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Building Pharmacist Skills in Opioid Analgesic Therapy: Understanding Mental Health in Pain Management

Introduction to the Connection Between Mental Health and Chronic Pain

In 2016, the Centers for Disease Control and Prevention (CDC) estimated that 20.4% of adults in the United States experienced chronic pain, representing approximately 50 million people.1 About 19.6 million people with chronic pain reported that their pain interferes with daily activities. 2-4 Out of those with chronic pain, it is estimated that between 23% to 78% of patients have comorbid depression and 10.6% to 62.5% have an anxiety disorder. There is also a higher prevalence of axis II personality disorders in chronic pain patients (approximately 21-70%), encompassing paranoid personality disorder, borderline personality disorder, and obsessive-compulsive disorder.5 Additionally, substance use disorder affects an estimated 4.3% to 40% of patients with chronic pain.2-4 In addition to the high reported prevalence of mental health disorders in chronic pain, patients with chronic pain also have a higher prevalence of mental health disorders compared to patients without pain, with one study showing that 50% of patients being treated for depression reported chronic pain.6

The relationship between chronic pain and mental health disorders is well established as bidirectional.6 In other words, patients with chronic pain are diagnosed with more mental health comorbidities than the general population, and patients with mental health disorders are more frequently reporting chronic pain. Additionally, chronic pain can impact a patient’s quality of life and daily activities, ultimately affecting a patient’s well-being. There are special considerations regarding pain management in patients with comorbid mental health disorders and substance abuse disorders. Stigma associated with chronic pain and addiction can also impact a patient’s pain management and further affect mental well-being.

Mechanism Connecting Chronic Pain and Mental Health

The mechanism explaining the relationship between chronic pain and mental health has been explored, and numerous explanations have been proposed.7,8 Imaging studies have shown that both pain and emotional stimuli activate the same regions of the brain. These regions include the thalamus, dorsal anterior cingulate cortex, anterior insula, and amygdala. Functional imaging studies have been performed for specific mental health disorders, such as depression and anxiety that have further confirmed the activation of similar cerebral regions.

Garcia-Larrea and Peyron described a pain matrix model to further explain the relationship between chronic pain and mental health.7,9 This pain matrix model consists of 3 regions of neural networks that process information in a hierarchical manner. In level 1, the regions in the spinothalamic tract, specifically the dorsal horn and spinal cord, are activated by nociceptive stimuli, which then extends to the posterior thalamic region. Following activation of level 1, nociceptive stimuli are processed in level 2. Level 2 consists of several brain regions including the anterior cingulate cortex, insula, prefrontal cortex, and posterior parietal cortex. Once stimuli are processed, nociceptive stimuli are perceived triggering “attentional” and “somatic” responses. Level 3 of the pain matrix includes the orbitofrontal region, perigenual anterior cingulate cortex, and the anterolateral prefrontal cortex. In this region of the brain, stimuli are reprocessed in the context of emotion and psychological factors, and memories are created pertaining to pain. The actions that occur in level 2 and 3 send signals to the descending tract in the spinal cord, which either inhibits or facilitates incoming nociceptive pain signals. There are several neurotransmitters involved in the pain signaling pathway, including serotonin and noradrenaline.10 Serotonin has been linked to both depression and several types of pain disorders such as tension type headaches and fibromyalgia.8 Therefore, dysregulation of this pathway could be linked to both mental health disorders and chronic pain.

Another common pathway that could explain the connection between chronic pain and mental health disorders involves the hypothalamic-pituitary-adrenal (HPA) axis.8 The HPA axis releases cortisol when activated by stress. Cortisol plays a role in the metabolism of serotonin and has been linked to several pain conditions, including daily headaches and fibromyalgia. Several mental health disorders including anxiety, depression, substance abuse, and post-traumatic stress disorder (PTSD) have been linked to dysregulation of the HPA axis. An irregularity in this pathway may contribute to comorbid mental health disorders and chronic pain.

