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Scandinavian Journal of Pain

Official Journal of the Scandinavian Association for the Study of Pain

Editor-in-Chief: Breivik, Harald

4 Issues per year


CiteScore 2017: 0.84

SCImago Journal Rank (SJR) 2017: 0.401
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1877-8879
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Volume 17, Issue 1

Central sensitization associated with low fetal hemoglobin levels in adults with sickle cell anemia

Deepika S. Darbari
  • Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
  • Center for Cancer and Blood Diseases, Children’s National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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/ Kathleen J. Vaughan
  • Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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/ Katherine Roskom
  • Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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/ Cassie Seamon
  • Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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/ Lena Diaw
  • Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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/ Meghan Quinn
  • Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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/ Anna Conrey
  • Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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/ Alan N. Schechter
  • Molecular Biology and Genetics Section, Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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/ Jennifer A. Haythornthwaite
  • Center for Mind-Body Research, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
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/ Myron A. Waclawiw
  • Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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/ Gwenyth R. Wallen / Inna Belfer
  • Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  • Office of Research on Women’s Health, National Institutes of Health, Bethesda, MD, USA
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/ James G. Taylor VI
  • Corresponding author
  • Genomic Medicine Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
  • Department of Medicine and Center for Sickle Cell Disease, Howard University College of Medicine, Washington, DC, USA
  • Email
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Published Online: 2017-10-01 | DOI: https://doi.org/10.1016/j.sjpain.2017.08.001

Abstract

Pain is the hallmark of sickle cell anemia (SCA), presenting as recurrent acute events or chronic pain. Central sensitization, or enhanced excitability of the central nervous system, alters pain processing and contributes to the maintenance of chronic pain. Individuals with SCA demonstrate enhanced sensitivity to painful stimuli however central mechanisms of pain have not been fully explored. We hypothesized that adults with SCA would show evidence of central sensitization as observed in other diseases of chronic pain.

Methods

We conducted a prospective study of static and dynamic quantitative sensory tests in 30 adults with SCA and 30 matched controls.

Results

Static thermal testing using cold stimuli showed lower pain thresholds (p = 0.04) and tolerance (p = 0.04) in sickle cell subjects, but not for heat. However, SCA subjects reported higher pain ratings with random heat pulses (p < 0.0001) and change in scores with temporal summation at the heat pain threshold (p = 0.002). Similarly, with the use of pressure pain stimuli, sickle cell subjects reported higher pain ratings (p = 0.04), but not higher pressure pain tolerance/thresholds or allodynia to light tactile stimuli. Temporal summation pain score changes using 2 pinprick probes (256 and 512 mN) were significantly greater (p = 0.004 and p = 0.008) with sickle cell, and delayed recovery was associated with lower fetal hemoglobin (p = 0.002 and 0.003).

Conclusions

Exaggerated temporal summation responses provide evidence of central sensitization in SCA.

Implications

The association with fetal hemoglobin suggests this known SCA modifier may have a therapeutic role in modulating central sensitization.

This article offers supplementary material which is provided at the end of the article.

Keywords: Sickle cell anemia; Pain; Central sensitization; Temporal summation; Fetal hemoglobin

References

  • [1]

    Ballas SK, Bauserman RL, McCarthy WF, Castro OL, Smith WR, Waclawiwa MA. Investigators of the multicenter study of hydroxyurea in sickle cell, utilization of analgesics in the multicenter study of hydroxyurea in sickle cell anemia: effect ofsex, age, and geographical location. Am J Hematol 2010;85:613–6.CrossrefGoogle Scholar

  • [2]

    Dampier C, Ely B, Brodecki D, O’Neal P. Characteristics of pain managed at home in children and adolescents with sickle cell disease by using diary self-reports. J Pain 2002;3:461–70.PubMedCrossrefGoogle Scholar

  • [3]

    Smith WR, Penberthy LT, Bovbjerg VE, McClish DK, Roberts JD, Dahman B, Aisiku IP, Levenson JL, Roseff SD. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med 2008;148:94–101.CrossrefPubMedGoogle Scholar

  • [4]

    Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR. Pain in sickle cell disease.Rates and risk factors. N Engl J Med 1991;325:11-6.PubMedCrossrefGoogle Scholar

  • [5]

    Darbari DS, Onyekwere O, Nouraie M, Minniti CP, Luchtman-Jones L, Rana S, Sable C, Ensing G, Dham N, Campbell A, Arteta M, Gladwin MT, Castro O, Taylor JGT, Kato GJ, Gordeuk V. Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia. J Pediatr 2012;160:286–90.CrossrefPubMedGoogle Scholar

  • [6]

