Etiology of Pain and Its Association with Quality of Life among Patients with Heart Failure

Abstract

Objective:

Describe the etiology of pain among HF patients and examine the relationship between pain and QoL.

Background:

Little is known about the etiology of pain in patients with heart failure (HF) and the impact it has on quality of life (QoL).

Methods:

A prospective cohort study of outpatients with NYHA Class II or III HF were surveyed at baseline and at three-month follow-up. The study was conducted in Heart Failure clinics affiliated with a large, urban, academic medical center.

Results:

Of 104 patients that completed a baseline survey, 73 (70%) completed a follow-up survey. At baseline, 48% of patients reported having pain the previous week. Patients on prescription pain medication (n = 16) had more severe pain (Mean = 4.5 vs. 2.6; p = 0.001). Physician documented pain etiologies included: musculoskeletal (50%, n = 16), cardiac (22%, n = 7), and headache/neurological (22%, n = 7). Linear regression revealed that significant contributions to QoL included HF Class (p = 0.0001), dyspnea (p = 0.0001), and depression (p = 0.01). Pain was not independently associated with QoL (p = 0.17), but moderately correlated with depression (r = 0.49). Although 15% (n = 11) of patients reported a clinically meaningful improvement in pain scores, it was not associated with improvements in QoL (χ² = 1.6, p = 0.2).

Discussion:

Pain is prevalent and persistent, due largely to non-cardiac causes. Although pain did not predict QOL, it was associated with depression, which did adversely affect QoL. Clinicians should screen for and treat both symptoms.

Introduction

Heart failure (HF) is a progressive disease that affects more than 5 million Americans and is a major source of morbidity and mortality.^1,2 More than 500,000 patients are diagnosed with HF each year and half of them will die within five years of first hospital admission, making the prognosis of HF worse than many cancers.^3,4 Despite the high morbidity and mortality rates associated with HF, there are many treatments for HF that help patients live longer and have improved quality of life (QoL).^5–7 Despite advances in the treatment of HF, many patients experience symptoms that should be amenable to palliation such as pain, dyspnea, fatigue, and depression. These symptoms cause unnecessary distress and diminish QoL.^8–12

Pain is prevalent and persistent among patients with HF.^8,13 Despite increased documentation that pain is associated with HF, little is known about the etiology of pain and the impact that pain has on the QoL of patients with HF. In previous studies, HF severity, number of comorbidities, age, and socioeconomic status have been reported to be associated with poorer QoL among HF patients.¹⁴ We sought to understand the etiology of pain and examine the relationship between pain and QoL among outpatients with HF receiving guideline-driven HF treatment to better target treatment and improve care. Given that HF is more prevalent in older patients, we hypothesized that pain would arise from a variety of etiologies commonly seen in elders such as musculoskeletal conditions as well as heart disease, would be independently associated with QoL, and therefore that changes in pain would be associated with changes in QoL.

Methods

Setting

This study was undertaken between July 2007 and November 2009 in HF clinics affiliated with a large, urban, academic medical center. The clinics serve an ethnically diverse population and provide care for ∼600 patients/year with HF.

Patients

The inclusion criteria for this study required patients to be 18 years or older with New York Heart Association (NYHA) Class II or Class III HF,¹⁵ irrespective of ejection fraction (EF). Patients were also required to be English speaking and able to provide written informed consent.

Procedure

The study was reviewed and approved by the UCSF Institutional Review Board. A research assistant provided a detailed overview of the study to eligible patients and obtained informed consent. Patients were then provided a baseline survey to complete at home and return using the stamped, self-addressed envelope provided. A follow-up survey was mailed to patients three months after completion of the initial survey. Research staff made follow-up telephone calls if completed baseline and follow-up surveys had not been received within four weeks after distribution.

HF treatment

We reviewed hospital medical records to assess the severity of HF at enrollment. Information collected included the EF and physician-documented presence and location of their patient's pain. We recorded medications for pain management (i.e., NSAID and opioids), angina, depression, anxiety, cholesterol, and diabetes that were included in the patient's medication list. We also documented guideline-driven heart-related therapies prescribed, including the use of angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), beta-blockers, diuretics, and spironolactone or eplerenone.

Survey

The survey collected demographic information such as date of birth, gender, race, and ethnicity. It also assessed comorbidities, pain, depression, dyspnea, and heart-related QoL, and asked patients with pain to what they attributed their pain. The number of comorbidities was calculated by summing the presence of high blood pressure, lung disease, diabetes, kidney disease, liver disease, anemia, cancer, osteoarthritis, back pain, and rheumatoid arthritis.

