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Depression explains the association between pain intensity and pain interference among adults with neurofibromatosis

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Abstract

Introduction

Neurofibromatoses (NFs; NF1, NF2 and Schwannomatosis) are incurable genetic syndromes characterized by nerve sheath tumors and often accompanied by substantial emotional distress (e.g., depression and anxiety). Pain is also common but understudied in adults with NF and interferes with daily living. In other medical populations, depression and anxiety have a strong association with pain interference. However, research has not explored the relationship of depression and anxiety to pain interference among adults with NF experiencing pain. The aim of this study was to test the hypothesis that depression and anxiety will mediate the association between pain intensity and pain interference among geographically diverse adults with NF who endorse pain.

Methods

We used baseline data from an RCT of a mind–body intervention aimed at improving quality of life in adults with NF. Participants (N = 214) who endorsed pain completed measures of demographics, clinical characteristics, baseline pain intensity, pain interference, depression, and anxiety. We constructed a multiple mediation model in R using the lavaan package to test our hypothesis.

Results

Preliminary analyses showed differences in pain interference by NF diagnostic subtype (F(2, 206) = 6.82, p = 001). In a model that controlled for NF diagnostic subtype, we found that depression (β = .07, p = .017), but not anxiety (β = -.003, p = .878), partially mediated the association between pain intensity and pain interference.

Conclusion

Improving depression has the potential to decrease pain interference among people with NF who experience pain.

Trial registration

Clinicaltrials.gov Registration #: NCT03406208

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References

  1. Plotkin SR, Wick A (2018) Neurofibromatosis and schwannomatosis. Semin Neurol 38(1):73–85. https://doi.org/10.1055/s-0038-1627471

    Article  PubMed  Google Scholar 

  2. Kongkriangkai AM, King C, Martin LJ et al (2019) Substantial pain burden in frequency, intensity, interference and chronicity among children and adults with neurofibromatosis Type 1. Am J Med Genet Part A 179(4):602–607. https://doi.org/10.1002/ajmg.a.61069

    Article  PubMed  Google Scholar 

  3. Créange A, Zeller J, Rostaing-Rigattieri S et al (1999) Neurological complications of neurofibromatosis type 1 in adulthood. Brain 122(3):473–481. https://doi.org/10.1093/brain/122.3.473

    Article  PubMed  Google Scholar 

  4. Wolters PL, Burns KM, Martin S et al (2015) Pain interference in youth with neurofibromatosis type 1 and plexiform neurofibromas and relation to disease severity, social-emotional functioning, and quality of life. Am J Med Genet Part A 167(9):2103–2113. https://doi.org/10.1002/ajmg.a.37123

    Article  Google Scholar 

  5. Merker VL, Esparza S, Smith MJ, Stemmer-Rachamimov A, Plotkin SR (2012) Clinical features of schwannomatosis: a retrospective analysis of 87 patients. Oncologist. https://doi.org/10.1634/theoncologist.2012-0162

    Article  PubMed  PubMed Central  Google Scholar 

  6. Fjermestad KW, Nyhus L, Kanavin ØJ, Heiberg A, Hoxmark LB (2018) Health survey of adults with neurofibromatosis 1 compared to population study controls. J Genet Counsel 27(5):1102–1110. https://doi.org/10.1007/s10897-018-0229-5

    Article  Google Scholar 

  7. Cosetti MK, Golfinos JG, Roland JT (2015) Quality of Life (QoL) assessment in patients with neurofibromatosis type 2 (NF2). Otolaryngol Head Neck Surg 153(4):599–605. https://doi.org/10.1177/0194599815573002

    Article  PubMed  Google Scholar 

  8. Jeong YH, Choi EJ, Nahm FS (2013) Concurrence of malignant peripheral nerve sheath tumor at the site of complex regional pain syndrome type 1—a case report. Korean J Pain 26(2):160–163. https://doi.org/10.3344/kjp.2013.26.2.160

    Article  PubMed  PubMed Central  Google Scholar 

  9. Buono FD, Grau LE, Sprong ME, Morford KL, Johnson KJ, Gutmann DH (2019) Pain symptomology, functional impact, and treatment of people with Neurofibromatosis type 1. J Pain Res 12:2555–2561. https://doi.org/10.2147/JPR.S209540

    Article  PubMed  PubMed Central  Google Scholar 

  10. Parsons CM, Canter RJ, Khatri VP (2009) Surgical management of neurofibromatosis. Surg Oncol Clin N Am 18(1):175–196. https://doi.org/10.1016/j.soc.2008.08.009

