melancholia), as well as physical pain, and more recent studies have suggested the use of opioids for treatment-resistant depression and anxiety. It is possible that depressed patients may experience their pain as more severe, which may prompt misuse.

"At this point, it is not clear whether opioids are substituting for, or even disrupting, the appropriate treatment of depression," Dr. Grattan and colleagues say. They emphasize that there is currently no evidence from controlled trials that opioids are adequate treatment for depression.

Dr. Divin believes this study has "several practical implications, which shouldn't be overlooked."

First, she explained, because opioids "can/do have depressant qualities on the body systems (eg, depressed affect, respiration, etc) that mimic signs/symptoms of depression, it's important to differentiate what is causing these changes in mood and behavior; is it using the opioids or is the patient suffering from depression?"

Second, "better tracking of [opioid] refills and refill requests, along with directly discussing with the patient the amount of drug being taken, if/why they are taking more than the amount prescribed, etc, should be done, especially considering the more severe the depression the more likely to use more opioids than prescribed," Dr. Divin said. Regular depression screening of patients on long-term opioid therapy is also needed, she said.

Move to More Conservative Prescribing

In an editorial accompanying the article, Michael Von Korff, ScD, from Group Health Research Institute in Seattle, who worked on the study, notes that the pendulum is swinging in the direction of "more selective and conservative" opioid prescribing, given epidemic levels of drug overdose and addiction involving prescription opioids.

Estimates are that the volume of prescribed opioids increased 600% from 1997 to 2007; during roughly the same period, the number of unintentional lethal overdoses involving prescription opioids increased more than 350%, from approximately 4000 in 1999 to more than 14,000 in 2007.

The coauthors of a second commentary assert that opioids are not appropriate therapy for chronic noncancer pain for most patients in primary care settings because of the power of opioids to do harm and the availability of safer, alternative treatments for chronic pain, including physical therapy, cognitive behavioral therapy, low-dose tricyclic medications, and treatment of co-occurring psychiatric illnesses.

In their article, Roger A. Rosenblatt, MD, MPH, and Mary Catlin, BSN, MPH, both from University of Washington, Seattle, suggest that when other interventions fail or are inadequate, "cautious evidence-based consideration of low-dose opioids as an adjunct to other therapies may be considered."

Yet they remind clinicians that entering into long-term opioid therapy "requires a long-term commitment by clinician and patient alike to use this powerful, precious, and dangerous medication with care and diligence. As clinicians and patients, we need to develop a generous measure of respect for the power of opioids to do harm as well as provide relief from pain."

REMS Approved for Opioids

In April 2011, as reported by Medscape Medical News, the US Food and Drug Administration (FDA) unveiled an opioid education program for prescribers, called the opioid Risk Evaluation and Mitigation Strategy (REMS).

On July 9, as reported by Medscape Medical News, the FDA approved REMS for extended-release and long-acting opioid analgesics in the treatment of moderate to severe chronic pain. The plan requires more than 20 opioid manufacturers to provide continuing education programs on proper use of these drugs, said Margaret Hamburg, MD, commissioner of the FDA, during a press conference.

The study was supported by the National Institute for Drug Abuse. The study authors, editorial writers, and Dr. Divin have disclosed no relevant financial relationships.

Ann Fam Med. 2012;10:302-303,304-311.Abstract, Editorial, Editorial

Clinical Implications

• In adults with no history of substance abuse who require long-term opioid therapy, moderate and severe depressive symptoms are associated with misuse of opioids for nonpain symptoms. Mild, moderate, and severe depressive symptoms are associated with misuse of opioids by self-increasing dose.
• In adults with no history of substance abuse who require long-term opioid therapy, depressive symptoms are not associated with giving opioids to or getting opioids from others.

CME Test