Assessing pain

Pain severity was determined using the brief pain inventory.¹⁶ Pain severity was calculated from the mean of 4 pain items (worst, least, and average pain in the past 24 hours as well as current pain) assessed using an 11-point numeric scale (0 = “no pain” to 10 = “pain as bad as you can imagine”). We considered a change of 2 or more points to be clinically meaningful.¹⁷ There was excellent internal consistency for pain severity (α = 0.92) among this study population. Patients were also asked to identify the specific location of their pain using an anatomical diagram.

Depression was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The 20-item measure includes items pertaining to a range of depressive symptoms.¹⁸ Patients reported the frequency of occurrence of each symptom in the past week on a 4-point numeric scale (0 = “rarely or none of the time” to 3 = “most or all of the time”) providing a composite score (range: 0–120). A score of 16 or higher was used to categorize patients with probable depression.^19,20 A change of 5 or more points was considered clinically meaningful.²¹ The CES-D demonstrated excellent internal consistency (α = 0.91) within this study population.

Dyspnea was assessed using the Borg Scale.²² Patients reported their degree of breathlessness as “none” (score 0) to “maximum possible” (score 10). An improvement of 1 or more points is considered clinically meaningful.²³

HF-related QoL was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ), which is a disease-specific instrument consisting of 21 items assessing perceptions of the effects of HF on life satisfaction.²⁴ Respondents rate the degree to which each HF-related impairment prevented them from living the life they wanted during the previous four weeks. QoL impairment is evaluated using a 6-point scale ranging from 0 (no impact) to 5 (severe impact). The 21 items comprising the MLHFQ produce a total score ranging from 0 to 105 with lower numbers indicating better QoL. A change of 5 or more points was considered clinically meaningful.²⁵ The MLHFQ demonstrated excellent internal consistency (α = 0.95) among our study population. Pain is not assessed in the MLHFQ, but depression and breathlessness are.

Statistical analysis

Descriptive statistics including frequencies, means, and standard deviations (SDs) were used to examine the distribution of measures. Chi-square (χ²) analysis was undertaken to examine bivariate associations between categorical variables, and analysis of variance (ANOVA) was undertaken to examine associations between categorical and continuous variables. Pearson correlation coefficient (r) was used to examine the relationship between continuous variables.

Multivariate linear regression analysis was undertaken to examine the participant characteristics associated with QoL at baseline. To examine potential differences in the mean scores for pain, dyspnea, depression, and QoL between the baseline and follow-up surveys, we conducted paired sample t tests. A multivariate logistic regression was used to identify predictors of achieving a clinically meaningful improvement in QoL from baseline to follow-up. Independent variables that were significant at p ≤ 0.10 in univariate analysis were included in all multivariate analyses. The Statistical Package for the Social Sciences (SPSS) version 22 for Mac²⁶ was used to conduct all analyses.

Results

Participant characteristics

A total of 194 HF clinic patients were approached to participate in the study, of which 151 (77.8%) consented. Baseline surveys were completed by 69% (n = 104) of those consenting. The follow-up survey was completed by 73 patients (70%) a median of four months (SD = 1.4, range = 3–10 months) after the completion of the initial survey.

Over half of patients had NYHA Class II HF (57%, n = 59) and 43% (n = 45) had Class III HF. A majority of patients (71%, 71/100) had systolic HF (EF of <50%) with a mean EF of 31.6% (SD = 9.1; range: 14.0–49.0). The remainder of patients (29%) had diastolic HF (EF ≥50%) with a mean EF of 59.8% (SD = 6.7; range: 57.2–62.3). Patients had been diagnosed with HF for a mean period of 7 years (median = 4.5, SD = 8.2, range: 0–46). Patients were on average 53 years of age (median = 55.5, SD = 14.2, range: 21–84), male (66%, n = 69), and white (66%, n = 69). Overall, 79% (n = 82) of patients reported having one or more comorbidities (mean = 1.8, SD = 1.6) (Table 1). The most frequently reported comorbidities included high blood pressure (36%, n = 37) and back pain (31%, n = 32). There were no differences between patients who completed only a baseline survey and those who completed a baseline and follow-up survey in terms of baseline HQoL scores (p = 0.3), presence of probable depression (p = 0.7), dyspnea (p = 0.1), HF class (p = 0.2), or gender (p = 0.8) except that patients who completed the follow-up survey were older (mean = 54.9 years, 95% confidence interval [CI] = 51.8–58.1 vs. 45.8 years, 95% CI = 40.6–51.0, p = 0.005).

Table 1.

