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17 Articles in Volume 19, Issue #7
Analgesics of the Future: Inside the Potential of 3 Drug Delivery Systems
Balancing Pain Care - and Opioids - in the Aging Adult
Book Review: A Useful Guide for New Pain Practitioners
Correspondence: Opioid Tapering & Discontinuation
Effective Interventions for Post-Stroke Shoulder Subluxation and Pain
Family: Their Role and Impact on Pain Management
Introducing the "Phoenix Sign:" Improved Vascular Perfusion of the Dorsalis Pedis Artery after a Subanesthetic Dose of Lidocaine
Medication Management of Chronic Pain in Patients with Comorbid Cardiovascular Disease
Multisite Pain May Be Associated with Fractures in the Elderly
Reconciling the New HHS Opioid Tapering Guideline with CDC and State Policies
Research Insights: Impaired Motor Imagery in Chronic Pain Conditions
Tapentadol: A Real-World Look at Misuse, Abuse, and Diversion
Temporomandibular Disorders in Performance Artists (Part 2)
Thoracic Outlet Syndrome Presenting as an Acute Stroke Mimic
Untangling Chronic Pain and Hyperarousal with Heart Rate Variability: A Case Report
What topicals exist for post-herpetic neuralgia pain?
When to Keep Your License: Older Physicians and Boundary Issues

Medication Management of Chronic Pain in Patients with Comorbid Cardiovascular Disease

Two cases provide insight into treatment options for osteoarthritis and diabetic peripheral neuropathy, complicated by CV diseases. (Part 5)
Pages 25-32

Patients suffering from chronic pain conditions rarely present to a healthcare professional with pain as their only medical condition. Approximately one-half of all patients will present with one or more comorbidity, with cardiovascular disease being the most common.1,2 According to the CDC, cardiovascular disease is the leading cause of death for both males and females of African American, Hispanic, and Caucasian descent.2,3 Interestingly, some chronic pain conditions, such as osteoarthritis (OA), are associated with an increased risk for cardiovascular disease.4 To effectively and safely treat pain, a holistic approach to therapy is warranted. Consideration of patient-specific factors, including type of pain, patient preferences, costs, concomitant medications, and comorbidities may help guide clinicians to provide a safe and effective treatment plan. This paper explores how a comorbidity of cardiovascular disease may play a role in the selection of both opioid and non-opioid medications for pain management using two examples of patients with cardiovascular disease, chronic OA, and diabetic peripheral neuropathy.

Patient 1: Chronic Osteoarthritic Pain with a History of MI and Hypertension

A 48-year-old obese, male veteran presented to the clinic with difficulty breathing and chronic OA pain in his right hip and knee that was limiting his ability to perform daily responsibilities at his job. He has a past medical history significant for a myocardial infarction that was complicated by heart failure (EF of 35% 6 months prior) and hypertension. He has tried over-the-counter (OTC) acetaminophen (650 mg every eight hours as needed) without benefit. The patient started taking OTC ibuprofen (800 mg three times daily) one week prior to his clinic appointment for pain control, which he said helped somewhat. In addition, he reported

that his hypertension was controlled on lisinopril (20 mg by mouth daily) with a blood pressure of 119/72 mmHg at this visit. The patient was willing to trying physical therapy but also requested medication in order to return to work.

Treatment Options and Guidelines

Physical Therapy and OTC Drugs

While the focus of this paper is on pharmacologic therapy options for patients with chronic pain, adjunctive nonpharmacologic approaches should be considered, as appropriate for each patient. For example, individuals with chronic OA, exercise, weight loss, walking aids, and physical/occupational therapy may be considered and discussed with the patient. The Veterans Health Administration/Department of Defense (VA/DoD) Clinical Practice Guideline for the Non-Surgical Management of Hip and Knee Osteoarthritis provides a recommended treatment algorithm for the management of patients with chronic knee and hip OA.5 Recommendations include physical therapy with or without adjunct acetaminophen or oral NSAIDs as first-line therapy, followed by duloxetine or tramadol as second-line options or as alternatives to oral NSAIDs. For patients at risk of or with known cardiovascular disease, the VA/DoD recommend avoiding NSAIDs and consider the use of acetaminophen as first-line. Patients with mild to moderate pain associated with OA of the knee may also be considered for topical capsaicin or intra-articular corticosteroid injection if the pain is moderate to severe and nonresponsive to first- or second-line therapies.