Common Concomitant Mental Health Disorders and Special Considerations


Several studies have demonstrated the relationship between chronic pain and depression.7 In 1995, Carroll and colleagues performed a population-based cohort study to examine the association between neck and lower back pain, collectively referred to as spinal pain and depression.11,12 In a sample of 845 people at risk for depression, people with severe spinal pain were more than twice as likely to develop depression compared to those without pain with 12 months of follow-up (adjusted hazard ratio [HR], 2.45; 95% confidence interval [CI], 1.06-5.69).11 Similarly, patients with mild pain were also more likely to be diagnosed with depression (adjusted HR 2.10, 95% CI, 1.09-4.04). In a sample of 790 people at risk for pain, patients with more severe depressive symptoms, defined as being in the upper quartile among patients, were almost 4 times as likely to develop spinal pain compared to patients with depression symptoms scoring in the lowest quartile (adjusted HR, 3.97; 95% CI, 1.81-8.72).12 This cohort study established a relationship between depression and spinal pain, highlighting that depression is a risk factor for pain and pain is a risk factor for depression.

A number of epidemiological studies show that rates of depression appear to be highest in patients with fibromyalgia, temporomandibular joint disorders, spinal pain, and chronic abdominal pain, followed by arthritis, migraine headaches, and pelvic pain.7 Patients with comorbid chronic pain and depression are impacted by more severe pain, higher rates of disability, and decreased function compared to chronic pain patients without depression.6 Untreated depression may contribute to pain and reduce effectiveness of pain management strategies; therefore, depression should be evaluated in patients with chronic pain. The CDC recommends screening chronic pain patients for depression using the Patient Health Questionnaire (PHQ)-9 so that treatment can be optimized appropriately.13


Several studies have shown that anxiety disorders are commonly associated with chronic pain.7 These anxiety disorders include generalized anxiety disorder, panic disorder, and PTSD. Studies have demonstrated a bidirectional relationship between pain and anxiety. For example, in patients with migraine headaches, there is a 2 to 3 times higher chance of being diagnosed with an anxiety disorder. Likewise, patients with anxiety disorder are 2 times as likely to experience migraines than those without anxiety. The CDC recommends screening for anxiety and PTSD in all chronic pain patients utilizing the Generalized Anxiety Disorder (GAD)-7, so that these conditions can be addressed and ultimately assist in pain control.13

Special considerations should be made regarding medication regimens for those with comorbid anxiety and chronic pain.13 Benzodiazepines are commonly prescribed for the treatment of anxiety. Concomitant use of benzodiazepines with opioids for chronic pain is associated with several safety concerns, and the CDC recommends against this combination if possible. Benzodiazepines are central nervous system (CNS) depressants and can lead to respiratory depression when used with opioids. Estimates have suggested that the combined effects increase the risk of opioid-related overdose by up to 4 times compared to patients prescribed an opioid alone. Additionally, patients should be warned about the potential for CNS depression to impact their ability to drive or operate machinery while taking both medications.

Substance use disorder

Substance use disorders, including opioid use disorder (OUD), are an important mental health consideration for patients with chronic pain.7,13 Similar to depression and anxiety, substance use disorder has a bidirectional relationship with chronic pain. Patients with chronic pain are 2 to 3 times more likely to develop a substance use disorder. In patients with substance use disorder, the risk of developing a chronic pain syndrome is 1.5 times higher than patients without substance use disorder. The prevalence of substance use disorder varies by chronic pain condition; it is detected most frequently in patients with fibromyalgia, spinal pain, and arthritis. The CDC guideline on opioids for chronic pain discusses the relationship between substance use disorders and chronic pain. The guideline recommends evaluating patients for substance use disorder and OUD at baseline and periodically throughout chronic pain treatment. Mental health disorders, a history of substance use disorders, and long-term opioid therapy are all risk factors for developing an OUD, and OUD is a risk factor for opioid-related death.

