Consistent and Breakthrough Pain in Diverse Advanced Cancer Patients: A Longitudinal Examination

Vol. 37 No. 5 May 2009 Journal of Pain and Symptom Management 831

Original Article

Consistent and Breakthrough Painin Diverse Advanced Cancer Patients:A Longitudinal ExaminationCarmen R. Green, MD, Laura Montague, BS, and Tamera A. Hart-Johnson, MSDepartment of Anesthesiology (C.R.G., T.A.H.-J.), University of Michigan Health System, Ann Arbor,

Department of Health Management and Policy (C.R.G.), University of Michigan School of Public

Health, Ann Arbor, and University of Michigan Medical School (L.M.), Ann Arbor, Michigan, USA

Abstract
Although cancer pain, both consistent and breakthrough pain ([BTP]; pain flaresinterrupting well-controlled baseline pain), is common among cancer patients, its prevalence,characteristics, etiology, and impact on health-related quality of life (HRQOL) are poorlyunderstood. This longitudinal study examined the experience and treatment of cancer-relatedpain over six months, including an evaluation of ethnic differences. Patients with Stage IIIor IV breast, prostate, colorectal, or lung cancer, or Stage IIeIV multiple myeloma with BTPcompleted surveys on initial assessment and at three and six months. Each survey assessedconsistent pain, BTP, depressed affect, active coping ability, and HRQOL. Among therespondents (n¼ 96), 70% were white, 66% were female, and had a mean age of 56� 10years. Nonwhites reported significantly greater severity for consistent pain at its worst(P¼ 0.009), least (P # 0.001), on average (P¼ 0.004), and upon initial assessment(P¼ 0.04), and greater severity for BTP at its worst (P¼ 0.03), least (P¼ 0.02), and atinitial assessment (P¼ 0.008). Women also had higher levels of some BTP measures. Ethnicdisparities persisted when data estimation techniques were used. Examined longitudinally,consistent pain on average and several BTP measures reduced over time, although notgreatly, indicating the persistence of pain in the cancer experience. These data provideevidence for the significant toll of cancer pain, while demonstrating further health caredisparities in the cancer pain experience. J Pain Symptom Manage 2009;37:831e847.� 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Key Words
Pain (breakthrough, cancer, and consistent), racial, ethnic, and gender disparities, healthcare and health policy, quality of care, quality of life, physician variability, painmanagement, longitudinal design
The authors thank Blue Cross/Blue Shield Foundationof Michigan for funding this research and the HartfordFoundation for funding Laura Montague’s time.

Address correspondence to: Carmen R. Green, MD,1H247 University Hospital, 1500 East Medical CenterDrive, SPC 5048, Ann Arbor, MI 48109-5048, USA.E-mail: [email protected]

Accepted for publication: May 17, 2008.

� 2009 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.

IntroductionGlobally, both cancer and pain are signifi-

cant public health problems. More specifically,cancer pain (i.e., pain associated with canceror its treatment) exacts a tremendous individ-ual and socioeconomic toll.1 In reality, painis the most common symptom associated withcancer,2 and patients with advanced cancer

0885-3924/09/$esee front matterdoi:10.1016/j.jpainsymman.2008.05.011

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832 Vol. 37 No. 5 May 2009Green et al.

usually experience pain.3 Despite national(e.g., Joint Commission on the Accreditationof Healthcare Organizations) and global(e.g., World Health Organization) efforts de-signed to improve both cancer and pain care,nearly 70% of people dying from cancer expe-rience unrelieved pain.3 Regardless of patientor cancer characteristics, when pain accom-panies cancer, it significantly impacts healthand quality of life (QOL).4,5 Thus, understand-ing how cancer pain impacts health and well-being in an increasingly aging, and raciallyand ethnically diverse population becomescritically important.6

Racial and ethnic disparities in health careare also significant public health problemsand are likely to affect cancer pain. However,the U.S. Institute of Medicine reports, UnequalTreatment: Confronting Racial and Ethnic Dispar-ities in Health Care and The Unequal Burden ofCancer: An Assessment of NIH Research andPrograms for Ethnic Minorities and the MedicallyUnderserved, devoted minimal attention topain but continued to document the unequalburden of cancer in minorities.7,8 For instance,blacks have a higher incidence of colorectal,lung, and prostate cancer compared withwhites,9e12 and higher mortality rates for colo-rectal, lung, prostate, and breast cancer com-pared with whites.9e13 Disparities have beendocumented in the prevalence, severity, andtreatment for all types of pain,14e16 withminorities having a higher prevalence andmore severe pain.17,18 Minorities are also lesslikely to have their pain complaints adequatelyassessed and treated when compared with non-Hispanic whites.19e24

Despite the many therapeutic modalitiesavailable to alleviate pain, the literature sup-ports an unequal burden of cancer and painfor racial and ethnic minorities. Both patientand physician factors contribute to poor painassessment. Cancer patients may be reluctantto discuss pain complaints because of fearsthat they may distract their physician fromtreating their cancer, or it is a sign the canceris getting worse. In Bernabei et al.’s study,21

minority elders with cancer were less likely tohave their pain score recorded, and evenwhen their score was recorded, they were lesslikely to receive adequate pain medication.Overall, minorities report less satisfactionwith pain treatment and less relief from pain

medication when compared with non-Hispanicwhites.25 Additionally, minority patients andwomen disproportionately receive inappropri-ate analgesic therapy for their cancerpain.25,26 Even when treated, minorities expe-rience additional barriers, with pharmacies inminority neighborhoods less likely to maintainadequate opioid analgesic supplies than phar-macies in predominantly white communities.15

These data provide few details, however, andthe toll of cancer pain on QOL over time ina diverse population is unknown.

