We describe 15 consecutive patients who received transplants and presented with an acute bone pain syndrome similar to that described by Lucas and colleagues [2] but that resolved when treated with calcium channel blockers. During the study period, 18 patients were referred from the kidney, liver, lung, and pancreas transplant services for evaluation of severe joint or bone pain. Inclusion criteria were the presence of severe, unexplained, usually bilateral, deep aching bone pain occurring in the lower extremities that began or worsened with recumbency. Three patients did not meet the criteria for inclusion and were diagnosed with gout or tendonitis. The transplant team ordered imaging studies (radiographs, bone scan, and magnetic resonance imaging) as appropriate for clinical evaluation of the symptoms. The treating physicians determined the selection and dosing of calcium channel blockers Table 1 to control hypertension or to successfully treat recurrent episodes of bone pain. The following cases show the character of this bone pain syndrome.

Case Reports

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Patient 1 was a 47-year-old white woman who presented 19 days after lung transplantation and had developed severe bilateral knee and ankle pain (10 on a 10-point pain scale) at 2 a.m. to 3 a.m. on each of five successive nights. The patient described no change in the pain with passive or active motion of the joints. She had no pain during the day and had no physical findings to explain her knee or ankle pain. She required intravenous morphine (as much as 10 mg every 2 hours) to relieve the nocturnal knee and ankle pain. On the sixth day of her pain episodes, she had mild bilateral tenderness along the epiphyseal regions of the distal femurs and proximal tibias and cool mottled skin over her knees. Noteworthy medications taken before and during the pain included cyclosporine at 300 mg orally twice a day with markedly fluctuating blood levels; a stable prednisone dose of 20 mg orally every morning and 10 mg orally every evening; azathioprine at 150 mg orally at evening 3 days per week; and nifedipine at 10 mg orally 3 times a day. She received her last nifedipine dose at 6 p.m. and her evening cyclosporine dose at 8 p.m., probably resulting in minimal calcium channel blockade at the time cyclosporine levels would peak. Radiographs and a bone scan were normal. Extended-release nifedipine at 30 mg orally at bedtime, given to treat presumed nocturnal vasoconstriction, relieved her bone pain.

Patient 3 experienced severe bilateral knee pain that began 40 days after lung transplantation. Results of his knee examination were negative, and his pain responded effectively to extended-release nifedipine. The patient elected to discontinue therapy because of edema and fatigue. He continued to experience episodes of pain thereafter but did not receive treatment for them. Magnetic resonance imaging of the knees done 4 months after the initial pain episode showed extensive bilateral femoral marrow infarctions (Figure 1).

View larger version (171K): [in this window] [in a new window]   Figure 1. Coronal spin-echo magnetic resonance image (TR = 500 ms, TE = 10 ms) of the distal femurs of patient 3 taken 4 months after the first episodes of bilateral knee pain. Although the first episodes of bone pain in this patient were treated with nifedipine, repeated episodes occurring over the succeeding months were untreated. Bilateral foci of osteonecrosis are noted in the metaphyses of each femur. Similar areas of osteonecrosis were seen in the proximal left femur.

Patient 9 was a 33-year-old woman with severe episodic bilateral knee and ankle pain that developed 21 days after liver transplantation. The pain was unrelieved with oral narcotics, heat, or massage for 3 nights. Results of her musculoskeletal examination were normal. On admission to the emergency department, she was given nifedipine at 10 mg sublingually, and her symptoms resolved within 10 minutes. She was subsequently treated with extended-release nifedipine that completely controlled her symptoms.

Results

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Twelve of the 15 patients with the bone pain syndrome presented in the first 2.5 months of their transplantation therapy (range, 7 to 67 days; median, 20 to 21 days). The severe, deep aching pain in the bone usually developed rapidly, was worse at night and with recumbency, was often relieved slightly when the leg was elevated above the heart, and was not associated with any physical examination findings that would explain the pain. The pain could relent as rapidly as it began but would typically persist for hours. Thirteen of the 15 patients had no history of joint or bone problems; 1 patient had an old plateau fracture of the tibia, and 1 had Paget disease. Chart review showed no recent rapid fluctuations in the prednisone dosing. Laboratory and clinical histories did not support the presence of renal osteodystrophy in the patients who received a renal transplantation. Radiographs of the knees were available for 10 of the 15 patients; 9 were normal and 1 showed only an old plateau fracture of the tibia. Bone scans of the knees and ankles were negative in 3 of the 4 patients examined; in the patient with known Paget disease (patient 4), the bone scan of the medial femoral condyles and iliac regions were positive. Magnetic resonance imaging scans of the knees and ankles were normal in patient 7 at the time of the pain; 2 patients had normal magnetic resonance imaging scans of the hip. Patient 3 had abnormal findings on the magnetic resonance imaging scans of his knees 4 months after the onset of pain Figure 1.

Calcium channel blockers were administered to 13 patients to treat the bone pain syndrome, often as a medication before bedtime (Table 1). Two patients did not receive calcium channel blockers and were treated with high-dose narcotics (patients 5 and 10) (Table 1). The bone pain of all patients treated with calcium channel blockers was relieved. Remarkably, patient 9, who was given sublingual nifedipine, noted relief within 10 minutes, a finding that was confirmed in subsequent patients. Although some patients received calcium channel blockers before the onset of pain, they were receiving submaximal doses.

Discussion

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This syndrome consists of acute and severe pain in discrete locations in patients who received solid organ transplants. Table 1 lists the first 15 patients prospectively evaluated. Retrospective sampling of charts of other patients who received transplants, however, showed that the episodic bone pain syndrome differs from patient reports of arthralgia and musculoskeletal complaints that accompany steroid withdrawal. It is unlike the bone pain of osteonecrosis induced with weight-bearing or the recently described bone microfractures in patients who received renal transplants [5]. This bone pain syndrome is similar to the bone pain that occurs at rest in some patients with osteonecrosis, sickle cell crisis, or osteoarthritis, all of which have been attributed to intraosseous hypertension [6, 7]. Persistent intraosseous hypertension is commonly believed to be involved in the pathogenesis of bone infarction and osteonecrosis [8], and although surgical decompression is a controversial treatment for osteonecrosis, its value in early pain relief is unquestioned.

Zizic and colleagues [8] have described two patients with elevated intraosseous pressure of the femoral head that decreased when intravenous nifedipine was administered intraoperatively. LaRoche and colleagues [9] have reported a diminution of bone pain within 30 to 60 minutes of oral nifedipine administration in patients with established osteonecrosis of the femoral head but not in patients with osteoarthritis of the hip. Aside from these studies and the relief of intraosseous pressure by experimental use of the vasodilator naftidrofuryl [10], the intentional pharmacologic alteration of intraosseous pressures has not been reported in humans.

Calcium channel blockers will be greatly beneficial in treating this episodic pain syndrome in transplant recipients. Further studies will show the pathophysiology of this syndrome, determine whether the pain relieved by calcium channel blockers was caused by intraosseous hypertension, and clarify its relation to the development of osteonecrosis.