Keywords
sickle cell disease
acute pain
chronic pain syndrome
opioids.
Abstract
Patients with sickle cell disease (SCD) suffer from severe pain that often begins in childhood and increases in severity over the course of a lifetime, leading to hospitalization and poor quality of life over the years. A unique feature of SCD is vase-occlusive crises (VOC) characterized by recurrent and unpredictable episodes of acute pain. Microvascular occlusion during a VOC results in decreased oxygen supply to the periphery and injury from ischemia and subsequent reperfusion, inflammation, oxidative stress and endothelial dysfunction, all of which can perpetuate a harmful pain-causing microenvironment. On the other hand, in addition to episodic acute pain, SCD patients also report chronic pain, defined as almost daily pain over a 6-month period associated to either sicologic or social morbidities. They may be due to chronic lesions such as skin ulcers, avascular bone necrosis or infarctions in various organs. In addition, central sensitization appears to be directly involved in the chronicity of pain and there is a clearly under-diagnosed and under-treated component of neuropathic pain. Current treatment of moderate to severe pain in SCD is based primarily on opioids; either as an oral quick release outpatient or in the form of patient-controlled intravenous analgesia in the hospital. However, long-term opioid use is associated with multiple side effects. This review presents the latest advances in the understanding of the pathology of pain in SCD and describes objectives based on mechanisms that may help to develop new therapeutic and/or preventive strategies to improve pain in SCD.References
1. Steinberg MH. Management of sickle cell disease. N Engl J Med. 1999;340(13):1021-30. DOI: 10.1056/NEJM199904013401307.
2. Hassell KL. Population estimates of sickle cell disease in the US. Am J Prev Med. 2010;38(4 Suppl.):S512-21. DOI: 10.1016/j.amepre.2009.12.022.
3. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. 2008;86(6):480-7. DOI: 10.2471/blt.06.036673.
4. Lanzkron S, Carroll CP, Haywood C Jr. The burden of emergency department use for sickle-cell disease: an analysis of the national emergency department sample database. Am J Hematol. 2010;85(10):797-9. DOI: 10.1002/ajh.21807.
5. Han J, Saraf SL, Zhang X, Gowhari M, Molokie RE, Hassan J, et al. Patterns of opioid use in sickle cell disease. Am J Hematol. 2016;91(11):1102-6. DOI: 10.1002/ajh.24498.
6. Brousseau DC, Owens PL, Mosso AL, Panepinto JA, Steiner CA. Acute care utilization and rehospitalizations for sickle cell disease. JAMA. 2010;303(13):1288-94. DOI: 10.1001/jama.2010.378.
7. Smith WR, Penberthy LT, Bovbjerg VE, McClish DK, Roberts JD, Dahman B, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008;148(2):94-101. DOI: 148/2/94 [pii].
8. Sil S, Cohen LL, Dampier C. Psychosocial and functional outcomes in youth with chronic sickle cell pain. Clin J Pain. 2016;32(6):527-33. DOI: 10.1097/AJP.0000000000000289.
9. Bakshi N, Ross D, Krishnamurti L. Presence of pain on three or more days of the week is associated with worse patient reported outcomes in adults with sickle cell disease. J Pain Res. 2018;11:313-8. DOI: 10.2147/JPR.S150065.
10. Brandow AM, Brousseau DC, Pajewski NM, Panepinto JA. Vaso-occlusive painful events in sickle cell disease: impact on child well-being. Pediatr Blood Cancer. 2010;54(1):92-7. DOI: 10.1002/pbc.22222.
11. Wong TE, Brandow AM, Lim W, Lottenberg R. Update on the use of hydroxyurea therapy in sickle cell disease. Blood. 2014;124(26):3850-7. DOI: 10.1182/blood-2014-08-435768.
12. FDA. Approved L-Glutamine Powder for the Treatment of Sickle Cell Disease. (Cited 1 October 2017). Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm566097.htm.
13. Tran H, Gupta M, Gupta K. Targeting novel mechanisms of pain in sickle cell disease. Blood. 2017;130(22):2377-85. DOI: 10.1182/blood-2017-05-782003.
14. Brandow AM, Zappia KJ, Stucky CL. Sickle cell disease: a natural model of acute and chronic pain. Pain. 2017;158(Suppl. 1):S79-S84. DOI: 10.1097/j.pain.0000000000000824.
15. Ezenwa MO, Molokie RE, Wang ZJ, Yao Y, Suarez ML, Dyal B, et al. Differences in sensory pain, expectation, and satisfaction reported by outpatients with cancer or sickle cell disease. Pain Manag Nurs. 2018;19(4):322-32. DOI: 10.1016/j.pmn.2017.11.010.
16. Dampier C, Palermo TM, Darbari DS, Hassell K, Smith W, Zempsky W. AAPT diagnostic criteria for chronic sickle cell disease pain. J Pain. 2017;18(5):490-8. DOI: 10.1016/j.jpain.2016.12.016.
17. Baliki MN, Apkarian AV. Nociception, pain, negative moods, and behavior selection. Neuron. 2015;87(3):474-91. DOI: 10.1016/j.neuron.2015.06.005.
18. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267-84. DOI: 10.4097/kjae.2009.57.3.277.
19. Porreca F, Navratilova E. Reward, motivation, and emotion of pain and its relief. Pain. 2017;158(suppl 1):S43-9. DOI: 10.1097/j.pain.0000000000000798.
20. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9(4):463-84. DOI: 10.1016/j.ejpain.2004.11.001.
21. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267-84. DOI: 10.1016/j.cell.2009.09.028.
22. Shibin Du, Corinna Lin, Yuan-Xiang Tao. Updated mechanisms underlying sickle cell disease-associated pain. Neurosci Lett. 2019;712:134471. DOI: 10.1016/j.neulet.2019.134471.
23. Bhatt RR, Martin SR, Evans S, Lung K, Coates TD, Zeltzer LK, et al. The effect of hypnosis on pain and peripheral blood flow in sickle-cell disease: a pilot study. J Pain Res. 2017;10:1635-44. DOI: 10.2147/jpr.s131859.
24. Vincent L, Vang D, Nguyen J, Gupta M, Luk K, Ericson ME, et al. Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood. 2013;122(11):1853-62. DOI: 10.1182/blood-2013-04-498105.
25. Vincent L, Vang D, Nguyen J, Benson B, Lei J, Gupta K. Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation. Haematologica. 2015;101(5):566-77. DOI: 10.3324/haematol.2015.136523.
26. Kohli DR, Li Y, Khasabov SG, Gupta P, Kehl LJ, Ericson ME, et al. Pain-related behaviors and neurochemical alterations in mice Expressing sickle hemoglobin: modulation by cannabinoids. Blood. 2010;116(3):456-5. DOI: 10.1182/blood-2010-01-260372.
27. 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. 2011;156(4):535-44. DOI: 10.1111/j.1365-2141.2011.08977.x.
28. Lei J, Benson B, Tran H, Ofori-Acquah SF, Gupta K. Comparative analysis of pain behaviours in humanized mouse models of sickle cell anemia. PLoS One. 2016;11(8):e0160608. DOI: 10.1371/journal.pone.0160608.
29. 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(4):722-30. DOI: 10.1097/j.pain.0000000000000104.
30. Valverde Y, Benson B, Gupta M, Gupta K. Spinal glial activation and oxidative stress are alleviated by treatment with curcumin or coenzyme Q in sickle mice. Haematologica. 2015;101(2):e44-e47. DOI: 10.3324/haematol.2015.137489.
31. Savage WJ, Everett AD, Casella JF. Plasma glial fibrillary acidic protein levels in a child with sickle cell disease and stroke. Acta Haematol. 2011;125(3):103-6. DOI: 10.1159/000321791.
32. Campbell CM, Moscou-Jackson G, Carroll CP, Kiley K, Haywood C Jr, Lanzkron S, et al. An evaluation of central sensitization in patients with sickle cell disease. J Pain. 2016;17(5):617-7. DOI: 10.1016/j.jpain.2016.01.475.
33. Brandow AM, Farley RA, Panepinto JA. Early insights into the neurobiology of pain in sickle cell disease: aA systematic review of the literature. Pediatr Blood Cancer. 2015;62(9):1501-11. DOI: 10.1002/pbc.25574.
34. Jacob E, Chan VW, Hodge C, Zeltzer L, Zurakowski D, Sethna NF. Sensory and thermal quantitative testing in children with sickle cell disease. J Pediatr Hematol Oncol. 2015;37(3):185-9. DOI: 10.1097/MPH.0000000000000214.
35. Darbari DS, Hampson JP, Ichesco E, Kadom N, Vezina G, Evangelou I, et al. Frequency of hospitalizations for pain and association with altered brain network connectivity in sickle cell disease. J Pain. 2015;16(11):1077-86. DOI: 10.1016/j.jpain.2015.07.005.
36. Case M, Zhang H, Mundahl J, Datta Y, Nelson S, Gupta K, et al. Characterization of functional brain activity and connectivity using EEG and fMRI in patients with sickle cell disease. Neuroimage Clin. 2017;14:1-17. DOI: 10.1016/j.nicl.2016.12.024.
37. Colombatti R, Ermani M, Rampazzo P, Renzo Manara, Maria Montanaro, Giuseppe Basso, et al. Cognitive evoked potentials and neural networks are abnormal in children with sickle cell disease and not related to the degree of anaemia, pain and silent infarcts. Br J Haematol. 2014;169(4):597-600 DOI: 10.1111/bjh.13232.
38. Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest. 2017;127(3):750-60. DOI: 10.1172/JCI89741.
39. Smith WR, Bauserman RL, Ballas SK, McCarthy WF, Steinberg MH, Swerdlow PS, et al. Climatic and geographic temporal patterns of pain in the Multicenter Study of Hydroxyurea. Pain. 2009;146(1-2):91-8. DOI: 10.1016/j.pain.2009.07.008.