    Article  PubMed  Google Scholar 

  11. Swann AC (2001) Major system toxicities and side effects of anticonvulsants. J Clin Psychiatry 62(suppl 14)

  12. Rodriguez RF, Castillo JM, Castillo MP et al (2008) Hydrocodone/acetaminophen and tramadol chlorhydrate combination tablets for the management of chronic cancer pain: a double-blind comparative trial. Clin J Pain 24(1):1–4. https://doi.org/10.1097/AJP.0b013e318156ca4d

    Article  PubMed  Google Scholar 

  13. Sperry L (2008) The biopsychosocial model and chronic illness: psychotherapeutic implications. J Indiv Psychol 64(3):369–376. https://doi.org/10.1037/11378-002

    Article  Google Scholar 

  14. Wade DT, Halligan PW (2017) The biopsychosocial model of illness: a model whose time has come. Clin Rehabil 31(8):995–1004. https://doi.org/10.1177/0269215517709890

    Article  PubMed  Google Scholar 

  15. Vranceanu AM, Merker VL, Plotkin SR, Park ER (2014) The relaxation response resiliency program (3RP) in patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis: results from a pilot study. J Neurooncol. https://doi.org/10.1007/s11060-014-1522-2

    Article  PubMed  Google Scholar 

  16. Vranceanu AM, Merker VL, Park E, Plotkin SR (2013) Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a systematic review of the literature. J Neurooncol 114(3):257–262. https://doi.org/10.1007/s11060-013-1195-2

    Article  PubMed  Google Scholar 

  17. Zale EL, Heinhuis TJ, Tehan T, Salgueiro D, Rosand J, Vranceanu AM (2018) Resiliency is independently associated with greater quality of life among informal caregivers to neuroscience intensive care unit patients. Gen Hosp Psychiatry 52:27–33. https://doi.org/10.1016/j.genhosppsych.2018.02.012

    Article  PubMed  Google Scholar 

  18. Carter S, Greenberg J, Funes CJ, Macklin EA, Vranceanu AM (2021) Effects of a mind-body program on symptoms of depression and perceived stress among adults with neurofibromatosis type 2 who are deaf: a live-video randomized controlled trial. Complement Ther Med. https://doi.org/10.1016/j.ctim.2020.102581

    Article  PubMed  Google Scholar 

  19. Robinson ME, Riley III JL (1999) The role of emotion in pain. In: Psychosocial factors in pain: critical perspectives. The Guilford Press, pp 74–88

  20. Talaei-Khoei M, Riklin E, Merker VL et al (2017) First use of patient reported outcomes measurement information system (PROMIS) measures in adults with neurofibromatosis. J Neurooncol 131(2):413–419. https://doi.org/10.1007/s11060-016-2314-7

    Article  PubMed  Google Scholar 

  21. Wang DL, Smith KB, Esparza S et al (2012) Emotional functioning of patients with neurofibromatosis tumor suppressor syndrome. Genet Med 14(12):977–982. https://doi.org/10.1038/gim.2012.85

    Article  PubMed  PubMed Central  Google Scholar 

  22. Allen TM, Struemph KL, Toledo-Tamula MA et al (2018) The relationship between heart rate variability, psychological flexibility, and pain in neurofibromatosis type 1. Pain Pract 18(8):969–978. https://doi.org/10.1111/papr.12695

    Article  PubMed  PubMed Central  Google Scholar 

  23. Adams MH, Lovejoy TI, Turk DC, Dobscha SK, Hauser P, Morasco BJ (2015) Pain-related anxiety mediates the relationship between depressive symptoms and pain interference in veterans with hepatitis C. Gen Hosp Psychiatry 37(6):533–537. https://doi.org/10.1016/j.genhosppsych.2015.07.003

    Article  PubMed  PubMed Central  Google Scholar 

  24. Nsamenang SA, Hirsch JK, Topciu R, Goodman AD, Duberstein PR (2016) The interrelations between spiritual well-being, pain interference and depressive symptoms in patients with multiple sclerosis. J Behav Med 39(2):355–363. https://doi.org/10.1007/s10865-016-9712-3

    Article  PubMed  PubMed Central  Google Scholar 

  25. Vranceanu A-M, Zale EL, Funes CJ et al (2018) Mind-body treatment for international english-speaking adults with neurofibromatosis via live videoconferencing: protocol for a single-blind randomized controlled trial. JMIR Res Protoc 7(10):e11008. https://doi.org/10.2196/11008

