Managing treatment-resistant depression in the setting of chronic pain





Among the many challenges of treating depression are the complications that arise when the depression is concurrent with other medical conditions. Not surprisingly, when a patient has two conditions, insufficient treatment of one condition may worsen the presentation or treatment outcome of the second condition. This is particularly true when dealing with concurrent mood problems and pain problems. Such complications arise from the bidirectional relationship between depression and pain ( ). Individuals with serious acute pain that progresses to chronic pain are at higher risk for developing various psychiatric disorders, particularly depression. Patients with depression experience various physical symptoms, and various attributes of depression, including reduced energy and reduced ability to exercise, may, in turn, predispose to exacerbation of pain conditions. Chronic pain often generates pessimistic thoughts and feelings of frustration and helplessness; in turn, this cognitive frame allows for the evolution of depression as a clinical problem. At an even more fundamental level, the neural pathways for pain and the neural pathways for mood disorders share some common brain regions and certainly share many common neurotransmitters, particularly serotonin as a major signaling molecule ( ; ). As the body tries to compensate for one condition by altering some attribute of the neurotransmitter in the initially affected system, this may in turn cause disruption of pathways that use the same neurotransmitter in the other system. Furthermore, once the individual has progressed to have depression and chronic pain, treatment for each condition independently may either help or hurt the other condition. Finally, when two disorders are present, it is common for both the patient and the clinician to focus treatment efforts on one disorder with the hope that any other sequelae will fade with the treatment of what is perceived to be the primary disorder. Treat the pain, and the depression might disappear, or treat the depression and the pain may lessen—so goes the mantra. Unfortunately, the reality is that by focusing on only one of two concurrent disorders, both conditions ultimately get treated more poorly.


In this chapter on the intersection between refractory depression and chronic pain disorders, we will begin by defining what constitutes chronic pain disorders since the definition of chronic or refractory depression is to be found elsewhere in this volume. We will look at the prevalence of pain disorders and in particular look at a couple of practical strategies to monitor the pain in the same spirit of measurement-based care that we typically apply to the management of mood disorders. Once we have established these common definitions in matrix, we systematically explore several key questions around the interface of depression and pain. From an epidemiologic perspective, we clarify how common pain is in depressed patients and conversely how common depression is in pain patients. Next, we moved to treatment by evaluating whether the presence of depression affects clinical outcomes in chronic pain treatment and the parallel question of whether pain affects depression outcomes. Finally, we look at the various treatments that have been explored for the interface of treating depression in the context of a chronic pain disorder.


Definition and measurement of chronic pain disorders


The International Association for the Study of Pain (IASP) defines chronic pain as pain that lasts beyond the expected time required for normal tissue healing and/or is intractable to treatment. From purely the pain perspective, it is estimated that just over 20% of the US adult population had a chronic pain disorder in 2016, representing approximately 50,000,000 adults. The impact of chronic pain is enormous in terms of suffering for the individual and families but also for society in terms of direct and indirect economic costs, which have been estimated to be over half a trillion dollars in 2010. Proper assessment and management of chronic pain is itself a major medical subspecialty and is certainly beyond the scope of this chapter. However, it is reasonable that the clinician treating depression and particularly refractory depression will need to be able to ask basic questions about the presence or absence of pain disorders and be able to measure whether the pain disorder is getting better or worse while depression is being treated.


For any patient, assessment of the various types of symptoms of pain along with their impact on social and occupational functioning is essential. Measuring that is exactly the same as measuring the social and occupational impact of a mood disorder, so a clinician skilled in treating depression can simply apply the same approach in measuring impairment related to pain. But getting a precise metric for the pain is also necessary. Much like depression, where many clinician and patient-rated scales exist, the pain literature is also full of many patient and clinician measures of pain. We have recently published a practical guide to measurement based care for depression, highlighting how to use commonly available rating scales and how frequently to implement them in daily practice ( ). In a parallel way, two pain questionnaires, namely the McGill Pain Questionnaire (MPQ) and the Brief Pain Inventory (BPI), have been validated and are widely used and quite practical even for the clinician who does not specializes in pain. Both of these scales were originally validated for one type of pain and in the English language; subsequently, both scales have been validated in multiple languages and across diverse types of pain. Both scales are self-administered and take less than 5 min to complete. We review both questionnaires below and suggest that the clinician pick one scale and use this periodically—perhaps monthly in tandem with a mood rating scale—in the assessment of a patient who has a mood disorder and a pain disorder.