Beyond consistent pain, breakthrough pain(BTP) (a transitory flare of moderate to severepain interrupting mild background pain that isbeing controlled by a stable analgesic regi-men) is a common problem among cancer pa-tients.27 In cancer patients, BTP may lead tofurther diminutions in QOL, while potentiallyindicating more severe pain syndromes or aninadequate response to opioid analgesics.28

BTP can be distinguished from other pain syn-dromes by describing its quality andcharacteristics.29e31 Studies have revealedthat patients with BTP have poorer health-re-lated quality of life (HRQOL) and mentalhealth than those without BTP.30 Most com-monly, BTP is precipitated by a particularmovement or the end of a medication course(often referred to as end of dose failure).31 Itis commonly treated with ‘‘rescue doses’’ ofopioid analgesics typically used to treat andcontrol consistent cancer pain.31

The prevalence, characteristics, and treat-ment of BTP in the cancer population varywidely, with prevalence estimates rangingfrom 19% to 93%.32e34 Among cancer patientsbeing admitted to a hospice facility, Zeppetellafound that 89% presented with BTP.29

Although Portenoy and Hagen provided anunderstanding of BTP’s characteristics andconsequences, these studies have significantlimitations.27 Most studies failed to report onpotential variations in the prevalence, charac-teristics, and quality of BTP based on race, eth-nicity, or gender. Furthermore, longitudinalstudies of cancer pain focus primarily on acutechanges in pain after procedures,35e40 pain inrelation to time of death,40,41 or pain in a sin-gle, specific type of cancer.42,43 Informationabout the course of pain (consistent painand BTP) across the cancer experience in a di-verse population is lacking.

Vol. 37 No. 5 May 2009 833Breakthrough Pain in Cancer

Physician variability in assessing and treatingpain based on sociodemographic factors is welldescribed.22e24,44 Physicians also continue tograpple with how best to manage cancer painand the unique challenges posed by BTP’sunpredictable onset and diverse pathophysiol-ogy. Considering the significant individual andpublic health implications of cancer, pain, andcancer pain, we designed a prospective longi-tudinal survey study examining the impact ofcancer pain (both consistent and BTP) onhealth and QOL in diverse patients withadvanced cancer. We hypothesized that cancerpain is present and would not change signifi-cantly over the six month time frame for thediverse sample. We also hypothesized that non-whites with advanced cancer experience morepain than whites, and women experience morepain than men. The current study seeks todescribe and compare consistent and BTPcharacteristics, quality, and treatment overtime in an ethnically diverse population ofmen and women.

MethodsParticipants

Approval for this prospective longitudinalstudy was granted by the University of Michi-gan Health System (UMHS) InstitutionalReview Board (IRB). English-speaking, adult(18e75 years old), nonwhite (i.e., Arabic,black, Hispanic, and Native American) andwhite cancer patients with Stage III or IVbreast, prostate, colorectal or lung cancer, orStage II, III, or IV multiple myeloma, whoexperienced BTP, were recruited from four ur-ban outpatient cancer centers across Michiganand from the University of Michigan CancerRegistry. People aged 75 years or more oftenhave several chronic comorbid conditionsand take multiple medications (the literaturesuggests 7e8). They also have pain (the litera-ture suggests that 30e50% of elders have per-sistent pain). Because QOL, pain, andnumber of medications were study endpoints,and advanced age may confound the results,people aged 75 years or more were not in-cluded in this study. Only patients reportingBTP and receiving around-the-clock analgesictherapy for cancer pain were included. AnEastern Cooperative Oncology Group Perfor-mance Status of 2 or less (no more than 50%

of the day spent in bed) also was required forinclusion.

Clinical and research staff identified a conve-nience sample of patients for screening and re-cruitment based on diagnosis and painmedication status. Written informed consentwas obtained from each study participantupon enrollment. Subjects completed threesurveys (upon recruitment, and at three andsix months) and a diary of cancer treatment,medications, and pain severity. Data from allthree surveys were included in analyses.

MeasuresValidated survey instruments were given to

each subject to assess pain quality and charac-teristics, patient attitudes about pain and itstreatment, depression, active coping skills,and QOL.

Sociodemographic data were obtained atscreening (age, race, and gender) and con-firmed in the baseline survey. Marital status,education, employment, and household in-come were all categorical variables. Cancertype and stage also were collected andconfirmed with the clinical database from theparticipating institution. Additionally, comor-bidities were measured by a checklist of19 different comorbid conditions (yes¼ 1,no¼ 0). For each comorbidity, participantswere asked if they were ever diagnosed bya health professional.

The Brief Pain Inventory (BPI) assessed paincharacteristics, severity, and interference withnormal physical and emotional functioning.45

Separate sections asked about consistent painand BTP. The section for consistent pain waspreceded with: ‘‘Questions B1eB9 refer toyour experiences with everyday, CONSISTENTPAIN, since you have been diagnosed with can-cer. Your everyday, consistent pain is the painfor which your doctor(s) has prescribed painmedication(s) on a set daily regimen (e.g.,every 4e6 hours).’’ The BTP section was pre-ceded with: ‘‘During periods of relatively con-sistent pain or periods that were relativelypain-free, you may have also experiencedTEMPORARY FLARES OF PAIN OR PAIN AT-TACKS.’’ These temporary pain flares may becaused by various types of movements. Theymay also occur near the end of pain medica-tion dose, or may be spontaneous and haveno apparent cause. These pain flares usually


