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Table of Contents
Year : 2018  |  Volume : 12  |  Issue : 2  |  Page : 125-135

Diagnosis and treatment of calcineurin inhibitor-induced pain syndrome in chronic Kidney disease Stage 5 transplantation

Division of Nephrology, Imam Khomeini Hospital Complex, College of Medicine, National University of Tehran Medical Sciences, Tehran, Iran

Date of Web Publication29-Jun-2018

Correspondence Address:
Dr. Fateme Shamekhi Amiri
Division of Nephrology, Imam Khomeini Hospital Complex, College of Medicine, National University of Tehran Medical Sciences, Tehran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_19_18

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Context: Musculoskeletal pain is a frequent manifestation in postrenal transplant recipients that caused by several diseases. Clinically used calcineurin inhibitors including cyclosporine A and tacrolimus can induce calcineurin inhibitor-induced bone pain syndrome which is characterized by severe pain, especially in both lower extremities. Aims: The aim of this study to investigate clinical studies about diagnostic and therapeutic modalities in renal transplant recipients. Settings and Design: In this retrospective study, patients with calcineurin inhibitor-induced pain syndrome after kidney transplantation were selected. Materials and Methods: This paper was searched via electronic PubMed and Google Scholar databases. Few full-text original articles in kidney transplant recipients were extracted. In this study, 18 articles were assessed for eligibility and 12 renal transplant recipients in 9 case reports were included. Statistical Analysis Used: Categorical variables as percentage, normally distributed measurements as mean ± standard deviation, and nonnormally distributed measurements as median and interquartile range were recorded. Results: Of 12 patients, 7 (58.3%) patients were male and 5 (41.6%) were female. At this study, bone magnetic resonance imaging (MRI) was diagnostic modality of choice. Radionuclide scintigraphy is also helpful. The most effective treatment of calcineurin inhibitor-induced pain syndrome consisted reduction dose of calcineurin inhibitors, calcineurin inhibitors change to another drug from the same drug class or mammalian target of rapamycin inhibitors. Conclusion: This study demonstrates that bone MRI is diagnostic modality of choice in patients with calcineurin inhibitor-induced pain syndrome. Moreover, reduction of calcineurin inhibitors and switching of immunosuppressants show the most effective treatment in these patients.

Keywords: Calcineurin inhibitor-induced pain syndrome, cyclosporine A, gamma-aminobutyric acid analogs, iloprost, renal transplant, tacrolimus

How to cite this article:
Amiri FS. Diagnosis and treatment of calcineurin inhibitor-induced pain syndrome in chronic Kidney disease Stage 5 transplantation. Indian J Transplant 2018;12:125-35

How to cite this URL:
Amiri FS. Diagnosis and treatment of calcineurin inhibitor-induced pain syndrome in chronic Kidney disease Stage 5 transplantation. Indian J Transplant [serial online] 2018 [cited 2022 Oct 2];12:125-35. Available from: https://www.ijtonline.in/text.asp?2018/12/2/125/235590

  Introduction Top

Musculoskeletal pain is reported by 19%–35% of patients after renal transplantation. Calcineurin inhibitor-induced pain syndrome (CIPS) has not been reported when calcineurin inhibitors are used to treat autoimmune disorders possibly because higher doses are used for transplantation.[1],[2] CIPS has recently been described in patients treated with calcineurin inhibitors (CNIs) for autoimmune diseases.[3],[4],[5] It was first described by Bouteiller et al.,[6] then Lucas et al. in renal transplant patients [7] and finally it was named CIPS by Grotz et al. in 2001.[8] Diagnosis of CIPS is confirmed by magnetic resonance imaging (MRI) and treatment contains reduction or switching of calcineurin inhibitors and other conservative modalities.