The CDC provides recommendations for safe opioid use in patients with substance use disorder if opioid therapy is necessary for chronic pain.13 These recommendations include increased monitoring, counseling, and offering the patient naloxone. Counseling should focus on the increased risk of developing OUD and opioid-related overdose. Increased monitoring should focus on detecting the development of OUD or active substance abuse. If substance abuse is detected, patients should be referred for treatment. Pain management in patients with substance use disorder is complex, and the CDC recommends consulting substance use disorder and pain specialists. Stigma associated with substance use disorder and OUD may create additional barriers for treatment.

Impact of Comorbid Chronic Pain and Mental Health

In addition to the relationship between chronic pain and mental health disorders, chronic pain can contribute to decreased quality of life and mental well-being.14 Studies have shown that patients with chronic pain face challenges completing chores, physical activities, walking, and maintaining an independent lifestyle. Additionally, some patients may experience significant limitations performing tasks such as sitting down and standing up. These limitations on physical activities may contribute to decreased mental health due to feelings of frustration and helplessness.

A number of studies have examined the effects of chronic pain on health-related quality of life.14 These studies have shown that chronic pain patients have a significantly decreased health-related quality of life affecting both physical and mental components compared to acute pain patients and people with no pain. Certain chronic pain populations may experience lower health-related quality of life than others. For example, chronic pain had a larger impact on the mental component of health-related quality of life in fibromyalgia patients. Additionally, sleep disturbances have been linked to chronic pain, further decreasing health-related quality of life. Lack of sleep may increase stress, impair concentration, and interfere with capabilities of completing tasks.

Chronic pain can interfere with social interactions and family relationships, leading to feelings of isolation.14 Patients may experience feelings of anger and irritability as a result of chronic pain, which can affect interpersonal relationships. According to one estimate, half of patients with pain had to miss a family or social event and/or had less contact with family members. Additionally, patients with physical or mental impairments due to chronic pain may make less of an effort to socialize.

Stigma Surrounding Chronic Pain and Addiction

Stigma is defined as the beliefs and views associated with a characteristic considered undesirable that can lead to negative stereotypes.15 Stigma may come from family members, friends, coworkers, health care providers, and society. In health care, stigma is often associated with chronic pain and addiction. This stigma may be due to the belief that patients with chronic pain are addicted to opioids, morally weak, or exhibiting drug seeking behaviors.16 Both patients and health care providers may face stigma associated with treating chronic pain and addiction.15

Stigma of chronic pain

Stigma creates various barriers for patients with chronic pain, particularly patients receiving opioid treatment.15,17 Patients may perceive stigma as feelings of not being believed by family, friends, and health care workers, or feeling like others perceive their pain as exaggerated. This stigma can result in negative feelings of shame, guilt, embarrassment, and judgment. Internalized feelings of stigma can contribute to the cycle of mental health and chronic pain, by causing anxiety and depression. These feelings may also reduce patient engagement and efficacy of treatment.

In addition to judgment, patients may be treated differently due to stigma surrounding chronic pain.17 Several studies have shown that health care providers discredit pain severity in chronic pain patients, since there is no acute trauma or physiological evidence of pain. When nurses and patients were both asked to rate a patient’s chronic pain, there was often a discrepancy between the nurse and patient rating, with the nurse typically rating pain as lower. This degree of discrepancy was not seen for acute pain ratings.

A study performed by Bulls and colleagues examined the stigma surrounding opioid use in cancer patients with chronic pain by surveying these patients.18 This survey found that 61% of respondents endorsed at least one aspect of opioid stigma. Respondents expressed concerns about becoming addicted (36%), revealed experiencing difficulty filling prescriptions (21%), expressed “awkward” feelings when discussing opioids with providers (15%), worried about appearing drug seeking (15%), or had difficulty obtaining a prescription (14%). Patients also reported concerns or feelings of judgment from providers, family, and friends.

