Key points

Introduction

A classic element of multiple sclerosis (MS) is the presence of multiple symptoms that impact functioning. In prior reviews, the authors have commented on the significance of individual problems, specifically pain and depression, reporting on prevalence rates and outlining recommendations for the treatment of each one individually. The reality, however, is that these problems often co-occur and likely have bidirectional effects, with each amplifying the other. The purpose of this article is to summarize the theory and existing literature on the comorbidity of pain and depression and describe how their presence impacts individuals with MS. Additionally, the article discusses how existing treatments for pain and depression could be adapted to address shared mechanisms and overcome barriers to treatment utilization.

Introduction

A classic element of multiple sclerosis (MS) is the presence of multiple symptoms that impact functioning. In prior reviews, the authors have commented on the significance of individual problems, specifically pain and depression, reporting on prevalence rates and outlining recommendations for the treatment of each one individually. The reality, however, is that these problems often co-occur and likely have bidirectional effects, with each amplifying the other. The purpose of this article is to summarize the theory and existing literature on the comorbidity of pain and depression and describe how their presence impacts individuals with MS. Additionally, the article discusses how existing treatments for pain and depression could be adapted to address shared mechanisms and overcome barriers to treatment utilization.

Prevalence of pain, depression, and their comorbidity

Several prior studies have reported that pain and depression are both common in individuals with MS. For example, 50% of the people with MS in clinical samples are reported to experience chronic pain at any one point in time. In a community sample of people with MS and pain, 75% reported experiencing some pain and 40% reported an average pain severity of 3 or greater on a scale of 0 to 10, which is understood to be pain of at least moderate intensity in people with MS. In another community sample of people with MS and pain, 25% described their pain as severe.

The 12-month prevalence of major depressive disorder in people with MS is about twice that of the general population (15.7% vs 7.4%, respectively). The lifetime prevalence of depressive disorders in MS is 2 to 3 times that of the general population. Many people with MS, as high as 50% at any one time, experience depressive symptoms that may not always reflect a clinical diagnosis of a mood disorder but are nonetheless clinically significant.

Although many studies described the associations between pain and depressive symptoms in individuals with MS, few have reported on the prevalence of their co-occurrence. A recent study using varying criteria to identify depression and pain in a community sample of people with MS reported that pain and depression co-occurred in 6% to 19% of the sample, depending on which criteria for pain and depression were used. Pain was experienced by 86% to 100% of people meeting depression criteria, and pain of moderate severity was experienced by 67% to 77% of people meeting depression criteria. In contrast, 11% to 34% of people experiencing any pain met depression criteria and 15% to 37% of people experiencing pain of at least moderate severity met criteria for clinical depression. In a prior study of a community sample of people with MS, 53% of the people with pain reported having clinically significant levels of depressive symptoms.

Amplifying effects of pain and depression on one another

Prior MS research has reported high associations between pain and depression, such that higher pain is associated with worse depressive symptoms. This finding suggests the possibility that the presence of one condition amplifies the presence or severity of the other. Indeed, cross-sectional studies in MS and longitudinal studies in the general population have shown that chronic pain is a risk factor for subsequent depression; similarly, depression is a risk factor for chronic pain. At the same time, a substantial percentage of individuals with MS have only pain or depression, suggesting that there may be both overlapping and unique aspects of the two conditions.

When looking at studies in this area in individuals who do not have MS, the evidence is mixed regarding whether pain has a larger impact on depression than depression has on pain. For example, an earlier review of 191 studies examining the association between pain and depression in a large variety of patient and nonpatient samples reported consistent support for the consequence hypothesis (depression is influenced by the presence or severity of chronic pain) and inconsistent support for the antecedent hypothesis (depression precedes pain). A recent longitudinal study of 95 adolescents diagnosed with chronic pain or depression reported evidence for a bidirectional association between depression and pain, although the impact of pain on depression was stronger than the impact of depression on pain. In contrast, a study of 500 primary care patients with chronic musculoskeletal pain demonstrated that the two had an equally adverse impact on the other. In their sample, change in severity of either depression or pain predicted a change in severity of the other symptom over time. Longitudinal research tracking pain and depression in people with MS would illuminate the nature and consequences of their relationships over time.