Number and Types of Comorbidities Reported by Patients

Comorbidities
No. of comorbidities, mean (SD)	1.8 (1.6)
Types of comorbidities reported, % (n)
High blood pressure	36 (37)
Back pain	31 (32)
Diabetes	23 (24)
Lung disease	16 (17)
Kidney disease	15 (16)
Anemic/blood disease	15 (16)
Osteoarthritis	14 (15)
Ulcer/stomach disease	8 (8)
Cancer	8 (8)
Rheumatoid arthritis	7 (7)
Liver disease	5 (5)

SD, standard deviation.

Prescribed medications and guideline-driven heart-related therapies

We were able to review the charts of 103 patients (Table 2). Patients received the following HF guideline-driven therapies: ACE-I/ARB (80.6%, n = 83), diuretics (78.6%, n = 81), spironolactone/eplerenone (44.7%, n = 46), and beta-blockers (18.4%, n = 19). Other frequently prescribed medications were for the management of cholesterol (55.3%, n = 57) and angina (25.2%, n = 26).

Table 2.

Medications (Prescription and Over the Counter) Included in the Medication List of Patients

	% (n)
Guideline-driven HF therapies
ACE-I/ARB	80.6 (83)
Diuretics	78.6 (81)
Spironolactone/eplerenone	44.7 (46)
Beta-blockers	18.4 (19)
Medications for other conditions
Cholesterol lowering medication	55.3 (57)
Anti-anginal	25.2 (26)
Diabetes medication	19.4 (20)
Antidepressants	18.4 (19)
Pain medication (NSAIDs and opioids)	17.5 (18)
Anxiety medication	9.7 (10)

HF, heart failure.

Pain

At baseline, 48% (50/104) of patients reported having pain in the past week. Of those with pain, 48 reported pain severity with a mean score of 3.3/10 (median = 3.0, SD = 1.7, range 0.5–7.5). Those patients taking pain medications (n = 16) had a significantly higher (F = 15.7, p = 0.001) level of pain (mean = 4.5, 95% CI: 3.5–5.4) than those not prescribed pain medications (mean = 2.6, 95% CI = 2.1–3.1). Across all patients, there was no significant change (t = 1.3, p = 0.2, n = 73) in pain from baseline (mean = 2.2, SD = 1.9) to follow-up (mean = 1.4, SD = 1.9). We found that 15% (n = 11) of patients reported a clinically meaningful improvement (2+ points). Overall 65.7% (n = 48) of patients reported no change in pain score and 19.2% (n = 14) reported that the severity of their pain had worsened.

Etiology of pain

Patients with pain were asked to report the cause of their pain and could provide multiple etiologies. Of the 50 patients reporting pain at baseline, 52% (n = 26) reported that the cause was the result of medical conditions other than HF: 30% (15/50) stated that it was due to their HF and 30% (15/50) stated that their pain was from the treatment they were receiving for their HF. Patients reported that they experienced pain at a mean number of four anatomical sites (median = 3.8, SD = 2.8, range: 0–12). The most common sites of pain were left chest (42%, 21/50), left lower back (40%, 20/50), right lower back (32%, 16/50), and right calf (32%, 16/50). We found physician documentation in the medical record regarding the source of pain for 32 patients. The most common sources of pain included musculoskeletal (50%, n = 16), cardiac (22%, n = 7), headache/neurological (22%, n = 7), and abdominal (6%, n = 2).

Depression

Nearly half of patients (45%, n = 47) were identified as having probable depression with a mean depression score of 26.0 (SD = 8.2). There was no difference (F = 0.3, p = 0.6) in the depression scores between those who were (mean = 26.9, 95% CI = 21.8–31.9) or were not (mean = 25.4, 95% CI = 23.2–28.4) taking antidepressants.

For those completing baseline and follow-up surveys, there was no significant change (t = −1.4, p = 0.17, n = 73) in the depression scores from baseline (mean = 16.2, SD = 11.7) to follow-up (mean = 17.8, SD = 7.6). Overall, 23.2% (n = 17) saw a clinically meaningful improvement in their depression score (5+ points).

Dyspnea

A total of 76 (73.8%) patients reported having dyspnea with a mean score of 2.7 (SD = 1.7, range: 0.5–10). There were no significant differences (t = 1.6, p = 0.12, n = 73) in the dyspnea scores from baseline (mean = 2.2, SD = 1.9) to follow-up (mean = 1.9, SD = 1.5). However, 35.6% (n = 26) reported their dyspnea had improved, 34.2% (n = 25) saw no change, and 28.8% (n = 21) reported that dyspnea was worse than reported at baseline.