  Materials And Methods Top

The paper has written based on searching PubMed and Google Scholar to identify potentially relevant articles or abstracts. The mentioned search included the following search terms: calcineurin inhibitor-induced pain syndrome, post-transplant distal limb syndrome (PTDLS), symmetric bone pain syndrome (SBPS), CIPS in chronic kidney disease (CKD), CIPS in chronic kidney disease stage 5 transplantation (CKD 5T). Search terms were used both discretely and combined with each other using the Boolean operator And. The author reviewed bibliographies of all selected articles to identify the additional relevant studies. After screening and eligibility of studies, 9 published articles included 12 case reports and patients [Figure 1].
Figure 1: Workflow for identification of clinical studies

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Statistical analysis

Categorical variables are recorded as frequency and percentage. Measurements normally distributed are reported as mean ± standard deviation of mean (SD) and range and nonnormally distributed as median and interquartile range (IQR).

  Results Top

Patients' characteristics

Among 18 full-text articles obtained in this review, 9 were included in this study. These 9 published articles included 12 case reports that were examined 12 renal transplant recipients for qualitative and quantitative synthesis. Studies of CIPS are summarized in [Table 1].[9],[10],[11],[12],[13],[14],[15],[16] Mean (± SD) age of patients at the time of diagnosis was 46.8 ± 2.38 years (ranging from 37 to 59 years). Of these, 7 (58%) patients were male and 5 (42%) were female. The type of kidney transplantation included cadaveric kidney transplant (n = 8, 66.7%), living donors (n = 3, 25%), and patient with insufficient data (n = 1, 8.3%). Causes of end-stage renal disease (ESRD) led to renal transplant included immunoglobulin A nephropathy (n = 2, 16.6%), hypertensive nephropathy (n = 2, 16.6%), autoimmune diseases (rheumatoid arthritis, systemic lupus erythematous, n = 2, 16.6%), analgesic nephropathy (n = 1, 8.3%), left-sided renal agenesis (n = 1, 8.3%), Berger's disease (n = 1, 8.3%), ESRD with unknown etiology (n = 2, 16.6%), and patients with insufficient data (n = 1, 8.3%).
Table 1: Complete clinical characteristics of patients with calcineurin inhibitor-induced pain syndrome patients in renal transplant recipients

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Anatomic region of articular involvement

The isolated and combined articular manifestations contain bilateral knee pains (n=4, 33.3%); bilateral symmetrical pain in feet (n=3, 25%); bilateral knee and feet pain (n=2, 16%); bilateral knee and ankle pain (n=1, 8.3%); bilateral wrist, elbow, hand, and knee joints pain(n=1, 8.3%); hand, knees, ankle and feet joints involvement (n=1, 8.3%) [Table 2]. Mean duration of appearance of clinical symptoms after renal transplantation is 11.4 ± 3.65 months, median of 1.25 months, and IQR of 1–6 months [Figure 2].
Table 2: Baseline characteristics of patients based on cause of end-stage renal disease, symptoms, and joint involvement at presentation

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Figure 2: Box plot interquartile range and median time for appearance of clinical symptoms after renal transplantation in CIPS. CIPS: Calcineurin inhibitor-induced pain syndrome

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Laboratory measurements

Utility of calcineurin inhibitors levels is not possible in this study because missing data of real therapeutic level (cutoff trough level) but a point must be talked that although elevated CNI levels is seen in CIPS but it can be associated with normal therapeutic range of CNI levels. Cyclosporine as initial immunosuppressive drug was started and measured in 6 (50%) patients. Cyclosporine as initial immunosuppressive drug was started in 6 (50%) patients and that cyclosporine level was measured in 6 patients. The mean (± SD) whole blood trough level of cyclosporine A (CsA) was 194.5 ± 8.57 ng/ml (ranging 38–278 ng/ml). There were high cyclosporine trough levels in three patients that mean (± SD) blood trough level was 268 ± 3 ng/ml (ranging 254–278 ng/ml). TAC was started as initial immunosuppressive drug in 6 (n=6, 50%) patients and that TAC level was measured in 3 (25%) patients. The mean (± SD) whole blood trough level of TAC was 11 ± 1.6 ng/ml (7–15 ng/ml) in three patients. There were increased alkaline phosphatase levels in 2 (16.6%) patients and there were insufficient data in 10 (83%) patients. There were increased parathyroid hormones (PTH) (n = 4, [33.3%]) with mean ± SD of 260 ± 16.9 ng/l (ranging 26–833 ng/l) and PTH levels were normal in 4 (33.3%) patients. There were insufficient data in 2 (16.6%) patients. There were hypercalcemia in 3 (25%) patients with mean ± SD calcium level of 11 ± 0.44 mg/dl (ranging 10.7–11 mg/dl) and serum calcium level was normal in 1 (8.3%) patient. There were insufficient data in 8 (66.6%) patients. There were hypophosphatemia in 2 (16.6%) patients, hyperphosphatemia in 1 (8.3%) patient and normophosphatemia in 1 (8.3%) patient. There were insufficient data in 8 (66.6%) patients. There was positive C-reactive protein in 1 (8.3%) patient and were normal in 7 (58%) patients. There were insufficient data in 4 (33.3%) patients.

