tacrolimus and Pain

Topical steroid-sparing agents (SSA), such as tacrolimus, pimecrolimus, and crisaborole, represent an important therapeutic option in the treatment of inflammatory dermatoses such as atopic dermatitis. While these agents lack the common side effects associated with topical corticosteroids, they all share application site pain as an important adverse effect.. Based on the available evidence and our experience, we suggest the following 7 practical strategies for decreasing the pain associated with SSA use. (1) Use a topical corticosteroid for a few days to reduce inflammation before starting the SSA treatment. (2) Use SSAs strategically. (3) Apply moisturizer before applying SSAs. (4) Store moisturizers in the refrigerator. (5) Ask the patient to apply the SSA on a small test area before broader application. (6) Apply the SSA on dry rather than on damp skin. (7) Consider using aspirin when appropriate for the patient.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Boron Compounds; Dermatitis; Dermatologic Agents; Humans; Pain; Skin Cream; Tacrolimus

Management of oral lichen planus (OLP) is challenging and therapeutic options are limited. The use of topical tacrolimus has shown promising results. We reviewed our daily life experience with topical tacrolimus in OLP patients.. This retrospective unicentre study included all 21 patients with OLP, which were evaluated over a 53-month period and treated with topical tacrolimus. Patients were initially given a topical preparation of 0.1% tacrolimus twice daily. The response to treatment was assessed using a 4-point scale at month 2 and 6: complete response of affected area (CR), major remission (>50%, MR), partial remission (25-50%, PR) and either no response (<25%) or worsening. The pain score was also assessed using a 3-point scale.. Four of 21 patients (19%) showed a CR at month 2, whereas at month 6, 7 (33%) had a CR. For patients who reported MR (n = 2) and PR (n = 8) at month 2, the therapy was continued. Of those, at 6 months, three patients showed a CR, while four maintained a PR. The pain score improved during treatment. After 2 months of therapy, eight of 10 patients with an initial high pain score achieved a significant improvement. In patients starting with moderate pain an improvement was observed in one of seven patients. Overall, for three patients there was a complete loss of pain, while in nine there was a reduction. Except for transitory burning sensation and altered taste sensation, no relevant side-effects were reported.. This retrospective analysis confirms that topical tacrolimus is a valuable therapeutic option in severe or treatment-resistant OLP. Our findings in daily practice suggested nevertheless that the efficacy of topical tacrolimus is overestimated with regard to both complete response and pain reduction.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Female; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Male; Middle Aged; Pain; Pain Measurement; Retrospective Studies; Tacrolimus; Treatment Outcome

Pimecrolimus is a non-steroidal immunosuppressant derived from ascomycin. This drug inhibits the action of calcineurin phosphatase and blocks the production of inflammatory substances that are thought to be important in causing skin lesions in inflammatory diseases. Pimecrolimus 1% cream (Elidel, Novartis Pharma, East Hanover, NJ, USA) was approved in the European Union, the United States and Japan as second-line therapy for the short- term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults and children aged 2 years and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable. This topical immunomodulator has also an enormous potential as topical treatment for numerous inflammatory skin diseases like psoriasis and vitiligo. Recently, some authors reported its efficacy in the treatment of skin manifestations of Lupus erytematosus.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphocyte Activation; Molecular Structure; Pain; Psoriasis; T-Lymphocytes; Tacrolimus; Vitiligo

Atopic dermatitis (AD) is a common eczematous skin condition; as many as 10-17 percent of all children are affected, and 35-60 percent of affected patients manifest symptoms manifest during the first year of life. Treatment principles for AD in young children involve conservative measures such as avoidance of hot water and environmental irritants, combined with liberal use of emollients after bathing. Low potency topical corticosteroids (TCS) are the current standard of therapy for AD in young children, reserving mid- and high-potency TCS for severe disease. However, complications of long-term use of TCS include skin atrophy, stria formation, telangiectasia, hypopigmentation, secondary infections, steroid acne, allergic contact dermatitis, and miliaria. The pediatric population is also at increased risk for systemic absorption because of their high ratio of skin surface to body mass. Systemic absorption may result in hypothalamic-pituitary-adrenal axis suppression and ultimately growth retardation. Although most topical and systemic corticosteroids are not approved by the Food and Drug Administration for use in children less than 2 years of age, conservative treatment often fails in this age group and frequently patients are treated with TCS, antibiotics, and antihistamines.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Anti-Bacterial Agents; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Evaluation; Drug Utilization Review; Emollients; Female; Histamine H1 Antagonists; Humans; Immunosuppressive Agents; Infant; Male; Ointments; Pain; Pruritus; Retrospective Studies; Tacrolimus; Treatment Outcome