    Article  PubMed  PubMed Central  Google Scholar 

  26. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42(2):377–381. https://doi.org/10.1016/j.jbi.2008.08.010

    Article  PubMed  Google Scholar 

  27. Kroenke K, Spitzer RL, Williams JB (2001) The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 16(9):606–613. https://doi.org/10.1046/j.1525-1497.2001.016009606.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC. https://doi.org/10.1176/appi.books.9780890425596

  29. Spitzer RL, Kroenke K, Williams JBW, Löwe B (2006) A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 166(10):1092–1097. https://doi.org/10.1001/archinte.166.10.1092

    Article  PubMed  Google Scholar 

  30. Von Korff M, Dworkin SF, Le Resche L (1990) Graded chronic pain status: an epidemiologic evaluation. Pain 40(3):279–291. https://doi.org/10.1016/0304-3959(90)91125-3

    Article  Google Scholar 

  31. Smith BH, Penny KI, Purves AM et al (1997) The Chronic Pain Grade questionnaire: validation and reliability in postal research. Pain 71(2):141–147. https://doi.org/10.1016/s0304-3959(97)03347-2

    Article  CAS  PubMed  Google Scholar 

  32. Osborne TL, Raichle KA, Jensen MP, Ehde DM, Kraft G (2006) The reliability and validity of pain interference measures in persons with multiple sclerosis. J Pain Symptom Manag 32(3):217–229. https://doi.org/10.1016/j.jpainsymman.2006.03.008

    Article  Google Scholar 

  33. Cella D, Choi SW, Condon DM et al (2019) PROMIS® Adult Health Profiles: efficient short-form measures of seven health domains. Value Health 22(5):537–544. https://doi.org/10.1016/j.jval.2019.02.004

    Article  PubMed  PubMed Central  Google Scholar 

  34. Fairchild AJ, McDaniel HL (2017) Best (but oft-forgotten) practices: mediation analysis. Am J Clin Nutr 105(6):1259–1271. https://doi.org/10.3945/ajcn.117.152546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Preacher KJ, Hayes AF (2008) Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav Res Methods 40(3):879–891. https://doi.org/10.3758/brm.40.3.879

    Article  PubMed  Google Scholar 

  36. R Core Team (2018) R: a Language and Environment for Statistical Computing [Computer Software]. Version 4.1.0. R Core Team, Vienna

  37. RStudio (2015) Integrated Development for R [Computer Software]. Version 1.4.1106. RStudio, Inc, Boston

  38. Gunzler D, Chen T, Wu P, Zhang H (2013) Introduction to mediation analysis with structural equation modeling. Shanghai Arch Psychiatry 25(6):390–394. https://doi.org/10.3969/j.issn.1002-0829.2013.06.009

    Article  PubMed  PubMed Central  Google Scholar 

  39. Rosseel Y. lavaan: an R package for structural equation modeling and more Version 0.5-12 (BETA)

  40. Kessler RC, DuPont RL, Berglund P, Wittchen HU (1999) Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys. Am J Psychiatry 156(12):1915–1923. https://doi.org/10.1176/ajp.156.12.1915

    Article  CAS  PubMed  Google Scholar 

  41. Little RJA (1988) A test of missing completely at random for multivariate data with missing values. J Am Stat Assoc 83(404):1198–1202. https://doi.org/10.1080/01621459.1988.10478722

    Article  Google Scholar 

  42. Tierney NJ, Cook DH (2020) Expanding tidy data principles to facilitate missing data exploration, visualization and assessment of imputations. http://arxiv.org/abs/1809.02264 [stat]. Accessed 4 June 2021

  43. Hayes AF, Scharkow M (2013) The relative trustworthiness of inferential tests of the indirect effect in statistical mediation analysis: does method really matter? Psychol Sci 24(10):1918–1927. https://doi.org/10.1177/0956797613480187

    Article  PubMed  Google Scholar 

  44. Shrout PE, Bolger N (2002) Mediation in experimental and nonexperimental studies: new procedures and recommendations. Psychol Methods 7(4):422–445. https://doi.org/10.1037/1082-989X.7.4.422

    Article  PubMed  Google Scholar 

  45. Hu L, Bentler PM (1999) Cutoff criteria for fit indexes in covariance structure analysis: conventional criteria versus new alternatives. Struct Equ Model 6(1):1–55. https://doi.org/10.1080/10705519909540118