In the research literature outside of MS, researchers have suggested several reasons why pain and depression co-occur and why the presence of either pain or depression makes the other more likely. In terms of pathophysiology, prior reviews of depression and pain have noted that central nociceptive and affective pathways overlap, which supports the understanding that chronic pain is modulated centrally. The experience of depressive symptoms and pain also share underlying neurotransmitters, with both norepinephrine and serotonin implicated in mood disorders and in the processing of pain. Beyond pathophysiology, there are potential psychological and behavioral reasons that pain and depression may amplify one another. For example, depressive symptoms have been found to impact the evaluative and affective aspects of pain and pain-related disability. Pain often impacts the extent to which individuals engage in physical activity, which can limit an individual’s participation in activities that were previously valued or enjoyed and, thus, puts the individual at risk for low mood. Although it is highly likely that these same mechanisms play a role in individuals with MS, additional research is needed to understand the importance of these mechanisms and to understand whether additional, unique factors may also be implicated in the MS population.

Overlapping impact of pain and depression on functioning and quality of life

Depression and chronic pain have a significant negative impact on individuals living with MS. Major depression is associated with poorer neuropsychological functioning, lower quality of life, increased time lost from work, social disruption, and poorer health. Chronic pain in MS has been associated with poorer health-related quality of life, including greater interference with daily activities, energy/vitality, mental health, and social functioning. Depression and pain have been linked to higher risk for unemployment ; both are also thought to affect fatigue negatively, another common and often disabling symptom of MS. For example, people with MS and clinically significant depressive symptoms are 6.2 times more likely to have disabling fatigue than nondepressed controls with MS. Studies in MS have highlighted that higher levels of depressive symptoms and pain are associated with lower quality of life independent of other confounding symptoms. Furthermore, research in other medical populations has shown that pain and depression have a reciprocal and additive adverse impact on quality of life and disability.

Depression and pain may also impact the ability of a person with MS to self-manage their condition and its effects on daily life. Depression is thought to affect self-management through its adverse effects on energy, motivation, concentration, self-efficacy, and interpersonal interactions. For example, a meta-analysis found that people with depression and chronic medical illness had a 3-fold higher rate of nonadherence to self-care regimens compared with nondepressed controls. Consistent with these findings, depression has been associated with a decreased ability to manage MS symptoms, including adherence to disease-modifying medications. Individuals with MS and chronic pain are also more likely to be inactive and to report lower self-efficacy for managing their MS, including pain. The extent to which comorbid pain and depression conjointly influence individuals’ MS self-management is an area worthy of further exploration.

Impact on treatment utilization and effectiveness

Depression and pain likely influence health care utilization and treatment effectiveness. For example, in a recent study, the authors described how the rates of pain treatment utilization of patients with MS were higher among the subset of patients who were also depressed. Individuals with comorbid pain and depression were found to have made more visits to medical providers for pain intervention, tried more pain treatments, and trended toward making more emergency department visits for pain intervention relative to individuals with pain alone. This finding is consistent with research in other medical populations that has shown that pain and depression are associated with higher rates of health care utilization. In other medical conditions, pain and depression are also thought to reduce the effectiveness of treatments for the other condition (see Bair and colleagues for a review of this literature). In other words, the presence of pain may interfere with depression treatment and vice versa. Such relationships have not been studied in people with MS, pain, and depression, however. Further, this prior research has suggested that the presence of pain distracts providers from detecting the presence of depression and subsequently results in the undertreatment of depression in pain populations. Whether pain is a contributing factor to the underidentification and treatment of depression among patients with MS is unknown.