    Shapiro BS, Dinges DF, Orne EC, Bauer N, Reilly LB, Whitehouse WG, Ohene-Frempong K, Orne MT. Home management of sickle cell-related pain in children and adolescents: natural history and impact on school attendance. Pain 1995;61:139–44.PubMedCrossrefGoogle Scholar

  • [7]

    Zempsky WT, O’Hara EA, Santanelli JP, Palermo TM, New T, Smith-Whitley K, Casella JF. Validation of the sickle cell disease pain burden interview-youth. J Pain 2013;14:975–82.PubMedCrossrefGoogle Scholar

  • [8]

    Ezenwa MO, Molokie RE, Wang ZJ, Yao Y, Suarez ML, Angulo V, Wilkie DJ. Outpatient pain predicts subsequent one-year acute health care utilization among adults with sickle cell disease. J Pain Symptom Manag 2014;48:65–74.CrossrefGoogle Scholar

  • [9]

    Dampier C, Palermo TM, Darbari DS, Hassell K, Smith W, Zempsky W. AAPT diagnostic criteria forchronic sickle cell disease pain. J Pain 2017.Google Scholar

  • [10]

    Darbari DS, Ballas SK, Clauw DJ. Thinking beyond sickling to better understand pain in sickle cell disease. EurJ Haematol 2014;93:89–95.CrossrefGoogle Scholar

  • [11]

    Belfer I, Youngblood V, Darbari DS, Wang Z, Diaw L, Freeman L, Desai K, Dizon M, Allen D, Cunnington C, Channon KM, Milton J, Hartley SW, Nolan V, Kato GJ, Steinberg MH, Goldman D, Taylor JGT. A GCHl haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia. AmJ Hematol 2014;89:187–93.CrossrefGoogle Scholar

  • [12]

    Kohli DR, Li Y, Khasabov SG, Gupta P, Kehl LJ, Ericson ME, Nguyen J, Gupta V, Hebbel RP, Simone DA, Gupta K. Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids. Blood 2010;116:456–65.CrossrefPubMedGoogle Scholar

  • [13]

    Campbell CM, Carroll CP, Kiley K, Han D, HaywoodJr C, Lanzkron S, Swedberg L, Edwards RR, Page GG, Haythornthwaite JA. Quantitative sensory testing and pain-evoked cytokine reactivity:comparison of patients with sickle cell disease to healthy matched controls. Pain 2016;157:949–56.PubMedCrossrefGoogle Scholar

  • [14]

    Campbell CM, Moscou-Jackson G, Carroll CP, Kiley K, Haywood Jr C, Lanzkron S, Hand M, Edwards RR, Haythornthwaite JA. An evaluation of central sensitization in patients with sickle cell disease. J Pain 2016;17:617–27.CrossrefPubMedGoogle Scholar

  • [15]

    Darbari DS, Hampson JP, Ichesco E, Kadom N, Vezina G, Evangelou I, Clauw DJ, Taylor VI JG, Harris RE. Frequency of hospitalizations for pain and association with altered brain network connectivity in sickle cell disease. J Pain 2015;16:1077–86.CrossrefPubMedGoogle Scholar

  • [16]

    Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian A, Lotsch J, Fillingim RB, Maixner W, Geisslinge G, Max MB, Woolf CJ. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med 2006;12:1269–77.CrossrefPubMedGoogle Scholar

  • [17]

    Lotsch J, Klepstad P, Doehring A, Dale O. A GTP cyclohydrolase l genetic variant delays cancerpain. Pain 2010;148:103–6.CrossrefGoogle Scholar

  • [18]

    Brandow AM, Stucky CL, Hillery CA, Hoffmann RG, Panepinto JA. Patients with sickle cell disease have increased sensitivity to cold and heat. Am J Hematol 2013;88:37–43.PubMedCrossrefGoogle Scholar

  • [19]

    Cataldo G, Rajput S, Gupta K, Simone DA. Sensitization of nociceptive spinal neurons contributes to pain in a transgenic model of sickle cell disease. Pain 2015;156:722–30.CrossrefGoogle Scholar

  • [20]

    Ezenwa MO, Molokie RE, Wang ZJ, Yao Y, Suarez ML, Pullum C, Schlaeger JM, Fillingim RB, Wilkie DJ. Safety and utility of quantitative sensory testing among adults with sickle cell disease: indicators of neuropathic pain? Pain Pract 2016;6:282–93.Google Scholar

  • [21]

    Hillery CA, Kerstein PC, Vilceanu D, Barabas ME, Retherford D, Brandow AM, Wandersee NJ, Stucky CL. Transient receptor potential vanilloid l mediates pain in mice with severe sickle cell disease. Blood 2011;118:3376–83.CrossrefGoogle Scholar

