Pain Management in a Patient with Renal and Hepatic Dysfunction

Introduction

Inpatient palliative medicine consultation services are often asked to provide symptom management for end-of-life patients. This commonly involves pain relief with the use of opioid analgesics. The patients involved have various clinical conditions that mandate individualization of therapeutic options. Recognition of these situations helps determine appropriate use of medications to enhance symptom relief and minimize side effects and complications. One of the most challenging situations is to safely manage pain control in a patient with concurrent renal and hepatic dysfunction. In recognition of the goal of good end-of-life symptom management, the challenges of balancing pain relief and potential opioid adverse effects must be considered.

Case

A 64-year-old woman was admitted for malaise and abdominal pain. She had recently been diagnosed with adenocarcinoma of the pancreas with liver metastasis. She had undergone an endoscopic retrograde cholangiopancreatography (ERCP) with an unsuccessful attempt at biliary stent placement for symptom relief. On admission, her blood urea nitrogen (BUN) was 93 mg/dL (8–24 mg/dL) and corresponding creatinine was 3.10 mg/dL (0.7–1.5 mg/dL). Her liver functions were also grossly abnormal with alkaline phosphatase of 968 IU/L (38–126 IU/L), serum glutamic-oxaloacetic transaminase (SGOT) of 183 IU/L (5–40 IU/L), serum glutamic-pyruvic transaminase (SGPT) of 114 IU/L (6–60 IU/L), albumin of 1.5 g/dL (3.2–5 g/dL), total bilirubin of 36.6 mg/dL (0.2–1.4 mg/dL), and an international normalized ratio (INR) of 13.91 (nonanticoagulated patient is usually <1.5). Clinically, it was not entirely clear how much the elevated liver function tests (LFTs) were due to hepatic metastasis versus biliary obstruction. Physical examination revealed significant skin and scleral icterus, muscle wasting, and right upper quadrant abdominal pain. After 3 hospital days with no symptom improvement and worsening renal function (BUN of 110 and creatinine of 4.00), a palliative medicine consultation was requested for symptom relief recommendations. The patient and her family asked that the goals of care be transitioned from active treatment to comfort care, with the primary goal being relief of her abdominal pain. The patient was opioid naïve and had used over-the-counter (OTC) medications and prescription nonsteroidal anti-inflammatory drugs (NSAIDs) prior to her hospitalization. Due to her heavy symptom burden, the use of prescription analgesics was decided upon by the medical team. Our goal was to optimize pain management with an eventual outpatient medication plan that excluded intravenous medications, and at the same time, decreased pill burden. After consultations with the patient's medical oncologist and the hospital pharmacist, we elected to start the patient on methadone elixir 2.5 mg twice daily. Methadone's safety profile in renal dysfunction, its long half-life, and the ability to administer it orally made it a strong option for pain management in this patient. While recognizing the need for careful monitoring when using methadone in patients with severe liver dysfunction, this medication was believed to be the best option for end-of-life care in this specific patient. The low dose and twice-daily administration of methadone were chosen to minimize adverse effects with a plan for slow titration. A baseline electrocardiogram (EKG) was also performed before initiation, displaying a normal QT interval. The patient's subjective evaluation of her pain score dropped from a 7/10 to a 3/10 after only two doses. She died peacefully in the hospital after 72 hours with no escalation of pain and no need for breakthrough analgesics. No further lab testing was performed after initiation of the methadone treatment.

Discussion

Palliative medicine consultation services are frequently asked to provide recommendations for symptom management, often in end-of-life situations. Patients with concurrent renal and hepatic dysfunction are becoming more common, and it is important for providers to carefully select and dose opioids to provide optimal patient care and safety.

There is an ample amount of pharmacokinetic information regarding opioids and their dependence on the hepatic and renal system. Medical literature supporting pain management with renal insufficiency is readily available, although it predominantly focuses on a few select opioids. Hepatic influence on opioid metabolism is often complicated as the liver's metabolic capacity may be altered by hepatic blood flow, plasma protein binding, and extrahepatic metabolism. Recommendations specific to the degree of hepatic insufficiency are not common in drug information sources. Unfortunately, there is a paucity of randomized controlled trials or clinical outcomes research studying specific analgesics in patients with concurrent renal and hepatic dysfunction.

One of the limitations of this study is that many available treatment recommendations are empiric or extrapolated based on pharmacokinetics or case studies. With such a medically complicated patient, it is difficult to know if the patient's elevated liver enzymes were due to liver failure or the hepatocellular mass. Due to the numerous mechanisms the liver utilizes for opioid biotransformation and elimination, it was difficult to predict what the impact would be regarding pharmacokinetics and opioid metabolism and how the patient would respond to other analgesics. Due to the lack of further laboratory testing and short treatment time, conclusions regarding safety and adverse events with this patient's methadone treatment were limited.

A search of the medical literature provides information and accompanying recommendations about the use of opioids in end-stage renal or end-stage liver disease, but limited literature exists regarding recommendations for patients with these concomitant conditions. However, as our population ages and comorbidities become more commonplace, patients with both significant renal and hepatic dysfunction will present more frequently. Our medical community will continue to depend on clinical evidence either promoting the safety of an opioid or reporting common adverse events to build strong clinical recommendations. Ideally, with enough research guidelines, it may be possible to help suggest dosing, especially in our medically complicated patients.

Conclusion

The case described above demonstrates a relatively common problem facing palliative medicine providers. In the management of pain, the clinician must assess the duration, etiology, pathophysiology, and intensity of pain as well as address potential pharmacological options. As the role of palliative medicine continues to evolve, patients with medical comorbidities will frequently be the rule rather than the exception. Referring providers will expect quality pain and symptom management from palliative medicine consulting services. The available literature lacks recommendations for pain management in patients with concomitant renal and hepatic dysfunction. Much of the currently available medical literature is known from outside the United States. Unfortunately, clinicians must often rely on anecdotal evidence and their own experience when addressing complex pain issues in treating patients with multiple organ-system disease. ² This study is limited as it highlights only one patient case. The pharmacist often has in-depth training in the pathophysiology of drug metabolism and clearance and may be helpful in solving challenging complex medication management cases. Knowledge of the pharmacology of opioids and collaboration with a pharmacist can enhance patient care and minimize symptom burden. Individualization of therapy and further discussion of such treatment challenges will hopefully provide more specific recommendations in the future. Ongoing clinical research, along with anecdotal evidence, will be helpful to define which opioids can be most effective while minimizing adverse events.