Erica Wegrzyn, PharmD

Recently we have received an increasing number of requests for consults on patients undergoing hemodialysis (HD) or with end-stage renal disease (ESRD). This presented an excellent opportunity for our Pharmacy Pain team to review a recent editorial in the Journal of Pain Research entitled “Pharmacotherapeutic Considerations for Chronic Pain in Chronic Kidney and End-Stage Renal Disease.”

 Complicating therapeutic selection is the lack of evidence-based consensus guidelines, the need for universal precautions, and the essential risk mitigation. 

The challenges inherent in treating patients with chronic pain increase exponentially when those patients also have ESRD or are on HD. Alterations in kidney function can affect far more than what is measured by estimated glomerular filtration rate (EGFR) and creatinine clearance (CrCl), including the common pharmacokinetic variables associated with medication use: absorption, distribution, metabolism, and elimination (ADME). Two goals to consider when treating patients with renal impairment are avoiding accumulation or drug toxicity and maintaining therapeutic effect. When an HD machine becomes part of the equation, selecting drugs and timing their doses wisely around HD can help to accomplish these goals. Providers should use clinical judgement and refer to evidence-based guidelines to facilitate decision making and guide pharmacotherapeutic choices, except in prohibitive cases when there are no evidence-based guidelines.

Despite the fact that up to 92% of patients with HD may suffer from chronic pain and that approximately 75% report inadequate pain management, there is no consensus—no universally accepted guidelines&mdash;on the best way to manage their pain. Then what? This is where the art of medicine meets the science of medicine. To date, there are no universally accepted guidelines for pain management in patients with HD. The onus falls on individual providers to analyze the literature, know the individual patient and choose prudently from the wide armamentarium. This requires a multifaceted approach that considers far more than just EGFR or CrCl. 

When choosing pharmacotherapy or dose-adjusting for a patient with renal impairment, it is often assumed that renal function (normally quantified by CrCl or EGFR) is the best and only way to inform the decision. Based on the far-reaching impact of kidney impairment, there is more to the story than what can be told by CrCl and EGFR. As pre- viously described, renal impairment impacts the ADME of medications. Elimination is even further convoluted by HD because certain drugs are more easily cleared via dialysis than others. Drugs that are least likely to be removed via dialysis are those with higher molecular weight, high volume of distribution, poor water solubility, and extensive protein binding. Using medications that undergo hepatic phase 2 metabolism and yield inactive metabolites can circumvent some of the issues inherent in decreased kidney function.

In addition to challenges associated with initiating a pharmacotherapeutic pain regimen, some providers will “inherit” patients who are already on a pain management regimen. These providers are then faced with the challenge of optimizing the regimen that they have inherited and mitigating the risk to the patient. One unique area of concern for patients with ESRD or those on HD who are anuric is therapeutic opioid drug monitoring via urine drug screens (UDS), particularly in patients who are on chronic opioid therapy. When a patient does not produce urine, a UDS, obviously, cannot be performed. In these situations, serum monitoring can and should take its place. The utility of such monitoring extends beyond identifying adherence issues and aberrant behavior, although it helps with those things, too. Routine therapeutic monitoring can provide insight on how a patient is metabolizing the medications and possibly help to identify genetic polymorphisms.

In the case of opioid therapy for patients with chronic pain who have ESRD or are on HD, concerns regarding ADME potentially increase their risk for an accidental overdose or life-threatening respiratory depression. This risk can be estimated using the Risk Index for Overdose or Serious Opioid-Induced Respiratory Depression (RIOSORD).

 In the study that developed this tool, impaired drug metabolism and excretion were identified as 2 of the 15 variables most highly associated with overdose or serious opioid-induced respiratory depression (OIRD) and chronic kidney disease with significant renal impairment is one of the risk factors listed in the risk index. Appropriate application of this tool can help mitigate the risk of those patients who have higher RIOSORD scores and therefore have a higher risk for opioid induced respiratory depression (OIRD), by arming them with a take-home naloxone kit and providing extensive counseling to family members and caregivers—as well as patients. 

