Advertisement

III. Detecting Treatment Effects in Clinical Trials With Different Indices of Pain Intensity Derived From Ecological Momentary Assessment

Published:October 23, 2020DOI:https://doi.org/10.1016/j.jpain.2020.10.003

      Highlights

      • Treatment effects based on alternative ecological momentary assessments (EMA) indices of pain intensity were compared.
      • Over 1 million EMA pain intensity ratings over 20+ weeks of treatment were analyzed.
      • Multiple EMA pain indices detected treatment effects in pain clinical trials.
      • Changes in all EMA indices were associated with patient global impression of change.
      • Alternative pain indices may inform understanding of clinical trial outcomes.

      Abstract

      Pain intensity represents the primary outcome in most pain clinical trials. Identifying methods to measure aspects of pain that are most sensitive to treatment may facilitate discovery of effective interventions. In this third of 3 articles examining alternative indices of pain intensity derived from ecological momentary assessments (EMA), we compare treatment effects based on Average Pain, Maximum Pain, Minimum Pain, Pain Variability, Time in High Pain, Time in Low Pain, and Pain After Wake-Up. We also examine which indices contribute to Patient Global Impressions of Change (PGIC). Data came from 2 randomized, double-blind, placebo-controlled trials examining the efficacy of milnacipran for fibromyalgia treatment; 2,084 patients provided >1 million EMA pain intensity ratings over 24 (Study 1) or 26 (Study 2) treatment weeks. Pain Variability and Time in High Pain produced significantly smaller treatment effects than Average Pain; other pain indices showed effects that were numerically smaller, but not significantly different from Average Pain. Changes in all pain indices were significantly associated with PGIC, with improvements in Maximum Pain and in Pain Variability offering small incremental contributions to understanding PGIC over Average Pain. Results suggest that different pain indices could be used to detect treatment effects in pain clinical trials.