  • [22]

    Vincent L, Vang D, Nguyen J, Gupta M, Luk K, Ericson ME, Simone DA, Gupta K. Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood 2013;122:1853–62.CrossrefPubMedGoogle Scholar

  • [23]

    Woolf CJ. Central sensitization: implications forthe diagnosis and treatment of pain. Pain 2011;152:S2-15.CrossrefGoogle Scholar

  • [24]

    Walk D, Sehgal N, Moeller-Bertram T, Edwards RR, Wasan A, Wallace M, Irving G, Argoff C, Backonja MM. Quantitative sensory testing and mapping: a review of nonautomated quantitative methods for examination of the patient with neuropathic pain. Clin J Pain 2009;25:632–40.PubMedCrossrefGoogle Scholar

  • [25]

    Yarnitsky D, Arendt-Nielsen L, Bouhassira D, Edwards RR, Fillingim RB, Granot M, Hansson P, Lautenbacher S, Marchand S, Wilder-Smith O. Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 2010;14:339.CrossrefPubMedGoogle Scholar

  • [26]

    Garrison SR, Kramer AA, Gerges NZ, Hillery CA, Stucky CL. Sickle cell mice exhibit mechanical allodynia and enhanced responsiveness in light touch cutaneous mechanoreceptors. Mol Pain 2012;8:62.PubMedGoogle Scholar

  • [27]

    O’Leary JD, Crawford MW, Odame I, Shorten GD, McGrath PA. Thermal pain and sensory processing in children with sickle cell disease. Clin J Pain 2014;30:244–50.PubMedCrossrefGoogle Scholar

  • [28]

    Jacob E, Chan VW, Hodge C, Zeltzer L, Zurakowski D, Sethna NF. Sensory and thermal quantitative testing inchildrenwith sickle cell disease. J PediatrHematol Oncol 2015;37:185–9.Google Scholar

  • [29]

    Kenyon N, Wang L, Spornick N, Khaibullina A, Almeida LE, Cheng Y, Wang J, Guptill V, Finkel JC, Quezado ZM. Sickle cell disease in mice is associated with sensitization of sensory nerve fibers. Exp Biol Med (Maywood) 2015;240:87–98.PubMedCrossrefGoogle Scholar

  • [30]

    Cain DM, Vang D, Simone DA, Hebbel RP, Gupta K. Mouse models for studying pain in sickle disease: effects of strain, age, and acuteness. Br J Haematol 2012;156:535–44.CrossrefPubMedGoogle Scholar

  • [31]

    Zappia KJ, Garrison SR, Hillery CA, Stucky CL. Cold hypersensitivity increases with age in mice with sickle cell disease. Pain 2014;155:2476–85.PubMedCrossrefGoogle Scholar

  • [32]

    Hurtig IM, Raak RI, Kendall SA, Gerdle B, Wahren LK. Quantitative sensory testing in fibromyalgia patients and in healthy subjects: identification of subgroups. Clin J Pain 2001;17:316-22.CrossrefPubMedGoogle Scholar

  • [33]

    Schreiber KL, Martel MO, Shnol H, Shaffer JR, Greco C, Viray N, Taylor LN, McLaughlin M, Brufsky A, Ahrendt G, Bovbjerg D, Edwards RR, Belfer I. Persistent pain in postmastectomy patients: comparison of psychophysical, medical, surgical, and psychosocial characteristics between patients with and without pain. Pain 2013;154:660–8.PubMedCrossrefGoogle Scholar

  • [34]

    Gracely RH, McGrath F, Dubner R. Ratio scales of sensory and affective verbal paindescriptors. Pain 1978;5:5–18.CrossrefPubMedGoogle Scholar

  • [35]

    Gracely RH, Kwilosz DM. The Descriptor Differential Scale: applying psychophysical principles to clinical pain assessment. Pain 1988;35:279–88.CrossrefPubMedGoogle Scholar

  • [36]

    Gracely RH, Dubner R, McGrath PA. Fentanyl reduces the intensity of painful tooth pulp sensations: controlling for detection of active drugs. Anest Analg 1982;61:751-5.Google Scholar

  • [37]

    Greenspan JD, Slade GD, Bair E, Dubner R, Fillingim RB, Ohrbach R, Knott C, Diatchenko L, Liu Q, Maixner W. Pain sensitivity and autonomic factors associated with development of TMD: the OPPERA prospective cohort study. J Pain 2013;14.T63–74.el-6.CrossrefPubMedGoogle Scholar

  • [38]

    Jaeger B, Reeves JL. Quantification of changes in myofascial trigger point sensitivity with the pressure algometer following passive stretch. Pain 1986;27:203–10.PubMedCrossrefGoogle Scholar

