Journal of NeuroVirology

, Volume 25, Issue 1, pp 57–71 | Cite as

Enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain

  • Michael A. Owens
  • Romy Parker
  • Rachael L. Rainey
  • Cesar E. Gonzalez
  • Dyan M. White
  • Anooshah E. Ata
  • Jennifer I. Okunbor
  • Sonya L. Heath
  • Jessica S. Merlin
  • Burel R. GoodinEmail author


Chronic pain in persons living with HIV (PLWH) may be related to alterations in endogenous pain modulatory processes (e.g., high facilitation and low inhibition of nociception) that promote exaggerated pain responses, known as hyperalgesia, and central nervous system (CNS) sensitization. This observational study examined differences in endogenous pain modulatory processes between 59 PLWH with chronic pain, 51 PLWH without chronic pain, and 50 controls without HIV or chronic pain. Quantitative sensory testing for temporal summation (TS) of mechanical and heat pain as well as conditioned pain modulation (CPM) were used to assess endogenous pain facilitatory and inhibitory processes, respectively. Associations among TS, CPM, and self-reported clinical pain severity were also examined in PLWH with chronic pain. Findings demonstrated significantly greater TS of mechanical and heat pain for PLWH with chronic pain compared to PLWH without chronic pain and controls. CPM effects were present in controls, but not in either PLWH with or without chronic pain. Among PLWH with chronic pain, greater TS of mechanical pain was significantly associated with greater average clinical pain severity. Results of this study suggest that enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain.


HIV Chronic pain Endogenous pain modulation Temporal summation Conditioned pain modulation 



This research was supported by the Creative and Novel Ideas in HIV Research Program (B.R.G.) through a supplement to the University of Alabama at Birmingham Center for AIDS Research funding (P30AI027767). This funding was made possible by collaborative efforts of the Office of AIDS Research, the National Institute of Allergy and Infectious Diseases, and the International AIDS Society. This research was also supported by the National Institutes of Health K23MH104073 (J.S.M.). None of the authors have any conflicts of interest to report.