come on rapidly and can last from a fewseconds to a few hours. Your doctor may haveprescribed additional pain medication(s) tospecifically treat these pain flares. Doctorsoften call these temporary pain flares, ‘‘Break-through Pain.’’ Four items for consistent pain(i.e., Please rate your consistent pain byCIRCLING THE ONE NUMBER that best de-scribes your consistent pain at its WORST inthe past 24 hours; reworded for least, averageand right now) and pain severity (0¼ nopain; 10¼ worst pain you can imagine)assessed pain. These items were reworded toassess BTP (i.e., Please rate your overall painflares by CIRCLING THE ONE NUMBERthat best describes your overall pain flares attheir WORST; reworded for least, averageand right now). A scale was calculated foreach from the mean of the four items. Themean of seven other BPI items was used todetermine the score on the pain-related inter-ference subscale (0¼ no interference,10¼ complete interference), which wasrelated only to consistent pain. Internal reli-ability for the BPI severity subscale rangedfrom a¼ 0.89e0.94 for consistent pain andfrom a¼ 0.83e0.87 for BTP, and for the BTPinterference subscale, ranged froma¼ 0.93e0.95 for the three data waves. TheBPI also includes items about pain characteris-tics (timing, duration, quality, and cause),medication, pain medication effectiveness,and an open-ended item regarding whatactions relieved pain. Pain characteristics,pain medication effectiveness (0e100%), anda dummy variable for any activity effectivelyalleviating some portion of pain (0¼ nothinghelps; 1¼ something can be done to lessenpain) were used for the analyses.

The Pain Management Index (PMI) was cre-ated by combining patient pain severity scoresat worst during the past week and their currentanalgesic (measured by collecting informationabout each patient’s current medications).Three medical staff (two anesthesiologistsand one PharmD) previously classified a listof medications into 38 classes. The agreementrate among health professionals was 99.5%.Any medication not in this list was classifiedby a physician according to the previously es-tablished guidelines. To yield the drug vari-able, the 38 classes of drugs were collapsedinto four groups based on their analgesic

function: 0¼ nonanalgesic; 1¼ nonopioid an-algesic; 2¼ weak opioid; 3¼ strong opioid.The strongest medication being used by thesubject for pain was the one classified. A dis-tinction was made in the question betweenconsistent pain medications (typically takenon a regular regimen) and BTP medications(prescribed ‘‘as needed’’). The BPI severitywas collapsed into four categories: 0¼ absenceof pain (0); 1¼mild pain (1e3); 2¼moderatepain (4e7); and 3¼ severe pain (8e10). ThePMI is the difference between the analgesiclevel and the categorized pain level (rangingfrom -3 and þ3). This ordinal variable was alsoused in its categorical form with 0¼ inadequateanalgesic therapy (PMI¼ -3 to -1) and1¼ adequate analgesic therapy (PMI¼ 0 toþ3).

The Center for Epidemiological Studies DepressionScale (CES-D) assessed depressed affect. Thefour positively worded items from the original20-item survey were dropped, because factoranalysis showed that the items did not accu-rately predict negative affect when reversed,and a literature review confirmed this in a can-cer population.46,47 The ordinal values for theremaining 16 items were summed andweighted to calculate an overall score compa-rable with the published scale range (0e60);scores more than 15 indicated severe psycho-logical distress and depression. Internal consis-tency for the 16-item CES-D was in the rangea¼ 0.81e0.92, consistent with publishedvalues,46 although the six month reliability of0.81 could be improved to 0.92 if the item‘‘everything I did was an effort’’ was dropped.

The John Henryism Active Coping Scale(JHACS) evaluated active coping strategies atbaseline. John Henryism is a high-output cop-ing strategy characterized by protracted strug-gles against seemingly insurmountableobstacles. The construct was reported amongaging African Americans, and is correlatedwith hypertension and bodily pain. The sumscore of 12 Likert-type items was calculated(1¼ completely false; 5¼ completely true;60¼maximum active coping score). Internalconsistency of the JHACS was a¼ 0.87, higherthan previously published values.48

The Barriers Questionnaire (BQ-II) assessedbarriers in patient attitudes toward painmanagement and treatment. The BQ-II ques-tionnaire has four separate subscales:


physiological effects, fatalism, communication,and harmful effects.49 Mean scores were calcu-lated for each Likert-type subscale and fatalismitems were reverse scored before analysis. Theinternal consistency of BQ-II subscales was inthe range a¼ 0.60e0.91 for the three waves.Although the fatalism subscale at baselineand communication barriers at three monthshad a reliability value below previously pub-lished values,49 in this sample the reliabilitieswere above the threshold of a¼ 0.60, andhence, were considered adequate. The small,diverse sample and low number of questionson these subscales may account for the differ-ence in reliabilities.

The European Organization for the Research andTreatment of Cancer Survey (EORTC QLQ-C30)assessed HRQOL.50 Five QOL functioningdomains were assessed: physical, role, cogni-tive, emotional, and social. In addition, eightsymptom-control domains (i.e., fatigue, pain,nausea and vomiting, dyspnea, anorexia, diar-rhea, and constipation) were evaluated fortheir contribution to QOL. Each symptom-control domain surveyed patients for thefrequency of a given symptom during thepast week. An additional measure assessedfinancial concerns, and another measuredglobal health and overall QOL. Scores werelinearly transformed to a 0e100 scale. Internalconsistency of the EORTC QLQ-C30 subscaleswas in the range a¼ 0.71e0.91, higher thanpreviously published results.50

Statistical AnalysisDescriptive statistics were calculated using

SPSS� 15.0. Analysis of variance (ANOVA)and Chi-squared analysis were used to deter-mine differences between whites and non-whites and between men and women insociodemographics, pain characteristics andexperiences, and for each QOL measureexamined. Our primary interest was to exam-ine whether disparities in care existed in thecancer pain experience. Consistent with theliterature providing extensive support for dis-parities, we were primarily interested in explor-ing potential differences in whether nonwhitesor women experienced poorer outcomes thanwhites or men, respectively. Thus, a one-tailedprobability of Type I error, or P # 0.10 wasspecified for significance for group differ-ences. For repeated measures analyses,