The McGill Pain Questionnaire and the Brief Pain Inventory


The McGill Pain Questionnaire ( ) and its more practical short form, the SF-MPQ ( ), evaluate sensory, affective-emotional, evaluative, and temporal aspects of the pain experience of the patient. The SF-MPQ consists of 15 questions which are divided into 11 sensory questions which identified the nature of the pain such as “sharp or shooting, etc.” and for affective verbal descriptions such as “sickening, fearful, etc.” The patient is asked to rate the intensity of each descriptor on a scale from 0 (none) to 3 (severe). Three pain scores are calculated: the sensory, the affective, and the total pain index; these are totaled to get an overall score, much like the PHQ-9. Typically, less than 5 min is needed for the patient to fill out the scale and to calculate a score. It is free to use, and widely available on the internet in multiple languages ( ).


The Brief Pain Inventory is a numeric rating scale from 0 to 10 that assesses the severity of pain and the degree of interference with functioning ( ). It measures both pain intensity and pain interference with different life domains. It includes six questions that ask for the intensity and temporal nature of the pain, including a diagram of the body on which the patient marks where the pain is felt. One question includes seven specific items to rate the impact of the pain, during the past 24 h, on functioning, mood, and enjoyment of life, again scored 0–10. Two other questions summarize pain treatment and asked the patient to rate relief of pain from the treatment. Since these questions cover a range of topics, there is no simple algorithm to generate an overall score; instead, specific answers to each question need to be compared from visit to visit. The scale is under copyright but is free for clinical practice.


Summary of recommendations for assessment practices in comorbid pain and depression scenarios


Measurement-based care is enormously helpful for the successful treatment of most medical conditions, including either depression or pain disorders. Given the additional complexity when there are two disorders, it is even more important to ensure that each condition is properly measured and monitored over time. We, therefore, make the following suggestions:



  • 1.

    As part of an assessment for a mood disorder, at a minimum ask the patient to complete the patient self-report form for depression, the Patient Health Questionnaire (PHQ-9), and the patient self-report for General Anxiety Disorder (GAD-7). Ideally, this would be complemented by a clinician-assessed scale; we recommend the Montgomery-Asberg Depression Rating Scale.


  • 2.

    As part of an assessment for a mood disorder, ask if there is a significant problem with pain, and document its location and intensity. If the patient indicates that the pain is significantly impairing, ask the patient to complete either the SF-MPQ or the BPI.


  • 3.

    In ongoing care, use a mood rating scale at regular intervals, such as once per month during active treatment without remission. During the same appointment, a single question should be asked about any chronic pain problems; if present, again administer the same pain questionnaire previously administered.


  • 4.

    In addition to reviewing depression treatment, ask about patient preferences and current practices of pain management. If the patient needs treatment of pain, explore with the patient and consider whether a referral to an outside resource for pain management is necessary.



How common is depression in pain patients?


Two recent reviews ( ; ) have clarified the prevalence of major depression across chronic medical illnesses more broadly and also specifically in a variety of chronic pain disorders. The findings vary enormously in terms of reported rates of prevalence since the studies that are summarized in these reviews span many different medical and psychiatric settings and use a variety of measurement instruments. While some of the underlying studies have reported low rates of prevalence, most studies across multiple settings have reported that a substantial percentage, usually below 50%, of patients with chronic pain disorders, have major depression. Other studies have clarified that those with multiple pain symptoms are three to five times as likely to have major depression as those without pain symptoms. Furthermore, there appears to be a “dose response” relationship where those with more pain are more likely to experience clinical depression. The highest rates of clinical depression were described in pain clinics (52%), rheumatology or orthopedic clinics (56%), and in dental clinics addressing facial pain (85%) as reported by IsHak and colleagues.


How common is pain in depression patients?


Painful symptoms are very common in patients with major depression. However, given the wide variety of pain symptoms and the wide variety of tools to measure both pain and depression, it is difficult to accurately report the prevalence of a chronic pain disorder in a patient with major depression. As reported by Lepine and Briley, an analysis by the World Health Organization from primary care centers around the world suggested that 22% of all primary care patients suffer from debilitating pain and that these patients with a chronic pain disorder are four times as likely to have a serious problem with anxiety or depression than primary care patients without pain. Furthermore, Lepine and Briley noted that 75% of patients with major depression being treated in a primary care setting had a significant painful physical symptom, most commonly headaches, stomach aches, and neck and back pain. They concluded that chronic pain should be seen as a harbinger of depression and not an explanatory factor. Furthermore, they felt that chronic pain should be seen as a cardinal symptom of depression requiring elimination in order to achieve good treatment outcomes for depression ( ).


