Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.1 Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.
Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.
This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.
The effectiveness of antidepressants for pain
The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 12-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 22,3,8,10,11-33).
Box 1
The pathophysiology of chronic pain
The pathophysiologic processes precipitating and maintaining chronic pain conditions are complex. Persistent and chronic pain results from changes in sensitivity within both ascending pathways (relaying pain information from the periphery to the spinal cord and brain) and descending pain pathways (functioning to modulate ascending pain information).2,3 Tissue damage or peripheral nerve injury can lead to a cascade of neuroplastic changes within the CNS, resulting in hyperexcitability within the ascending pain pathways.
The descending pain pathways consist of the midbrain periaqueductal gray area (PGA), the rostroventral medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT). The axons of the RVM (the outflow of which is serotonergic) and DLPT (the outflow of which is noradrenergic) terminate in the dorsal horn of the spinal cord,4 and thereby dampen pain signals arising from the periphery. Diminished output from descending pain pathways can heighten the pain experience. Input from the cortex, hypothalamus, and amygdala (among other structures) converges upon the PGA, RVM and DLPT, and can influence the degree of pain modulation emerging from descending pathways. In this way, thoughts, appraisals, and mood are believed to comprise cognitive and affective modifiers of pain experiences.
Devising effective chronic pain treatment becomes challenging; multimodal treatment approaches often are advocated, including pharmacologic treatment with analgesics in combination with co-analgesic medications such as antidepressants. Although a description of multimodal treatment is beyond the scope of this article, such treatment also would encompass physical therapy, occupational therapy, and psychotherapeutic interventions to augment rehabilitative efforts and the functional capabilities of patients who struggle with persisting pain.
Although the direct pain-mitigating effects of antidepressants are not fully understood, it is believed that augmentation of monoamine neurotransmission from supraspinal nuclei (ie, the RVM and DLPT) modulate pain transmission from the periphery.5,6 In addition, there is evidence that some effects of tricyclic antidepressants can modulate several other functions that impact peripheral and central sensitization.7-10
During the last several decades, antidepressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,34,35 FM,36,37 headache,38 and IBS.39,40
Box 2
Antidepressants’ direct and indirect pain-mitigating effects and psychiatric comorbidities
The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects (impacting neurotransmission of descending pathways independent of influences on mood) and indirect effects (presumably impacting cortical and limbic output to the periaqueductal gray area, the rostroventral medulla, and the dorsolateral pontomesencephalic tegmentum brought about by improvement in mood and/or cognitive appraisals) (Figure2,3,8,10,11,15,20,22,28,29). Support for the direct analgesic effects has been garnered from initial empirical work that demonstrated pain relief among patients with pain who are not depressed. Additionally, among patients who have depression and experience pain, analgesia reportedly often occurs within 2 weeks, which is before antidepressant effects are appreciated,11-15 and, at least for some antidepressants, occurs at doses far lower than those required to produce mood-elevating effects.11,12,16
On the other hand, it is well established that significant comorbidities exist between chronic pain states and psychiatric disorders (eg, depression and somatic symptom and related disorders).17-21 There may be common physiological substrates underlying chronic pain and depression.20,22 There are bidirectional influences of limbic (affective) systems and those CNS structures involved in pain processing and integration. The effects of pain and depression are reciprocal; the presence of one makes the management of the other more challenging.23-27 Mood disturbances can, therefore, impact pain processing by acting as affective and cognitive amplifiers of pain by leading to catastrophizing, pain severity augmentation, poor coping with pain-related stress, etc.28,29 It is plausible that the mood-elevating effects of antidepressants can improve pain by indirect effects, by modulating limbic activity, which in turn, impacts coping, cognitive appraisals of pain, etc.
Patients with somatoform disorders (using pre-DSM-5 terminology) frequently present with chronic pain, often in multiple sites.19 Such patients are characterized by hypervigilance for, and a predisposition to focus on, physical sensations and to appraise these sensations as reflecting a pathological state.30 Neuroimaging studies have begun to identify those neural circuits involved in somatoform disorders, many of which act as cognitive and affective amplifiers of visceral-somatic sensory processing. Many of these neural circuits overlap, and interact with, those involved in pain processing.31 Antidepressants can mitigate the severity of unexplained physical complaints, including pain, among patients who somatize32,33; however, due to the heterogeneity of studies upon which this claim is based, the quality of the evidence is reportedly low.33 There is uncertainty whether, or to what extent, antidepressant benefits among patients who somatize are due to a direct impact on pain modulation, or indirect effects on mood or cognitive appraisals/perceptions.
Despite the uncertainties about the exact mechanisms through which antidepressants exert analgesic effects, antidepressants can be appropriately used to treat patients with selected chronic pain syndromes, regardless of whether or not the patient has a psychiatric comorbidity. For those patients with pain and psychiatric comorbidities, the benefits may be brought about via direct mechanisms, indirect mechanisms, or a combination of both.
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