Several studies have also shown that the perception of stigma may be associated with presence and severity of depression. A study by Scott and colleagues measured stigma experienced in chronic pain patients attending an interdisciplinary pain treatment program.19 An 8-item scale was utilized to measure the amount of stigma experienced by patients. This study found that higher stigma scores were associated with worse depression and disability among patients. Naushad and colleagues examined the perception of stigma in 4 groups of patients.20 These groups included patients with depression only, chronic pain only, comorbid depression and chronic pain, and healthy controls. Patients with comorbid depression and pain were found to perceive more stigma compared to those with only chronic pain.

Providers may also face stigma associated with chronic pain and addiction.15 Health care providers have reported feeling stigmatized when they prescribe opioids for acute and chronic pain. The reported source of this stigma was from other colleagues or society, with societal pressure coming from opioid prescribing oversight of state regulatory boards and the Drug Enforcement Agency (DEA). This stigma may lead to inappropriate prescribing of opioids – with lower doses or shorter durations than required. Additionally, this can lead to over-referral of patients for pain management and patient abandonment.

Following the release of the 2016 CDC guideline for opioid prescribing in chronic pain, it was reported that providers were incorrectly implementing the recommendations by abruptly tapering or discontinuing opioid therapy, as well as discharging patients from their care.21 The CDC noted that abruptly tapering and discontinuing opioids will lead to patient harm in most cases. Although the CDC did not address if this practice was directly related to stigma, a patient testimonial provided to the Department of Health and Human Services’ Pain Management Best Practices Inter-agency task force highlights the detriment of this practice as it relates to stigma.15 In 2018, a patient with chronic pain due to cervical spinal stenosis and myelopathy was forced to taper from her opioid pain medications. Following the taper, the patient became bedridden, was accused of drug seeking behavior, and blamed for causing the opioid epidemic. The patient described this stigma as “demoralizing.”

Stigma Surrounding Opioid Use Disorder

In addition to stigma associated with chronic pain treatment, significant stigma exists surrounding OUD and medication assisted treatment (MAT).22 OUD is a chronic condition that does not have a cure; however, the use of MAT (ie, buprenorphine, methadone, or naltrexone) has been shown to decrease associated drug use, infectious diseases, and mortality. Stigma associated with OUD has created various barriers to treatment. Only 12.2% of people with substance use disorder will seek treatment, with 20.5% not seeking treatment due to potential consequences associated with their job.15 An additional 17% of patients report not seeking treatment out of fear of judgment.

In a 2016 national survey, almost 75% of respondents felt that people with OUD lack self-control and are to blame for their substance use.23 The majority of the respondents also indicated that they would not want an individual with OUD to marry into their family and felt that it was appropriate to deny employment because of the disorder. This stigma may also stem from the lack of distinction between addiction and treatment of addiction.22 Some health care professionals may stigmatize patients taking MAT and treat them as though they are still abusing opioids.

Despite the established benefit of MAT in the treatment of OUD, there is a lot of stigma surrounding its use.22 For example, the use of MAT has been viewed as a substitute for narcotics and therefore does not align with the Narcotics Anonymous philosophy of abstinence. Some treatment facilities may require residents to taper off methadone or buprenorphine prior to being provided housing. Additionally, some reports have noted that patients maintained on methadone or buprenorphine prior to incarceration were not allowed to continue treatment leading to symptomatic withdrawal. Furthermore, there have been reports suggesting that not all communities welcome treatment centers, with some communities proposing rezoning so that treatment centers are not included in community boundaries.

Overcoming Stigma

Several factors contributing to the stigma surrounding OUD and its treatment have been proposed, and ethods for overcoming stigma should address these factors.22 Methods for overcoming stigma include increasing awareness that OUD is a medical condition and utilizing medically appropriate words when discussing OUD. Barriers stemming from stigma that limit access to MAT should also be addressed.