Interventions for comorbid pain and depression

Descriptions of pharmacologic and cognitive-behavioral interventions for depression and pain have been provided in prior articles. However, the authors are unaware of research on combined treatments for depression and pain in MS, despite their co-occurrence and presumed bidirectional impact on each other. Effective treatment of depression has been shown to have a secondary effect of improving pain in primary care patients. Research in other medical populations also points to the potential for successful treatment of comorbid pain and depression through antidepressant therapy, cognitive-behavioral therapy (CBT), and self-hypnosis training, although results have been far from definitive to this point.

Antidepressants are commonly prescribed to patients with MS with neuropathic pain to address not only pain but also depression and sleep. However, little is known about the efficacy of antidepressants for treating neuropathic pain in MS. Tricyclic antidepressants have some evidence for their efficacy in treating chronic pain in other neuropathic pain disorders, although they are typically prescribed at doses lower than those needed for depression treatment. Side effects of tricyclic antidepressants can also be a deterrent to their use for pain and depression. There is also evidence that the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine are effective in the treatment of neuropathic pain in a range of conditions, although their efficacy in MS pain has not been studied. Only a few antidepressants have been evaluated for their benefits in treating depression in MS via randomized controlled trials for depression, and no studies were found reporting the benefits of treating depression with antidepressants on pain.

Among the available psychological treatments for depression and pain, CBT has the most evidence supporting its efficacy in individuals with MS. In a series of randomized controlled trials, Mohr and colleagues demonstrated that CBT, delivered both in person and by telephone, is efficacious in reducing depression as well as fatigue, disability, and quality of life. CBT for chronic pain has been less extensively studied in MS populations, although preliminary evidence in MS and a substantial body of evidence in other painful conditions support its use for chronic pain in MS. However, although CBT for depression and pain share many ingredients (such as relaxation training, cognitive restructuring, behavioral activation), treatments targeting both have not been developed or tested, to the authors’ knowledge.

One of the treatments for pain with the longest history, hypnosis, had not been tested in controlled trials until recently. However, research has established its efficacy for several chronic pain conditions. Even more recently, controlled trials of hypnosis in individuals with MS and chronic pain have demonstrated its efficacy for reducing pain intensity and pain interference. In addition, preliminary research suggests that hypnotic interventions may also be effective for reducing depressive symptoms. Although research is needed to confirm that hypnosis and hypnotic interventions are as effective in individuals with MS and depression as they are in individuals who present with pain or depression as a primary problem, there is no a priori reason to hypothesize the benefits would not generalize to an MS population.

Utilization of and access to interventions for comorbid pain and depression

Outside of the development of treatments targeting the pain-depression comorbidity, a pressing issue is the ability of patients to access and appropriately use the interventions that are currently available. Specifically, prior research has shown that although effective treatments for pain and depression are available, these two conditions remain underidentified and undertreated in MS populations. An estimated two-thirds of people with MS and major depression are untreated. Similarly, although psychosocial interventions specifically targeting MS and depression have been found to be effective, both real and perceived barriers impact the follow-through with depression treatment referrals. The MS literature also reflects poor utilization of screening information to improve treatment referrals, even when screening is systematically implemented. Pain is also inadequately treated; treatments that patients identify as most helpful are not necessarily the most frequently used, and nonpharmacologic pain management strategies are used at very low rates despite their potential to reduce pain and associated suffering. (Ehde DM, Osborne TL, Hanley MA, et al. Use and perceived effectiveness of treatments for pain associated with multiple sclerosis. submitted for publication) These studies highlight the need to implement and evaluate new systems of care for pain and depression to address the undertreatment of depression and pain in people with MS.