Radiologic imagings

Radiological imaging (conventional X-ray) included mild osteopenia on feet (n = 1, 8.3%), patchy osteoporosis in the knees (n = 1, 8.3%), patchy osteoporosis on foot (n = 1, 8.3%), renal osteodystrophy (n = 1, 8.3%), and osteoporosis in head of knee, ankle, and foot joints (n = 1, 8.3%). MRI results included patchy, migratory areas of abnormal increased T2 signal within the epiphyseal and metaphyseal marrow (n = 4, 33.3%); bone marrow edema on feet (n = 1, 8.3%); bilateral calcaneal incomplete stress fracture (n = 1, 8.3%); presence of bone marrow edema in the femur condyles and tibial plateau (n = 1, 8.3%); an area of bone edema in the external condyle of the femur and wearing the cartilage (n = 1, 8.3%); and diffuse involvement of the talus, bones of the middle foot and to a lesser extent, the distal sector of the calcaneus, demonstrating inflammatory changes of the adjacent soft tissues, preferably at the bases of the first third metatarsal bones (n = 1, 8.3%). Bone scintigraphy results included uptake in femoral condyles and around the tibial plateaus, corresponding to the areas of pain in 4 (33.3%) patients, increased tracer uptake in the tibial plateau, metatarsi, and elbows (n = 1, 8.3%), increased radionuclide uptake in the hands, knees, ankles, and feet joints (n = 1, 8.3%), intense uptake in both the osseous and vascular phases in the knees (n = 1, 8.3%), and pathological fixation of the radiotracer in feet with no differentiation between two foot (n = 1, 8.3%). There were no insufficient data in 4 (33.3%) patients. Whole-body computerized tomography scan was normal in 1 (8.3%) patient and computerized bone mineralometry revealed slight reduction of bone mass in 1 (8.3%) patient and 1 (8.3%) showed marked demineralization.

  Treatment and Outcome Top

Treatment and follow-up of CIPS in these patients contain conservative therapy, cyclosporine dose adjustment in 4 (33.3%) patients. Resolving of the symptoms occurred 3 months after treatment. In 1 (8.3%) patient, cyclosporine was replaced by everolimus. Two weeks after discharge and 4 months later, an improvement of pain was noted. In 1 (8.3%) patient, starting amlodipine did not improve the patient's symptoms, and with change of low-dose cyclosporine regimen to everolimus, the pain was significantly improved. Six months later, MRI showed resolution of the bone marrow edema and mild periarticular fluid collection. One year later, serum creatinine maintained at normal range and the patient remained well. Reduction of TAC dose caused improvement in their symptoms in 2 (16.7%) patients. The symptoms disappeared within 1 week after stopping TAC and replacement by CsA in 1 (8.3%) patient. The postsurgical course was good with normal serum creatinine level, and there was no acute rejection and pain after kidney transplantation. Change of TAC to sirolimus improved the symptoms in 1 (8.3%) patient, but the patient was expired due to intracerebral hemorrhage induced by warfarin several weeks later, but no further imaging was obtained. With everolimus change to low-dose cyclosporine improved symptoms in 1 (8.3%) patient after 2 months and disappeared 7 months from their onset without any specific therapy. In 1 (8.3%) patient, there was improvement in ambulation after starting intravenous (IV) pamidronate [Table 3]. The mean follow-up duration of patients was 4.48 ± 1.5 months in ten patients and duration of this follow-up was not characterized in two patients.
Table 3: Different drug therapy and duration of treatment in calcineurin inhibitor-induced pain syndrome