    Article  Google Scholar 

  46. Kuyken W, Byford S, Taylor RS, Watkins E, Holden E, White K, Barrett B et al (2008) Mindfulness-based cognitive therapy to prevent relapse in recurrent depression. J Consult Clin Psychol 76(6):966. https://doi.org/10.1037/a0013786

    Article  PubMed  Google Scholar 

  47. Allen NB (2002) Cognitive therapy of depression. Aaron T Beck, A John Rush, Brian F Shaw, Gary Emery. New York: Guilford Press, 1979. Aust N Z J Psychiatry 36(2):275–278. https://doi.org/10.1046/j.1440-1614.2002.t01-5-01015.x

    Article  PubMed  Google Scholar 

  48. Lester E, DiStefano S, Mace R, Macklin E, Plotkin S, Vranceanu A-M (2020) Virtual mind-body treatment for geographically diverse youth with neurofibromatosis: a pilot randomized controlled trial. Gen Hosp Psychiatry 62:72–78. https://doi.org/10.1016/j.genhosppsych.2019.12.001

    Article  PubMed  Google Scholar 

  49. Hiller W, Zaudig M, Bose M (1989) The overlap between depression and anxiety on different levels of psychopathology. J Affect Disord 16(2–3):223–231. https://doi.org/10.1016/0165-0327(89)90077-3

    Article  CAS  PubMed  Google Scholar 

  50. Wetzler S, Katz MM (1989) Problems with the differentiation of anxiety and depression. J Psychiatr Res 23(1):1–12. https://doi.org/10.1016/0022-3956(89)90013-7

    Article  CAS  PubMed  Google Scholar 

  51. McCracken LM, Zayfert C, Gross RT (1992) The pain anxiety symptoms scale: development and validation of a scale to measure fear of pain. Pain 50(1):67–73. https://doi.org/10.1016/0304-3959(92)90113-P

    Article  PubMed  Google Scholar 

  52. Dahan A, van Velzen M, Niesters M (2014) Comorbidities and the complexities of chronic pain. Anesthesiology 121(4):675–677. https://doi.org/10.1097/ALN.0000000000000402

    Article  PubMed  Google Scholar 

  53. Blackburn-Munro G, Blackburn-Munro RE (2001) Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol 13(12):1009–1023. https://doi.org/10.1046/j.0007-1331.2001.00727.x

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was funded by a grant from the Department of Defense (W81XWH-17-1-0121) to the senior author (AMV), and a K23 grant from NCCIH (1K23AT01065301A1) to the co-first author (JG).

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Author notes

  1. James D. Doorley and Jonathan Greenberg are joint first authors and contributed equally.

Authors and Affiliations

  1. Integrated Brain Health Clinical and Research Program, Massachusetts General Hospital, 1 Bowdoin Square, Suite 100, 1st Floor, Boston, MA, 02114, USA

    James D. Doorley, Jonathan Greenberg, Jafar Bakhshaie, Nathan S. Fishbein & Ana-Maria Vranceanu

  2. Harvard Medical School, Boston, MA, 02115, USA

    James D. Doorley, Jonathan Greenberg, Jafar Bakhshaie & Ana-Maria Vranceanu

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  1. James D. Doorley
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  2. Jonathan Greenberg
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  3. Jafar Bakhshaie
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  5. Ana-Maria Vranceanu
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Contributions

All authors significantly contributed to this manuscript. JDD, JG, JB and AMV collaboratively developed the study aims. JDD analyzed the data and drafted the methods and results sections. JG drafted the introduction and discussion sections. JB assisted with data analysis. NSF assisted with materials and manuscript preparation. AMV provided oversight and guidance on study design, data interpretation and writing. All authors read, edited, and approved the final manuscript.

Corresponding author

Correspondence to Ana-Maria Vranceanu.

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The authors certify that this study was approved by the Massachusetts General Hospital Institutional Review Board and was performed in accordance with the ethical standards set forth in the 1964 Declaration of Helsinki and its later amendments.

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The authors certify that all participants provided informed consent to participate in the study. The authors certify that, as part of the informed consent process, all study participants consent to having their de-identified data published within a scientific journal article.

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Doorley, J.D., Greenberg, J., Bakhshaie, J. et al. Depression explains the association between pain intensity and pain interference among adults with neurofibromatosis. J Neurooncol 154, 257–263 (2021). https://doi.org/10.1007/s11060-021-03826-3

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