40. Glassberg J, Spivey JF, Strunk R, Boslaugh S, DeBaun MR. Painful episodes in children with sickle cell disease and asthma are temporally associated with respiratory symptoms. J Pediatr Hematol Oncol. 2006;28(8):481-5. DOI: 10.1097/01.mph.0000212968.98501.2b.
41. Yoong WC, Tuck SM. Menstrual pattern in women with sickle cell anaemia and its association with sickling crises. J Obstet Gynaecol. 2002;22(4):399-401. DOI: 10.1080/01443610220141362.
42. Resar LM, Oski FA. Cold water exposure and vaso-occlusive crises in sickle cell anemia. J Pediatr. 1991;118(3):407-9. DOI: 10.1016/s0022-3476(05)82156-0.
43. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765-9. DOI: 10.1126/science.288.5472.1765.
44. Wilkie DJ, Molokie R, Boyd-Seal D, Kim YO, Zong S, Wittert H, et al. Patient-reported outcomes: descriptors of nociceptive and neuropathic pain and barriers to effective pain management in adult outpatients with sickle cell disease. J Natl Med Assoc. 2010;102(1):18-27 DOI: 10.1016/s0027-9684(15)30471-5.
45. Brandow AM, DeBaun MR. Key Components of Pain Management for Children and Adults with Sickle Cell Disease. Hematol Oncol Clin North Am. 2018;32(3):535-50. DOI: 10.1016/j.hoc.2018.01.014.
46. McClish DK, Smith WR, Levenson JL, Aisiku IP, Roberts JD, Roseff SD, et al. Comorbidity, pain, utilization, and psychosocial outcomes in older versus younger sickle cell adults: the PiSCES project. BioMed Res Int 2017;2017:4070547. DOI: 10.1155/2017/4070547.
47. Han J, Zhou J, Saraf SL, Gordeuk VR, Calip GS. Characterization of opioid use in sickle cell disease. Pharmacoepidemiol Drug Saf. 2018;27(5):479-86. DOI: 10.1002/pds.4291.
48. Schatz AA, Oliver TK, Swarm RA, Paice JA. Darbar DE, Dowel Deborah, el al. Bridging the gap among clinical practice guidelines for pain management in cancer and sickle cell disease. J Natl Compr Canc Netw. 2020;18(4):392-9. DOI: 10.6004/jnccn.2019.7379.
49. Jonassaint CR, Jones VL, Leong S, Frierson GM. A systematic review of the association between depression and health care utilization in children and adults with sickle cell disease. Br J Haematol. 2016;174(1):136-47. DOI: 10.1111/bjh.14023.
50. Levenson JL, McClish DK, Dahman BA, Bovbjerg VE, Citero VA, Penberthy LT, et al. Depression and anxiety in adults with sickle cell disease: the PiSCES project. Psychosom Med. 2008;70(2):192-6. DOI: 10.1097/PSY.0b013e31815ff5c5.
51. Brandow AM, Farley RA, Panepinto JA. Neuropathic pain in patients with sickle cell disease. Pediatr Blood Cancer. 2014;61(3):512-7. DOI: 10.1002/pbc.24838.
52. Brandow AM, Farley RA, Dasgupta M, Hoffmann RG, Panepinto JA. The use of neuropathic pain drugs in children with sickle cell disease is associated with older age, female sex, and longer length of hospital stay. J Pediatr Hematol Oncol. 2015;37(1):10-5. DOI: 10.1097/MPH.0000000000000265.
53. Molokie RE, Wilkie DJ, Wittert, Suarez HM, Yao Y, Zhao Z, et al. Mechanism-driven phase I translational study of trifluoperazine in adults with sickle cell disease. Eur J Pharmacol. 2014;723:419-24. DOI: 10.1016/j.ejphar.2013.10.062.
54. Schlaeger JM, Molokie RE, Yao Y, Suarez ML, Golembiewski J, Wilkie DJ, et al. Management of sickle cell pain using pregabalin: a pilot study, Pain Manag Nurs. 2017;18(6):391-400. DOI: 10.1016/j.pmn.2017.07.003.
55. Rousseau V, Morelle M, Arriuberge C, Darnis S, Chabaud S, Launay V, et al. Efficacy and tolerance of lidocaine 5% patches in neuropathic pain and pain related to vaso-occlusive sickle cell crises in children: a prospective multicenter clinical study. Pain Pract. 2018;18(6):788-97. DOI: 10.1111/papr.12674.
56. Lubega FA, DeSilva MS, Munube D, Nkwine R, Tumukunde J, Agaba PK, et al. Low dose ketamine versus morphine for acute severe vaso occlusive pain in children: a randomized controlled trial. Scand. J Pain 2018;18(1):19-27. DOI: 10.1515/sjpain-2017-0140.
57. Palm N, Floroff C, Hassig TB, Boylan A, Kanter J. Low-dose ketamine infusion for adjunct management during vaso-occlusive episodes in adults with sickle cell disease: a case series. J Pain Palliat Care Pharmacother. 2018;32(1):1-7- DOI: 10.1080/15360288.2018.1468383.