Provoked cytokine response is not associated with distress or induced secondary hyperalgesia in people with suppressed HIV

doi:10.1097/j.pain.0000000000003748

. 2025 Aug 7.

doi: 10.1097/j.pain.0000000000003748. Online ahead of print.

Provoked cytokine response is not associated with distress or induced secondary hyperalgesia in people with suppressed HIV

Victoria J Madden^{1

2}, Luyanduthando Mqadi^{1

2}, Gwendoline Arendse¹, Gillian J Bedwell¹, Ncumisa Msolo¹, Maia Lesosky³, Mark R Hutchinson^{4

5}, Jonny G Peter^{6

7}, Andrew Schrepf⁸, Romy Parker¹, Robert R Edwards⁹, John A Joska²

Affiliations

¹ African Pain Research Initiative, Department of Anaesthesia and Perioperative Medicine, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
² HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³ National Heart and Lung Institute, Imperial College London, London, United Kingdom.
⁴ School of Biomedicine, University of Adelaide, South Australia, Australia.
⁵ Institute for Photonics and Advanced Sensing, University of Adelaide, South Australia, Australia.
⁶ Division of Allergy and Clinical Immunology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Rondebosch, South Africa.
⁷ Allergy and Immunology Unit, University of Cape Town Lung Institute, University of Cape Town, Cape Town, South Africa.
⁸ Chronic Pain and Fatigue Research Center, Department of Anesthesiology, Michigan Medicine, University of Michigan, Ann Arbor, MI, United States.
⁹ Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Boston, MA, United States.

PMID: 40788259
DOI: 10.1097/j.pain.0000000000003748

Provoked cytokine response is not associated with distress or induced secondary hyperalgesia in people with suppressed HIV

Victoria J Madden et al. Pain. 2025.

. 2025 Aug 7.

doi: 10.1097/j.pain.0000000000003748. Online ahead of print.

Authors

Affiliations

¹ African Pain Research Initiative, Department of Anaesthesia and Perioperative Medicine, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
² HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³ National Heart and Lung Institute, Imperial College London, London, United Kingdom.
⁴ School of Biomedicine, University of Adelaide, South Australia, Australia.
⁵ Institute for Photonics and Advanced Sensing, University of Adelaide, South Australia, Australia.
⁶ Division of Allergy and Clinical Immunology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Rondebosch, South Africa.
⁷ Allergy and Immunology Unit, University of Cape Town Lung Institute, University of Cape Town, Cape Town, South Africa.
⁸ Chronic Pain and Fatigue Research Center, Department of Anesthesiology, Michigan Medicine, University of Michigan, Ann Arbor, MI, United States.
⁹ Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Boston, MA, United States.

PMID: 40788259
DOI: 10.1097/j.pain.0000000000003748

Abstract

Psychological distress predicts the onset and worsening of persistent pain, but the mechanisms that underpin this influence are poorly understood. Proinflammatory signalling is a plausible link, given its known connections to distress, pain, and neural upregulation. Sustained distress may prime the inflammatory system to respond more strongly to a phasic noxious challenge, supporting neuroimmune upregulation of central nociceptive signalling and persistent pain. This cross-sectional study tested the hypotheses that in vitro endotoxin-provoked expression of typically proinflammatory cytokines (IL1β, IL6) is a partial mediator between distress and persistent pain, and that it is associated with experimentally induced secondary hyperalgesia, in people with suppressed HIV. Study participants were 99 adults (mean [range] age: 43 [28-64 y/o; 72 females]) with either no pain (n = 54) or persistent pain (n = 45), mostly of black South African ethnicity, low socio-economic status, and with high social support. The results replicated previous reports that distress is associated with persistent pain status and pain severity, and distress was associated with the anatomical extent of pain. However, distress was not associated with provoked cytokine expression, nor was provoked cytokine expression associated with secondary hyperalgesia. The conflict between our findings and prior evidence could reflect the influence of differentially trained immune systems or a more complex relationship arising from diverse psychoneuroimmunological interactions in this sample. This sample's combination of HIV status, African genetic ancestry, financial impoverishment, and rich social interconnectedness is poorly represented in current research and provides an opportunity to deepen insight into psychoneuroimmunological interactions in persistent pain.

Trial registration: ClinicalTrials.gov NCT04757987.

Keywords: Cytokines; HIV; Hyperalgesia; Hypersensitivity; Inflammation; Neuroimmunomodulation; Pain; Psychological distress; Secondary hyperalgesia.

