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13 Articles in Volume 18, Issue #3
Anger Expression & Chronic Pain
Ask the Expert: Should reliance on gabapentin/pregabalin be limited?
Chronic Pain in Children
Considering Comorbidities When Selecting Medications for Chronic Pain Management (Part 1)
Dousing the Physician Burnout Epidemic: An AMA Perspective
Harnessing the Power of Words
Inside ASRA with David Provenzano, MD
Management of Intrathecal Therapies by Interprofessional Teams
Nurse Burnout in Pediatric Pain Management: A Model and Pilot Intervention
Physician Burnout: An Oldtimer’s View
Reporting Metrics, Media Coverage...Letters from the Minds of Peers and Patients
The Case for Slow-Release Anesthetics
The Impact of Pain Practice

Considering Comorbidities When Selecting Medications for Chronic Pain Management (Part 1)

In Part 1 of this series, this case examines treatment options for managing a patient with chronic pain, complicated by hypertension and post-traumatic stress disorder.

Chronic pain complicated by... Rarely do patients with chronic pain present with pain as their only medical or mental health condition. To effectively treat pain, a biopsychosocial approach to treat the whole person is needed. Both nonpharmacological (including standard and complementary and integrative methods) and pharmacologic approaches may be used. A variety of factors need to be considered when selecting pharmacotherapy for chronic pain, including the type of pain, patient preferences, cost, formulary options, concomitant medications, routes of delivery, and comorbidities.

Examining comorbidities, in particular, may help guide clinicians toward specific medications that treat more than one diagnosis as well as medications that may be eliminated from consideration due to their potential negative impact on the diagnosed conditions.

This case is the first in a four-part series examining how comorbidities play a role in the selection of medications for pain management. Case 2 focused on the use of buprenorphine in a patient with osteoarthritic pain, complicated by chronic obstructive pulmonary disease; Case 3 examined treatment options for managing a patient with diabetic peripheral neuropathy, kidney disease, and substance use disorder; Case 4 focused on the use of opioids in those with chronic kidney disease and diabetic peripheral neuropathy; and Case 5 addressed diabetic neuropathy and osteoarthritis, complicated by cardiovasvular challenges.

The Patient

Mr. Thompson is a 39-year-old male veteran presenting to the clinic with low back pain that is limiting his ability to perform normal daily activities. He has tried acetaminophen, ibuprofen, and naproxen without benefit. He reports flashbacks and nightmares of war. For the past few months, he has been avoiding his military friends and isolating himself at home.

Additionally, he reports hypertension controlled with hydrochlorothiazide/lisinopril (25 mg/20 mg by mouth daily) with a blood pressure on the initial visit at 128/79 mmHg. Further work-up is completed and the patient is diagnosed with degenerative disc disease and post-traumatic stress disorder (PTSD). The patient is open to physical therapy and working with a psychologist but also requests medication, noting that his symptoms are distressing.

Discussion of Options

Antidepressant medications may be useful in both the treatment of mental health disorders as well as for the management of chronic pain. Traditionally, tricyclic antidepressants (TCAs) have been considered the “gold standard;” however, their use may be limited due to adverse reactions.1 In the treatment of PTSD, the TCA, imipramine, is listed as a possible second-line option in the Veterans Administration (VA) guidelines.2 Otherwise the VA guidelines suggest against the use of amitriptyline due to side effects or for which there is not enough information to recommend for or against use of TCAs (eg, desipramine, doxepin, nortriptyline).2

Better-tolerated selective serotonin reuptake inhibitors (SSRIs) may also be considered in the treatment of mental health disorders. In PTSD, SSRIs are considered a first-line pharmacologic treatment according to the American Psychiatric Association.3 Additionally, the VA guidelines for PTSD recommend the use of SSRIs—sertraline, paroxetine, and fluoxetine—as first-line pharmacotherapy.2

Results of studies examining the effects of SSRIs on the treatment of chronic pain have had mixed outcomes, and may therefore have a limited role in the treatment of chronic pain conditions.1,4

Serotonin norepinephrine reuptake inhibitors (SNRIs), including venlafaxine, duloxetine, and milnacipran, offer another class of antidepressant therapy. Compared to SSRIs, research on SNRIs has demonstrated improved effectiveness in the treatment of chronic pain with a similar adverse effect profile.1

When comparing SNRIs to TCAs for the management of chronic pain, there is similar efficacy between the two groups, while SNRIs hold a more favorable adverse effect profile.1 The US Food and Drug Administration has approved duloxetine for major depressive disorder and generalized anxiety disorder in addition to several pain-related conditions, including fibromyalgia, chronic musculoskeletal pain (ie, low back pain and osteoarthritis), and diabetic peripheral neuropathic pain.See Table I for more details.