IsHak and colleagues, in their 2018 review, explored this question with a bidirectional approach, starting with 14 studies where individuals were first identified as depressed and then assessed for pain. Next, they examined 42 articles looking at patients with a painful condition who were then subsequently assessed for depression. They found multiple difficulties in evaluating this evidence given that studies varied greatly in sample size, thoroughness of the pain assessment, and variability in the assessment of depression. Nevertheless, they did suggest that the prevalence of significant pain in depressed patients ranged from 15% to 100% with a mean prevalence of 65%. Together, the two review papers strongly emphasize high rates of pain symptoms if not full-fledged chronic pain disorder in patients with depression. They also emphasize that the presence of such pain complicates and potentially prolongs the treatment of depression, underscoring the need for mental health professionals to assess and help manage pain even if their primary goal is to treat a mood disorder. In essence, effective management of major depression requires attention to the management of the pain condition, whether it is a severe and chronic pain disorder or a more isolated significant pain symptom. Thus, there is the need for routine assessment of pain symptoms in patients with depression—ideally with the McGill Pain Questionnaire or the Brief Pain Inventory!


What is the impact of pain and depression comorbidity, in terms of outcomes either for depression or for pain?


As noted earlier, chronic pain conditions have a substantial impact on suffering, overall functioning, and financial burden for both the individual and for society. Similarly, major depressive disorders are well known to be impairing across a variety of functional domains and have recently emerged to be the major cause of disability worldwide, according to the World Health Organization (Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: World Health Organization; 2017). When an individual has the misfortune to experience both a pain disorder and mood disorder, it can only be expected that suffering increases and functioning is even further impaired. More specifically, it would be reasonable to predict that pain symptoms would worsen depression outcomes, and depression symptoms would worsen pain outcomes. Indeed, extensive studies by identified a number of pain complaints that are associated with increased symptoms of depression. These researchers also found that the worse the pain at baseline, the worse the depression outcome both in terms of symptoms and functioning. As reviewed by ( ), a number of studies have substantiated this point, demonstrating that inadequate pain control clearly worsens depressive symptoms over time and conversely that improvement in pain symptoms was associated with a decrease in depressive symptoms.


Approaches to treatment of comorbid pain and depression


Both pain and depression share etiologies that are a blend of neurobiological, psychological, and environmental factors. Since the environmental or social determinants of health are beyond the scope of this chapter, medications remain a cardinal intervention that is widely applicable and feasible. Psychological factors and psychological interventions are common to both pain and disorder management and depression management, but access and implementation of psychological treatments for either disorder remains problematic. In particular, while cognitive behavior therapy for depression is widely available in a variety of formats such as individual therapy, group interventions, and online intervention via apps and websites, cognitive behavior therapy for pain disorders or other kinds of psychosocial treatments for pain disorders is much less available. Psychosocial interventions for pain disorders have a substantial evidence base and are widely used in specialized pain clinics, but the interventions are often specific to the type of pain and are not readily accessible to the average practitioner who wishes to prescribe it. Two useful articles include a comprehensive summary of psychosocial processes in pain ( ) and a brief review of psychosocial treatments ( ). In addition, a key resource in this area is the 2019 book, Handbook of Psychosocial Interventions for Chronic Pain: An Evidence-Based Guide, edited by Andrea Kohn Maikovich-Fong; Routledge, 2019. Additionally, some other “mind-body” interventions may be useful for comorbid pain and depression, such as yoga. A recent review summarizes this evidence ( ).


Medication treatment of comorbid pain and depression


Evidence-based medicine is predicated on the use of well-designed and well-conducted research studies, preferably randomized controlled trials. Such well-designed studies would include rigorously established diagnoses, carefully defined treatments, and standardized outcome scales that are statistically analyzed according to widely accepted methods. Furthermore, when there are multiple studies for the treatment of a particular condition, a properly designed metaanalysis should be conducted to synthesize all high-quality evidence into a more definitive answer.


As we have established to our earlier review, almost none of these conditions are met when examining the issue of comorbid depression and pain disorders. While there are a significant number of studies of treatments, they suffer from the same kinds of problems identified in studies of prevalence and outcome—great variability in how either pain or depression is diagnosed or measured, how the patient population is defined, and what outcome is used. It is also unclear how a metaanalysis of say multiple trials for one type of pain such as back pain and a particular medication would be applicable to another type of pain concomitant with depression. In order to deal with this heterogeneity of research, we will summarize key medication treatments and the relevant evidence. Most of the evidence reviewed will be individual studies, although there are occasional review articles and very rarely a med analysis that is available for interpretation. Therefore, clinical practice will depend on the clinician interpreting the evidence and identifying those parts of the evidence which may be relevant for the patient that they are trying to treat. We begin our medication treatment summary by exploring key review articles. Subsequently, we report evidence for specific medications, including whether this is supported by reviews or high-quality evidence, or other types of studies.