because there was not the same a priori direc-tion specified, an error level of P # 0.05 wasconsidered significant for those analyses. Addi-tionally, owing to the retention difficulty withan advanced cancer population and the result-ing small sample size in the three- and six-month follow-ups, we examined later wavesboth with the data that were actually present,and using the ‘‘last point measured’’ for thepain and QOL measures as a substitutewhen data were missing in later waves. Multi-variate analysis of variance (MANOVA) wasused to examine differences by race/ethnicityand gender in overall consistent pain, BTPseverity, QOL functioning, and QOL symp-tom control, because the subscales for thesemeasures are highly correlated. ANOVA andMANOVA techniques are relatively robust interms of assumptions of normality. Addition-ally, for the 36 continuous or ordinal vari-ables used in analyses, only one hada skewness of more than 2 (number of painsites). Most (83%) variables had skewness ofless than 1, including all of the BPI subscalesand all the EORTC QLQ-C30 subscales ex-cept nausea and diarrhea. The combinedmeasures were all normally distributed.Repeated measures ANOVA was then per-formed to test whether consistent pain, BTP,depression, or QOL changed significantlyover waves, with least significance differencetests performed post hoc to examine pairedcomparisons.

ResultsDemographics

One hundred and twenty-four subjects wereconsented. Thirty consenting subjects diedbefore the end of the study or within sixmonths from original consent (deathsoccurred on average of 15� 9 weeks after con-sent). Table 1 summarizes study retention overthe three waves of data collection. Longitudinalresults are presented for all data collected andfor subjects with complete data only. Nonwhiteswere more likely than whites to decline afterinitial consent (21% vs. 7%, P¼ 0.05). Subjectswho consented and then declined most oftenresponded that they no longer felt well enoughto fill out the surveys because of their cancer.For the sample completing the baseline survey(n¼ 96), 29% were nonwhite (n¼ 28; 20 black,

Table 1Retention Over the Study Duration

SubjectStatus Baseline (n)

3-MonthSurvey (n)

6-MonthSurvey (n)

After6 Months (n) Total (n)

Consented initially 124 103 94Surveys collected 96 (93%) 66 (81%) 46 (54%)Nonresponse/still consented 7 15 39Declined/left study 12 8 3 0 23Deceased/exited 9 14 6 1 30


four Native American, three Hispanic, two Ara-bic, and one black/Native American), mostwere females (66%), and their ages rangedfrom 24 to 75 years. There were no significantdifferences between whites and nonwhites inage, sex, education, or employment. Therewere significant differences in marital status be-tween the two groups, with whites more likely tobe married (74% vs. 32%) and less likely to bedivorced (17% vs. 36%) when compared withthe nonwhites (P¼ 0.001). There were also ra-cial differences in annual household income,with whites more likely to fall into the high in-come group ($100,000 or more) than non-whites (P¼ 0.08). Women were significantlyless likely than men to be married (50% vs.84%, P¼ 0.01), and also fell into lower incomegroups than men (P¼ 0.06).

Cancer DiagnosisBreast cancer was the most common diagno-

sis (32%), followed by lung cancer (28%), mul-tiple myeloma (21%), colorectal cancer(15%), and prostate cancer (3%). Therewere no significant differences between whitesand nonwhites in primary cancer diagnosislocation or cancer stage. Women were morelikely to have breast cancer, whereas men hadhigher rates of all other cancers (P< 0.001).Table 2 provides additional sociodemographicinformation for the sample.

Consistent PainThe most common pain locations were non-

midline back (36%), spine (31%), and legs(28%). Although there were no significant dif-ferences in the number of pain locations, non-whites experienced pain more often thanwhites in non-midline back (54% vs. 29%,P¼ 0.03), upper non-midline back (32% vs.15%, P¼ 0.05), lower non-midline back (36%vs. 12%, P¼ 0.006), arm and shoulder (32%vs. 16%, P¼ 0.08), and head (14% vs. 1%,

P¼ 0.01). Women experienced more spinepain than men (37% vs. 18%, P¼ 0.06).

Figure 1 shows mean scores on the four con-sistent pain measures over the study’s dura-tion. None of the consistent pain measureschanged over time. However, pain at worstand pain on average differences between base-line and six month data were significantly dif-ferent (P¼ 0.05). Table 3 shows consistentpain, BTP, and pain interference by ethnicity(using estimated values, where missing, forthe three- and six-month surveys). Nonwhitesreported significantly higher pain scores forconsistent pain than whites at baseline andacross the other data points, respectively: base-line, three, and six months [F(4,90)¼ 5.49,P¼ 0.001; 5.88, P< 0.001, and 4.17,P¼ 0.004]. There were no differences in con-sistent pain in later waves when only the datacollected were used. However, all the consis-tent pain measures remained significantlydifferent by ethnicity when the estimateddata were used. There were no significant dif-ferences in consistent pain or pain interfer-ence by gender at any data collection timepoint. The mean PMI of -1.01 suggests thatmost participants were prescribed adequatepain medications (range¼ -3 to þ3; negativenumbers reflecting medication stronger thanpain strength and positive numbers reflectingpain stronger than medication). When PMIwas examined as a continuous variable, therewere no racial or gender differences in medi-cation strength or subject-reported consistentpain relief received from medication (62%,56%, and 60% over the three waves). Furtherexamination of the dummy variable for ‘‘ade-quate’’ vs. ‘‘inadequate’’ medication showedonly that women (n¼ 6) were prescribed inad-equate pain medication (P¼ 0.07). Pain inter-ference was also a significant issue forparticipants, with mean interference rangingfrom 3.6 (relationships) to 5.5 (work) at

Table 2Sociodeographic Characteristics of the Sample

Measure Total n (%) White n (%) Nonwhite n (%)Difference

P-value

n 96 67 (70) 29 (30)Age (years) 56.5 57.3 54.3 0.09Women 33 (34) 20 (29) 13 (46) 0.11

EducationLess than high school 14 (15) 10 (15) 4 (14) 0.18High school graduate 32 (33) 21 (31) 11 (39)Some college 25 (26) 21 (31) 4 (14)College graduate or more 25 (26) 16 (24) 9 (32)