  1. Annual update of the HHS poverty guidelines. (2017) Department of Health and Human Services, Accessed June 21, 2018
  2. Arnow BA, Hunkeler EM, Blasey CM, Lee J, Constantino MJ, Fireman B et al (2006) Comorbid depression, chronic pain, and disability in primary care. Psychosom Med 68(2):262–268. Google Scholar
  3. Bannister K, Dickenson AH (2016) What do monoamines do in pain modulation? Curr Opin Support Palliat Care 10(2):143–148. Google Scholar
  4. Bulls HW, Freeman EL, Anderson AJ, Robbins MT, Ness TJ, Goodin BR (2015) Sex differences in experimental measures of pain sensitivity and endogenous pain inhibition. J Pain Res 8:311–320. Google Scholar
  5. Cruz-Almeida Y, Fillingim RB (2014) Can quantitative sensory testing move us closer to mechanism-based pain management? Pain Med 15(1):61–72. Google Scholar
  6. Dalakas MC (2001) Peripheral neuropathy and antiretroviral drugs. J Peripher Nerv Syst 6(1):14–20Google Scholar
  7. Dobalian A, Tsao JC, Duncan RP (2004) Pain and the use of outpatient services among persons with HIV: results from a nationally representative survey. Med Care 42(2):129–138. Google Scholar
  8. Edens JL, Gil KM (1995) Experimental induction of pain: utility in the study of clinical pain. Behav Ther 26:197–216Google Scholar
  9. Ehde DM, Dillworth TM, Turner JA (2014) Cognitive-behavioral therapy for individuals with chronic pain: efficacy, innovations, and directions for research. Am Psychol 69(2):153–166. Google Scholar
  10. Eide PK (2000) Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain 4(1):5–15. Google Scholar
  11. Evans S, Weinberg BA, Spielman L, Fishman B (2003) Assessing negative thoughts in response to pain among people with HIV. Pain 105(1–2):239–245Google Scholar
  12. Gabbai AA, Castelo A, Oliveira AS (2013) HIV peripheral neuropathy. Handb Clin Neurol 115:515–529. Google Scholar
  13. Geisser ME, Roth RS, Robinson ME (1997) Assessing depression among persons with chronic pain using the Center for Epidemiological Studies-Depression Scale and the Beck depression inventory: a comparative analysis. Clin J Pain 13(2):163–170Google Scholar
  14. Goodin BR, McGuire L, Allshouse M, Stapleton L, Haythornthwaite JA, Burns N, Edwards RR (2009) Associations between catastrophizing and endogenous pain-inhibitory processes: sex differences. J Pain 10(2):180–190. Google Scholar
  15. Goodin BR, Glover TL, Sotolongo A, King CD, Sibille KT, Herbert MS et al (2013) The association of greater dispositional optimism with less endogenous pain facilitation is indirectly transmitted through lower levels of pain catastrophizing. J Pain 14(2):126–135. Google Scholar
  16. Goodin, B. R., Bulls, H. W., Herbert, M. S., Schmidt, J., King, C. D., Glover, T. L., … Fillingim, R. B. (2014). Temporal summation of pain as a prospective predictor of clinical pain severity in adults aged 45 years and older with knee osteoarthritis: ethnic differences. Psychosom Med, 76(4):302–310. doi:
  17. Goodin BR, Owens MA, Yessick LR, Rainey RL, Okunbor JI, White DM, Merlin JS (2017) Detectable viral load may be associated with increased pain sensitivity in persons living with HIV: preliminary findings. Pain Med 18(12):2289–2295. Google Scholar
  18. Granovsky Y, Yarnitsky D (2013) Personalized pain medicine: the clinical value of psychophysical assessment of pain modulation profile. Rambam Maimonides Med J 4(4):e0024. Google Scholar
  19. Griffith LE, Shannon HS, Wells RP, Walter SD, Cole DC, Cote P, Langlois LE (2012) Individual participant data meta-analysis of mechanical workplace risk factors and low back pain. Am J Public Health 102(2):309–318. Google Scholar
  20. Griswold GA, Evans S, Spielman L, Fishman B (2005) Coping strategies of HIV patients with peripheral neuropathy. AIDS Care 17(6):711–720. Google Scholar
  21. Heinricher MM, Tavares I, Leith JL, Lumb BM (2009) Descending control of nociception: specificity, recruitment and plasticity. Brain Res Rev 60(1):214–225. Google Scholar
  22. Holguin A, O'Connor KA, Biedenkapp J, Campisi J, Wieseler-Frank J, Milligan ED, Watkins LR (2004) HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS). Pain 110(3):517–530. Google Scholar
  23. Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Stat 6:65–70Google Scholar
  24. Jensen MP, Karoly P (1992) Self-report scales and procedures for assessing pain in adults. In: Turk DC, Melzack R (eds) Handbook of pain assessment. Guilford Press, New York, pp 135–151Google Scholar
  25. Ji RR, Nackley A, Huh Y, Terrando N, Maixner W (2018) Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology 129:343–366. Google Scholar
  26. Jiao JM, So E, Jebakumar J, George MC, Simpson DM, Robinson-Papp J (2016) Chronic pain disorders in HIV primary care: clinical characteristics and association with healthcare utilization. Pain 157(4):931–937. Google Scholar