Overall results from antidepressants


Since tricyclic antidepressants have been marketed for over 50 years, they have been extensively used both for depression and for pain disorders. Few placebo-controlled studies, however, have been conducted, and so no metaanalysis is available. In a 2003 review by Bair and colleagues ( ), specific positive findings in pain relief was summarized by conditions such as pain syndromes like fibromyalgia, irritable bowel syndrome, and migraines; for these conditions, a variety of antidepressants provided pain relief. In fact, a broader review of antidepressants for conditions featuring “somatic symptoms” (pain was only one type of somatic disorder included), found TCAs more useful than SSRIs in relieving somatic symptoms. Bair et al. also found 22 studies where individuals with comorbid pain and depression were treated, with the pain outcome as the primary outcome, and depression as the main secondary outcome. The review noted that 18 studies involved tricyclics, while four used SSRIs. Most of the tricyclic studies were uncontrolled, but demonstrated improvement in both pain and depression, while the results from SSRIs were less clear. A more recent review by used a more rigorous study selection process, insisting on only placebo-controlled studies, and found only 19 studies, with 11 testing only SNRIs (principally venlafaxine and duloxetine), 3 testing both SNRIs and SSRIs, 3 only testing SSRIs, and just 2 studies employing tricyclics. Based on comparison to placebo, TCAs surprisingly did not beat placebo for analgesic relief, while both SSRIs and SNRIs beat placebo with a small effect size. The authors surmised that on balance, in view of the many positive uncontrolled studies of TCAs, the expectation is that TCAs should also have a small but positive benefit in reducing pain in individuals with comorbid depression. In summary, SNRIs should be the first choice in treating pain and depression, while SSRIs and TCAs have some use. For more specific conditions such as neuropathic pain or musculoskeletal pain, no generalizations about can be made, but there are positive studies with a variety of compounds ( ; ).


Key antidepressants for special consideration


Amitriptyline is the most widely studied and used TCA for a variety of somatic conditions, with most studies reporting a primary outcome in the somatic condition and occasionally reporting depressive symptom change. A key limitation of this literature is the choice of dosing; for most somatic conditions, doses employed are usually well below the doses shown to be effective for depression. Such studies often find 25–50 mg of amitriptyline to be helpful for the pain or other somatic disorder—for instance, summarized that 10 of 11 RCTs found amitriptyline reduced the pain of fibromyalgia. The majority of patients in such studies of somatic conditions may have depressive symptoms but not major depression, so only a few studies report improvement in depression. Since amitriptyline is considered a second-line antidepressant due to its high side effect burden and potential toxicity in overdose, it should not be used for comorbid major depression and pain unless SNRIs and SSRIs have both been tried first.


Venlafaxine is widely used in comorbid pain and depression, but clinical studies are few, resulting in a lack of review articles. conducted the only significant study of chronic pain and depression treated with venlafaxine and reported improvement in both pain and depression scores after 1 year in this uncontrolled trial. Another trial of venlafaxine versus placebo in depressed spinal cord injury patients with pain showed benefit only on secondary measures of efficacy ( ). As such, while compelling evidence is lacking, the previous metaanalysis of SNRIs had shown potential value, and venlafaxine’s potent efficacy in moderate and severe depression makes it worth considering here. A derivative compound, desvenlafaxine , unfortunately, did not show efficacy compared to placebo for the treatment of fibromyalgia pain ( ), while depression was not assessed. While desvenlafaxine is a safe and effective treatment for major depression, no evidence exists to support the use of desvenlafaxine in pain and depression, or in refractory depression.


Duloxetine is the only modern antidepressant with an extensive research portfolio in various pain or somatic conditions. In fact, it is FDA-approved for many conditions including GAD, MDD, fibromyalgia, diabetic peripheral neuropathy, and musculoskeletal pain. The evidence for direct effect on pain, largely independent of the impact of the medication on depression, is substantial for fibromyalgia ( ), neuropathy ( ), and musculoskeletal pain, both arthritic and post orthopedic surgery ( ; ). In the situation of a specific study of comorbid depression and pain, no specific trial of MDD patients with pain was done with depression outcomes as a primary outcome. Nevertheless, improvement in pain and depression symptoms (via secondary outcomes in RCTs) is demonstrated across a variety of patient populations and types of pain. Hence, duloxetine should be considered as a first-line treatment for those individuals with pain and depression comorbidity.