Recurrent and painful genital ulcers are the hallmark of Behçet's disease.. To determine the efficacy of pimecrolimus (PIM) cream on the pain and healing time of genital ulcers.. A total of 76 patients were randomized to either receive PIM cream plus colchicine (COL) tablets (1-2 g/day) or COL tablets (1-2 g/day) alone for 1 month. Clinical evaluations were performed in 68 patients at the baseline and on the 3rd, 7th, 10th, 14th and 28th days of treatment. Also, genital ulcer pain was evaluated using a verbal pain score at each visit. Safety was monitored through adverse event reporting and laboratory tests.. The mean healing time of genital ulcers was shorter in the PIM + COL group (4.2 +/- 1.5 days) than the COL group (4.7 +/- 1.8 days), without statistical significance (p = 0.399). Visual analog scale scores decreased in both groups significantly. Neither of the treatment modalities was found to be superior to the other; however, pain was relieved in 4.2 +/- 0.5 days in PIM + COL group and in 5.5 +/- 1.2 days in COL group in the intention to treat population (p = 0.023). Observed adverse events were transient.. Compared to COL alone, COL + PIM cream shortens the pain duration without any significant effect on healing time.

Topics: Adult; Behcet Syndrome; Colchicine; Dermatologic Agents; Drug Therapy, Combination; Emollients; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Pain; Pain Measurement; Retrospective Studies; Scrotum; Tablets; Tacrolimus; Treatment Outcome; Turkey; Ulcer; Vagina

Lichen planus is a common chronic inflammatory mucocutaneous disease, affecting 0.1% to 4% of the general population. There is no published randomized active control clinical trial on pimecrolimus for the treatment of oral lichen planus (OLP).. The purpose of this study was to compare the efficacy and safety of pimecrolimus 1% cream with triamcinolone acetonide 0.1% paste in treating OLP.. In this investigator-blinded parallel-group randomized clinical trial, 40 patients were randomly assigned in two equal groups to receive either pimecrolimus 1% cream or triamcinolone acetonide 0.1% paste 4 times daily for a total of 2 months and followed up for another 2 months. The patients were assessed for painful symptoms measured by visual analog scale, the Oral Health Impact Profile score, and objective clinical score. Nonparametric tests were used to assess the main outcomes. Intention-to-treat analysis was used.. Eighteen patients in pimecrolimus group and 17 patients in triamcinolone group finished the 4-month trial course. Both pimecrolimus and triamcinolone groups showed significant improvement in all measured efficacy end points throughout the visits. There was no significant difference between changes from baseline median values of pimecrolimus and triamcinolone groups after treatment termination in terms of visual analog scale score (-9.8 +/- 11.3 vs -8.4 +/- 18.3, P = .70), Oral Health Impact Profile score (-1.5 +/- 2.6 vs -1.6 +/- 2.1, P = .38), and clinical score (-0.7 +/- 0.6 vs -0.8 +/- 0.7, P = .86), respectively. Two patients in pimecrolimus group experienced prominent but transient burning sensation whereas none of the patients in triamcinolone group had any prominent adverse event (P = .24).. Blood levels in pimecrolimus group were not measured and carcinogenicity of pimecrolimus, especially in its long-term use for OLP, is yet to be determined.. This study showed that patients with OLP may benefit from both topical pimecrolimus and triamcinolone acetonide therapy with minimal side effects. Further studies should be conducted to assess the maintenance effects and long-term safety of both drugs (Cochrane skin group identifier: CSG TrialNo. 22).