Heart-related QoL

At baseline, the QoL mean score across all patients was 49.5 (median = 51.0, SD = 24.7, range 0–93). Patients with Class III HF had significantly worse QoL scores (mean = 66.0, 95% CI = 60.1–71.8) than those with Class II (mean = 36.7, 95% CI = 31.3–42.1, p = 0.0001) (Table 3). Patients with probable depression also had a worse QoL score (mean = 65.3, 95% CI = 59.6–71.0) than those who did not screen positive for depression (mean = 36.7, 95% CI = 31.1–43.5, p = 0.0001). Pain was moderately associated (r = 0.29, p = 0.003) with QoL and dyspnea (r = 0.54, p = 0.0001) was strongly associated.

Table 3.

Patient Characteristics and Minnesota Living with Heart Failure Questionnaire Quality of Life Scores at Baseline (n = 104)

	MLHFQ QoL total score at baseline (range: 0–105)
Variable	Mean (95% CI)	p
HF class
Class II	36.7 (31.3–42.1)	0.0001
Class III	66.0 (60.1–71.8)
HF type
Systolic (<50%)	50.0 (43.9–56.0)	0.9
Diastolic (≥50%)	49.6 (40.3–58.8)
Gender
Female	49.5 (40.8–58.2)	0.99
Male	49.5 (43.5–55.4)
Depression (CES-D)		0.0001
None	36.7 (31.1–42.3)
Probable	65.3 (59.6–71.0)

	R
Age	−0.15	0.12
Years with HF	−0.001	0.99
Comorbidities	0.13	0.21
Pain (BPI)	0.29	0.003
Dyspnea (Borg)	0.54	0.0001

MLHFQ, Minnesota Living with Heart Failure Questionnaire: higher scores mean worse QoL.

BPI, brief pain inventory; CES-D, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; QoL, quality of life.

Linear regression revealed three factors that made a significant unique contribution to QoL: depression (r² = 0.18, p = 0.0001), HF class (r² = 0.11, p = 0.0001), and dyspnea (r² = 0.02, p = 0.01). Overall, the regression model explained 63% (r²_adj: 0.63, F = 35.3, p = 0.0001) of the total variance in QoL scores (Table 4). Although pain was significantly associated with QoL in univariate analysis, the correlation matrix (Table 5) illustrates that pain and depression were moderately associated (r = 0.49) and depression had a stronger correlation with QoL (r = 0.67) than did pain (r = 0.29).

Table 4.

Multivariate Linear Regression Models for Patient Characteristics Predicting Quality of Life at Baseline

Variable	B (95% CI)	r² change	t	p
HF class	19.1 (12.4 to 25.7)	0.11	5.7	0.0001
Depression (CES-D)	1.1 (0.9 to 1.5)	0.18	7.1	0.0001
Dyspnea (Borg)	2.4 (0.5 to 4.2)	0.02	2.5	0.013
Pain severity (BPI)	−1.2 (−2.9 to 0.5)	0.007	−1.4	0.17

QoL overall model: r², 0.65; R²_adj, 0.63 (n = 103, df = 4, F = 44.5, p = 0.0001).

Table 5.

Correlation Matrix Baseline Quality of Life

	QoL	HF class	Depression	Dyspnea	Pain
QoL	1.0	0.59	0.67	0.54	0.29
HF class		1.0	0.29	0.42	0.24
Depression			1.0	0.40	0.49
Dyspnea				1.0	0.21
Pain severity					1.0

Change in QoL from baseline to follow-up

Of the 73 patients with follow-up QoL data, there was a significant improvement (t = 2.5, p = 0.01) in QoL from baseline (mean = 51.7, 95% CI = 46.1–57.2) to follow-up (mean = 46.9, 95% CI = 41.5–52.2). Overall, 47.9% (n = 35) reported a clinically meaningful improvement in QoL (5+ points). A worsening in the QoL scores was observed among 34.2% (n = 25) of patients.

We examined participant characteristics and their association with achieving a clinically meaningful improvement in QoL. Univariate analysis revealed that the only variables that were significantly associated with improvement in QoL were NYHA HF Class III (p = 0.0007) and patients who achieved a clinically meaningful improvement in their depression scores (p = 0.002). Patients with NYHA HF Class III were 3.9 (95% CI = 1.4–10.9) times more likely to have a clinically meaningful improvement in QoL than those with NYHA HF Class II. Furthermore, patients who reported to have a clinically meaningful improvement in their depression scores were 4.3 (95% CI = 1.2–14.6) times more likely to report a clinically meaningful improvement in their QoL. Other characteristics examined included age (p = 0.4), years with HF (p = 0.4), comorbidities (p = 1.0), gender (p = 0.6), and clinically meaningful improvements in pain (p = 0.2) and depression (p = 0.6), and none were independently associated with improvement in QoL.