Isolated trials suggest the utility of several other antidepressants. Bupropion has a single trial of individuals with NO depression but with neuropathic pain showed improvement in pain ( ). A large observational study of patients with chronic pain and depression showed no clear efficacy of mirtazapine ( ). One recent study of vortioxetine in a specific condition—burning mouth syndrome—with modest benefit ( ). No studies of vortioxetine’s effect on comorbid depression and pain were found. One placebo-controlled trial has demonstrated benefit in both pain and depression in fibromyalgia from quetiapine , which is approved as a monotherapy treatment for depression despite its original development as an antipsychotic ( ). No relevant studies were found involving vilazodone or levomilnacipran ( ).


Ketamine has emerged as a major new treatment for refractory depression but also has a long history in the management of chronic pain. Ketamine has multiple levels of complexity; it has two enantiomers, multiple metabolites some of which may be active, and affects multiple brain systems, including particularly the glutamate system, but also the opioid, monoamine, and cholinergic systems. Furthermore, ketamine also has multiple widely used methods of administration—most often IV infusion of racemic ketamine, but also intranasal, sublingual, intramuscular, and oral routes. For TRD, IV administration of racemic ketamine has established value in treating depression and also independently in reducing suicidality ( ). The two enantiomers, (R) and (S), each may have different efficacy and side effect profiles ( ). One of these, esketamine, has been approved as an add-on treatment for TRD via intranasal administration ( ). Preliminary evidence also indicates the efficacy of oral and sublingual ketamine for TRD ( ).


Predating ketamine’s use in TRD was off-label use for pain of many different types, sometimes refractory chronic pain, sometimes for very specific types of pain, and often as part of palliative care in cancer-related pain ( ). While such applications are often based on uncontrolled studies, the evidence is sufficiently compelling that many health care entities provide guidelines for its routine administration ( ). Its use in pain, however, differs in one dramatic way from psychiatric use of ketamine—much like other analgesics, it is often administered several times a day.


Differing frequencies and dosing of ketamine, compounded by the fact that ketamine for pain is more commonly administer orally while ketamine for depression is commonly by IV, complicate recommendations about the use of ketamine in comorbid TRD and pain. In the absence of any specific studies, only expert opinion can provide recommendations that must remain tentative. Firstly, treat TRD with ketamine in a fashion that is recommended and effective for that person’s TRD. While it is common to administer either IV ketamine or intranasal esketamine twice per week initially, patients may use ketamine less frequently after the depression improves. However, the pain benefits of ketamine do not last beyond 24 h. As such, other analgesics will particularly be needed for pain management beyond the 24-h period. Alternatively, it may be possible to administer lower doses of ketamine, particularly orally, on a daily basis to manage the pain and derive some benefit for the treatment of depression. Here, data from a metaanalysis of oral ketamine ( ) may provide support for the administration of 100–200 mg daily for TRD; this dosage is at the low end of dosages for oral ketamine in pain conditions but may be useful for the less severe pain situations. Careful evaluation of the side effects of such frequent and potentially higher-than-usual dosing of ketamine will be essential, as will management of any addiction potential and careful monitoring of other analgesics.


Conclusion


Management of TRD with comorbid pain is difficult for the clinician. It is even more difficult for the patient. Pain complicates depression, and depression complicates pain. There is little value in arbitrarily deciding which comes first and aggravates the other (the chicken or egg first dilemma). Instead, humane management compels careful measurement of both pain and depression, and consistent monitoring of both outcomes when pursuing the improvement of TRD. We have identified easy-to-use pain measures that are self-reports (such as the short form of the McGill Pain Questionnaire) that may be used in conjunction with traditional psychiatric scales like the PHQ-9, and recommend this strategy to evaluate and monitor progress in patients with these two conditions. But measurement of outcomes by even simpler methods can be useful, such as asking the patient to rate the pain in the preceding week on a 1 (no pain) to 10 (maximum pain). Once both TRD and pain are measured, both should be monitored and specifically targeted in order to improve both conditions. Improvement of pain management will often improve depression symptoms; improvement of depression will often reduce pain. Since it is often unwieldy to have the patient have a separate “pain physician,” it is useful for the psychiatrist to measure and manage both conditions. Fortunately, a number of antidepressants—particularly duloxetine and venlafaxine—have special value in TRD and in pain disorders, and should be considered first. Other antidepressants may also have a role, but ketamine will likely emerge in the future as a major advance not only to TRD but also to TRD with comorbid pain.



References

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Oct 27, 2024 | Posted by in PSYCHIATRY | Comments Off on Managing treatment-resistant depression in the setting of chronic pain

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