Topics: Administration, Topical; Adult; Dermatologic Agents; Female; Glucocorticoids; Humans; Lichen Planus, Oral; Male; Middle Aged; Pain; Pain Measurement; Sickness Impact Profile; Single-Blind Method; Tacrolimus; Treatment Outcome; Triamcinolone Acetonide

Topics: Administration, Cutaneous; Adult; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Occlusive Dressings; Ointments; Pain; Patient Dropouts; Pyoderma Gangrenosum; Tacrolimus; Treatment Outcome

To determine whether myalgias/arthralgias occurring in cancer patients who receive quinupristin/dalfopristin are associated with biliary tract dysfunction.. We studied 56 patients with vancomycin-resistant enterococcal infections who were treated with quinupristin/dalfopristin 7.5 mg/kg every 8 h for a mean duration of 12 days (range 2-52 days). Liver function tests, including a test for alkaline phosphatase, were performed before, during and after the end of therapy. All patients were followed for 1 month after completion of therapy.. Thirty-eight (68%) of the 56 patients responded. Myalgias/arthralgias were the leading adverse events occurring in 20 (36%) of the patients. Patients with myalgias/arthralgias had significantly higher levels of alkaline phosphatase (mean 318.7 IU/L) during the mid-term therapy cycle compared with patients without any joint or muscular pain (mean 216.3 IU/L, P = 0.05). In addition, 3/18 (16.6%) patients with myalgias/arthralgias had more than five-fold the normal levels of alkaline phosphatase, which did not occur in any of the other patients who did not develop myalgias/arthralgias (P = 0.04). All myalgias/arthralgias resolved after the discontinuation of quinupristin/dalfopristin. By univariate analysis, other factors associated with myalgias/arthralgias were relapse of haematological malignancy (P = 0.01), receiving tacrolimus within 1 month prior to treatment (P = 0.04) and receiving methotrexate during antimicrobial therapy (P = 0.05).. Myalgias/arthralgias occur frequently in cancer patients receiving quinupristin/dalfopristin and may be associated with biliary tract dysfunction, as measured by alkaline phosphatase or other factors that could lead to intra-hepatic cholestasis, such as relapse of haematological malignancy or treatment with tacrolimus or methotrexate.

Topics: Aged; Alkaline Phosphatase; Anti-Bacterial Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Arthralgia; Biliary Tract Diseases; Enterococcus; Female; Gram-Positive Bacterial Infections; Humans; Immunosuppressive Agents; Liver Function Tests; Male; Methotrexate; Middle Aged; Muscular Diseases; Neoplasms; Pain; Recurrence; Risk Factors; Tacrolimus; Virginiamycin

Reduction of allograft rejections remains a primary goal for patients after orthotopic heart transplantation. In an open, multicentre, prospectively randomised, parallel group study, patients with primary orthotopic heart transplantation under oral immunosuppressive treatments with tacrolimus (FK506) or cyclosporine (sandimmun) were compared with respect to medical outcome data. As health-related quality-of-life (HRQOL) is also supposed to be an important outcome parameter, it was assessed as a secondary variable in these two patient groups. Patients' self-rated generic HRQOL was assessed 6 weeks, 3 months, 6 months and 12 months after surgery with the SF-36 questionnaire, a generic HRQOL instrument. For 70 patients (46 under tacrolimus, 24 under cyclosporine), intent-to-treat analyses were carried out. The tacrolimus group showed improvements in the different HRQOL subscales of the SF-36 compared to the cyclosporine group. Especially the SF-36 subscales 'vitality' and 'mental health' showed statistically higher scores for the tacrolimus group. Aggregating psychological and cognitive subscales in the 'mental component score', patients treated with tacrolimus showed a statistically significant improvement compared to the cyclosporine group. The assessment of HRQOL variables in the evaluation of treatment effects proved to be an outcome parameter in this study. The results demonstrate the benefit of tacrolimus with respect to the HRQOL of patients, especially in the psychological dimension.