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  Discussion Top


Calcineurin may play a significant role in the modulation of nociception and contribute to maintain aspects of normal baseline physiologic sensory neural and/or glial function via its role in maintaining homeostatic potassium currents of resting membrane potentials. Furthermore, it appears that interruption of this variable role of calcium may spark nociception process and/or hyperexcitability and hence may be involved in nociceptive signaling pathways, thereby potentially facilitating algesia. Calcineurin (calcium/calmodulin-dependent phosphatase 2b) is associated with the enhancement of calcium. Calcineurin has been shown to bind directly to nuclear factors of activated T-cells (NFATs) like docking site on TWIK-related spinal cord K + channels (TRESK) and dephosphorylation of TRESK. The phosphorylation of TRESK in NFAT-like docking sites can be inhibited by FK506, an inhibitor of calcineurin. CIPS, which is characterized by severe pain in the lower limbs after use of calcineurin inhibitors, has been recognized in both organs (kidney and liver) and stem cell transplantation. A possible mechanism for CIPS is that an inhibitor of calcineurin blocks the TRESK channel which downregulates the background current and, thus, enhances the excitatory signal transduction by affecting the velocity of action potential propagation.[17] The pathophysiological mechanism leading to CIPS is unknown. Grotz et al. proposed the hypothesis that CNI-induced vascular disturbance leads to an increased permeability of bone marrow vessels with bone marrow edema. Experimental data suggest CNI-induced perfusion alterations such as an endothelium-mediated vasoconstriction of the microvasculature. TAC can lead to unrestricted nociceptive input by potentially N-methyl-D-aspartate receptor (NMDAR) activity, and phosphorylation state is dynamically controlled by a balance between the activity of protein kinase and protein phosphatases. Casein kinase II (CK2) activation increased the phosphorylation and activity of NMDARs, whereas calcineurin can negatively regulate the phosphorylation and function of NMDARs in the brain. CK2 is an endogenous serine/threonine protein kinase widely expressed in many types of cells and is distributed in the central nervous system (CNS). CK2 is specifically distributed in postsynaptic densities which are crucial for modulating synaptic NMDR function. Although the mechanisms responsible for increased spinal NMDAR activity by calcineurin inhibitors are not fully known, it is possible that in CIPS, the phosphorylation/dephosphorylation cycles of NMDARs in the spinal dorsal horn are shifted to a predominantly phosphorylated state through reduced calcineurin activity.[18],[19] Because increased bone uptake and mild bone marrow edema in the femur of some patients with CIPS have been reported, some studies have suggested that CIPS results from calcineurin-induced vascular changes that disturb bone perfusion and permeability. The first sensory synapse between the central terminals of primary sensory neurons and spinal dorsal horn neurons is critically involved in the transmission and transformation of sensory information. Glutamate is an essential excitatory neurotransmitter, and NMDARs play a critical role in spinal synaptic plasticity associated with dorsal pain conduction.[20]

Clinical manifestations

After solid organ transplantation, 1%–17% of patients report symptoms, which vary from deep, aching rest pain to the sudden onset of severe, symmetrical, periarticular bone pain. The onset of pain is generally within the 1st month of transplantation resolving with 3 months, but it has occasionally been described to occur up to 14 months' posttransplant with resolution over periods up to 18 months. Pain worsens with walking and standing and pain is decreased with rest and elevation of the legs. Clinically, CIPS is characterized by symmetrical pain located primarily in the lower limbs (ankles, feet, and knees) while the hip and supine are typically spared. While majority (33.3% or 4/12) of our patients presented with bilateral symmetrical knee pain, 3 (25%) patients suffered bilateral feet pain. Pain worsens in an upright position during movement and in resting state while the legs put in a position below the heart level. Symptoms may start from 1 to 6 months posttransplantation and characteristically involve multiple skeletal sites and resolve after a period of 3–18 months.