Employment 0.41Full time 12 (14) 7 (11) 5 (20)Part time 7 (8) 4 (6) 3 (12)Retired 39 (44) 27 (43) 12 (48)Voluntarily unemployed 14 (16) 12 (19) 2 (8)Involuntarily unemployed 16 (18) 13 (21) 3 (12)

Income 0.08$9999 or less 12 (13) 6 (9) 6 (22)$10,000e$30,000 32 (34) 20 (30) 12 (44)$30,001e$100,000 42 (45) 35 (53) 7 (26)>$100,000 7 (8) 5 (8) 2 (7)

Marital statusNever married 8 (9) 4 (9) 4 (14) 0.002Married 58 (62) 49 (74) 9 (32)Divorced/separated 22 (23) 11 (17) 11 (39)Widowed 6 (6) 2 (3) 4 (14)

Cancer typeBreast 31 (33) 24 (35) 7 (26) 0.72Colon 14 (15) 8 (12) 6 (22)Lung 27 (28) 20 (29) 7 (26)Multiple myeloma 20 (21) 14 (21) 6 (22)Prostate 3 (3) 2 (3) 1 (4)Comorbidities 2.22 2.12 2.50 0.38


baseline on a 0e10 scale. Pain interferenceover time did not change significantly with theexception of interference with sleep, which im-proved (P¼ 0.07). Nonwhites had significantly

5.43

4.6

3.052.6

4.42

3.53.58

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0.00

1.00

2.00

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4.00

5.00

6.00

Baseline 3 mo

worstleastaveragenow

Pain

S

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ge 0-10)

Fig. 1. Consistent pain in can

higher scores on pain interference acrossthe three data collection time points[F(7,81)¼ 2.36, P¼ 0.03; 2.81, P¼ 0.01; and4.39, P< 0.001] when compared with whites.

7

3.95

6 2.59

83.52

53.05

nth 6 month

cer patients over time.

Table 3Differences by Ethnicity Over Time in Consistent Pain, Breakthrough Pain, and Pain Interference

Measure Collection Waved White Nonwhite Multivariate F Difference P

Consistent pain Baseline 5.49 0.0013 months 5.88 <0.0016 months 4.17 0.004

At its worst Baseline 4.71 6.57 0.0043 months 4.50 6.07 0.0286 months 4.39 5.64 0.080

At its least Baseline 2.21 4.75 <0.0013 months 2.24 4.81 <0.0016 months 2.45 4.64 <0.001

On average Baselinea 3.84 5.36 0.0043 months 3.43 5.15 0.0026 monthsb 3.41 4.93 0.006

Right now Baseline 3.03 4.50 0.0153 months 3.09 4.41 0.0996 months 2.92 4.46 0.013

Breakthrough pain Baseline 2.48 0.0503 months 1.99 0.0886 months 1.65 0.158

At its worst Baselinea 6.95 8.11 0.0183 monthsb 6.52 7.63 0.0626 monthsc 5.56 6.68 0.132

At its least Baselinea 3.09 4.64 0.0413 months 2.78 4.52 0.0046 monthsb 2.69 4.32 0.007

On average Baselinea 5.00 5.96 0.1253 monthsa 4.84 5.85 0.0756 monthsb 4.39 5.28 0.155

Right now Baseline 3.02 4.89 0.0053 months 2.84 4.26 0.0466 months 3.03 4.64 0.023

Most recent flare at worst Baselinea 6.83 8.11 0.0123 monthsb 6.39 7.41 0.1056 monthsb 6.68 7.20 0.386

Pain interference Baseline 2.36 0.0313 months 2.81 0.0116 months 4.39 <0.001

General activity Baseline 4.04 6.33 0.0023 months 3.74 5.59 0.0106 months 3.81 5.52 0.015

Mood Baseline 3.84 6.07 0.0063 months 3.40 5.56 0.0056 months 3.70 5.59 0.014

Walking ability Baseline 3.92 5.50 0.0183 months 3.90 5.41 0.0586 months 4.56 4.56 0.993

Work, in and out ofhome

Baseline 5.26 6.11 0.1813 months 4.90 5.48 0.4836 months 5.30 5.22 0.926

Relations with others Baseline 3.06 4.68 0.0143 months 3.06 4.74 0.0216 months 3.31 4.44 0.120

Sleep Baselinea 4.95 6.29 0.0763 monthsb 4.27 5.44 0.1106 monthsb 4.47 5.04 0.439

Enjoyment of life Baselinea 4.84 6.43 0.0153 monthsb 4.18 5.96 0.0226 months 4.48 5.41 0.235

Pairwise comparisons without superscripts are statistically nonsignificant.a,b,c Time series paired comparisons: pairs sharing like letters are not statistically different; those with different letters are statistically different atP # 0.05.d Includes estimated data for three and six months where missing.



Nonwhites had higher interference scores ongeneral activity, mood, walking, relationships,sleep, and enjoyment of life, although onlysome of these differences continue over time (Ta-ble 3). Figure 2 shows consistent pain by ethnicityover time.

Breakthrough PainFigure 3 shows means in BTP over the study

course. All pain measures other than ‘‘painflare right now’’ fell significantly over time(P< 0.05) when estimated values were in-cluded. BTP history was required for study in-clusion, but there was variability in BTPcharacteristics. On average, participants expe-rienced BTP for 619 days at baseline, andBTP duration ranged from 0 to 168 months.There were no ethnic or gender differencesin BTP duration or in BTP episodes experi-enced on average per week. Participants attrib-uted the precipitating event for BTP to severalcauses (e.g., movement, the end of a course ofpain medication). Although there was greatvariability within each group, there were no sig-nificant ethnic or gender differences in theability to predict BTP onset. Overall, most sub-jects (79%) reported that BTP could be at leastpartially palliated (most commonly throughmedications). Medications relieved only 62%of the BTP. Other methods for reducing BTP

0

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0)

Fig. 2. Consistent pain over time (with estimated values(P< 0.10).

included lying down, limiting movement, andusing heating pads. There were no significantethnic or gender differences in BTP placability,strategies, or effectiveness for BTP relief.