Topics: Analysis of Variance; Cyclosporine; Emotions; Health Status; Heart Transplantation; Humans; Immunosuppressive Agents; Pain; Quality of Life; Surveys and Questionnaires; Tacrolimus

Topics: Calcineurin Inhibitors; Cord Blood Stem Cell Transplantation; Humans; Pain; Roseolovirus Infections; Tacrolimus

Topics: Calcineurin; Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Pain; Stem Cell Transplantation; Tacrolimus

Topics: Hemangioma; Humans; Pain; Skin Neoplasms; Tacrolimus

FK506 (tacrolimus) is an immunosuppressant widely used as an ointment in the treatment of atopic dermatitis. However, local application of FK506 can evoke burning sensations in atopic dermatitis patients, and its mechanisms are unknown. In this study, we found that FK506 activates transient receptor potential ankyrin 1 (TRPA1) channels. In Ca

Topics: Animals; Calcium; Calcium Channels; Cell Line; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pain; Sensation; Sensory Receptor Cells; Tacrolimus; TRPA1 Cation Channel

Topics: Aged; Calcineurin Inhibitors; Combined Modality Therapy; Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hip; Humans; Lower Extremity; Male; Myelodysplastic Syndromes; Pain; Pregabalin; Severity of Illness Index; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Topics: Administration, Cutaneous; Adolescent; Adult; Dermatitis, Atopic; Emollients; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pain; Pain Measurement; Prospective Studies; Pruritus; Skin; Tacrolimus; Treatment Outcome; Water Loss, Insensible; Young Adult

Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Cav3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphorylation with protein kinase A and also play a role in pancreatitis-related pain. Calcineurin, a phosphatase, negatively regulates various channel functions including TRPV1, and calcineurin inhibitor-induced pain syndrome by tacrolimus, a calcineurin inhibitor, used as an immunosuppressant, has been a clinical problem. We thus examined the effect of tacrolimus on pancreatitis-related pain in mice. Repeated treatment with cerulein caused referred hyperalgesia accompanying acute pancreatitis, which was unaffected by tacrolimus. Pancreatitis-related symptoms disappeared in 24 h, whereas the referred hyperalgesia recurred following the administration of tacrolimus, which was abolished by the blockers of TRPV1 but not T-type Ca2+ channels. Thus, tacrolimus appears to cause the TRPV1-dependent relapse of pancreatitis-related pain, suggesting the involvement of calcineurin in the termination of pancreatic pain.

Topics: Anilides; Animals; Benzimidazoles; Ceruletide; Cinnamates; Cyclopropanes; Hyperalgesia; Male; Mice; Naphthalenes; Pain; Pancreatitis; Recurrence; Tacrolimus; TRPV Cation Channels

Topics: Administration, Topical; Bariatric Surgery; Drug Administration Schedule; Female; Femoral Neuropathy; Follow-Up Studies; Humans; Hypertension; Middle Aged; Nerve Compression Syndromes; Obesity, Morbid; Pain; Postoperative Period; Pruritus; Tacrolimus; Treatment Outcome

Tacrolimus and cyclosporin are calcineurin inhibitors (CIs) commonly used in organ transplants. These agents rarely cause a severe, debilitating pain syndrome of especially lower extremities, known as CI pain syndrome (CIPS). Although the pathogenesis is not well understood, neuropathic pain mechanisms have started to be discussed in the recent literature. Here, presenting a 48-year-old male with CIPS who recovered after pregabalin 150 mg twice daily, we aimed to emphasize the importance of this syndrome and offer a new approach for the treatment. This is the first report in the literature where pregabalin is demonstrated to be effective in CIPS.

Topics: Analgesics; Calcineurin Inhibitors; Cyclosporine; Humans; Male; Middle Aged; Organ Transplantation; Pain; Pregabalin; Tacrolimus

A 23-year-old woman was admitted with a relapse of ulcerative colitis. Tacrolimus therapy was initiated following inadequate response to corticosteroid therapy. Although the symptoms partially improved, she suddenly developed severe pain localized to the lower limbs on day 16 of tacrolimus therapy. By day 17, she was unable to move. Magnetic resonance imaging revealed born marrow edema in the lower limbs. We suspected calcineurin-inhibitor induced pain syndrome (CIPS) due to tacrolimus therapy. The pain improved within approximately four weeks of tacrolimus cessation. CIPS that is not associated with organ transplantation is a rare occurrence. Here we report a rare case of CIPS that was caused by tacrolimus therapy in a patient with ulcerative colitis.

