|| Checking for direct PDF access through Ovid
Each year, millions of patients receive prescription opioids in an effort to reduce the suffering associated with chronic pain. Although the effectiveness of long-term opioid therapy has never been convincingly established,5 several of its more serious consequences (including addiction, overdose, and death) are well known and have increased in tandem with the more liberal prescribing of the past 2 decades.5,10However, chronic opioid prescribing on a large scale has also revealed some of the drugs' subtler harms. Opioids are clearly associated with an increased risk of falls, fractures, and motor vehicle collisions; they suppress testosterone in men and can lead to infertility in women; and in some patients, they can paradoxically worsen pain, particularly at high doses.3,5 Converging lines of evidence now suggest that depression—a common comorbidity in the setting of chronic pain—may in some patients represent an unrecognized yet potentially reversible harm of opioid therapy. This possibility bears directly on treatment decisions and the well-being of millions of patients living with chronic pain. We briefly review the emerging evidence suggesting that opioid therapy may be a component cause of depression, and show that the association satisfies many classic elements of causal inference.Endogenous opioids produce analgesia by activating mu, delta, and kappa opioid receptors. Although activation of mu and delta receptors typically imparts a pleasant or euphoric experience, activation of the kappa receptor typically relays dysphoria, a strong correlate of depression23,34 and, behaviorally, an aversive cue. Animal studies demonstrate that endogenous kappa receptor signaling increases with chronic stress or repeated painful stimuli, generating depressive phenotypes accordingly.17Pharmaceutical opioids confer similar effects. Although most currently used opioids are mu receptor–selective, activation of lesser-affinity kappa receptors becomes increasingly relevant during chronic use as tolerance develops and doses escalate over time.24,32 Together with opioid-related modulation of serotonin and dopamine neurotransmission,20 these changes in opioid signaling may predispose to the development of depressive symptoms. In animals, repeated morphine administration produces a depressive phenotype comparable with that of chronic stress.22 In humans, pharmaceutical opioids can impart a wide range of negative subjective effects, including dysphoria after only a single dose.36 Indeed, reductions in gray matter volume in several mood- and reward-regulating brain regions have been observed after only 30 days of morphine therapy.18In a survey of more than 1800 patients receiving chronic opioid therapy, those using high doses (more than 120 mg of morphine or equivalent per day [MED]) were more than twice as likely to be depressed (defined as a Patient Health Questionnaire–8 [PHQ-8] score of 10 or higher), and more likely to attribute their psychosocial difficulties to opioids, relative to those using lower doses.21 Similarly, in a cross-sectional study of nearly 32,000 individuals using opioids, depressive symptoms and antidepressant use were significantly more common among those prescribed more than 120 MED relative to those using lower doses.11 The association between opioid dose and depression has also been observed among patients using lower doses. In a study comparing one group (n = 935) of patients with chronic pain receiving an average dose of 40 mg MED with another group (n = 653) receiving an average of 65 mg MED, the group receiving lower daily doses reported significantly lower depressive symptom scores. Importantly, there were no differences in pain severity, function, or quality of life between groups.33In a cohort of 355 patients with chronic pain, the use of opioids at doses higher than 50 MED was associated with a nearly 3-fold increase (odds ratio 2.65, 95% confidence interval 1.17-5.