There were significant ethnic differences inBTP severity as can be seen in Table 3. Non-whites reported significantly higher BTP scoresthan whites at its worst (P¼ 0.03), least(P¼ 0.02), and at initial survey administration(P¼ 0.008). BTP disparities appear to reduceover time, becoming nonsignificant in the col-lected data, with only the pain flares at leastand pain flares right now maintaining signifi-cance over the three- and six-month datapoints. Figure 4 shows the BTP subscales by eth-nicity over time. Women reported that theirBTP on average was worse (P¼ 0.09), and theirmost recent pain flare was stronger (7.7 vs. 6.6,P¼ 0.04). Gender disparities in BTP did notpersist over time. Nonwhites also experienceda significantly greater number of differenttypes of pain flares than whites (3.0 vs. 1.8,P¼ 0.001). There was great variability in BTPquality, with subjects most commonly reportingaching (27.9%), sharp (23.5%) or throbbing(14.7%) pain, although there were no ethnicor gender differences. Nonwhites were morelikely to experience BTP in their upper non-midline back (29% vs. 12%, P¼ 0.05), lowernon-midline back (36% vs. 15%, P¼ 0.02)

Base

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Average Right now

White

Non-white

) by ethnic group: all differences are significant

7.30

6.607.11

3.57

2.892.64

5.294.92 4.81

3.61

2.84 2.91

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

Baseline 3 month 6 month

Pain

sco

re (ran

ge 0-10)

worstleastaveragenow

Fig. 3. Breakthrough pain in cancer patients over time; without estimates.


and head (14% vs. 3%, P¼ 0.04), and therewere no gender differences in BTP location.

Comorbidities, Depression, Coping Strategies,and Quality of Life

Comorbidities, depression (by means ofCES-D), coping strategies, as defined by theBQ-II and the JHACS, and QOL as measuredby the EORTC QLQ-C30, are shown in Table4. Comorbidities did not differ by ethnicity

0

1

2

3

4

5

6

7

8

9

Base

line

3 m

onth

6 m

onth

Base

line

3 m

onth

6 m

onth

Base

line

3 m

onth

Worst Least Avera

Pain

sco

re (ran

ge

1-10)

White

Non-white*

*

* * *

*

Fig. 4. Breakthrough pain over time (with estima

or gender, although minorities and men dis-played higher levels of chest pain and angina.The number of comorbidities in the sampledropped significantly over time (from 2.32 to1.52, P¼ 0.001). The subjects experiencedsignificant psychological distress and depres-sion when measured with the CES-D (meanbaseline¼ 22.7� 13.6; maximum possiblescore¼ 60, and scores> 15 indicate depres-sion). CES-D scores did not significantly

6 m

onth

Base

line

3 m

onth

6 m

onth

Base

line

3 m

onth

6 m

onth

ge Right now Most recent

*

** *

ted values) by ethnic group (*P < 0.10).

Table 4European Organization for Research and Treatment of Cancer Scales Over Time

Measure Collection Pointc White Nonwhite Multivariate F Difference P

EORTC FunctioningSubscales

Baseline 0.62 0.713 months 0.31 0.936 months 0.29 0.94

General health Baseline 54.17 51.59 0.693 months 53.97 55.16 0.836 months 52.79 54.71 0.69

Physical Baseline 61.77 59.05 0.653 months 58.87 62.22 0.596 months 57.08 62.61 0.38

Role Baseline 48.96 46.83 0.773 months 46.67 52.38 0.476 months 45.57 50.00 0.57

Emotional Baseline 63.28 59.13 0.553 monthsa 65.51 61.90 0.606 monthsb 62.50 60.51 0.78

Cognitive Baseline 66.41 64.29 0.763 months 65.13 64.29 0.906 months 66.93 63.04 0.52

Social Baseline 52.34 38.10 0.083 months 51.79 49.21 0.746 months 50.52 50.72 0.98

EORTC Symptoms Baseline 0.97 0.463 months 2.04 0.056 months 1.07 0.10

Fatigue Baseline 58.75 62.67 0.493 months 60.14 61.78 0.806 months 60.59 63.56 0.63

Nausea/vomiting Baseline 21.79 24.67 0.743 months 16.67 26.00 0.096 months 19.05 24.67 0.34

Pain Baselinea 53.85 66.67 0.053 monthsb 49.47 60.67 0.126 monthsb 50.26 56.00 0.46

Trouble sleeping Baselinea 57.95 68.00 0.203 monthsb 53.97 53.33 0.926 monthsb 54.50 53.33 0.86

Appetite Baseline 38.97 45.33 0.523 months 38.10 38.67 0.996 months 40.74 42.67 0.86

Shortness of breath Baseline 29.23 45.33 0.053 months 29.10 48.00 0.026 months 30.69 44.00 0.09

Constipation Baseline 35.38 48.00 0.173 months 31.75 44.00 0.156 months 29.63 41.33 0.19

Diarrhea Baseline 14.87 20.00 0.373 months 12.17 28.00 0.0086 months 10.05 22.67 0.03

Financial difficulties Baselinea 44.10 60.00 0.053 months 38.31 64.20 0.0026 monthsb 40.30 56.79 0.07

Pairwise comparisons without superscripts are statistically nonsignificant.a,b Time series paired comparisons: pairs sharing like letters are not statistically different; those with different letters are statistically different atP # 0.05.c Includes estimated data for three and six months where missing.


change over time, nor were there any signifi-cant ethnic or gender differences.