Table I provides treatment recommendations for osteoarthritis from the 2012 American College of Rheumatology (ACR), soon to be updated.6

NSAIDs and Acetaminophen

NSAIDs and acetaminophen are approved for the treatment of osteoarthritic pain and other chronic pain conditions.7 Their proposed mechanism of action is through inhibition of prostaglandin synthesis by inhibition of central cyclooxygenase (COX) enzymes. While oral NSAIDs are recommended as first-line options for general patients with OA, the 2012 ACR guidelines, 2014 VA/DoD guidelines, and American Heart Association (AHA) recommend using NSAIDs with caution in patients with cardiovascular disease.5,6,8 This caution stems from the concern that NSAIDs can increase the risk of serious cardiovascular events, including myocardial infarctions (MI), stroke, and development or worsening of heart failure.

A cohort study conducted in Denmark on 82,000 patients with a history of MI and NSAID use, found that use of selective and non-selective NSAIDs increases the risk for cardiovascular death or recurrent MI by 45%.9 A large meta-analysis of 639 trials found that use of selective COX-2 inhibitors (such as celecoxib) increased the risk of fatal MI, non-fatal MI, and stroke by 37%.10 Contributing to this data, a recent longitudinal study published on the role of NSAIDs in increased cardiovascular disease among patients with OA, found that NSAID use increased the risk for congestive heart failure, ischemic heart disease, and stroke by 23 to 64%.11 Due to this increased risk for MI and stroke, the FDA has labeled all NSAIDs with a Black Box warning for serious cardiovascular thrombotic events.

While all NSAIDs have a boxed warning for cardiovascular events, there may be some that are more dangerous than others, although the current data is conflicting. The PRECISION trial was a multi-center, randomized, double-blind, noninferiority trial of 24,081 patients that compared the risk of cardiovascular death, nonfatal MI, and nonfatal stroke among patients with arthritis requiring daily celecoxib 100 mg BID, ibuprofen 600 TID, or naproxen 375 mg BID. Among patients with arthritis and elevated cardiovascular risk, the trial found that daily use of celecoxib was noninferior to ibuprofen and naproxen regarding cardiovascular events after 3 years of follow-up.12 The rate of cardiovascular events was approximately 2 to 3% in each of the groups.

On the other hand, a meta-analysis of 87 trials found that the cardiovascular risk was slightly higher for selective COX-2 inhibitors compared to nonselective NSAIDs, such as ibuprofen, diclofenac, or naproxen.13 Of the nonselective NSAIDs, diclofenac has demonstrated the highest cardiovascular risk.14 This finding may be due to diclofenac being slightly more selective for COX-2 compared to ibuprofen or naproxen.15 Naproxen appears to be the safest of the NSAIDs for patients with cardiovascular disease. Clinical trials have shown naproxen to not be associated with an increased cardiovascular risk compared to other nonselective NSAIDs.16,17

In addition to increasing the risk of serious cardiovascular thrombotic events, NSAID use has also been attributed to increasing the risk for worsening heart failure. NSAIDs decrease pain by decreasing prostaglandin synthesis, but the kidney requires prostaglandins to maintain renal perfusion and salt and water balance. Use of NSAIDs in a patient with heart failure may increase blood pressure and precipitate fluid retention causing a worsening of their symptoms and potentially lead to an exacerbation requiring hospitalization.18 If NSAID use is medically necessary, the AHA recommends using the lowest dose possible of a non-selective NSAID.8 Topical NSAIDs, including methyl salicylate or diclofenac gel or patches, may be considered as monotherapy or adjunctive therapy in patients with hand or knee osteoarthritis. Due to the topical formulation, minimal systemic absorption is expected from drug administration, which may potentially decrease the risk for cardiovascular events.19,20 However, topical NSAIDs possess the same boxed warning for serious cardiovascular thrombotic events as oral NSAIDs, despite significantly lower systemic bioavailability.

NSAID medications have an additional FDA boxed warning for serious gastrointestinal bleeding (GIB), ulceration, and perforation. Like the kidneys, the stomach requires prostaglandins in order to create a protective film to prevent the acidic environment from damaging the lining of the stomach. By decreasing prostaglandin synthesis, NSAIDs remove this line of defense leading to an increase risk of GIB and ulceration. NSAIDs may also prolong a patient’s bleeding time by decreasing platelet adhesion and aggregation.21 This concern is important in a patient with pre-existing cardiovascular disease, because many of these patients will already be taking aspirin, an antiplatelet, and/or an anticoagulant which have similar effects. Due to this pharmacodynamic drug interaction, patients on concomitant NSAID and aspirin, antiplatelet, and/or anticoagulant therapy should be monitored for bleeding and anemia. The AHA recommends that patients requiring dual therapy with NSAIDs plus aspirin and/or antiplatelets should be treated with a proton pump inhibitor to prevent GI injury.22 Use of NSAIDs with an anticoagulant, such as rivaroxaban or apixaban, is cautioned. Results from the ROCKET AF and ARISTOTLE trials found that use of an NSAID in conjunction with an anticoagulant can independently increase the risk of major bleeding.23,24 In patients taking an anticoagulant, an alternative pain medication should be considered.

