Background & Aims

Sickle cell disease (SCD) is a hemoglobinopathy characterized by the presence of sickle hemoglobin and sickleing of red blood cells. Individuals with SCD experience episodes of acute pain also known as vaso-occlusive crises. Chronic pain is also common in this population. Successful curative treatments, e.g., gene therapy and hematopoietic stem-cell transplants, lead to marked reduction or resolution of acute painful vaso-occlusive crises. However, some post-curative therapy SCD (PC-SCD) patients continue to experience pain despite successful reversal of SCD. Thus, the aim of the present study is to investigate the neural mechanism underlying persistent pain in PC-SCD patients as compared to healthy controls (HC).

Methods

A subset of participants from a larger study (N=27) were able to participate in the present MRI task. Six PC-SCD patients (four with chronic pain) and 14 HC completed two functional MRI scans. Participants received high and low noxious heat stimuli that were individually calibrated (~8s pulse, 2 blocks each, 6 trials per block) on their lower left leg. Each block was followed by a VAS pain scale to assess pain intensity (0 = no pain, 10 = worst pain imaginable). MRI images were acquired on a 3T Siemens Skyra scanner with a 20ch coil (resolution, 1x1x1mm3 for structural images and 3.5×3.5×3.5mm3 for functional images). All MRI data were analyzed using FSL with a cluster correction of z>2.3, p<0.05, mixed effects. Results are presented as mean+/-SD.

Results

The calibrated heat temperatures were comparable between groups (high PC-SCD 47C+/-1.98, HC 46.91C+/-1.77, p=0.93; low PC-SCD 45C+/-1.69; HC 44.90C+/-1.71, p=0.98). However, PC-SCD patients rated both heat stimuli as less painful compared to HC (high PS-SCD 5.10+/-2.98, HC 8.13+/-1.58, p<0.01; low PS-SCD 3.00+/-2.16, HC 4.87+/-1.49, p=0.01). Pain responsive regions were activated in both groups (e.g., insula, ACC, S2) during both heat stimuli, but PC-SCD patients had greater activity within the ACC than HC during high heat (corrected for age, sex, and ongoing clinical pain during the scan). No group differences were observed during low heat. To account for the perceptual differences of the heat and examine responses to equalized nociceptive input, the pain ratings were regressed in addition to the covariates above. This revealed greater activations in the ACC, right insula, and bilateral S2 areas during high heat and right S2 and insula during low heat in the PC-SCD > HC contrasts.

Conclusions

Although PC-SCD patients reported significantly lower pain in response to equalized experimental heat pain, the amplified nociceptive response to the heat stimuli, compared to HC, suggests increased central sensitization. These findings, together with previously presented reports of increased temporal summation and decreased conditioned pain modulation in the same patients compared to HC, suggest that despite being cured of SCD, persistent pain observed in PC-SCD patients may be attributed to sensitized brain and spinal mechanisms.

References

Darbari, D. S., J. Liljencrantz, A. Ikechi, S. Martin, M. C. Roderick, C. D. Fitzhugh, J. F. Tisdale, S. L. Thein and M. Hsieh (2018). “Pain and opioid use after reversal of sickle cell disease following HLA-matched sibling haematopoietic stem cell transplant.” Br J Haematol.

Presenting Author

Binquan Wang

Poster Authors

Binquan Wang

PhD

NIH

Lead Author

E-mail

Nwamaka Ijeh

National Center for Complementary and Integrative Health, National Institutes of Health

Lead Author

E-mail

Hayley Owens

National Center for Complementary and Integrative Health, National Institutes of Health

Lead Author

E-mail

Michelle Singh

National Center for Complementary and Integrative Health, National Institutes of Health

Lead Author

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Deepika Darbari

Children's National Hospital

Lead Author

E-mail

Matthew Hsieh

MD

Sickle Cell Branch, National Heart, Lung, and Blood Institute, National Institutes of Health

Lead Author

E-mail

Swee Lay Thein

F.R.C.P.

Sickle Cell Branch, National Heart, Lung, and Blood Institute, National Institutes of Health

Lead Author

E-mail

M. Catherine Bushnell

Ph.D

National Center for Complementary and Integrative Health, National Institutes of Health

Lead Author

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Eleni Frangos

Ph.D

National Center for Complementary and Integrative Health, National Institutes of Health

Lead Author

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Topics

  • Pain Imaging