Topics: Calcineurin Inhibitors; Colitis, Ulcerative; Female; Humans; Pain; Syndrome; Tacrolimus; Young Adult

Topics: Adolescent; Adult; Calcineurin Inhibitors; Cyclosporine; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Pain; Radiography; Retrospective Studies; Syndrome; Tacrolimus; Transplantation, Homologous

Chronic GVHD (cGVHD) frequently affects the oral cavity. The purpose of this study was to estimate the efficacy of combined topical dexamethasone (DEX) and tacrolimus (TAC) solutions in the management of oral cGVHD. The records of 14 patients with oral cGVHD treated with combined topical DEX/TAC were reviewed retrospectively. Pre-to-post treatment changes in subjective and objective measures were evaluated at a median follow-up of 60 days. Serum TAC levels were examined. Marginal objective improvement was detected at follow-up. The median pre-to-post treatment differences were 0.5 (range, -1 to 1) for erythema score, and 0.5 (range, 0 to 2) for lichenoid score, (P=0.06, 0.07 and 0.02, respectively). Subjective improvement was noted in three of four measures at the follow-up visit. The median differences in pain, sensitivity and dryness scores were 1 (range -1 to 6), 1 (range -3 to 5) and 2.5 (range, -5 to 5), respectively (0-10 scale, P<0.05). Four patients (37%) showed increased serum TAC levels; however, all remained within therapeutic range. In conclusion, combined topical DEX/TAC therapy appears to be effective in reducing symptoms attributable to oral cGVHD. Our data has shown minimal evidence of systemic TAC absorption.

Topics: Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Dexamethasone; Drug Therapy, Combination; Erythema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lichenoid Eruptions; Male; Middle Aged; Mouth; Pain; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Burning sensation at the site of application is the most common side effect of topical calcineurin inhibitors and is considered the most common reasons for premature discontinuation. Here, we analyze the possible mechanism(s) and offer a simple practical tip to mitigate this adverse effect. Simple cooling of the tube, immediately before use, does reduce the burning sensation and enable most intolerant patients to use the medication comfortably. We also discuss the possible explanation(s) for the success of this maneuver.

Topics: Administration, Topical; Calcineurin Inhibitors; Cold Temperature; Dermatitis, Atopic; Dermatologic Agents; Humans; Pain; Tacrolimus

We report a 10-yr-old boy who developed CIPS after a second allogeneic BMT for severe aplastic anemia. He received the second BMT from the same HLA-matched sibling donor 16 months after the first BMT due to secondary graft failure. The preparative regimen for the second BMT consisted of fludarabine, cyclophosphamide, and anti-thymocyte globulin. Prophylaxis for acute GVHD was tacrolimus and oral PSL. Engraftment was achieved on day 15. On day 19, he suddenly complained of intermittent pain in the bilateral lower limbs. Electric shock-like pain continued for a few minutes in succession. This intractable pain was not ameliorated by various analgesic drugs including pentazocine. MRI demonstrated bone marrow edema with high T2 signal intensity in the femur. He was diagnosed as CIPS based on his symptoms and MRI findings. The trough concentration of tacrolimus (10.1 ng/mL) at the onset of CIPS was within the therapeutic range. Bouts of severe pain naturally resolved after day 43 without the discontinuation of tacrolimus. CIPS is a rare complication in HSCT. This is the first non-malignant, and the first pediatric, case who developed CIPS after HSCT.

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Transplantation; Calcineurin Inhibitors; Child; Cyclophosphamide; Edema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Pain; Tacrolimus

FK1706, a derivative of FK506, is a non-immunosuppressive immunophilin ligand with significant neurotrophic activity mediated via FKBP-52 and the RAS/RAF/MAPK signaling pathway. Here, we tested the effect of FK1706 on painful diabetic neuropathy in rat model of diabetes induced by streptozotocin (STZ). FK1706 ameliorated mechanical allodynia in this model at doses over 0.32 mg/kg, p.o., even if treatment was initiated after neuropathy was established, and did not affect plasma glucose levels. Furthermore, this improvement continued at least 4 weeks after the last administration. In morphological analysis, FK1706 treatment also restored intraepidermal nerve fiber density in footpad skin to almost normal levels. Gabapentin also improved mechanical allodynia in the same model, but efficacy disappeared the day after administration stopped. Allodynia responses were potentiated by co-administration of both compounds. Thus, FK1706 ameliorated painful diabetic neuropathy via a different mechanism from gabapentin and improved morphological outcomes, indicating that FK1706 improves painful diabetic neuropathy by modifying the underlying disease pathology.

