74 - A Case Report of Pain Management in Calciphylaxis Associated with End Stage Renal Disease

¹Carilion Clinic, Roanoke, VA, USA. ²Salem VA Medical Center, Salem, VA, USA

Purpose
Current estimate for prevalence of calciphylaxis is 3.5 new cases/1000 patient-years.¹ Risk factors include obesity, female sex, diabetes, and ESRD on dialysis.² Development of calciphylaxis is thought to be due to decreased expression of calcification inhibitors which in term increases precipitation of calcium phosphate in microvessels, leading to infarctions in the subcutaneous adipose tissue and dermis.^3,4 The resulting presentation is an overlying necrotic skin tissue with frequent development of painful lesions.⁴ The necrotic skin tissue can be further complicated by sepsis. Other associated symptoms include depression, anorexia, skeletal myopathy, intestinal bleeding, and visual impairment. Mortality is much higher if patient has ESRD with 1-year mortality rate of 45-80% than those without ESRD (25-45%).
The gold standard diagnostic test is skin biopsy. Key diagnostic features are stippled calcifications of media layer of capillaries or peri-eccrine glands, pauci-inflammatory intravascular thrombi, fibrointimal hyperplasia or thrombosis in the capillaries.^4,5 However, the pathognomonic presentation of painful ulcer with eschar in the setting of ESRD may not warrant a biopsy for diagnosis.⁴ Although calcium plays a central role in the pathophysiology, its serum level can be variable and is not a diagnostic feature in calciphylaxis.
Since calciphylaxis affects multiple organ systems, an interdisciplinary approach composed of dermatology, nephrology, nutrition, pain, and plastic surgery can achieve the best patient care.³ PTH should be maintained in normal range. Excess calcium and vitamins D supplements should be stopped. Reports regarding cinacalcet in reducing incidences of calciphylaxis are emerging and warrant further studies. Cinacalcet is described in multiple studies to be helpful in treating skin lesions.^3,6 Warfarin can increase risk of calciphylaxis while vitamin K₁ is being studied for efficacy to slow down progression of calciphylaxis by halting the calcification process. Sodium thiosulfate has shown to be promising in improvements in ulcers in calciphylaxis. Possible mechanisms of sodium thiosulfate action include vasodilatory properties and inhibiting the calcification process.
Pain management can be challenging due to pain severity, especially during removal of necrotic tissues. Often a combination of acetaminophen, topical anesthetics, opioids, gabapentin, ketamine, and/or spinal anesthetic agents are needed.^4,7
Methods
The patient is a 61-year-old male with history of diabetes, ESRD with kidney transplant on chronic steroids, coronary artery disease status-post myocardial infarction and percutaneous coronary intervention, and peripheral arterial disease (PAD). The diagnosis of calciphylaxis was explored when the patient continued to experience pain despite improvement in perfusion of his PAD. The diagnosis was confirmed by pathology report and radiologic imaging including CT and XR. Patient’s lab showed a calcium level of 9.1 mg/dL and phosphate level of 4.2 mg/dL.
For treatment, patient withheld calcium and vitamin D supplement. He underwent IV sodium thiosulfate treatment and took cinacalcet 30mg daily. However, neither thiosulfate nor calcitonin prevented subsequent attacks or alleviated pain.
The patient continued to have intermittent ischemic events in his hands and feet leading to gangrene and osteomyelitis. As a result of tissue destruction, there were multiple limb-conservation procedures required, including amputations of portions of his right index and middle finger, as well as the distal portion of the left middle finger. He also had transphalangeal amputation of the left hallux and open transmetatarsal amputation of left toes two through five. During inpatient admissions, his pain was managed using combinations of varied opioid and non-opioid medications. For opioids, he initially received oxycodone 7.5mg five times daily plus oxycodone 5mg four times which was effective for five admissions. He then had to be rotated to tramadol 50mg every 12 hours for one admission and finally onto hydromorphone up to 2mg every four hours as needed. Depending on the pain severity, he received additional pain medications, including gabapentin 300mg three times daily or pregabalin 50mg three times a week, diclofenac 1% gel four times daily, and/or topical lidocaine patches daily as needed. He received diazepam 2 mg daily as needed and trazodone 50mg nightly for anxiety and insomnia. He is currently taking hydromorphone 6mg every 6 hours as needed and mirtazapine 15mg nightly for insomnia. He reported good pain relief on a follow up appointment four months after his last admission. He continued to live alone and was able to perform activities of daily living independently.