  27. King CD, Sibille KT, Goodin BR, Cruz-Almeida Y, Glover TL, Bartley E, Fillingim RB (2013) Experimental pain sensitivity differs as a function of clinical pain severity in symptomatic knee osteoarthritis. Osteoarthr Cartil 21(9):1243–1252. Google Scholar
  28. Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10(9):895–926. Google Scholar
  29. Le Bars D (2002) The whole body receptive field of dorsal horn multireceptive neurones. Brain Res Brain Res Rev 40(1–3):29–44Google Scholar
  30. Lucey BP, Clifford DB, Creighton J, Edwards RR, McArthur JC, Haythornthwaite J (2011) Relationship of depression and catastrophizing to pain, disability, and medication adherence in patients with HIV-associated sensory neuropathy. AIDS Care 23(8):921–928. Google Scholar
  31. Magerl W, Wilk SH, Treede RD (1998) Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans. Pain 74(2–3):257–268Google Scholar
  32. Martini C, van Velzen M, Drewes A, Aarts L, Dahan A, Niesters M (2015) A randomized controlled trial on the effect of Tapentadol and morphine on conditioned pain modulation in healthy volunteers. PLoS One 10(6):e0128997. Google Scholar
  33. Merlin JS, Cen L, Praestgaard A, Turner M, Obando A, Alpert C, Frank I (2012a) Pain and physical and psychological symptoms in ambulatory HIV patients in the current treatment era. J Pain Symptom Manag 43(3):638–645. Google Scholar
  34. Merlin JS, Westfall AO, Raper JL, Zinski A, Norton WE, Willig JH et al (2012b) Pain, mood, and substance abuse in HIV: implications for clinic visit utilization, antiretroviral therapy adherence, and virologic failure. J Acquir Immune Defic Syndr 61(2):164–170. Google Scholar
  35. Merlin JS, Westfall AO, Chamot E, Overton ET, Willig JH, Ritchie C, Mugavero MJ (2013) Pain is independently associated with impaired physical function in HIV-infected patients. Pain Med 14(12):1985–1993. Google Scholar
  36. Merlin JS, Long D, Becker WC, Cachay ER, Christopolous KA, Claborn K, Gross R (2018) The association of chronic pain and long-term opioid therapy with HIV treatment outcomes. J Acquir Immune Defic Syndr 79:77–82. Google Scholar
  37. Miaskowski C, Penko JM, Guzman D, Mattson JE, Bangsberg DR, Kushel MB (2011) Occurrence and characteristics of chronic pain in a community-based cohort of indigent adults living with HIV infection. J Pain 12(9):1004–1016. Google Scholar
  38. Myers TA (2011) Goodbye listwise deletion: presenting hotdeck imputation as an easy and effective tool for handling missing data. Communication Measures & Methods 5:297–310Google Scholar
  39. Nahman-Averbuch H, Nir RR, Sprecher E, Yarnitsky D (2016) Psychological factors and conditioned pain modulation: a meta-analysis. Clin J Pain 32(6):541–554. Google Scholar
  40. Natamba BK, Achan J, Arbach A, Oyok TO, Ghosh S, Mehta S, Young SL (2014) Reliability and validity of the center for epidemiologic studies-depression scale in screening for depression among HIV-infected and -uninfected pregnant women attending antenatal services in northern Uganda: a cross-sectional study. BMC Psychiatry 14:303. Google Scholar
  41. Niesters M, Aarts L, Sarton E, Dahan A (2013) Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study. Br J Anaesth 110(6):1010–1016. Google Scholar
  42. Nir RR, Yarnitsky D (2015) Conditioned pain modulation. Curr Opin Support Palliat Care 9(2):131–137. Google Scholar
  43. O'Brien AT, Deitos A, Trinanes Pego Y, Fregni F, Carrillo-de-la-Pena MT (2018) Defective endogenous pain modulation in fibromyalgia: a meta-analysis of temporal summation and conditioned pain modulation paradigms. J Pain.
  44. O'Donnell LA, Agrawal A, Jordan-Sciutto KL, Dichter MA, Lynch DR, Kolson DL (2006) Human immunodeficiency virus (HIV)-induced neurotoxicity: roles for the NMDA receptor subtypes. J Neurosci 26(3):981–990. Google Scholar
  45. Ohrbach R, Gale EN (1989) Pressure pain thresholds in normal muscles: reliability, measurement effects, and topographic differences. Pain 37(3):257–263Google Scholar
  46. Ossipov MH The perception and endogenous modulation of pain. Scientifica (Cairo) 2012, 2012:561761–561725.
  47. Ossipov MH, Dussor GO, Porreca F (2010) Central modulation of pain. J Clin Invest 120(11):3779–3787. Google Scholar
  48. Ossipov MH, Morimura K, Porreca F (2014) Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care 8(2):143–151. Google Scholar
  49. Owens MA, Bulls HW, Trost Z, Terry SC, Gossett EW, Wesson-Sides KM, Goodin BR (2016) An examination of pain catastrophizing and endogenous pain modulatory processes in adults with chronic low Back pain. Pain Med 17(8):1452–1464. Google Scholar
  50. Parker R, Stein DJ, Jelsma J (2014) Pain in people living with HIV/AIDS: a systematic review. J Int AIDS Soc 17:18719. Google Scholar
  51. Piche M, Arsenault M, Poitras P, Rainville P, Bouin M (2010) Widespread hypersensitivity is related to altered pain inhibition processes in irritable bowel syndrome. Pain 148(1):49–58. Google Scholar
  52. Price DD, Hu JW, Dubner R, Gracely RH (1977) Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses. Pain 3(1):57–68Google Scholar