Discussion

We found that pain was pervasive and persistent among patients with NYHA Class II–III HF. Almost half of HF patients reported having pain. Although there was improvement in pain for some patients, four months after the initial assessment one in five reported a worsening of their pain. The most common etiologies of pain included musculoskeletal conditions and neurological/headache in addition to heart disease and its treatment. The range of etiologies highlights a central role for both cardiologists and primary care clinicians in managing pain in these patients. The fact that patients taking medications for pain reported higher pain scores suggests that many may be undertreated and additional screening for these symptoms by the primary care team may be required. Alternatively, they could be referred to specialist palliative care for evaluation by clinicians with expertise in managing these pervasive symptoms.²⁷

We found a strong association between pain and depression, and the relatively high prevalence of these symptoms is consistent with previous research.²⁸ Although depression was an independent predictor of QoL, pain was not. Importantly, the QoL instrument we used, which was developed for assessing heart-related QoL, includes items about depression but not pain, and thus might be expected to be sensitive to changes in depression. In future studies, it would be helpful to use a general QoL instrument to assess the relationship between pain, depression, and QoL. From our data, it is difficult to deduce with certainty the causal relationship between pain and depression, though it is likely bidirectional.²⁹ Depression can manifest as a somatic complaint such as pain and can exacerbate pain syndromes, and chronic pain can lead to depression. However, there is evidence the two symptoms are independent. For example, studies of tricyclic antidepressants for treating neuropathic pain demonstrate efficacy in depressed and nondepressed patients, suggesting that pain relief is not simply due to improvements in depressive symptoms.³⁰ The fact that many patients ascribed their pain to HF and that depression and HF share a similar neurohormonal mechanism through norepinephrine suggests that optimal management of HF may impact depression.³¹ However, the differential role of norepinephrine in the heart and brain and of medications that act on norepinephrine receptors in those target organs requires further research to guide approaches to treatment. Regardless of the mechanism, the complex relationship between pain and depression and the fact that many patients with HF have both symptoms argues for the routine screening for these symptoms and treating both aggressively.³²

Given the prevalence of distressing symptoms in patients with HF and evidence of persistent and undertreatment of pain, involving interdisciplinary palliative care teams may prove effective.^33,34 These teams could work alongside cardiology teams and primary care clinicians and would be responsible for the management of patients with multiple or more severe symptoms while serving as a resource to their colleagues.

Interpretation of our findings should be tempered by the following limitations. Given that our HF population was somewhat younger than those usually assessed, generalizability may be limited. Older patients may be expected to have more symptoms of greater severity and are also likely to have more comorbidities. It may be that, in an older population, pain would be shown to independently drive QoL. However, comorbidities were common in our patients, making this possibility less likely. Patients who completed follow-up surveys were older than those who completed only a baseline survey, thereby introducing potential bias; however, we determined that age was not associated with QoL.

Our findings add to the burgeoning body of evidence demonstrating the high prevalence of pain in patients with HF. They also provide new information suggesting that etiology of pain relates to cardiac and noncardiac causes. Given that many patients with HF have pain from noncardiac causes, treatments that are effective for these other etiologies would be expected to be helpful for these patients. One important caveat is that although nonsteroidal anti-inflammatory drugs are standard treatment for musculoskeletal pain, they promote retention of sodium and water in the kidney that can lead to volume overload and exacerbations of HF and thus should be avoided in this population. Opioids can be effective and nonpharmacological treatments, especially for patients already on complex medication regimens, can play an important role in management. Routine assessment of patients with HF for pain and its etiology as well as for depression could lead to better care. Referral to palliative care teams for those patients with the most severe symptoms or those who do not respond to standard therapies could further improve care.³⁵ Regardless of whether symptom management is performed by cardiologists, primary care clinicians, or palliative care experts, optimal medical management of HF combined with routine screening for and aggressive treatment of distressing symptoms including pain may prove an effective strategy for improving care that should be investigated formally.

Footnotes

Acknowledgments

We thank all patients who participated in this study. We would like to thank the doctors and nurses involved with the HF clinic for allowing us to recruit patients. We would also like to thank Dr. Steven Paul for his guidance with regard to the statistical analysis. The Alafi Family Foundation funded this study.

Author Disclosure Statement

No competing financial interests exist.

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