      Perspective

      Alternative summary measures of pain intensity derived from EMA may broaden the scope of outcomes useful in pain clinical trials. In this analysis of a pharmacological treatment for fibromyalgia, most pain summary measures indicated similar effects; improvements in Maximum Pain and Pain Variability contributed to understanding PGIC over Average Pain.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Allen KD
        The value of measuring variability in osteoarthritis pain.
        J Rheumatol. 2007; 34: 2132-2133
        • Arnold LM
        • Clauw DJ
        • Wohlreich MM
        • Wang F
        • Ahl J
        • Gaynor PJ
        • Chappell AS
        Efficacy of duloxetine in patients with fibromyalgia: Pooled analysis of 4 placebo-controlled clinical trials.
        Primary Care Comp J Clin Psychiatry. 2009; 11: 237
        • Arnold LM
        • Gendreau RM
        • Palmer RH
        • Gendreau JF
        • Wang Y
        Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: Results of a randomized, double-blind, placebo-controlled trial.
        Arthritis Rheum. 2010; 62: 2745-2756
        • Atkinson TM
        • Mendoza TR
        • Sit L
        • Passik S
        • Scher HI
        • Cleeland C
        • Basch E
        The brief pain inventory and its "pain at its worst in the last 24 hours" item: Clinical trial endpoint considerations.
        Pain Med. 2010; 11: 337-346
        • Bellamy N
        • Sothern R
        • Campbell J
        • Buchanan W
        Rhythmic variations in pain, stiffness, and manual dexterity in hand osteoarthritis.
        Ann Rheum Dis. 2002; 61: 1075-1080
        • Boonstra AM
        • Preuper HRS
        • Balk GA
        • Stewart RE
        Cut-off points for mild, moderate, and severe pain on the visual analogue scale for pain in patients with chronic musculoskeletal pain.
        PAIN. 2014; 155: 2545-2550
        • Broderick JE
        • Schwartz JE
        • Schneider S
        • Stone AA
        Can End-of-day reports replace momentary assessment of pain and fatigue?.
        J Pain. 2009; 10: 274-281
        • Broderick JE
        • Schwartz JE
        • Vikingstad G
        • Pribbernow M
        • Grossman S
        • Stone AA
        The accuracy of pain and fatigue items across different reporting periods.
        Pain. 2008; 139: 146-157
        • Clauw DJ
        • Mease P
        • Palmer RH
        • Gendreau RM
        • Wang Y
        Milnacipran for the treatment of fibromyalgia in adults: A 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial.
        Clin Ther. 2008; 30: 1988-2004
        • Cohen J
        Statistical Power Analysis for the Behavioral Sciences.
        Lawrence Erlbaum, Hillsdale, NJ1988
        • Cook RJ
        • Sackett DL
        The number needed to treat: A clinically useful measure of treatment effect.
        BMJ. 1995; 310: 452
        • Cording M
        • Derry S
        • Phillips T
        • Moore RA
        • Wiffen PJ
        Milnacipran for pain in fibromyalgia in adults.
        Cochrane Database Syst Rev. 2015; 2015: CD008244https://doi.org/10.1002/14651858.CD008244.pub3
        • Du H
        • Wang L
        Reliabilities of intraindividual variability indicators with autocorrelated longitudinal data: Implications for longitudinal study designs.
        Multivar Behav Res. 2018; 53: 502-520
        • Dworkin RH
        • Turk DC
        • Farrar JT
        • Haythornthwaite JA
        • Jensen MP
        • Katz NP
        • Kerns RD
        • Stucki G
        • Allen RR
        • Bellamy N
        • Carr DB
        • Chandler J
        • Cowan P
        • Dionne R
        • Galer BS
        • Hertz S
        • Jadad AR
        • Kramer LD
        • Manning DC
        • Martin S
        • McCormick CG
        • McDermott MP
        • McGrath P
        • Quessy S
        • Rappaport BA
        • Robbins W
        • Robinson JP
        • Rothman M
        • Royal MA
        • Simon L
        • Stauffer JW
        • Stein W
        • Tollett J
        • Wernicke J
        • Witter J
        Core outcome measures for chronic pain clinical trials: IMMPACT recommendations.
        Pain. 2005; 113: 9-19
        • Dworkin RH
        • Turk DC
        • Peirce-Sandner S
        • Burke LB
        • Farrar JT
        • Gilron I
        • Jensen MP
        • Katz NP
        • Raja SN
        • Rappaport BA
        • Rowbotham MC
        • Backonja MM
        • Baron R
        • Bellamy N
        • Bhagwagar Z
        • Costello A
        • Cowan P
        • Fang WC
        • Hertz S
        • Jay GW
        • Junor R
        • Kerns RD
        • Kerwin R
        • Kopecky EA
        • Lissin D
        • Malamut R
        • Markman JD
        • McDermott MP
        • Munera C
        • Porter L
        • Rauschkolb C
        • Rice ASC
        • Sampaio C
        • Skljarevski V
        • Sommerville K
        • Stacey BR
        • Steigerwald I
        • Tobias J
        • Trentacosti AM
        • Wasan AD
        • Wells GA
        • Williams J
        • Witter J
        • Ziegler D
        Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.
        Pain. 2012; 153: 1148-1158
        • Dworkin RH
        • Turk DC
        • Wyrwich KW
        • Beaton D
        • Cleeland CS
        • Farrar JT
        • Haythornthwaite JA
        • Jensen MP
        • Kerns RD
        • Ader DN
        Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.
        J Pain. 2008; 9: 105-121
        • Farrar JT
        • Pritchett YL
        • Robinson M
        • Prakash A
        • Chappell A
        The clinical importance of changes in the 0 to 10 numeric rating scale for worst, least, and average pain intensity: Analyses of data from clinical trials of duloxetine in pain disorders.
        J Pain. 2010; 11: 109-118
        • Farrar JT
        • Troxel AB
        • Haynes K
        • Gilron I
        • Kerns RD
        • Katz NP
        • Rappaport BA
        • Rowbotham MC
        • Tierney AM
        • Turk DC
        • Dworkin RH
        Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: An ACTTION study.
        Pain. 2014; 155: 1622-1631
        • Farrar JT
        • Young Jr., JP
        • LaMoreaux L
        • Werth JL
        • Poole RM
        Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale.
        Pain. 2001; 94: 149-158
        • Fields HL
        • Heinricher MM
        • Mason P
        Neurotransmitters in nociceptive modulatory circuits.
        Annu Rev Neurosci. 1991; 14: 219-245
        • Fillingim RB
        • Loeser JD
        • Baron R
        • Edwards RR
        Assessment of chronic pain: Domains, methods, and mechanisms.
        J Pain. 2016; 17: T10-T20
        • Harris RE
        • Williams DA
        • McLean SA
        • Sen A
        • Hufford M
        • Gendreau RM
        • Gracely RH
        • Clauw DJ
        Characterization and consequences of pain variability in individuals with fibromyalgia.
        Arthritis Rheum. 2005; 52: 3670-3674
        • Jensen MP
        • Hu X
        • Potts SL
        • Gould EM
        Single vs composite measures of pain intensity: Relative sensitivity for detecting treatment effects.
        Pain. 2013; 154: 534-538
        • Jensen MP
        • Hu X
        • Potts SL
        • Gould EM
        Measuring outcomes in pain clinical trials: The importance of empirical support for measure selection.
        Clin J Pain. 2014; 30: 744-748
        • Jensen MP
        • Karoly P
        Self-report scales and procedures for assessing pain in adults.
        in: Turk DC Melzack R Handbook of Pain Assessment. Guilford Press, New York, NY2001: 15-34
        • Krueger AB
        • Stone AA
        Assessment of pain: A community-based diary survey in the USA.
        Lancet. 2008; 371: 1519-1525
        • Litcher-Kelly L
        • Martino SA
        • Broderick JE
        • Stone AA
        A systematic review of measures used to assess chronic musculoskeletal pain in clinical and randomized controlled clinical trials.
        J Pain. 2007; 8: 906-913
        • Ma G
        • Troxel AB
        • Heitjan DF
        An index of local sensitivity to nonignorable drop‐out in longitudinal modelling.
        Stat Med. 2005; 24: 2129-2150
        • Mease PJ
        • Clauw DJ
        • Gendreau RM
        • Rao SG
        • Kranzler J
        • Chen W
        • Palmer RH
        The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial.
        J Rheumatol. 2009; 36: 398-409
        • Mun CJ
        • Suk HW
        • Davis MC
        • Karoly P
        • Finan P
        • Tennen H
        • Jensen MP
        Investigating intraindividual pain variability: Methods, applications, issues, and directions.
        Pain. 2019; 160: 2415-2429
      1. Muthén LK, Muthén BO: Mplus User's Guide. Los Angeles, CA: Muthén & Muthén, 1998-2017.