In patients with cardiovascular disease, the preferred first-line option for OA is acetaminophen as it does not have a cardiovascular risk warning on its label.6,25 Acetaminophen has been shown to reduce resting, moving, sleeping, and overall pain in patients with knee and hip OA compared to placebo.25 Unlike NSAIDS, acetaminophen does not provide an anti-inflammatory effect, so it may not be a good option for patients with pain caused by inflammation.7 Typical dosing of acetaminophen for OA is 325 to 1000 mg every four to six hours, with the maximum dose of 4 grams per day. In patients with hepatic dysfunction or on warfarin, the recommended maximum daily dose is decreased to 2 grams per day as the liver is required to metabolize and excrete acetaminophen.

It is important to note that acetaminophen is available as a single drug product but may also be found in combination products, such as hydrocodone/acetaminophen or over-the-counter medications. Patient education on monitoring the amount of acetaminophen used each day is recommended to ensure the patient does not ingest more than the recommended daily amount. The current ACR osteoarthritis guideline recommends that patients have an adequate trial of scheduled acetaminophen at a dose of 2 to 3 grams for several weeks prior to considering them nonresponsive.

Opioids and Tramadol

Prescription opioids are typically prescribed and used for managing many types of pain. However, long-term efficacy of opioids for chronic pain is limited.27 For patients with OA, use of opioids is recommended for moderate to severe knee or hip pain in patients that are contraindicated or nonresponsive to other therapies.6 Use of opioids is associated with serious risks, including addiction, abuse, overdose, respiratory and central nervous system depression, and cardiovascular changes. Short-term opioid use may lead to hypotension and syncope, even at therapeutic doses. Long-term opioid use has also been associated with cardiovascular death and atrial fibrillation development.

The REGARDS trial of 29,000 patients found that prescription opioid use was associated with a 24% increased risk of cardiovascular death.28 Another study of 850,000 veterans found that prescription opioid use increased the risk of the development of atrial fibrillation by 34%.29 Buprenorphine and methadone both may increase the risk for QTc prolongation and Torsades de Pointes.30,31 Risk factors for QTc prolongation include electrolyte abnormalities, hepatic dysfunction, heart disease, and the concomitant use of other QTc prolonging agents, such as tricyclic antidepressants and venlafaxine.30 Patients with risk factors for QTc prolongation, a history of QTc prolongation, or a history of ventricular arrhythmias are recommended to screen for a baseline prolonged QTc (> 450 to 500 msec) before starting methadone. If the QTc is borderline prolonged (450 to 500 msec), then a different opioid should be used. Methadone is contraindicated in a patient whose QTc exceeds 500 msec.

Unlike other opioids, the synthetic mu opioid receptor agonist tramadol has a low risk of cardiovascular adverse effects.32 In addition, tramadol inhibits both norepinephrine and serotonin reuptake (similar to the antidepressants venlafaxine and duloxetine), which may contribute to its effectiveness at treating chronic pain. Both the ACR and VA/DoD recommend tramadol as second-line therapy for patients with OA.5,6 Packaging information suggests starting at 25 mg and titrating to prevent adverse effects, but patients can be started at 50 or 100 mg by mouth every four, six, or eight hours as needed for pain, with a maximum dose of 400 mg per day, for those requiring rapid analgesia.32 However, tramadol should be used with caution in patients over 65 years of age due to the risk for orthostatic hypotension and falls and recommends a maximum daily dose of 300 mg in patients older than 75 years. In patients with renal dysfunction (CrCl < 30 mL/min), the dosing interval should be stretched to every 12 hours with a max daily dose of 200 mg. Similarly, patients with severe hepatic impairment (Child-Pugh class C) should have their tramadol dose adjusted to 50 mg every 12 hours. The extended-release formulation of tramadol should be avoided in severe hepatic impairment. Use of tramadol should also be cautioned in patients with a history of seizures or head trauma, as the medication may lower the seizure threshold.