The subscales of the BQ-II also did not differby ethnicity or gender, but all three scalesdharmful effects, fatalism, and communicationbarriersdchanged over time. Patterns of

change differed by subscale, with the physio-logical and communication subscales goingdown at three months and then rebounding,and the fatalism going up at three monthsand dropping again. All participants scoredhighly on the JHACS (mean¼ 47.6, maximum


possible score¼ 60), although men scoredhigher than women (P¼ 0.03), but scores didnot differ by race.

Regardless of ethnicity or gender, similari-ties were found on both the EORT QLQ-C30,functioning and symptom control scales atbaseline. Table 4 details the EORTC QLQ-C30 by ethnicity and over time. Nonwhiteshad consistently poorer outcomes on each sub-scale as seen in Fig. 5a and b, although theMANOVA showed that, overall, there were noethnic differences for the functioning sub-scales at baseline [F(6,78)¼ 0.62, P¼ 0.71].The nonwhites also had higher scores on thepain (P¼ 0.05) and dyspnea (P¼ 0.05) symp-tom control subscales of the EORTC QLQ-

54.2

61.8

49.051.6

59.1

46.8

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

E-GlobalHealth

E-Physical E-Role

Tran

sfo

rm

ed

sco

res (ran

ge 0-100)

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

Tran

sfo

rm

ed

sco

res (ran

ge 0-100)

WhitesNon-whites

58.8

21.8

53.958.0

39.0

62.7

24.7

66.7 68.0

Fatigue Nausea/Vomiting

Pain Insomnia Anor

*

a

b

Fig. 5. (a) Functioning subscales of the EORTC by ethnicity

C30, although this multivariate comparisonwas also not significant for the symptom sub-scales at baseline [F(8,82)¼ 0.97, P¼ 0.46].Later waves, however, do show significance ofthe multivariate symptom comparison whenestimated data are included, with nonwhitesreporting higher average scores on severalQOL symptom control subscales than whites,indicating poorer symptom control. Addition-ally, there were differences between whitesand nonwhites in financial difficulty(P¼ 0.05). When all symptom subscales werecombined into a single ‘‘Symptom’’ scale, therewere differences (P¼ 0.08) between the scoresbased on ethnicity. Although not significantlydifferent, nonwhites reported lower average

63.366.4

52.3

59.1

64.3

38.1

E-Emotional lE-Cognitive E-Social

*

29.2

35.4

14.9

44.145.3 45.348.0

20.0

60.0

exia Dyspnea Consti-pation

Diarrhea Finances

*

*WhitesNon-whites

; (b) symptom subscales of the EORTC by ethnicity.


scores on each QOL functioning subscale.There were also no differences when the func-tion domains were combined into a single‘‘Function’’ scale. There were no such disparitypatterns by gender. Other than emotionalfunctioning, significantly poorer at six monthsthan at three months, functioning among par-ticipants was moderate and did not changeover time. Of the symptom subscales, fatigueand pain were the most commonly experi-enced (60.4 and 58.4, respectively, at baseline).Multivariate gender comparisons were not sig-nificant at any point for either functioning orsymptoms.

DiscussionUnfortunately, cancer and its treatment are

often associated with pain. Most cancer pain re-searchers have focused on single cancer typesor treatments. Until now, there have been nolongitudinal studies examining both consistentpain and BTP in a diverse population, althoughdisparities in pain care based on race, ethnicity,and gender are well described.38 Overall, ourlongitudinal analysis showed high consistentpain severity, with pain on average reducingover time. Likewise, we demonstrated highBTP severity over time. We complement the lit-erature by finding a high prevalence of cancerpain and pain severity, while also showing thatpain persists over time. However, we extendthe literature by also identifying ethnic dispar-ities in cancer pain, with nonwhites impactedmore so than whites.

Portenoy et al.30 brought national attentionto BTP’s impact on QOL; however, racial, eth-nic, and gender variations were not examined.Although there is compelling research demon-strating racial and ethnic disparities in acute,chronic, and cancer pain, there is minimalinformation assessing BTP characteristics andits impact on HRQOL in an ethnically diversepopulation.16,30 As expected, we found thatnonwhites experienced significantly more con-sistent cancer pain and pain interference thanwhites;16 however, we also found higher levelsof BTP. These disparities did not persist overtime in the actual collected data, althoughwhen we used most recent measure of thesame item as a substitute for missing values,the disparities persisted. Because the mostcommon reason for attention given by subjects

was no longer feeling well enough, an in-creased burden of disease is a possibility andthe estimated results support this probability.

The BTP severity at worst and most recentwas slightly higher for women than for men.Literature providing insights on ethnic or gen-der differences in cancer pain is rare.51

Although the few published studies rarelyshow differences in pain severity, we foundwomen experienced more BTP and weremore likely to receive inadequate treatment.52

Nonetheless, inadequate pain treatment inwomen when compared with men is consistentwith previous findings,26,52 although gender-based disparities in BTP have not been previ-ously described.

Overall, minorities and women have a higherprevalence of pain syndromes than non-Hispanic whites and men.16,19 The etiology ofthe ethnic and gender differences observedwere consistent, but the mechanisms for thesedifferences remain unclear. Important consid-erations include physician variability in assess-ing and treating pain, leading to suboptimalcancer pain management. This is consistentwith literature revealing an unequal burdenof pain and clinician variability in painmanagement decision making.16,20 Structuralbarriers to quality pain care are well docu-mented and may influence pain severity and re-ported pain scores.53e55 Although examiningphysician decision making was not an aim, fu-ture studies examining the prevalence of BTPand consistent pain in ethnically diverse popu-lations with cancer should attempt to do so.