CIPS is a diagnosis of exclusion. Bone scintigraphy shows an increased tracer uptake by the foot bones indicating hyperperfusion, hypervascularity, and hypermetabolism. MRI demonstrates a bone marrow edema that is limited at the epiphysis of the distal tibia and in the border of different vascular supply terrorities. High or normal cyclosporine or TAC levels are helpful in diagnosis of CIPS. A rise in serum alkaline phosphatase levels and to a lesser extent in serum calcium levels in renal transplant patients may serve as early indicators of PTLDS as elevated alkaline phosphatase in two patients and elevated serum calcium levels in three patients in this study have been seen. Plain X-rays complement MRI and may help exclude other pathologies that may be causing the bone marrow edema. Reduced regional bone density (regional osteoporosis) on plain X-rays is usually a late feature of bone marrow edema syndromes and may persist for some time after the resolution of symptoms. Radiological imaging revealed mild osteopenia on feet to patchy osteoporosis in knee, ankle, and feet in this study. The diagnosis is generally confirmed by MRI that identifies areas of hyperemia and marrow edema, often associated with soft tissue swelling and joint effusions, because in some cases radionuclide bone scans are reported to be normal. In our study, MRI of affected bone showed bone marrow edema, incomplete fracture, and abnormal increased T2 signal within bone marrow of the lower extremity bones. Furthermore, radionuclide scintigraphy revealed increased tracer uptake on bones, joints, and periarticular soft tissues [Figure 3].
Figure 3: Diagrammatic distribution of diagnostic imagings in CIPS. CIPS: Calcineurin inhibitor-induced pain syndrome, MRI: Magnetic resonance imaging

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Differential diagnosis

Differential diagnosis of CIPS in postrenal transplant according to these studies is reported in [Table 4].
Table 4: Differential diagnosis of calcineurin inhibitor-induced pain syndrome in postrenal transplant

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Nonsteroidal anti-inflammatory drugs may relieve symptoms but can adversely affect renal function, and the efficacy of Vitamin D is unproven. Core decompression is reported to rapidly improve symptoms of transient marrow edema, but when managed conservatively, CIPS and transient marrow edema generally improve over 2–4 months. The use of clodronate and calcitonin seems to help attenuate pain by inhibiting osteolysis (calcitonin also seems to have a central effect). The reduction or withdrawal of calcineurin inhibitor doses, even in the presence of normal blood values, seems to alleviate pain symptoms. In many cases, exchange of CNIs (from TAC to CsA or from CsA to TAC) is effective. Resting the legs in a raised position is recommended. The use of calcium antagonists (preferably nifedipine or nitrendipine) which do not inhibit the cytochrome P450 seems to be equally useful in reducing intraosseous hypertension. Effective doses of extended release nifedipine were in the range of 30–60 mg daily. The syndrome is completely reversible over a period of a few months, without sequelae of any kind. The prostacyclin analog iloprost may be a new and safe therapeutic option at least in more severely affected patients. Tillmann et al. in an original study treated ten patients with MRI-proven diagnosis of PTLDS following a standardized regimen of IV iloprost over 5 days from August 2003 to April 2005. Iloprost led to prompt pain relief measured on a visual analogous scale ranging from 1 to 10 (5.6 ± 1.5 before vs. 2.1 ± 1.3 after treatment, P = 0.0004).[24] Recently, gamma-aminobutyric acid (GABA) analogs such as gabapentin or pregabalin which are commonly and effectively used in neuropathic pain have been described for the first time in a case report by Tasoglu et al. The authors presented a 48-year-old male patient who underwent liver transplantation who suffered severe, deeply aching and more intense in the feet sometimes extending to the knees. Pregabalin 150 mg twice daily was prescribed to him and subsided his pain dramatically.[25] There are controversies about the usefulness of bisphosphonates (30 mg) in these cases, although the improvement in symptoms after their application is described. Overall, treatment of CIPS in this study contains conservative therapy, calcium channel blockers, IV pamidronate, reduction of calcineurin inhibitor dose, and change of calcineurin inhibitors to another drug from the same drug class [Figure 4]. Resolving of bone pain occurred from 1 week until 3 months after reduction or withdrawal of drug and disappearance of bone marrow edema revealed after 6 months on MRI.
Figure 4: Diagrammatic distribution of therapeutic modalities in CIPS. CIPS: Calcineurin inhibitor-induced pain syndrome, CsA: Cyclosporine A, ERL: Everolimus, SRL: Sirolimus, TAC: Tacrolimus