Due to tramadol’s mechanism of serotonin reuptake inhibition, use of tramadol with other serotonergic agents may increase the risk for serotonin syndrome, thus should be monitored closely upon initiation. Signs and symptoms of serotonin syndrome include tremor, hyperreflexia, mydriasis, diaphoresis, confusion, agitation, and cardiovascular changes, such as tachycardia, high blood pressure, and arrhythmias.33

Intra-articular Corticosteroids

Glucocorticoids, such as prednisone, are often used to help manage a variety of inflammatory conditions, including rheumatoid arthritis. Even short-term use (< 1 month) of glucocorticoids, however, may cause side effects including hyperglycemia, hypertension, dyslipidemia, and fluid retention.34 The mechanism of steroid-induced hypertension is not completely understood but is thought to be due to an increase in peripheral vascular resistance and sodium and water retention. Due to the effects of glucocorticoids on blood

pressure and fluid retention, use of glucocorticoids in uncontrolled hypertension and heart failure is not recommended.34,35 While oral glucocorticoids are not recommended for the treatment of OA, patients with moderate to severe knee or hip OA with signs of local inflammation that have failed or are contraindicated for other therapies may be considered for an intra-articular corticosteroid injection.

There are currently five FDA-approved injectable corticosteroids available for intra-articular injection: methylprednisolone acetate, triamcinolone acetate, betamethasone acetate and betamethasone sodium phosphate, triamcinolone hexacetonide, and dexamethasone.36 Intra-articular injections work by providing a local anti-inflammatory action.37,38 Similar to topical NSAIDs, these injections have limited systemic side effects compared to their oral alternative. Potential disadvantages include injection site pain and swelling and risk of local infection. As intra-articular corticosteroid injections are considered low-risk procedures, patients receiving anticoagulant therapy with warfarin or a direct oral anticoagulant (DOAC) are not required to withhold their anticoagulant therapy.39 Studies have shown there is minimal risk of bleeding complications with joint and soft tissue infections in patients receiving warfarin with an INR < 3.0 or with patients receiving a DOAC.40,41

Patient Case 1 Revisited

Due to this patient’s cardiovascular history, use of oral NSAIDs, opioids, and corticosteroids should be avoided. NSAIDs may induce hypertension and lead to sodium and water retention, which may exacerbate his heart failure. As noted, he presented to the clinic with difficulty breathing, which may be due to his ibuprofen use. The patient trialed acetaminophen, but only used it as needed instead of scheduled. If the patient is willing, he may re-try acetaminophen 650 mg every 6 hours scheduled for the pain. In addition, he could use topical capsaicin or topical NSAIDs as adjunctive therapy due to a decreased concern for systemic absorption and adverse effects. If the patient continues to experience pain on acetaminophen and adjunctive topical therapy after several weeks, initiation of tramadol 100 mg every 6 hours as needed could be trialed.

Patient 2: DPN with a History of Uncontrolled Hypertension and MI with CABG

A 64-year-old male with diabetic peripheral neuropathy presented for help with his pain. He has a past medical history significant for type 2 diabetes mellitus, chronic kidney disease (CrCl 50 mL/min), hypertension, and atrial fibrillation. He came to the clinic for the first time with numbness and tingling in his feet and would like to start a medication to help with his symptoms. He is currently taking lisinopril (40 mg) and amlodipine (5 mg) by mouth daily for his hypertension. His blood pressure at this visit was 166/94 mmHg. His atrial fibrillation is currently controlled on metoprolol tartrate 50 mg by mouth twice daily and amiodarone (200 mg) by mouth daily.

Treatment Options and Guidelines


Antidepressants that inhibit the reuptake of norepinephrine and serotonin have been found to help improve neuropathic pain by augmenting the analgesic effect in the spinal cord. Antidepressants that inhibit the reuptake of both norepinephrine and serotonin, like tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), have been found to be more efficacious at decreasing neuropathic pain than antidepressants that inhibit serotonin reuptake alone.42 TCAs are recommended by various guidelines as first-line options for neuropathic pain.43-46 One significant adverse effect of TCAs is the cardiovascular risk associated with the drugs. Use of TCAs is cautioned in patients with a history of cardiovascular disease including previous MI, stroke, tachycardia, and conduction abnormalities, because TCAs can slow cardiac conduction, prolong the QTc interval, induce or exacerbate arrhythmias, worsen ischemic heart disease, and cause tachycardia and orthostatic hypotension.47,48 TCA doses of more than 100 mg per day were associated with sudden cardiac death.49 Thus, the American College of Cardiology (ACC) recommends avoiding TCA drugs completely in patients at risk of a serious arrhythmias and those with coronary artery disease.50

