Clinical features of calcineurin inhibitor-induced pain syndrome after allo-SCT

Kakihana, Kazuhiko; Ohashi, Kazuteru; Murata, Yutaka; Tsubokura, Masaharu; Kobayashi, Takeshi; Yamashita, Takuya; Sakamaki, Hisashi; Akiyama, Hideki

doi:10.1038/bmt.2011.120

Cited by 20 publications

(19 citation statements)

References 9 publications

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“…Calcineurin inhibitors can cause pain and pain hypersensitivity in patients receiving organ and tissue transplants (Grotz et al, 2001;Fujii et al, 2006;Noda et al, 2008;Kakihana et al, 2012). The primary treatment of CIPS is discontinuation of these agents, which could endanger the transplanted organs and tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine A, are commonly used immunosuppressants and have greatly improved the long-term survival of patients after organ and tissue transplantation. However, these drugs can result in unexplained severe pain and pain hypersensitivity, clinically known as calcineurin inhibitor-induced pain syndrome (CIPS) (Grotz et al, 2001;Collini et al, 2006;Noda et al, 2008;Kakihana et al, 2012). CIPS predominantly affects the lower limbs, and the pain is particularly excruciating during standing and walking (Grotz et al, 2001;Fujii et al, 2006;Noda et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Casein Kinase II Inhibition Reverses Pain Hypersensitivity and Potentiated Spinal N-Methyl-d-aspartate Receptor Activity Caused by Calcineurin Inhibitor

Chen

et al. 2014

J Pharmacol Exp Ther

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Clinically used calcineurin inhibitors, including tacrolimus (FK506) and cyclosporine A, can induce calcineurin inhibitor-induced pain syndrome (CIPS), which is characterized as severe pain and pain hypersensitivity. Increased synaptic N-methyl-D-aspartate receptor (NMDAR) activity in the spinal dorsal horn plays a critical role in the development of CIPS. Casein kinase II (CK2), a serine/ threonine protein kinase, can regulate synaptic NMDAR activity in the brain. In this study, we determined whether spinal CK2 is involved in increased NMDAR activity and pain hypersensitivity caused by systemic administration of FK506 in rats. FK506 treatment caused a large increase in the amplitude of NMDARmediated excitatory postsynaptic currents (EPSCs) evoked by primary afferent stimulation and in the frequency of miniature EPSCs of spinal dorsal horn neurons. CK2 inhibition with either 5,6-dichloro-1-b-D-ribofuranosylbenzimidazole (DRB) or 4,5,6,7-tetrabromobenzotriazole (TBB) completely normalized the amplitude of evoked NMDAR-EPSCs of dorsal horn neurons in FK506-treated rats. In addition, DRB or TBB significantly attenuated the amplitude of NMDAR currents elicited by puff application of N-methyl-D-aspartate to dorsal horn neurons in FK506-treated rats. Furthermore, treatment with DRB or TBB significantly reduced the frequency of miniature EPSCs of spinal dorsal horn neurons increased by FK506 treatment. In addition, intrathecal injection of DRB or TBB dosedependently reversed tactile allodynia and mechanical hyperalgesia in FK506-treated rats. Collectively, our findings indicate that CK2 inhibition abrogates pain hypersensitivity and increased pre-and postsynaptic NMDAR activity in the spinal cord caused by calcineurin inhibitors. CK2 inhibitors may represent a new therapeutic option for the treatment of CIPS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Casein Kinase II Inhibition Reverses Pain Hypersensitivity and Potentiated Spinal N-Methyl-d-aspartate Receptor Activity Caused by Calcineurin Inhibitor

Chen

et al. 2014

J Pharmacol Exp Ther

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“…CN-deficient mice display behavioral characteristics similar to humans with schizophrenia, memory impairment, and attention deficit disorder (33). Inhibition of CN results in CN inhibitor-induced pain syndromes (34,35). The activation of CN by DREAM/KChIP3 requires full-length protein, Ca 2ϩ , and CaM.…”

Section: Discussionmentioning

confidence: 99%

The Potassium Channel Interacting Protein 3 (DREAM/KChIP3) Heterodimerizes with and Regulates Calmodulin Function

