Monica Zolezzi, BPharm, MSc, ACPR, PhD
It is well recognized that a bidirectional relationship exists between depression and chronic pain.1 For patients, living with pain is difficult, but living with both is harder. For healthcare practitioners, managing these comorbid conditions simultaneously may be challenging. Because chronic pain alters psychosocial functioning, it is often associated with mood changes. On the other hand, depression impairs an individual’s ability to cope with pain, adding to the disability caused by chronic pain. In addition to major depression, generalized anxiety disorder, post-traumatic stress disorder and substance use disorders have also been described as being associated with chronic pain.2
A thorough symptom assessment is vital to characterize the pain, recognize what seems to worsen or relieve it, and to determine its impact on function. A variety of measurement scales are available to assess chronic pain. The most commonly used are numerical rating scales (NRS) which use numbers to rate pain, and visual analog scales (VAS), which typically ask a patient to mark a place on a scale that aligns with their level of pain.3 Pain diaries, completed by the patient over one week at the beginning and end of treatment, are also useful for assessing pain and monitoring treatment outcomes. In some cases, a more comprehensive assessment may need input from a variety of disciplines.
The management of comorbid depression and chronic pain should be a coordinated approach which should start by identifying shared treatment goals and collaborative multidisciplinary care that involves physical and/or occupational therapy to increase function, psychological treatment, and pharmacologic treatment.4-6 Psychological treatment can include cognitive behavioral therapy and mindfulness based stress reduction programs. Antidepressants have the most evidence in the pharmacological treatment of comorbid depression and chronic pain. Antidepressants that treat both depression and chronic neuropathic pain include the tricyclic antidepressants (TCAs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs).
TCAs and SNRIs have analgesic properties independent of their antidepressant effect. The presumed mode of analgesic action is by increasing the synaptic concentration of norepinephrine and/or serotonin in the dorsal horn, thereby inhibiting the release of excitatory neurotransmitters and blunting pain pathways.7-10 The selective serotonin reuptake inhibiors (SSRIs) have virtually no analgesic effect, possibly due to lack of norepinephrine activity.4 Depression treatment guidelines recommend the SNRIs as first line treatment in patients with comorbid neuropathic pain, fibromyalgia, diabetic neuropathy, and chronic fatigue syndrome.11,12 Duloxetine is the only SNRI with FDA-approved indications for MDD and pain disorders.10 Doses higher than 60mg/day may be required for managing depression.
The TCAs have been shown to be effective in neuropathic pain and migrane, but the analgesic dose is usually lower than what is required to effectively treat depression.4,7,8 Unfortunately, higher TCA doses are associated with increased incidence of cholinergic side effects and cardiac conduction abnormalies which is why they are usually considered as second line treatment for the management of depression with comorbid pain.11,12 The secondary amines nortriptyline and desipramine are better tolerated than imipramine and amitriptyline in medically ill patients and may also be preferable in patients with pain.10-12
As SSRIs are often used as first-line treatment of major depression, one option that is used in practice is to combine a low dose TCA with the patient’s SSRI to manage pain. Unfortunately, this combination poses a risk for developing serotonin syndrome. Similar concerns with serotonin syndrome apply when other pain medications, such as tramadol and sumatriptan, are used in combination with antidepressants. Using an SSRI with the lowest potential for drug interactions, such as escitalopram and mirtazapine, would help mitigate this risk.12
Ketamine and its enantiomer esketamine are anesthetics with analgesic and sedative properties which are also effective in the management of treatment-resistant unipolar depression.13 Although most studies have given ketamine intravenously, it can also be administered with intramuscular, intranasal, oral, subcutaneous, and sublingual formulations. However, much remains to be learned about ketamine’s optimal dosing, method of administration, short- and long-term adverse effects, and duration and frequency of treatment.14 In addition, there is little evidence evaluating ketamine’s effect on both pain scores and depression symptoms.
Pharmacists are in an ideal position to form therapeutic alliances with patients and other healthcare providers to address pain and depression comorbidity. Assessment should include a longitudinal approach that fosters health promotion which addresses both the effects of pain on depression and the effects of depression on pain. Treatment should start early and vigorously to avoid unfavorable biological and psycho-social consequences.
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