Results
Opioid choice can partly depend on renal function of patients who often have impaired GFR. Codeine and its main active metabolite morphine are renally excreted and accumulate over time in patients undergoing hemodialysis.⁸ Morphine metabolites can accumulate in renally impaired patients and can cause respiratory depression and seizures.^8,9 Although its metabolite can be dialyzed, it’s slow to diffuse from CNS to circulation. Hydrocodone and its metabolites can accumulate in renal failure.⁹ Meperidine metabolites can accumulate during renal failure and cause seizures. Because of these characteristics, they are not recommended for use if a patient develops ESRD.
The three opioids our patient has used are tramadol, oxycodone and hydromorphone. Tramadol is used frequently in CKD patients as it’s not nephrotoxic. Although its metabolite is renally excreted, it can be used in lower doses even in patients undergoing dialysis.¹⁰ It should be noted that it can cause serotonin syndrome when combined with other serotonergic agents such as SSRI.¹¹ Oxycodone is dialyzable based on the fact it’s hydrophilic; Studies show plasma oxycodone and noroxycodone concentration decrease during dialysis.¹² Hydromorphone is also hydrophilic but its metabolite 3-glucuronide metabolite can accumulate in dialysis. ^8,9 It is still recommended that dosage be adjusted/reduced when using tramadol, oxycodone and hydromorphone in ESRD.^9-11
Other opioids to consider using in renally impaired patients are methadone, fentanyl and buprenorphine. Methadone can be safely used in ESRD patients as the parent compound and its metabolites are excreted through the GI system.^8,9 Fentanyl is interesting in that its metabolites are inactive and the parent compound maybe adsorbed onto the dialysis filter itself.⁸ Buprenorphine is excreted through the liver.¹³ It also appears buprenorphine does not accumulate in ESRD.¹⁴ Furthermore, it’s not removed by dialysis so redosing is not necessary post dialysis. Currently, opinions are divided whether methadone dose needs to be adjusted in ESRD.⁸ However, buprenorphine and fentanyl appear to not need dose adjustment with studies demonstrating safety in high doses up to 70mcg/hour for buprenorphine and 500mcg/hour for fentanyl in ESRD.^14,15
Conclusions
Although literature shows promise with disease-modifying medications such as calcitonin and sodium thiosulfate, our patient continued to experience calciphylaxis episodes with severe pain. It is thought that the pain in calciphylaxis is of neurogenic origin with nerve inflammation.^16,17 Our patient found temporary relief with gabapentin and pregabalin. Complications of opioids in the setting of renal impairment include hyperactive delirium. Benzodiazepines are used for treatment of agitation, delirium and briefly for sleep disturbances.⁹ Though oral NSAIDS are contraindicated in renal dysfunction, topical NSAIDs can be used due to limited systemic absorption. Diclofenac 1% gel had 5-17 fold lower systemic exposure than oral tablets.¹⁸
Our patient’s pain was treated using combinations of non-opioids and opioids during his 8 inpatient hospitalizations spanning 2 years. His pain was eventually controlled with hydromorphone alone. It is possible that oxycodone and tramadol were very effective but he developed tolerance to them. In the future, he can rotate opioids, especially methadone and buprenorphine. Our patient’s pain episodes are frequently accompanied by PAD which also causes ischemia evidenced by low transcutaneous oxygen tension. The ischemia causes poor wound healing which further exacerbates pain. Further studies may be needed to understand the association between PAD and calciphylaxis.