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.5,10
However, 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.17
Pharmaceutical 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.18
3. Opioids and depression
3.1. Opioids exhibit a dose-dependent association with depression
In 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.33
In 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 1.17-5.98) in the risk of depression relative to patients with chronic pain not using opioids.28 In another study of 43 burn patients, a higher cumulative opioid dose was associated with more severe depressive symptoms 2 weeks after injury, independent of burn severity.13
The risk of opioid-related depression may also be influenced by the rate of dose escalation. Among more than 7000 new opioid users without depression, those in the highest quartile of dose escalation were 58% (hazard ratio 1.58, 95% confidence interval 1.30-1.93) more likely to develop depression than those whose doses remained stable. Those whose doses escalated more slowly were 22% (hazard ratio 1.22, 95% confidence interval 1.06-1.42) more likely to develop depression than those who remained on stable doses.25 Importantly, these trends were independent of pain intensity or history of substance abuse.
Not all studies have linked opioids with incident depression. In a cohort of more than 1200 patients with chronic pain, depressive symptom severity did not increase over 12 months of opioid therapy, and there was no difference in symptom severity between high- and low-dose users. However, 20% of patients who discontinued opioid therapy did so because of intolerable emotional effects,35 consistent with the possibility that opioids can sometimes adversely influence mood.
3.2. Prolonged opioid therapy is associated with depression
In a cross-sectional study of nearly 5400 individuals with chronic low back pain, those filling opioid prescriptions more frequently throughout the year (more than 12 prescriptions per year vs 2-12 prescriptions per year vs 1 or fewer prescriptions per year) were more likely to have higher depressive symptom scores on the PHQ-2.31
Longitudinal studies strongly suggest that depression may be a direct consequence of opioid therapy. In 3 cohorts involving more than 100,000 patients, 9% to 12% developed new-onset depression (defined using ICD-9-CM criteria) within 30 days of initiating opioid therapy.26 Moreover, the incidence of depression in those cohorts increased with longer duration of opioid therapy. Relative to patients treated with opioids for 30 days or less, those treated for 90 days were up to 33% (hazard ratio 1.33, 95% confidence interval 1.16-1.52) more likely to develop depression, whereas those treated for more than 90 days were more than twice (hazard ratio 2.05, 95% confidence interval 1.75-2.40) as likely to develop depression. In another study combining 2 independent cohorts of more than 6200 patients with depression in remission, the risk of a recurrent depressive episode was doubled (hazard ratio 2.17, 95% confidence interval 2.01-2.34) among those initiating opioid therapy relative to those who remained opioid-free.27 Moreover, in a cohort of nearly 2000 patients with polyneuropathy, those using opioids for 90 days or longer were 53% (hazard ratio 1.53, 95% confidence interval 1.29-1.82) more likely to be depressed than those using opioids for less than 90 days.12 Again, these studies found that the associations between opioid therapy and new-onset or recurrent depression were independent of pain and other factors that might play a causal role.
3.3. Opioids predispose to antidepressant failure
Initiation of opioid therapy is associated with failure of first-line antidepressant interventions. In a cohort of more than 6000 patients with depression, nearly 1 in 5 required intervention with electroconvulsive therapy, a monoamine oxidase inhibitor, concomitant use of more than one conventional antidepressant, or augmentation with a mood stabilizer or atypical antipsychotic within 30 days of commencing opioid therapy. The need for alternative or augmentative therapy was further increased in patients using opioids for a longer duration, a finding again independent of several pain indicators.30
3.4. Opioid dose reduction may improve depressive symptoms
The notion that opioids might contribute to depression is further supported by the observation that patients with depression in the setting of high-dose opioid therapy might benefit from a controlled reduction in dose. In a small study of 16 patients with chronic pain using an average dose of 945 mg MED, a gradual dose reduction of roughly 70% over 17 weeks was associated with a significant decrease in depressive symptom severity (from an average of 13.5-9.5 on the PHQ), with no accompanying increase in pain intensity.15
Emerging evidence suggests that the association between opioids and depression satisfies many of the classic elements of causal inference (Table 1). Collectively, these findings accord with evidence from clinical trials that antagonists of mu and kappa opioid receptors, such as the combination of buprenorphine and samidorphan, are associated with improvement in depressive symptoms.8 These findings also support the possibility that opioids may in some cases contribute to suicide, an association that has been strongly suggested,1,14 but for which there is insufficient evidence to infer causation. Conversely, euphoria is a well-documented result of acute mu opioid receptor activation, and clinical studies using mu receptor agonists (such as tianeptine) have demonstrated antidepressant effects.16 Although depression may of course have other etiologies (including chronic pain itself and the psychosocial factors associated with it19) and many patients receiving opioids do not develop depression, the available evidence supports the notion that opioid therapy may in some patients lead to the development or worsening of depression.