Topics: Amines; Analgesics; Animals; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Gabapentin; gamma-Aminobutyric Acid; Immunohistochemistry; Immunophilins; Ligands; Male; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Sprague-Dawley; Tacrolimus

Voriconazole is an anti-fungal agent active against Aspergillus infection that is used for prophylaxis and curative treatment in lung transplant patients. We present nine cases of painful neuromuscular disorders, an unusual and rare side effect of high-dose voriconazole in association with tacrolimus.

Topics: Adolescent; Adult; Aspergillosis; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Lung Transplantation; Male; Middle Aged; Neuromuscular Diseases; Pain; Postoperative Complications; Pyrimidines; Retrospective Studies; Risk Assessment; Severity of Illness Index; Tacrolimus; Treatment Outcome; Triazoles; Voriconazole

Calcineurin-inhibitor-induced pain syndrome (CIPS), a rare complication seen in patients with organ transplants, is associated with the use of calcineurin inhibitors (CIs) such as cyclosporine (CSP) and tacrolimus (FK). Patients with this syndrome usually present with severe leg pain. This case report demonstrates the successful pain control of this pain syndrome in a 42-year-old female patient who had been given CIs (FK and CSP) as an immunosuppressive agent after a bone marrow transplant. Twenty-one days after the transplantation, she complained of severe pain in her bilateral lower extremities; this lasted several weeks, and was resistant to ordinary analgesics such as intramuscular pentazocine, intravenous morphine, and even oral nifedipine, which is generally accepted as an effective analgesic agent for the pain in this syndrome. Due to the presence of allodynia, our patient's pain had neuropathic pain-like characteristics, unlike the pain in previously reported patients with other organ transplants. Her pain was successfully relieved by the administration of oral amytriptyline, clonazepam, oxycodone, and intravenous lidocaine, all of which ordinarily have an analgesic effect on neuropathic pain. CIPS in patients with hematopoietic stem cell transplants treated with FK may have a mechanism by which neuropathic pain may develop that is different from that in patients with other organ transplants.

Topics: Adult; Bone Marrow Transplantation; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Leg; Pain; Pain Management; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Syndrome; Tacrolimus; Treatment Outcome

The calcineurin inhibitors (CIs) cyclosporine A and tacrolimus are essential for graft-versus-host disease prophylaxis but are associated with adverse effects, including neurotoxicity. We report a case of irreversible CI-induced neuropathic pain following allogeneic hematopoietic stem cell transplantation. The patient developed dysesthesia, electric shock-like pain, and severe itching followed by intractable analgesic-resistant pain in the lower extremities. There were no abnormal radiographic findings, and there was no improvement with a reduction of CI dosage or with administration of a calcium channel blocker. These clinical findings are similar to but inconsistent with CI-induced musculoskeletal pain syndromes previously reported in organ transplantation.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Pain; Peripheral Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiography; Tacrolimus; Transplantation, Homologous

Topics: Adult; Bone and Bones; Calcineurin Inhibitors; Cyclosporins; Everolimus; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Osteoporosis; Pain; Postoperative Period; Radiography; Radionuclide Imaging; Sirolimus; Syndrome; Tacrolimus; Time Factors

FK506 (tacrolimus), an immunosuppressive drug, improves quality of life (QOL) for patients with rheumatoid arthritis (RA). However, the mechanism of FK506 behind the improvement in QOL is still uncharacterized. To explain the improvement of QOL by FK506, we investigated the effect of FK506 on spontaneous locomotor activity in rats with collagen-induced arthritis (CIA). CIA was induced in 7- to 8-week-old female Lewis rats by immunization with bovine type II collagen. After initiation of paw inflammation (paw swelling, histopathological analysis), CIA rats were therapeutically administered FK506 or methotrexate (MTX) from day 15. Therapeutic treatment with FK506 ameliorated spontaneous locomotor activity without suppressing paw inflammation in CIA rats from day 27. FK506 also improved hyperalgesia and grip strength from day 27. Therapeutic treatment with MTX did not improve spontaneous locomotor activity, and simultaneously did not recover hyperalgesia or grip strength in CIA rats. Our results indicate that spontaneous locomotor activity in CIA rats correlates mainly with hyperalgesia and muscle strength, but not paw inflammation, implying that therapeutic treatment with FK506 ameliorates spontaneous locomotor activity via improvement of hyperalgesia and muscle strength in CIA rats.