There are several barriers limiting access to MAT that perpetuate the stigma of OUD.22 For example, methadone treatment for addiction is restricted to treatment centers, which silos treatment for OUD within the health care system. Methadone treatment centers require patients to return to the clinic daily to receive treatment, which further distinguishes OUD from other disorders. Additionally, in order to treat OUD with buprenorphine, providers must receive additional training (8 hours) and certification from the DEA. Providers have reported not obtaining buprenorphine certification for OUD due to stigma. Insurance companies also contribute to stigma by limiting the days’ supply for MAT in a single prescription fill.

The separation between OUD treatment and the rest of the health care system perpetuates the belief that OUD may be due to a lack of willpower or moral weakness as opposed to a mental health disorder. Additionally, the separation of OUD treatment means that patients do not necessarily receive treatment for concomitant substance abuse disorders or other comorbidities including mental health disorders. This could lead to the misperception that a MAT is the direct cause of a patient’s comorbidities.

Language utilized to discuss OUD and treatment does not always reflect treatment of a medical condition. For example, urine test results may be labeled as “clean” or “dirty” as opposed to “positive” or “negative.” The status of a patient’s condition may be referred to as “clean” if in recovery or “dirty” if the patient’s condition remains uncontrolled. Additionally, the use of the term “drug-free” may reflect negatively, if a patient is maintained on MAT. One health care professional recommends selecting words similar to those that would be used for other medical conditions such as diabetes and hypertension.24

It is important to express to patients being treated for OUD that they are entitled to privacy and confidentiality.25 Patients should be made aware that they do not need to disclose treatment to others, since they may face stigma surrounding their choice to use MAT. The Substance Abuse and Mental Health Services Administration (SAMSHA) acknowledges that patients being treated for OUD may experience fear of judgment, shame, or disappointment from their family and friends over their OUD. Due to this stigma, SAMHSA recommends that patients carefully consider whether to share information about their recovery with friends and family and what information they are comfortable sharing.

Chronic Pain Management in Patients with Comorbid Mental Health Disorder

General patient approach

Several organizations have published guidelines for chronic pain management.13,15,26 Pain management for the chronic pain patient should include a multimodal regimen, utilizing various approaches with differing mechanisms of action. Pharmacologic regimens should be paired with nonpharmacologic strategies, such as physical therapy, weight loss, and psychological therapy. Psychological therapy and other nonpharmacologic interventions have been shown to benefit pain control and patient function.13 Studies have found that the combination of psychological treatment with exercise improved outcomes compared with exercise alone. Guidelines recommend an interdisciplinary approach that incorporates physical, mental, and social support to treat chronic pain.13,15,26 The treatment team should include primary care, mental health care, and specialists as needed. It should be noted that insurance coverage may limit accessibility of nonpharmacologic treatment services, including psychological treatment, and primary care providers should alter regimens appropriately.

The American Society of Anesthesiologists (ASA) and American Society of Regional Anesthesia (ASRA) chronic pain management guideline and the CDC opioids for chronic pain guideline recommend that psychological treatment be included as a component of chronic pain management.13,26 There are a number of psychological treatment modalities that can be utilized. Common psychological treatment strategies include cognitive behavioral therapy, biofeedback, relaxation training, supportive psychotherapy, group therapy, and counseling. These approaches encourage patients to be active participants in their care and address the impact of pain on functional activities. Psychological treatment should be tailored to meet the patient’s specific needs. For example, some patients may benefit from relaxation training and coping mechanisms provided by a primary care service or group therapy, while other patients may benefit from formal one-on-one therapy. The CDC recommends an evaluation of mental health and other comorbid disorders to assist in establishing and optimizing an individualized patient treatment plan, as the presence of mental health disorders may diminish pain control.