SNRIs (duloxetine and venlafaxine) are also recommended as first- and second-line options for neuropathic pain.43-46 Duloxetine is currently FDA-approved for the treatment of neuropathic pain, while venlafaxine is used off-label.51,52 Both medications inhibit norepinephrine reuptake resulting in an increase in peripheral norepinephrine causing an increase in blood pressure. The norepinephrine reuptake inhibition effect of venlafaxine is dose-dependent and occurs at doses of 150 mg or more. SNRIs may not be an appropriate option in patients with uncontrolled hypertension for this reason; however, the demonstrated blood pressure effect appears to be dose-related. In addition, venlafaxine has been found to cause QTc prolongation at both therapeutic and supratherapeutic doses, so baseline QTc monitoring may be appropriate in patients with risk factors for QTc prolongation. Additionally, both duloxetine and venlafaxine require renal dose adjustments in patients with renal dysfunction. In patients with hepatic dysfunction, duloxetine should be avoided, and venlafaxine’s dose should be adjusted as appropriate. In addition, SNRIs have a significant pharmacodynamic drug interaction with aspirin, antiplatelets, and anticoagulants. Serotonin uptake into platelet cells is a key component to platelet aggression. Thus, inhibition of serotonin reuptake with SNRIs can increase the risk of bleeding. This risk is increased up to 3-fold when SNRIs are concomitantly used with NSAIDs, aspirin, antiplatelets, and/or anticoagulants.53 Patients on SNRI and NSAIDs, aspirin, antiplatelet, and/or anticoagulant therapies should be monitored for signs and symptoms of bleeding.


In addition to antidepressants, both gabapentin and pregabalin are recommended as first-line options for neuropathic pain.5,6 Gabapentin is used off-label for neuropathic pain, while pregabalin is FDA-approved for various pain indications including diabetic peripheral neuropathy, fibromyalgia, and neuropathic pain.54,55 (See a separate report on the abuse potential of gabapentinoids.) Gabapentinoids are a nice first-line option with minimal cardiovascular side effects. Common side effects of gabapentinoids include dizziness, drowsiness, sedation, and peripheral edema. A recommended starting dose of gabapentin is 100 to 300 mg by mouth at bedtime or in divided doses, titrated to desired effect with a maximum daily dose of 3600 mg. Pregabalin is recommended to be started at a dose of 75 mg twice daily, titrated to desired effect with a maximum daily dose of 450 mg. In addition, both medications may require renal dose adjustment in patients with renal dysfunction and a CrCl < 60 mL/min. Dose titration should be done slowly every 3 to 7 days to lessen side effects.

Additional second-line options for neuropathic pain include tramadol, topical capsaicin, and opioids (see above for more details). See also Table II.

Patient Case 2 Revisited

Due to this patient’s atrial fibrillation, trialing a TCA would not be safe and may exacerbate both his arrhythmia and his uncontrolled hypertension. In addition, SNRIs may worsen his blood pressure. Gabapentinoids may be most appropriate in this patient as it is recommended as first-line for neuropathic pain and has minimal cardiovascular side effects. Due to his renal function, his gabapentinoids dose should be renally adjusted. One option for this patient could be to initiate gabapentin at 300 mg once daily and titrate up to the desired effect with a maximum dose of 700 mg twice daily due to his renal function.


When choosing pharmacologic therapy for treatment of chronic pain conditions, such as osteoarthritis and diabetic peripheral neuropathy, it is important to review the whole patient prior to choosing a pain management regimen. Patient- specific factors, including comorbidities, may guide practitioners in choosing the most safe and effective treatment for a patient’s pain. 


Editor's Note: This case is the fifth in a PPM series examining how comorbidities play a role in the selection of medications for pain management. Case 1 reviewed non-opioid options for a patient with chronic pain complicated by hypertension and post-traumatic stress disorder; Case 2 focused on the use of buprenorphine in a patient with osteoarthritic pain, complicated by chronic obstructive pulmonary disease; Case 3 examined options for managing diabetic peripheral neuropathy (DPN), kidney disease, and substance use disorder; and Case 4 focused on the use of opioids in those with chronic kidney disease and diabetic peripheral neuropathy.

Last updated on: December 30, 2019
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