        • Nagelkerke NJ
        A note on a general definition of the coefficient of determination.
        Biometrika. 1991; 78: 691-692
        • Okifuji A
        • Bradshaw DH
        • Donaldson GW
        • Turk DC
        Sequential analyses of daily symptoms in women with fibromyalgia syndrome.
        J Pain. 2011; 12: 84-93
        • Older SA
        • Battafarano DF
        • Danning CL
        • Ward JA
        • Grady EP
        • Derman S
        • Russell IJ
        The effects of delta wave sleep interruption on pain thresholds and fibromyalgia-like symptoms in healthy subjects; Correlations with insulin-like growth factor I.
        J Rheumatol. 1998; 25: 1180-1186
        • Ono M
        • Schneider S
        • Junghaenel DU
        • Stone AA
        What affects the completion of ecological momentary assessments in chronic pain research? An individual patient data meta-analysis.
        J Med Internet Res. 2019; 21: e11398
        • Raudenbush SW
        • Bryk AS
        Hierarchical Linear Models.
        Sage, Thousand Oaks, CA2002
        • Raykov T
        • Marcoulides GA
        Using the delta method for approximate interval estimation of parameter functions in SEM.
        Struct Equation Model. 2004; 11: 621-637
        • Redelmeier DA
        • Katz J
        • Kahneman D
        Memories of colonoscopy: A randomized trial.
        Pain. 2003; 104: 187-194
        • Roizenblatt S
        • Moldofsky H
        • Benedito‐Silva AA
        • Tufik S
        Alpha sleep characteristics in fibromyalgia.
        Arth Rheum. 2001; 44: 222-230
        • Schafer JL
        • Graham JW
        Missing data: Our view of the state of the art.
        Psychol Methods. 2002; 7: 147-177
      2. Schneider S, Junghaenel DU, Broderick JE, Ono M, May M, Stone AA: Indices of pain intensity derived from ecological momentary assessments and their relationships with patient functioning: An indivdiual patient data meta-analysis. J Pain, (under review)