Topics: Animals; Arthritis, Experimental; Body Weight; Female; Femur Head; Hyperalgesia; Immunosuppressive Agents; Inflammation; Methotrexate; Motor Activity; Muscle, Skeletal; Pain; Proteoglycans; Rats; Rats, Inbred Lew; Tacrolimus

We report two renal transplant patients who experienced onset of severe bilateral knee pain 1 and 3 months after transplantation, respectively, while on tacrolimus therapy. Tacrolimus, like cyclosporine A, is an immunosuppressive agent that inactivates the enzyme calcineurin phosphatase. A bone pain syndrome was reported in 1989 in organ transplant recipients treated with cyclosporine A. Our cases suggest that tacrolimus may induce the same syndrome. Technetium 99m bone scanning shows increased uptake in the affected areas, and magnetic resonance imaging changes are consistent with bone marrow edema. The tacrolimus dosage need not be reduced unless trough levels are too high. The symptoms resolve completely within a few months. Imaging studies should be done to rule out avascular necrosis. The pathophysiology of this syndrome is discussed. Since tacrolimus was introduced recently, similar cases should be published.

Topics: Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Transplantation; Knee; Magnetic Resonance Imaging; Male; Middle Aged; Pain; Pain Measurement; Radionuclide Imaging; Risk Assessment; Syndrome; Tacrolimus; Technetium

Topics: Bone and Bones; Calcineurin Inhibitors; Foot; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leg; Male; Middle Aged; Myelodysplastic Syndromes; Pain; Radionuclide Imaging; Shoulder; Syndrome; Tacrolimus; Transplantation, Homologous

Calcineurin-inhibitor induced pain syndrome (CIPS) is a newly described entity with a characteristic feature of sudden onset of severe lower limb pain, and high levels of cyclosporine or tacrolimus may be involved in the pathogenesis. This syndrome is rarely seen in recipients of hematopoietic stem cell transplantation (HSCT) compared with other organ transplant recipients, however, heightened awareness of this complication after HSCT may be needed for hematologists, as misdiagnosis can result in catastrophic consequences. We report herein two cases of lower limb pain syndrome, with some clinical features resembling CIPS, occurring during the early phase of cord blood stem cell transplantation for hematological malignancy.

Topics: Adolescent; Adult; Cord Blood Stem Cell Transplantation; Cyclosporine; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Leukemia; Lower Extremity; Male; Pain; Tacrolimus

The occurrence of a post-renal transplant syndrome of lower limbs joint pain has been reported extensively over the last decade. Clinical examination of the symptomatic joints is often unremarkable and magnetic resonance imaging reveals abnormalities of the bone marrow suggestive of edema and/or hemorrhage. The main striking features of this syndrome are the spontaneous resolution of the symptoms within a few weeks as well as of the marrow abnormalities. This syndrome has been attributed to cyclosporine, given in the immunosuppression regimen or to epiphyseal impactions. We here document the occurrence of this syndrome in 5 kidney graft recipients given a tacrolimus-based immunosuppression.