Naloxotel is an automated software tool that predicts percent risk of OIRD using the validated RIOSORD, elevates those risks based on drug interactions, and provides a comprehensive note for pharmacy or medical records, with an automated prior authorization for third-party payers. Reducing chronic pain can lead to improved dialysis adherence and greatly improved quality of life for patients with ESRD and HD. 

Providers should not be frightened by the lack of evidence-based guidelines or inability to monitor in anuric patients and should engage the expertise of pharmacists. We are uniquely trained to apply therapeutic knowledge based on rational assessment of pharmacology and pharmacokinetics for each individual drug prescribed to the individual patient and to customize a pharmacotherapeutic pain regimen to assist prescribing clinicians. 

This commentary was collaboratively written with Amelia Persico and Dr. Erica Wegrzyn. This article is the sole work of the authors and stated opinions/assertions do not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies listed. ​

Dr. Jeff Fudin graduated from Albany College of Pharmacy and Health Sciences with a bachelor’s degree and PharmD. He is a diplomate to the American Academy of Pain Management, a fellow to the American College of Clinical Pharmacy and the American Society of Health-System Pharmacists and a member of several other professional organizations. He is president and director of scientific and clinical affairs at Remitigate, LLC (remitigate.com), a software platform for interpreting urine drug screens (Urintel) and predicted opioid-induced respiratory depression (Naloxotel). Dr. Fudin is a section editor for Pain Medicine and serves on the editorial board for Practical Pain Management. He practices as a clinical pharmacy specialist (WOC) and director of PGY-2 pharmacy pain residency program at the Stratton Veterans Administration Medical Center in Albany, NY. He is an adjunct associate professor of pharmacy practice at Western New England University College of Pharmacy and Albany College of Pharmacy and Health Sciences. 

Amelia L. Persico, MBA, is a 2017 doctor of pharmacy candidate at Albany College of Pharmacy and Health Sciences. Amelia received her MBA with a focus on health care management at Union Graduate College in Schenectady, NY in 2106. Amelia’s professional interests include geriatrics, community pharmacy and health care operations management. 

Dr. Erica Wegrzyn is currently completing a PGY-2 pain and palliative care residency at the Stratton VA Medical Center, Albany, NY. Dr. Wegrzyn received her PharmD from Western New England University College of Pharmacy, Spring eld, MA, and completed a PGY-1 residency at Maine General Medical Center, Augusta, ME. Prior to completing her PharmD, Dr. Wegrzyn also received her bachelors’ degrees in biochemistry and music (trombone) from Ithaca College. 

Mathew RO, Bettinger JJ, Wegrzyn EL, Fudin J. Pharmacotherapeutic consid- erations for chronic pain in chronic kidney and end-stage renal disease. J Pain Res. 2016;9:1191-1195.

Atkinson TJ, Fudin J, Wegrzyn EL, Bettinger JJ. Dialysis, opioids, and pain management: where’s the evidence? Pract Pain Manag. 2014;14(8):49-57.

Murtagh FE, Chai MO, Donohoe P, Edmonds PM, Higginson IJ. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. J Pain Palliat Care Pharmacother. 2007;21(2):5-16.

Hammett-Stabler CA, Webster LR. A clinical guide to urine drug testing: augmenting pain management & enhancing patient care. Jeffrey Fudin website. paindr.com/wp-content/uploads/2012/06/A-Clinical-Guide-to-URINE-DRUG- TESTING.pdf. Published May 2008. Accessed January 31, 2017.

Zedler B, Xie L, Wang L, et al. Development of a risk index for serious prescription opioid-induced respiratory depression or overdose in veterans’ health administration patients. Pain Med. 2015. 16(8):1566-1579. doi: 10.1111/ pme.12777

Raouf M, Atkinson TJ, Crumb MW, Fudin J. Rational dosing of gabapentin and pregabalin in chronic kidney disease. J Pain Res. 2017;1:275-277. doi: 10.2147/JPR.S130942. 

Articles

Recently we have received an increasing number of requests for consults on patients undergoing hemodialysis (HD) or with end-stage renal disease (ESRD).  