        • Schneider S
        • Junghaenel DU
        • Keefe FJ
        • Schwartz JE
        • Stone AA
        • Broderick JE
        Individual differences in the day-to-day variability of pain, fatigue, and well-being in patients with rheumatic disease: Associations with psychological variables.
        Pain. 2012; 153: 813-822
        • Schneider S
        • Junghaenel DU
        • Ono M
        • Stone AA
        Temporal dynamics of pain: An application of regime-switching models to ecological momentary assessments in patients with rheumatic diseases.
        Pain. 2018; 159: 1346-1358
        • Schneider S
        • Stone AA
        Distinguishing between frequency and intensity of health-related symptoms from diary assessments.
        J Psychosom Res. 2014; 77: 205-212
        • Shaver JL
        • Lentz M
        • Landis CA
        • Heitkemper MM
        • Buchwald DS
        • Woods NF
        Sleep, psychological distress, and stress arousal in women with fibromyalgia.
        Res Nurs Health. 1997; 20: 247-257
        • Shiffman S
        • Stone AA
        • Hufford MR
        Ecological momentary assessment.
        Annu Rev Clin Psychol. 2008; 4: 1-32
        • Smith SM
        • Amtmann D
        • Askew RL
        • Gewandter JS
        • Hunsinger M
        • Jensen MP
        • McDermott MP
        • Patel KV
        • Williams M
        • Bacci ED
        Pain intensity rating training: Results from an exploratory study of the ACTTION PROTECCT system.
        Pain. 2016; 157: 1056-1064
        • Smith SM
        • Jensen MP
        • He H
        • Kitt R
        • Koch J
        • Pan A
        • Burke LB
        • Farrar JT
        • McDermott MP
        • Turk DC
        A comparison of the assay sensitivity of average and worst pain intensity in pharmacologic trials: An ACTTION systematic review and meta-analysis.
        J Pain. 2018; 19: 953-960
        • Smith WR
        • Bauserman RL
        • Ballas SK
        • McCarthy WF
        • Steinberg MH
        • Swerdlow PS
        • Waclawiw MA
        • Barton BA
        • Hydro IMS
        Climatic and geographic temporal patterns of pain in the multicenter study of hydroxyurea.
        Pain. 2009; 146: 91-98
      3. Stone AA, Broderick JE, Goldman RE, Junghaenel DU, Bolton A, May M, Schneider S: Indices of pain intensity derived from ecological momentary assessments: Rationale and stakeholder interviews. J Pain, (under review)

        • Stone AA
        • Broderick JE
        • Schneider S
        • Schwartz JE
        Expanding options for developing outcome measures from momentary assessment data.
        Psychosom Med. 2012; 74: 387-397
        • Stone AA
        • Broderick JE
        • Schwartz JE
        Validity of average, minimum, and maximum end-of-day recall assessments of pain and fatigue.
        Contemp Clin Trials. 2010; 31: 483-490
        • Stone AA
        • Schneider S
        • Broderick JE
        • Schwartz JE
        Single-day pain assessments as clinical outcomes: not so fast.
        Clin J Pain. 2014; 30: 739-743
        • Stone AA
        • Schwartz JE
        • Broderick JE
        • Shiffman SS
        Variability of momentary pain predicts recall of weekly pain: A consequence of the peak (or salience) memory heuristic.
        Pers Soc Psychol Bull. 2005; 31: 1340-1346
        • Tighe PJ
        • Bzdega M
        • Fillingim RB
        • Rashidi P
        • Aytug H
        Markov chain evaluation of acute postoperative pain transition states.
        Pain. 2016; 157: 717-728
        • Troxel AB
        • Ma G
        • Heitjan DF
        An index of local sensitivity to nonignorability.
        Stat Sin. 2004; : 1221-1237
      4. US Department of Health and Human Services Food and Drug Administration: Guidance for industry: Analgesic indications: Developing drug and biological products. Available at:https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm384691.pdf. Accessed April 26, 2019.

        • Xie H
        • Gao W
        • Xing B
        • Heitjan DF
        • Hedeker D
        • Yuan C
        Measuring the impact of nonignorable missingness using the R package isni.
        Comput Methods Programs Biomed. 2018; 164: 207-220