Pharmacologic pain management strategies for patients with mental health disorders

Several antidepressant and anticonvulsant classes of medications have been utilized off-label as part of a multimodal approach for chronic pain management. These are outlined in Table 1.27 Various organizations support the use of specific antidepressants in pain conditions since these agents may provide concomitant analgesic and antidepressant effects. The antidepressant classes that have been studied and used most commonly for analgesia include tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Additionally, bupropion, a second-generation atypical antidepressant, and selective serotonin reuptake inhibitors (SSRIs) have been studied for chronic pain management. The ASRA and ASA guideline for chronic pain and the CDC supports the use of SNRIs and TCAs as part of a multimodal regimen for the management of chronic pain.13,26 Likewise, the American Psychiatric Association (APA) recommends that TCAs and SNRIs be considered as depression treatments for patients with co-occurring pain syndrome.28 The APA also notes that SSRIs have been beneficial in treating depressive symptoms, which in turn has reduced chronic pain. The majority of evidence examining the use of antidepressants for chronic pain supports their use for treating neuropathic pain; however, several agents have also been utilized successfully for non-neuropathic pain, such as lower back pain and migraines.29,30 The anticonvulsant class most commonly utilized for both mental health and pain conditions is the gamma-aminobutyric acid (GABA) analog class.7 Guidelines recommend GABA analogs for use in neuropathic pain and as an adjunct for depression; however, recommendations do not emphasize their use for a dual indication.26,28

Table 1. Antidepressants Utilized for Chronic Pain Management.31,34
Class Common Agents Safety precautions Use in pain
SGA antidepressant Bupropion
  • Lowers seizure threshold
  • CNS stimulation (ie, insomnia, anxiety, anorexia)
  • Weight loss
  • Hypertension
  • Neuropathic pain*†
  • Inflammatory bowel disorder*†
SNRI Duloxetine
  • Bleeding risk
  • Hypertension
  • QTc prolongation
  • Dizziness, drowsiness fatigue
  • Dry mouth, constipation, nausea
  • Withdrawal
  • Fibromyalgia
  • Diabetic neuropathy
  • Musculoskeletal pain
  • Migraine prophylaxis†
  • Fibromyalgia
  • Musculoskeletal pain†
  • Neuropathic pain†
  • Migraine prophylaxis†
TCA Amitriptyline
  • Confusion, drowsiness, memory impairment, hallucinations
  • Tachycardia, cardiac conductance abnormalities
  • Dry mouth, urinary retention
  • Orthostatic hypotension
  • Fibromyalgia†
  • Musculoskeletal pain (eg, low back pain) †
  • Migraine prophylaxis†
  • Neuropathic pain†
GABA analog Gabapentin
  • Dizziness, drowsiness
  • Respiratory depression
  • Potential for abuse and physical dependence
  • Weight gain, visual disturbances, exacerbation of underlying cardiovascular disease, decreased platelet count (pregabalin only)
  • Fibromyalgia¥
  • Neuropathic pain¥
  • Postherpetic neuralgia¥
  • Restless leg syndrome†
  • Postoperative pain†
* Use has not been incorporated into national clinical practice guidelines.
† Off-label use.
¥ Off-label use for gabapentin. On label indication for pregabalin.

Abbreviations: CNS, central nervous system; GABA, gamma-aminobutyric acid; SGA, second-generation atypical; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.

Tricyclic antidepressants are utilized for a variety of off-label chronic pain conditions.31,32 Agents within the TCA class consist of nortriptyline and desipramine, which are notably utilized for pain management, as well as amitriptyline, amoxapine, clomipramine, doxepin, imipramine, protriptyline, and trimipramine. While the mechanism of action for analgesia is unclear, it is thought to be related to serotonin and norepinephrine modulation. Drugs within the TCA class have most notably been used for neuropathic pain, such as in diabetic neuropathy, postherpetic neuralgia, and fibromyalgia.10 Additionally, TCAs may be utilized for other types of chronic pain syndromes, such as tension-type headaches and musculoskeletal pain.29,33 Dosing required to achieve analgesic effects from TCAs are typically lower than the doses recommended for antidepressant effects, so patients without depression may still benefit.32