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Update of

Provoked cytokine response is not associated with distress or induced secondary hyperalgesia in people with suppressed HIV.
Madden VJ, Mqadi L, Arendse G, Bedwell GJ, Msolo N, Lesosky M, Hutchinson MR, Peter JG, Schrepf A, Parker R, Edwards RR, Joska JA. Madden VJ, et al. medRxiv [Preprint]. 2025 May 27:2025.01.21.25320673. doi: 10.1101/2025.01.21.25320673. medRxiv. 2025. Update in: Pain. 2025 Aug 7. doi: 10.1097/j.pain.0000000000003748. PMID: 39973982 Free PMC article. Updated. Preprint.
Distress is positively associated with induced secondary hyperalgesia in people with suppressed HIV.
Mqadi L, Bedwell GJ, Msolo N, Arendse G, Lesosky M, Kamerman PR, Hutchinson MR, Schrepf A, Edwards RR, Joska JA, Parker R, Madden VJ. Mqadi L, et al. medRxiv [Preprint]. 2025 Apr 30:2025.01.27.25321015. doi: 10.1101/2025.01.27.25321015. medRxiv. 2025. Update in: Pain. 2025 Aug 7. doi: 10.1097/j.pain.0000000000003748. PMID: 39974111 Free PMC article. Updated. Preprint.

References

1. Albrecht D, Kim M, Torrado-Carvajal A, Akeju O, Edwards R, Wasan A, Zhang Y, Bergan C, Protsenko E, Hooker J, Napadow V, Loggia M. Glial activation in chronic back pain: replication of the original observation and association with negative affect. J Pain 2018;19:S2.
1. Albrecht DS, Kim M, Akeju O, Torrado-Carvajal A, Edwards RR, Zhang Y, Bergan C, Protsenko E, Kucyi A, Wasan AD, Hooker JM, Napadow V, Loggia ML. The neuroinflammatory component of negative affect in patients with chronic pain. Mol Psychiatry 2021;26:864–74.
1. Amoani B, Sakyi S, Barnie P, Pomeyie K, Aniagyei W, Opoku S, Sewor C, Saahene R. Effect of ART on cytokine profile amongst HIV patients: a systematic review and meta-analysis. Focus Med Sci J 2021;7.
1. Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw 2015;67:1–48.
1. Bedwell G, Mqadi L, Kamerman P, Hutchinson M, Parker R, Madden V. Inflammatory reactivity is unrelated to childhood adversity or provoked modulation of nociception. PAIN 2025. doi: 10.1097/j.pain.0000000000003658. - DOI

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[1] Albrecht D, Kim M, Torrado-Carvajal A, Akeju O, Edwards R, Wasan A, Zhang Y, Bergan C, Protsenko E, Hooker J, Napadow V, Loggia M. Glial activation in chronic back pain: replication of the original observation and association with negative affect. J Pain 2018;19:S2.

[2] Albrecht D, Kim M, Torrado-Carvajal A, Akeju O, Edwards R, Wasan A, Zhang Y, Bergan C, Protsenko E, Hooker J, Napadow V, Loggia M. Glial activation in chronic back pain: replication of the original observation and association with negative affect. J Pain 2018;19:S2.

[3] Albrecht DS, Kim M, Akeju O, Torrado-Carvajal A, Edwards RR, Zhang Y, Bergan C, Protsenko E, Kucyi A, Wasan AD, Hooker JM, Napadow V, Loggia ML. The neuroinflammatory component of negative affect in patients with chronic pain. Mol Psychiatry 2021;26:864–74.

[4] Albrecht DS, Kim M, Akeju O, Torrado-Carvajal A, Edwards RR, Zhang Y, Bergan C, Protsenko E, Kucyi A, Wasan AD, Hooker JM, Napadow V, Loggia ML. The neuroinflammatory component of negative affect in patients with chronic pain. Mol Psychiatry 2021;26:864–74.

[5] Amoani B, Sakyi S, Barnie P, Pomeyie K, Aniagyei W, Opoku S, Sewor C, Saahene R. Effect of ART on cytokine profile amongst HIV patients: a systematic review and meta-analysis. Focus Med Sci J 2021;7.

[6] Amoani B, Sakyi S, Barnie P, Pomeyie K, Aniagyei W, Opoku S, Sewor C, Saahene R. Effect of ART on cytokine profile amongst HIV patients: a systematic review and meta-analysis. Focus Med Sci J 2021;7.

[7] Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw 2015;67:1–48.

[8] Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw 2015;67:1–48.

[9] Bedwell G, Mqadi L, Kamerman P, Hutchinson M, Parker R, Madden V. Inflammatory reactivity is unrelated to childhood adversity or provoked modulation of nociception. PAIN 2025. doi: 10.1097/j.pain.0000000000003658. - DOI

[10] Bedwell G, Mqadi L, Kamerman P, Hutchinson M, Parker R, Madden V. Inflammatory reactivity is unrelated to childhood adversity or provoked modulation of nociception. PAIN 2025. doi: 10.1097/j.pain.0000000000003658. - DOI

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Provoked cytokine response is not associated with distress or induced secondary hyperalgesia in people with suppressed HIV

Affiliations

Provoked cytokine response is not associated with distress or induced secondary hyperalgesia in people with suppressed HIV

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