Topics: Adult; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Knee Joint; Magnetic Resonance Imaging; Male; Middle Aged; Pain; Syndrome; Tacrolimus

1. FK506 and cyclosporin A (CsA) are immunosuppressive drugs, that specifically inhibit T-cell activation via calcineurin inhibition. This study was undertaken to investigate whether calcineurin inhibitors exert analgesic actions in rat adjuvant-induced arthritis (AIA), an animal model of rheumatoid arthritis (RA). 2. AIA was induced in female Lewis rats. Single doses of FK506 and CsA were orally administered to arthritic rats 17 days after arthritis induction. Intensity of hyperalgesia was assessed by measuring the pain threshold of hind paws. Tumor necrosis factor (TNF)-alpha, IL-1beta and PGE(2) levels in paw extracts were determined by ELISA. TNF activity was measured by L929 cell cytotoxicity assay. IL-1beta and cyclooxygenase (COX) mRNA expression in arthritic paws were measured by RT-PCR. 3. Single doses of FK506 and CsA markedly reduced joint hyperalgesia 24 h after drug administration, without affecting inflammation in an advanced stage of AIA. 4. The calcineurin inhibitors partially reduced the elevated level of TNF-alpha in arthritic paws, however, the analgesic effects of these drugs were not associated with the reduction in TNF-alpha level. 5. Moreover, treatment with anti-rat TNF-alpha antibody did not affect the hyperalgesia, when TNF-alpha activity was suppressed in arthritic paws by that treatment. 6. Both calcineurin inhibitors reduced the elevated level of IL-1beta in arthritic paws to a normal level, 24 h after drug administration. 7. FK506 reduced IL-1beta and COX-2 mRNA expression and PGE(2) level in arthritic paws. 8 In conclusion, calcineurin inhibitors rapidly reduce joint hyperalgesia probably by downregulating IL-1beta, but not TNF-alpha, in AIA. Our findings may provide a new strategy for the treatment of pain in RA.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Female; Pain; Pain Threshold; Rats; Rats, Inbred Lew; Tacrolimus

Bone pain after transplantation is a frequent complication that can be caused by several diseases. Treatment strategies depend on the correct diagnosis of the pain. Nine patients with severe pain in their feet, which was registered after transplantation, were investigated. Bone scans showed an increased tracer uptake of the foot bones. Magnetic resonance imaging demonstrated bone marrow oedema in the painful bones. Pain was not explained by other diseases causing foot pain, like reflex sympathetic dystrophy, polyneuropathy, Morton's neuralgia, gout, osteoporosis, avascular necrosis, intermittent claudication, orthopaedic foot deformities, stress fractures, and hyperparathyroidism. The reduction of cyclosporine- or tacrolimus trough levels and the administration of calcium channel blockers led to relief of pain. The Calcineurin-inhibitor Induced Pain Syndrome (CIPS) is a rare but severe side effect of cyclosporine or tacrolimus and is accurately diagnosed by its typical presentation, magnetic resonance imaging and bone scans. Incorrect diagnosis of the syndrome will lead to a significant reduction of life quality in patients suffering from CIPS.

Topics: Adult; Bone and Bones; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Female; Foot; Heart Transplantation; Humans; Kidney Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Organ Transplantation; Pain; Pain Management; Radionuclide Imaging; Syndrome; Tacrolimus

Topics: Bone Diseases; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Leg Bones; Middle Aged; Pain; Syndrome; Tacrolimus

The presence of severe and mild neurotoxicity in our pediatric renal transplant recipients treated with tacrolimus was determined by chart review (severe neurotoxicity) and patient survey (mild neurotoxicity). 14 patients were studied (mean age 15 yr, 5 month, +/- 4.4 yr). 1 patient experienced seizures, felt to be related to malignant hypertension. No other episode of severe neurotoxicity was documented. Most patients (12/14) reported at least one mild neurologic symptom, and half stated their symptoms were present at least 'most of the time'. The most frequent complaints were myalgias (7/14, 50%) and tremors (7/14, 50%) followed by fatigue (5/14, 38%). Severe neurotoxicity may be relatively infrequent in pediatric renal transplant patients treated with tacrolimus. Milder neurologic complaints may be commonly seen in this population, but in general are not severe enough to cause discontinuation of tacrolimus.

Topics: Adolescent; Adult; Child; Evaluation Studies as Topic; Eye; Fatigue; Follow-Up Studies; Headache; Humans; Hyperesthesia; Hypertension, Malignant; Immunosuppressive Agents; Kidney Transplantation; Muscle, Skeletal; Pain; Peripheral Nervous System Diseases; Retrospective Studies; Seizures; Sleep Initiation and Maintenance Disorders; Tacrolimus; Tremor