  • [39]

    Kosek E, Ordeberg G. Abnormalities of somatosensory perception in patients with painful osteoarthritis normalize following successfultreatment. EurJ Pain 2000;4:229–38.CrossrefGoogle Scholar

  • [40]

    Carroll CP, Lanzkron S, Haywood Jr C, Kiley K, Pejsa M, Moscou-Jackson G, Haythornthwaite JA, Campbell CM. Chronic opioid therapy and central sensitization in sickle cell disease. AmJ Prev Med 2016;51:S69-77.CrossrefGoogle Scholar

  • [41]

    Arendt-Nielsen L. Central sensitization in humans: assessment and pharmacology. Handb Exp Pharmacol 2015;227:79–102.PubMedCrossrefGoogle Scholar

  • [42]

    Sato H, Saisu H, Muraoka W, Nakagawa T, Svensson P, Wajima K. Lackoftemporal summation but distinct aftersensations to thermal stimulation in patients with combined tension-type headache and myofascial temporomandibular disorder. J Orofac Pain 2012;26:288–95.PubMedGoogle Scholar

  • [43]

    Schliessbach J, Siegenthaler A, Streitberger K, Eichenberger U, Nuesch E, Juni P, Arendt-Nielsen L, Curatolo M. The prevalence of widespread central hypersensitivity in chronic pain patients. Eur J Pain 2013;17:1502-10.PubMedGoogle Scholar

  • [44]

    Li J, Simone DA, Larson AA. Windup leads to characteristics of central sensitization. Pain 1999;79:75–82.PubMedCrossrefGoogle Scholar

  • [45]

    Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004;140:441–51.PubMedCrossrefGoogle Scholar

  • [46]

    Richards N, McMahon SB. Targeting novel peripheral mediators forthe treatment of chronic pain. Br J Anaesth 2013;111:46-51.CrossrefGoogle Scholar

  • [47]

    King CD, Wong F, Currie T, Mauderli AP, Fillingim RB, Riley3rd JL. Deficiency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder. Pain 2009;143:172–8.CrossrefPubMedGoogle Scholar

  • [48]

    Campbell CM, France CR, Robinson ME, Logan HL, Geffken GR, Fillingim RB. Ethnic differences in diffuse noxious inhibitory controls. J Pain 2008;9:759–66.CrossrefPubMedGoogle Scholar

  • [49]

    Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639–44.PubMedCrossrefGoogle Scholar

  • [50]

    Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SCdisease. Blood Rev 2003;17:167–78.PubMedCrossrefGoogle Scholar

  • [51]

    Cruccu G, Sommer C, Anand P, Attal N, Baron R, Garcia-Larrea L, Haanpaa M, Jensen TS, Serra J, Treede RD. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol 2010;17:1010-8.PubMedCrossrefGoogle Scholar

  • [52]

    Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–87.CrossrefPubMedGoogle Scholar

  • [53]

    Wang ZJ, Molokie RE, Wilkie DJ. Does cold hypersensitivity increase with age in sickle cell disease? Pain 2014;155:2439–40.PubMedCrossrefGoogle Scholar

  • [54]

    Kosek E, Ordeberg G. Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief. Pain 2000;88:69–78.CrossrefPubMedGoogle Scholar

About the article

Department of Medicine and Center for Sickle Cell Disease, Howard University College of Medicine, 2041 Georgia Avenue, Washington, DC20060, USA


Received: 2017-04-10

Revised: 2017-07-26

Accepted: 2017-08-01

Published Online: 2017-10-01

Published in Print: 2017-10-01


Ethical issues: Written informed consent was required of all enrolled subjects after protocol approval by the Institutional Review Board at the National Institutes of Health. The study was registered with Clinicaltrials.gov (identifier NCT01441141).

Conflict of interest:The authors report no conflicts of interest.

Author contributions:Conceived and designed study: DSD, CS, GRW, IB, JGT. QST and research coordination: KV, CS, KC, AC. Statistical analysis: KV, MQ, MAW, JGT. Data interpretation: DSD, KV, CS, KC, MQ, AC, LD, ANS, JAH, MAW, GRW, IB, JGT. Logistical support and QST training: AC, LD, GRW, ANS, JAH, IB. Drafted manuscript: JGT with contributions from DSD and KV. All authors contributed to manuscript writing and editing.


Citation Information: Scandinavian Journal of Pain, Volume 17, Issue 1, Pages 279–286, ISSN (Online) 1877-8879, ISSN (Print) 1877-8860, DOI: https://doi.org/10.1016/j.sjpain.2017.08.001.

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