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Similar studies

A study by Tillmann et al. investigated 639 renal transplant recipients and evaluated CIPS in 37 patients. There was no association to steroid-medication, age, gender, PTH levels, or delayed graft function. As an important finding, they saw a significant rise in alkaline phosphatase from 160 ± 54 to 271 ± 108 U/l (P = 0.008) and calcium from 2.46 ± 0.18 to 2.58 ± 0.18 mmol/l (P = 0.013) preceding the onset of pain by several weeks. The mean duration of clinical symptoms was 5.1 ± 3.1 months; however, all patients experienced remission without signs of chronic damage on long-term follow-up.[26] Furthermore, a study by Grotz et al. investigated nine patients with severe pain in their feet, which was registered after transplantation. Bone scan showed increased tracer uptake of the foot bones. MRI demonstrated bone marrow edema in the painful bones. The reduction of cyclosporine or TAC trough levels and the administration of calcium channel blockers led to relief of pain.[8]

  Conclusion Top

Calcineurin inhibitors, cyclosporine, and TAC are effective immunosuppressants that widely used in organ transplant recipients. Different diagnostic methods are used in CIPS, but MRI is the diagnostic measure of choice in affected patients. The most effective treatment of CIPS is reduction dose of calcineurin inhibitors and other treatment modalities include switching of immunosuppressants, calcium channel blockers, GABA analogs, IV pamidronate and conservative therapies. Furthermore, both clinical and imaging modalities in follow-up outcome have an important role in cure of this disease.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Elder GJ. From marrow oedema to osteonecrosis: Common paths in the development of post-transplant bone pain. Nephrology (Carlton) 2006;11:560-7.  Back to cited text no. 1
Grøvle L, Hasvik E, Rashid HU, Haugen AJ. Primary bone marrow oedema syndrome: Proposed outcome measures for pain and physical functioning. Rheumatology (Oxford) 2014;53:1910-1.  Back to cited text no. 2
Isaacs KL. Severe bone pain as an adverse effect of cyclosporin therapy for Crohn's disease. Inflamm Bowel Dis 1998;4:95-7.  Back to cited text no. 3
Lawson CA, Fraser A, Veale DJ, Emery P. Cyclosporin treatment in psoriatic arthritis: A cause of severe leg pain. Ann Rheum Dis 2003;62:489.  Back to cited text no. 4
Rahman AH, O'Brien C, Patchett SE. Leg bone pain syndrome in a patient with ulcerative colitis treated with cyclosporin. Ir J Med Sci 2007;176:129-31.  Back to cited text no. 5
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Lucas VP, Ponge TD, Plougastel-Lucas ML, Glemain P, Hourmant M, Soulillou JP, et al. Musculoskeletal pain in renal-transplant recipients. N Engl J Med 1991;325:1449-50.  Back to cited text no. 7
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Coates PT, Tie M, Russ GR, Mathew TH. Transient bone marrow edema in renal transplantation: A distinct post-transplantation syndrome with a characteristic MRI appearance. Am J Transplant 2002;2:467-70.  Back to cited text no. 14
Villaverde V, Cantalejo M, Balsa A, Mola EM. Leg bone pain syndrome in a kidney transplant patient treated with tacrolimus (FK506) Ann Rheum Dis 1999;58:653-4.  Back to cited text no. 15
Collini A, De Bartolomeis C, Barni R, Ruggieri G, Bernini M, Carmellini M, et al. Calcineurin-inhibitor induced pain syndrome after organ transplantation. Kidney Int 2006;70:1367-70.  Back to cited text no. 16
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Hu YM, Chen SR, Chen H, Pan HL. Casein kinase II inhibition reverses pain hypersensitivity and potentiated spinal N-methyl-D-aspartate receptor activity caused by calcineurin inhibitor. J Pharmacol Exp Ther 2014;349:239-47.  Back to cited text no. 18
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4]


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