Although nearly all the included studies controlled for pain intensity, the possibility exists that the known relationship between pain and depression6 could confound the observed relationship between opioids and depression. It has also been shown that depression is associated with an increased risk of opioid use and dose escalation.2 To account for this, we excluded studies that included patients diagnosed with depression before opioid initiation. Despite this, it is possible that the development of depression after initiating opioid therapy was confounded in part by other patient factors predictive of opioid use and dose escalation. Future research to clarify the pharmacological and clinical relationships between opioids, pain, and depression is warranted.
The prescribing of opioids for chronic pain is often viewed as a compassionate intervention. The paucity of evidence supporting the practice and the addition of depression to an already long list of potential yet subtle harms invites reconsideration of the overall merits of chronic opioid therapy. Although some have argued that withholding opioids may exacerbate pain and worsen depression in patients with chronic pain, this is at odds with several studies showing reduction in pain and improvement in function after transition from chronic opioid therapy to interdisciplinary nonopioid pain management.9 Indeed, managing opioid-induced depression with optimized antidepressant therapy seems to facilitate opioid cessation.29 We suggest that for patients with depression who are receiving chronic opioid therapy, particularly at high doses, a cautious, gradual taper4,7 under close medical supervision should be entertained in light of the possibility that depressive symptoms may represent an occult but reversible adverse effect of treatment.
Conflict of interest statement
M.D. Sullivan and D.N. Juurlink are members of Physicians for Responsible Opioid Prescribing (PROP; www.supportprop.org/), a volunteer organization with the goal of promoting safer opioid prescribing. D.N. Juurlink has received payment for lectures and expert testimony related to opioids.
. Braden JB, Edlund MJ, Sullivan MD. Suicide deaths with opioid poisoning in the United States: 1999-2014. Am J Public Health 2017;107:421–6.
. Braden JB, Sullivan MD, Ray GT, Saunders K, Merrill J, Silverberg MJ, Rutter CM, Weisner C, Banta-Green C, Campbell C, Von Korff M. Trends in long-term opioid therapy for noncancer pain among persons with a history of depression. Gen Hosp Psychiatry 2009;31:564–70.
. Brush DE. Complications of long-term opioid therapy for management of chronic pain: the paradox of opioid-induced hyperalgesia. J Med Toxicol 2012;8:387–92.
. Busse JW, Craigie S, Juurlink DN, Buckley DN, Wang L, Couban RJ, Agoritsas T, Akl EA, Carrasco-Labra A, Cooper L, Cull C, da Costa BR, Frank JW, Grant G, Iorio A, Persaud N, Stern S, Tugwell P, Vandvik PO, Guyatt GH. Guideline for opioid therapy and chronic noncancer pain. Can Med Assoc J 2017;189:E659–E666.
. Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, Dana T, Bougatsos C, Deyo RA. The effectiveness and risks of long-term opioid for chronic pain: a systematic review for the national institutes of health pathways to prevention workshop. Ann Intern Med 2015;162:276–86.
. de Heer EW, Ten Have M, van Marwijk HWJ, Dekker J, de Graaf R, Beekman ATF, van der Feltz-Cornelis CM. Pain as a risk factor for common mental disorders. Results from The Netherlands Mental Health Survey and Incidence Study-2: a longitudinal population-based study. PAIN 2018;159:712–18.
. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep 2016;65:1–49.
. Fava M, Memisoglu A, Thase ME, Bodkin JA, Trivedi MH, de Somer M, Du Y, Leigh-Pemberton R, DiPetrillo L, Silverman B, Ehrich E. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry 2016;173:499–508.
. Frank JW, Lovejoy TI, Becker WC, Morasco BJ, Koenig CJ, Hoffecker L, Dischinger HR, Dobscha SK, Krebs EE. Patient outcomes in dose reduction or discontinuation of long-term opioid therapy: a systematic review. Ann Intern Med 2017;167:181–91.
. Harned M, Sloan P. Safety concerns with long-term opioid use. Expert Opin Drug Saf 2016;15:955–62.
. Hauser W, Schubert T, Scherbaum N, Tolle T. Guideline-recommended vs high-dose long-term opioid therapy for chronic noncancer pain is associated with better health outcomes: data from a representative sample of the German population. PAIN 2018:159;85–91.
. Hoffman EM, Watson JC, St Sauver J, Staff NP, Klein CJ. Association of long-term opioid therapy with functional status, adverse outcomes, and mortality among patients with polyneuropathy. JAMA Neurol 2017;74:773–9.
. Hong N, Jung MH, Kim JW, Chun W, Choi IG, Kang TC, Kee BS, Lee BC. Opioid analgesics and depressive symptoms in burn patients: what is the real relationship? Clin Psychopharmacol Neurosci 2016;14:295–8.
. Juurlink DN, Herrmann N, Szalai JP, Kopp A, Redelmeier DA. Medical illness and the risk of suicide in the elderly. Arch Intern Med 2004;164:1179–84.
. Kalra R, Zak K, Chopra T. Safe and effective high-dose opioid reduction guideline. Las Vegas: PAINWeek; 2013:Abstract 45.