Drugs within the TCA class are associated with significant side effects due to their nonspecific mechanism of action for depression, which may limit their use in practice.10 Common side effects are dry mouth, tachycardia, cardiac conductance abnormalities, and urinary retention. Patients may experience orthostatic hypotension, as well as confusion, drowsiness, memory impairment, and hallucinations. Additionally, TCA overdose can be deadly due to cardiac and anticholinergic toxicities; therefore, use should be avoided in patients at risk for suicide. Side effects for TCAs may be more pronounced in the elderly and their use in this population should be performed cautiously. Because of these adverse effects, some guidelines give preference to other antidepressant classes for chronic pain.

Agents within the SNRI drug class utilized for pain management include milnacipran, venlafaxine, and duloxetine.10,31 Duloxetine is Food and Drug Administration (FDA)-approved for generalized anxiety disorder and major depressive disorder, as well as the pain indications fibromyalgia, diabetic peripheral neuropathy, and chronic musculoskeletal pain. Milnacipran is FDA-approved for fibromyalgia, while depression is an off-label use. Venlafaxine is FDA-approved for a variety of mental health disorders including major depressive disorder and generalized anxiety disorder, and use for chronic pain is off-label. The SNRI mechanism of analgesic action is due to the inhibition of serotonin and norepinephrine reuptake.34 These agents have been studied for chronic pain due to a variety of disorders, with most studies examining neuropathic pain.10,31 In addition to neuropathic pain, duloxetine and venlafaxine have shown benefit for treating musculoskeletal pain due to chronic lower back pain and tension-type headaches. These agents, particularly venlafaxine, have also been used successfully for migraine prophylaxis. Studies have shown inconsistent results for milnacipran in neuropathic pain caused by conditions other than fibromyalgia. Doses utilized for SNRIs are similar for pain and depression; however, SNRIs may still be beneficial for treating pain in patients without depression.

The SNRI class is associated with a more favorable adverse event profile than TCAs; however, there are still several safety precautions of note.10,31,34 Use of SNRIs is contraindicated with concomitant use of monoamine oxidase inhibitors (MAOIs), and SNRI initiation should not occur in patients receiving linezolid or methylene blue. Common side effects with SNRIs are insomnia, nausea, constipation, dry mouth, drowsiness, dizziness, and fatigue. Hypertension can occur with these agents; therefore, pre-existing hypertension should be controlled prior to SNRI initiation. Additionally, venlafaxine can prolong the QTc interval, and it should be used with caution in patients who have cardiovascular risk factors or those receiving other QTc-prolonging medications. There is an increased risk for bleeding with SNRIs, particularly when used with other medications that concomitantly increase the risk, such as nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, and corticosteroids. Additional caution and dose adjustments are warranted in patients with renal or hepatic impairment, with specific dosing recommendations differing by agent. Withdrawal may occur following abrupt discontinuation, so regimens should be tapered when discontinuing therapy.

Bupropion is FDA-approved for the treatment of major depressive disorder and prevention of depression due to seasonal affective disorder.31 Several studies have examined the off-label use of bupropion for neuropathic pain; however, supporting literature is limited and the agent has not been incorporated into pain management guidelines.10, 35-37 The mechanism of analgesic action is thought to be due to the inhibition of norepinephrine and dopamine reuptake. Studies have also shown a potential benefit of bupropion in treating chronic pain related to inflammatory bowel disorders. Bupropion may lower the seizure threshold and should be used cautiously in patients with risk factors for seizures and avoided in patients with existing seizure disorders.31 Bupropion is also contraindicated in patients taking MAOIs, linezolid, or methylene blue. Bupropion may cause central nervous system activation resulting in insomnia, restlessness, and anorexia. Use should be avoided in patients with a history of an eating disorder or in patients in which weight loss is undesirable.