Ramachandran

Craig

Atanasova

et al. 2012

Journal of Biological Chemistry

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Background:The calcium-binding protein DREAM/KChIP3 binds DNA and other proteins to regulate neuronal function. Results: DREAM/KChIP3 binds the EF-hand protein, calmodulin, in the presence but not in the absence of calcium. Calciumbound DREAM/KChIP3 enhances calmodulin-dependent calcineurin activity. Conclusion: DREAM/KChIP3 binds and regulates calmodulin activity. Significance: DREAM/KChIP3 heterodimerizes with the EF-hand protein, calmodulin, and regulates calmodulin activation of calcineurin.

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“…4,5 To date, however, HHV6-associated pleurisy has not been recognized as a complication of HSCT. In this report, we describe an adult HSCT recipient who developed HHV6-associated pleurisy after an unrelated cord blood transplantation (CBT).…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4] The characteristic clinical features of CIPS include severe pain localized in the bilateral lower limbs, elevated CI trough levels at the onset, lack of response to common analgesics, bone marrow edema as seen with magnetic resonance imaging, and increased uptake as seen with bone scintigraphy. Calcineurin inhibitor(CI) -induced pain syndrome(CIPS)is a rare complication after allogeneic hematopoietic stem cell transplantation(allo-HSCT) .…”

mentioning

confidence: 99%

Clinical characteristics of calcineurin inhibitor-induced pain syndrome (CIPS) after allogeneic hematopoietic stem cell transplantation

Doki

Kakihana

Ashizawa

et al. 2017

Journal of Hematopoietic Cell Transplantation

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Calcineurin inhibitor CI -induced pain syndrome CIPS was first described in an organ transplant recipient in 1991, 1 and has been subsequently reported among patients undergoing allogeneic hematopoietic stem cell transplantation allo-HSCT . [2][3][4] The characteristic clinical features of CIPS include severe pain localized in the bilateral lower limbs, elevated CI trough levels at the onset, lack of response to common analgesics, bone marrow edema as seen with magnetic resonance imaging, and increased uptake as seen with bone scintigraphy. Calcineurin inhibitor(CI) -induced pain syndrome(CIPS)is a rare complication after allogeneic hematopoietic stem cell transplantation(allo-HSCT) . However, because of its rarity, the optimal management of this complication remains unknown. We analyzed the clinical features and treatment outcomes of the patients who developed CIPS after allo-HSCT. The study included patients who underwent allo-HSCT between January 2003 and December 2014 at the hospitals participating in the KSGCT. Sixteen patients developed CIPS. The most common symptom was leg pain, which was observed in 9 patients, followed by leg pain associated with pruritus in five, and pruritus only in two. The median time from allo-HSCT to CIPS was 16 days. CIPS occurred within 30 days of starting CIs in 14 patients(87.5%) . CI was discontinued in four patients; the dose of CI was reduced in two patients, and seven patients were switched to another CI. The symptoms in all of those 13 patients with intervention resolved within 6 days from the onset of CIPS. The possibility of CIPS must be considered when patients who have undergone allo-HSCT develop intolerable leg pain and／or pruritus. Our findings suggest that withdrawal／dose reduction of the CI or substitution with another CI is an effective treatment for

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Clinical features of calcineurin inhibitor-induced pain syndrome after allo-SCT

Cited by 20 publications

References 9 publications

Casein Kinase II Inhibition Reverses Pain Hypersensitivity and Potentiated Spinal N-Methyl-d-aspartate Receptor Activity Caused by Calcineurin Inhibitor

Casein Kinase II Inhibition Reverses Pain Hypersensitivity and Potentiated Spinal N-Methyl-d-aspartate Receptor Activity Caused by Calcineurin Inhibitor

The Potassium Channel Interacting Protein 3 (DREAM/KChIP3) Heterodimerizes with and Regulates Calmodulin Function

Clinical characteristics of calcineurin inhibitor-induced pain syndrome (CIPS) after allogeneic hematopoietic stem cell transplantation

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