Innovative approaches to the management of comorbid depression and pain

In other medical populations whereby depression and/or chronic pain are common, the collaborative care model has been found to be an effective systems-based approach to managing chronic comorbid conditions. This model emphasizes implementing systemic changes complete with self-management support, clinical information systems, delivery system redesign, decision support, health care organization, and community resources. Health professionals are not simply colocated; they use established principles of chronic care management and interdisciplinary collaborative care teams in which professionals with complementary skills work closely together to care for a population of patients with complex medical conditions. Specialists and primary medical providers actively collaborate in providing integrated care, usually assisted by a care manager who guides patients collaboratively through various decisions about and aspects of care. The specialists, such as psychiatrists or pain specialists, supervise the care managers. The specialists are also available to consult primary medical providers on patients who are clinically challenging or who need additional specialty services and to see patients themselves when required. Collaborative care also typically features a stepped-care approach in which interventions are titrated based on the response to treatment. Collaborative care emphasizes measurement-based care, including screening and ongoing measurement and monitoring of treatment outcomes. Thus, the severity of problems such as depression and pain are repeatedly measured, and the treatment is systematically intensified or modified to ensure that the targeted improvements are achieved.

Collaborative care has repeatedly proven to be an effective model for maximizing access to, and efficacy of, medical treatment of chronic conditions. Collaborative care has improved depression outcomes and quality of care in patients with co-occurring chronic conditions, such as diabetes, coronary heart disease, and osteoarthritis. A meta-analysis of 37 randomized controlled trials showed that collaborative care is more effective than standard care in improving short-term and long-term (up to 5 years) depression outcomes in primary care settings. Recent trials have successfully tested collaborative care for patients with chronic pain (with or without depression) and produced useful benefits over usual care in improving pain, depression, and functional outcomes.

The collaborative care approach is consistent with many of the conclusions of a 2002 MS stakeholder consensus conference on the identification and treatment of depression in MS. Their recommendations for improving depression care in patients with MS included standardization of depression treatment, individualized care based on patient preferences, treatment to remission, and integrated biopsychosocial treatments that include options for both pharmacologic and psychosocial care. Although they did not mention collaborative care in their published statement, their recommendations are consistent with a collaborative care model of depression care. Despite these recommendations made 10 years ago, collaborative care is not yet standard practice in MS care. In fact, the authors are aware of only one small, nonrandomized study that used the collaborative care model to treat depression in MS. Results showed that at 6 months after baseline, fewer (33.3%) patients who received care management met diagnostic criteria for major depression relative to historical controls who received standard care (55.2%, P = .15). Although preliminary, this study supports the need for further evaluation of a collaborative care intervention, including by tailoring the intervention to match the needs of people with MS.

Given the tremendous barriers to receiving adequate behavioral health services, an additional direction for future intervention development and research is the use of technology to deliver pain and depression care. Although not previously studied in people with MS, literature from other patient populations suggests that only one-third of patients with depression receive any psychotherapy. Of these, 25% attend only one session and only 50% attend 4 or more sessions. The barriers for people with MS may be even greater, spanning across limited transportation, inability to drive, and other motivational (eg, fatigue), cognitive, social, and financial problems that interfere with their ability to attend regularly scheduled in-person appointments. Telehealth and other forms of technology hold promise for overcoming some of these barriers to care in MS.

Evidence is building for the feasibility and efficacy of telehealth interventions in MS care. Various telehealth technologies have been used to treat MS-related fatigue, to deliver MS self-management support, and to monitor MS symptoms remotely. It has also been used to treat depression and pain. In a series of randomized controlled trials, Mohr and colleagues demonstrated that telephone-delivered CBT is efficacious in treating depression in MS. In the authors’ clinical trials of behavioral interventions for pain, they have found telephone-delivered CBT to also be a feasible and effective treatment of reducing chronic pain and its negative impact on functioning in people with MS. Neither of these lines of research specifically targeted both depression and pain, however. Telephone-based care overcomes some of the associated barriers as well as the potential stigma associated with seeking mental health care. Whether telehealth interventions will be adopted in real-world (eg, clinic) settings remains to be seen.