The GABA analog class, consisting of gabapentin and pregabalin, works by regulating voltage-gated calcium channels.4 Gabapentin and pregabalin are FDA-approved as an adjunct for partial seizures and for postherpetic neuralgia.31 Pregabalin has additional FDA-approved pain indications for fibromyalgia, neuropathic pain, and diabetic peripheral neuropathy. Both agents are utilized off-label for various mental health conditions. For example, gabapentin is used as an adjunct for bipolar disorder, and pregabalin is used for generalized anxiety disorder. Guidelines for depression and pain management note the utility of GABA analogs; however, guidelines do not emphasize their use in patients with concomitant mental health and pain disorders. These agents are recommended for neuropathic pain as part of a multimodal regimen.13,26 Additionally, the APA notes that anticonvulsants can be utilized to augment antidepressant therapy.28 Gabapentin and pregabalin should be used with caution in the elderly, as they can cause syncope and increase fall risk.31 Central nervous system adverse effects, such as dizziness and drowsiness, are common.

Discussing Quality of Life with Patients

Chronic pain can significantly decrease quality of life by limiting physical activities, impairing ability to work, and impacting mental health by creating fear and isolation.38 Goals for pain management should ultimately address both pain level and function, which are indicative of quality of life.13 The CDC notes that improvement in function may not be a realistic goal for pain due to certain underlying conditions, such as spinal cord injuries and diseases with progressive impairment.

In order to improve quality of life while living with pain, the American Chronic Pain Association has suggested 10 steps, referred to as “moving from patient to person.”38 Step 1 involves accepting the pain and understanding the cause and prognosis. This step is necessary to understand whether there is a cure for the pain and acceptance if there is not. Following acceptance, the next step involves becoming an active participant in care. Patients should follow the provider’s instructions and initiate conversations about becoming a more active partner in their care. Steps 3 and 4 require the patient to set priorities and realistic goals to achieve these priorities. Priorities should involve tasks relating to important aspects of the patient’s life and may include functional goals and activities. Once the patient identifies these priorities, they can then set goals that can be broken down into manageable steps. Step 5 emphasizes the understanding of basic rights, including the right to be treated with respect, make mistakes, and say no. Steps 6 and 7 are to recognize emotion and learn to relax. Emotions are linked to physical health, and stress can lead to physical pain. When patients are able to recognize their emotions and the presence of stress, they can employ various coping mechanisms to address these negative feelings. Exercise, which is step 8, may also help with emotional well-being and pain. All of these steps can help a patient to shift their focus from pain onto other aspects of their life, which is step 9, and in turn support others in achieving pain management, which is step 10.

Validated tools can be utilized to evaluate quality of life associated with pain. These should account for social, physical, and emotional domains.13 One tool recommended by the CDC is the pain average, interference with enjoyment of life, and interference with general activity scale, also referred to as the PEG scale. Each of the 3 domains in this scale are scored from 0 to 10, and the 3 scores are averaged to get the final score. A 30% reduction in PEG score is considered clinically relevant. Additionally, progress toward functional goals can be utilized to track quality of life.


The bidirectional relationship between chronic pain and mental health adds a layer of complexity to chronic pain management.6 Patients with untreated mental health disorders are likely to have more severe pain; therefore, the CDC recommends all chronic pain patients should be screened for mental health disorders.13 Psychological interventions should be implemented in all chronic pain patients to address mental health well-being and encourage active participation in care. Several antidepressant agents can be utilized as part of a multimodal pain management regimen to address both depression and chronic pain.13,26-28 Management of chronic pain may be further complicated in patients with mental health disorders due to an increased risk of OUD and overdose in patients with substance use disorder and drug interactions between benzodiazepines and opioids in patients with anxiety. Stigma may further complicate pain management through limited treatment access and judgment, which can further contribute to worsened mental health; therefore, health care providers should utilize steps to reduce stigma when treating chronic pain and OUD.22


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