. Kasper S, Olie JP. A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the short-term treatment of depression. Eur Psychiatry 2002;17(suppl 3):331–40.
. Knoll AT, Carlezon WA Jr. Dynorphin, stress, and depression. Brain Res 2010;1314:56–73.
. Lin JC, Chu LF, Stringer EA, Baker KS, Sayyid ZN, Sun J, Campbell KA, Younger JW. One month of oral morphine decreases gray matter volume in the right amygdala of individuals with low back pain: confirmation of previously reported magnetic resonance imaging results. Pain Med 2016;17:1497–504.
. Lumley MA, Cohen JL, Borszcz GS, Cano A, Radcliffe AM, Porter LS, Schubiner H, Keefe FJ. Pain and emotion: a biopsychosocial review of recent research. J Clin Psychol 2011;67:942–68.
. Lutz PE, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosciences 2013;36:195–206.
. Merrill JO, Von Korff M, Banta-Green CJ, Sullivan MD, Saunders KW, Campbell CI, Weisner C. Prescribed opioid difficulties, depression and opioid dose among chronic opioid therapy patients. Gen Hosp Psychiatry 2012;34:581–7.
. Molina VA, Heyser CJ, Spear LP. Chronic variable stress or chronic morphine facilitates immobility in a forced swim test: reversal by naloxone. Psychopharmacology 1994;114:433–40.
. Mukaetova-Ladinska EB, Steel M, Coppock M, Cosker G, James P, Scully A, McNally RJ. Dysphoria is a risk factor for depression in medically ill older people. Int J Geriatr Psychiatry 2016;31:1233–40.
. Peckham EM, Traynor JR. Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague-Dawley rats. J Pharmacol Exp Ther 2006;316:1195–201.
. Salas J, Scherrer JF, Schneider FD, Sullivan MD, Bucholz KK, Burroughs T, Copeland LA, Ahmedani BK, Lustman PJ. New-onset depression following stable, slow, and rapid rate of prescription opioid dose escalation. PAIN 2017;158:306–12.
. Scherrer JF, Salas J, Copeland LA, Stock EM, Ahmedani BK, Sullivan MD, Burroughs T, Schneider FD, Bucholz KK, Lustman PJ. Prescription opioid duration, dose, and increased risk of depression in 3 large patient populations. Ann Fam Med 2016;14:54–62.
. Scherrer JF, Salas J, Copeland LA, Stock EM, Schneider FD, Sullivan M, Bucholz KK, Burroughs T, Lustman PJ. Increased risk of depression recurrence after initiation of prescription opioids in noncancer pain patients. J Pain 2016;17:473–82.
. Scherrer JF, Salas J, Lustman PJ, Burge S, Schneider FD. Change in opioid dose and change in depression in a longitudinal primary care patient cohort. PAIN 2015;156:348–55.
. Scherrer JF, Salas J, Sullivan MD, Ahmedani BK, Copeland LA, Bucholz KK, Burroughs T, Schneider FD, Lustman PJ. Impact of adherence to antidepressants on long-term prescription opioid use cessation. Br J Psychiatry 2018;212:103–11.
. Scherrer JF, Salas J, Sullivan MD, Schneider FD, Bucholz KK, Burroughs T, Copeland L, Ahmedani B, Lustman PJ. The influence of prescription opioid use duration and dose on development of treatment resistant depression. Prev Med 2016;91:110–16.
. Smith JA, Fuino RL, Pesis-Katz I, Cai X, Powers B, Frazer M, Markman JD. Differences in opioid prescribing in low back pain patients with and without depression: a cross-sectional study of a national sample from the United States. Pain Rep 2017;2:e606.
. Stoller DC, Sim-Selley LJ, Smith FL. Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats. Brain Res 2007;1142:28–36.
. Thakral M, Walker RL, Saunders K, Shortreed SM, Parchman M, Hansen RN, Ludman E, Sherman KJ, Dublin S, Von Korff M. Comparing pain and depressive symptoms of chronic opioid therapy patients receiving dose reduction and risk mitigation initiatives with usual care. J Pain 2018;19:111–20.
. van Loo HM, Cai T, Gruber MJ, Li J, de Jonge P, Petukhova M, Rose S, Sampson NA, Schoevers RA, Wardenaar KJ, Wilcox MA, Al-Hamzawi AO, Andrade LH, Bromet EJ, Bunting B, Fayyad J, Florescu SE, Gureje O, Hu C, Huang Y, Levinson D, Medina-Mora ME, Nakane Y, Posada-Villa J, Scott KM, Xavier M, Zarkov Z, Kessler RC. Major depressive disorder subtypes to predict long-term course. Depress Anxiety 2014;31:765–77.
. Von Korff M, Shortreed SM, LeResche L, Saunders K, Thielke S, Thakral M, Rosenberg D, Turner JA. A longitudinal study of depression among middle-aged and senior patients initiating chronic opioid therapy. J Affect Disord 2017;211:136–43.
. Zacny JP, Lichtor SA. Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers. Psychopharmacology 2008;196:105–16.