According to the American College of Physicians’ guidelines for low back pain, duloxetine is considered a second-line pharmacologic option after failure of a nonsteroidal anti-inflammatory drug (NSAID).6 In this class, milnacipran is FDA-approved for fibromyalgia.7 While venlafaxine is not approved for any pain-related conditions, the medication has shown to benefit patients with diabetic peripheral neuropathy, painful polyneuropathy, chemotherapy-induced neuropathy, fibromyalgia, and low back pain.8-12 For the treatment of PTSD, in particular, venlafaxine may be a first-line psychopharmacologic option, according to the VA guidelines.2 Inadequate evidence is available, however, to recommend for or against the use of duloxetine in the treatment of PSTD.2

Considering the literature and recommended guidelines, venlafaxine may be the best option for targeting both the patient’s chronic pain and PTSD. To initiate venlafaxine SA, it is recommended to start with a dosage of 37.5 mg orally once daily for 4 to 7 days, and then increase dosage to 75 mg/day. The dose may be increased in 75 mg increments to a maximum of 225 mg/day no sooner than every four days.13 It should be noted that higher doses of venlafaxine may be needed to achieve norepinephrine activity; lower doses of the medication provide activity similar to SSRIs.14

Addressing Other Comorbidities

In addition to selecting pharmacotherapy that may benefit more than one condition, such as PTSD and low back pain as described above, it is also important for clinicians to consider how a medication may negatively impact other disease states. For example, because of its activity on norepinephrine, venlafaxine and other SNRIs may lead to hypertension. This effect is thought to be dose-related.13 Prior to starting a SNRI, blood pressure should be controlled, and during therapy, blood pressure should be monitored.13

The case study patient presented herein has hypertension that is controlled with medication, so a trial of venlafaxine may be appropriate with monitoring of blood pressure. If blood pressure is significantly elevated from baseline, a dose reduction or taper off venlafaxine may be warranted.13 Gradual dose reduction may be recommended when discontinuing venlafaxine to avoid potential withdrawal symptoms.13

Additional Considerations

While not specifically related to the patient case, there are a few more considerations to be noted regarding the use of SNRIs. Venlafaxine has been associated with QTc prolongation at therapeutic and supratherapeutic doses.13,15,16 Caution is advised when using venlafaxine in patients with cardiovascular disease or risk factors for QTc prolongation. Although not universally recommended, ECG monitoring could be considered prior to initiation and during therapy in those at risk.15 The use of duloxetine and milnacipran should be avoided in those with chronic liver disease or in patients who consume large quantities of alcohol due to the potential for worsening liver function.5,7

Further, venlafaxine comes with recommended dose adjustments based on hepatic and renal function.13 Whereas duloxetine should be avoided with creatinine clearance (CrCl) < 30 mL/min,5 milnacipran also is to be avoided in end-stage renal disease; reducing the milnacipran dose by 50% with CrCl 5-29 mL/min is advised.7 SNRIs may alter the amount of serotonin take-up by the platelet leading to potential increased risk of bleeding.17 Mixed evidence is available on this topic.18,19 Combining SNRIs with NSAIDs, corticosteroids, anticoagulants, or anti-platelets may add to bleeding risk.17,20


Patient-specific factors, including comorbidities, are crucial considerations when selecting nonopioid medications for the management of chronic pain conditions. These factors may help the practitioner determine the best medication to treat more than one diagnosis concurrently.

This work is the sole opinion of the author and does not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies mentioned or specific drugs discussed. It was not prepared as part of official government duties.

Last updated on: December 4, 2019
Continue Reading:
Medication Selection for Comorbid Pain Management (Part 2)
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