Beyond increased pain severity, racial andethnic minorities with chronic pain also reportmore negative sequelae (e.g., pain-related dis-ability, depression, and post-traumatic stressdisorder [PTSD]) than whites.16 Access toquality pain care can be problematic, espe-cially for nonwhites, even when they are as-sessed and treated for their pain complaints.Patient preferences and attitudes about cancerand pain may play a significant role in theirwillingness to report pain and to seek treat-ment.25,56 Although we did not find ethnic orgender differences in the barriers to pain treat-ment scales, future studies examining BTP inadvanced cancer patients must also seek toaddress patient preferences and attitudes in re-porting pain and in seeking pain care in a pro-spective longitudinal fashion.


Appropriate pain management improvesoverall health and HRQOL.57e59 Yet, nonwhitesconsistently reported poorer scores on all func-tioning and symptom control subscales of theEORTC QLQ-C30 than whites; most persistedover time, although differences were not signif-icant for functioning. Thus, when analyzing thedisparate consistent and BTP scores, the corre-sponding reductions in HRQOL are not sur-prising. Nonwhites reported poorer QOLsymptom control, with significant differencesin dyspnea control and pain control. The ethnicdifferences on the pain control subscale areconsistent with higher pain scores reported bynonwhites for both consistent pain and BTP.When all symptom control subscales were com-bined into a single scale, there were differencessupporting less symptom control for nonwhitesthan whites. Consistent with literature citingdisparities in pain treatment and other condi-tions, we found poor QOL symptom controlamong nonwhites.7 To our surprise, only onedifference in the QOL functioning subscaleswas found. Although average scores for non-whites were lower on every subscale, in themultivariate analysis, nonwhites only had signif-icantly poorer social functioning. Another sur-prising finding was that higher pain levels didnot translate to poorer functioning. We also ob-served differences in financial difficulty in theQOL survey consistent with lower annualhousehold incomes reported by nonwhites. Fu-ture studies should examine whether and howfinancial difficulties, health insurance, andpain severity are correlated with HRQOL.

When we examined psychological impair-ment by the CES-D, no significant ethnic or gen-der differences were found, although the entiresample experienced clinically important depres-sive symptoms and psychological distress. Theliterature provides overwhelming evidence forthe high prevalence of depression in both can-cer and chronic pain populations, as observedin our sample.60e63 However, when cancer andpain occur together, the exact mechanism fordepression and diminished HRQOL is unclear.The literature also reports increased depressionand PTSD in minorities with chronic pain.19,20

Because both groups were equally depressed,future studies should attempt to disentanglecancer pain’s impact on emotional healthusing structural equation modeling techniquesin an ethnically diverse population.

Maladaptive coping strategies diminishQOL and the ability to cope with significantillnesses. Although James et al. introducedthe concept of John Henryism, with a stronglink to African Americans,48 we found JohnHenryism was prevalent in the entire sample,although more so in men. Thus, it seems sub-jects were using this coping strategy for chal-lenges posed by their cancer rather than forconsistent or BTP syndromes. The lack of eth-nic differences was surprising, but suggeststhat, when faced with a life threatening illnesssuch as cancer, and when dealing with cancerpain, John Henryism may be common amongcancer patients regardless of race or ethnicity.Future studies should seek to confirm ourfindings and to examine whether the JohnHenryism is an adaptive or maladaptive cop-ing strategy phenomenon in an ethnically di-verse population with advanced cancer andpain.

Although this study provides many signifi-cant implications for improving health andQOL in cancer patients, there are potentiallimitations. First, the small sample size usedfor data analysis may have limited the potentialobserved differences between whites and non-whites on many QOL measures and on com-paring BTP characteristics. It is conceivablethat these differences in the combined symp-tom control scale and on individual subscalesrepresent differences that could become statis-tically significant in a larger population. Thus,it is likely that any differences noted representsignificant ethnic disparities on a populationlevel, suggesting the need for further study ina larger population. Participant retentionproved to be difficult, although not unex-pected, given the nature of cancer. Nonethe-less, our retention rates were comparablewith other longitudinal cancer studies.39 Usingthe most recent measure for missing values al-lowed us to estimate what longitudinal datamight find. However, these methods of estima-tion have some limitations, and thus, thesefindings should be considered tentative.Third, self-report and nonresponse bias mustbe considered, although the surveys were com-pleted privately and kept confidential. Finally,because subjects were recruited through a con-venience sampling method, with carefulscreening criteria at cancer care facilities, ourresults may only reflect those with access to


care, those meeting the screening criteria, andthose in the catchment area of the includedclinics. Thus, further study is needed to assessthe generalizability of findings.

To our knowledge, this is the first prospec-tive longitudinal study examining both consis-tent pain and BTP in a diverse population.Worrisome was the high severity of cancerpain and the subsequent reductions in QOLregardless of race, ethnicity, and gender. Weshowed that BTP characteristics were highlyvariable while confirming shortcomings intreating BTP and reductions in HRQOL. Weextend the literature by confirming these find-ings for the first time in an ethnically diversepopulation. More specifically, nonwhites experi-enced significantly more symptoms, increasedconsistent pain, BTP, pain interference, andreductions in HRQOL than whites, and thesedisparities persisted over time. However, thesefindings also point toward important dispar-ities in the quality of care (pain assessmentand management), with clinically importantreductions in health and well-being. This studyprovides new and critically important informa-tion on racial and ethnic disparities in health,pain care, and cancer care, and an unequalburden of cancer pain. Overall, our findingshave critically important public health implica-tions for health, cancer, and pain care as wellas for health policy. They also serve as a novelmodel for future health services researchaddressing the impact cancer pain and BTPhave at a population level while providinga guide for interventions designed to alleviatesuffering and to improve the quality of paincare for all.

AcknowledgmentsThe authors thank Sam Silver, MD, the Uni-

versity of Michigan Cancer Center Network,and Ms. Melanie Grierson for their ongoingsupport. They also thank Ms. Susan Sessionsfor her excellent editorial assistance, technicalsupport, and patience.

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Documents

Consistent and Breakthrough Pain in Diverse Advanced Cancer Patients: A Longitudinal Examination