  53. Quartana PJ, Campbell CM, Edwards RR (2009) Pain catastrophizing: a critical review. Expert Rev Neurother 9(5):745–758. Google Scholar
  54. Radloff LS (1977) A self-report depression scale for research in the general population. Appl Psychol Meas 1(3):385–401Google Scholar
  55. Rhudy JL, Martin SL, Terry EL, France CR, Bartley EJ, DelVentura JL, Kerr KL (2011) Pain catastrophizing is related to temporal summation of pain but not temporal summation of the nociceptive flexion reflex. Pain 152(4):794–801. Google Scholar
  56. Ryscavage P, Kelly S, Li JZ, Harrigan PR, Taiwo B (2014) Significance and clinical management of persistent low-level viremia and very-low-level viremia in HIV-1-infected patients. Antimicrob Agents Chemother 58(7):3585–3598. Google Scholar
  57. Sarmati L, D'Ettorre G, Parisi SG, Andreoni M (2015) HIV replication at low copy number and its correlation with the HIV reservoir: a clinical perspective. Curr HIV Res 13(3):250–257Google Scholar
  58. Spudich S, Gonzalez-Scarano F (2012) HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment. Cold Spring Harb Perspect Med 2(6):a007120. Google Scholar
  59. Starkweather AR, Heineman A, Storey S, Rubia G, Lyon DE, Greenspan J, Dorsey SG (2016) Methods to measure peripheral and central sensitization using quantitative sensory testing: A focus on individuals with low back pain. Appl Nurs Res 29:237–241Google Scholar
  60. Staud R (2012) Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions. Expert Rev Neurother 12(5):577–585. Google Scholar
  61. Staud R (2013) The important role of CNS facilitation and inhibition for chronic pain. Int J Clin Rheumtol 8(6):639–646. Google Scholar
  62. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD (2001) Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 91(1–2):165–175Google Scholar
  63. Staud R, Weyl EE, Riley JL 3rd, Fillingim RB (2014) Slow temporal summation of pain for assessment of central pain sensitivity and clinical pain of fibromyalgia patients. PLoS One 9(2):e89086. Google Scholar
  64. Sullivan MJL, Bishop SR, Pivik J (1995) The pain catastrophizing scale: development and validation. Psychol Assess 7(4):524–532Google Scholar
  65. Tan G, Jensen MP, Thornby JI, Shanti BF (2004) Validation of the brief pain inventory for chronic nonmalignant pain. J Pain 5(2):133–137. Google Scholar
  66. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, … Wang SJ (2015) A classification of chronic pain for ICD-11. Pain 156(6):1003–1007. doi:
  67. van Wilgen CP, Vuijk PJ, Kregel J, Voogt L, Meeus M, Descheemaeker F, … Nijs J (2018) Psychological distress and widespread pain contribute to the variance of the central sensitization inventory: a cross-sectional study in patients with chronic pain. Pain Pract, 18(2):239–246. doi:
  68. Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152(3 Suppl):S2–S15. Google Scholar
  69. Yarnitsky D (2015) Role of endogenous pain modulation in chronic pain mechanisms and treatment. Pain 156(Suppl 1):S24–S31. Google Scholar
  70. Yarnitsky D, Arendt-Nielsen L, Bouhassira D, Edwards RR, Fillingim RB, Granot M, Wilder-Smith O (2010) Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 14(4):339. Google Scholar
  71. Yarnitsky D, Granot M, Granovsky Y (2014) Pain modulation profile and pain therapy: between pro- and antinociception. Pain 155(4):663–665. Google Scholar
  72. Yarnitsky D, Bouhassira D, Drewes AM, Fillingim RB, Granot M, Hansson P, Wilder-Smith OH (2015) Recommendations on practice of conditioned pain modulation (CPM) testing. Eur J Pain 19(6):805–806. Google Scholar
  73. Yuan SB, Shi Y, Chen J, Zhou X, Li G, Gelman BB, Tang SJ (2014) Gp120 in the pathogenesis of human immunodeficiency virus-associated pain. Ann Neurol 75(6):837–850. Google Scholar
  74. Zelman DC, Gore M, Dukes E, Tai KS, Brandenburg N (2005) Validation of a modified version of the brief pain inventory for painful diabetic peripheral neuropathy. J Pain Symptom Manag 29(4):401–410. Google Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2018

Authors and Affiliations

  • Michael A. Owens
    • 1
  • Romy Parker
    • 2
  • Rachael L. Rainey
    • 1
  • Cesar E. Gonzalez
    • 1
  • Dyan M. White
    • 1
  • Anooshah E. Ata
    • 1
  • Jennifer I. Okunbor
    • 1
  • Sonya L. Heath
    • 3
  • Jessica S. Merlin
    • 4
  • Burel R. Goodin
    • 1
    • 5
    Email author
  1. 1.Department of PsychologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of Anesthesia & Perioperative MedicineUniversity of Cape TownCape TownSouth Africa
  3. 3.Department of Medicine, Division of Infectious DiseasesUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Divisions of General Internal Medicine and Infectious DiseasesUniversity of PittsburghPittsburghUSA
  5. 5.Department of Anesthesiology & Perioperative Medicine, Division of Pain MedicineUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations