Dialysis, Opioids, and Pain Management: Where’s the Evidence?
According to the 2010 U.S. Census report, life expectancy continues to increase, and those 65 years and older appear to be the greatest beneficiaries of this increased life expectancy, with growth in this group predicted to nearly double by 2030.1 Treating this growing elderly population presents many challenges. For example, the incidence of chronic kidney disease (CKD) in people ≥65 years old more than doubled from 2000 to 2008, and end-stage renal disease (ESRD) grew by 600% from 1980 to 2009.2 Mortality rates among patients with ESRD and dialysis peaked in 2001; since then, mortality rates in these patient groups have declined, with the rate among patients undergoing dialysis decreasing to early 1980s numbers.2 Increased survival for ESRD and dialysis patients requires a paradigm shift in the treatment approach of many difficult but common comorbid disease states that threaten their quality of life, in particular chronic pain.
A decade ago, it was found that 50% of long-term dialysis patients reported suffering from chronic pain.3 Musculoskeletal pain is the most common type of pain reported, but neuropathy and peripheral vascular pain also is quite common.3,4 Approximately 75% of patients on dialysis describe their pain management as inadequate, with 55% reporting a severe pain episode during the last 24 hours.3
Unfortunately, there is an absence of pain management recommendations for dialysis patients. There are no published clinical practice guidelines addressing medications for chronic pain specifically for patients with ESRD or requiring dialysis. Nephrologists often are forced to address analgesic needs for their patients with ESRD or dialysis because primary care providers often feel uncomfortable prescribing analgesics and other therapies in this specialized population. This has become a catch-22, because neither provider is an expert at pain management. Likewise, certified pain clinicians who focus on interventional therapy often feel equally inadequate prescribing medications to this unique population.
In our experience, most ESRD patients seek analgesic help from their nephrologist who they may see several times per week compared to a primary care provider who they may see once or twice a year. Experts and pain societies acknowledge this deficiency, but point out that even if they were to assemble an expert panel to review the evidence, the dearth of quality studies would leave them with nothing to review.
The purpose of this commentary is to suggest adaptation of current guidelines, address common misconceptions, highlight deficient areas for research, and capitalize on available scientific evidence to promote a practical approach that can maximize therapeutic outcomes while maintaining safety in this vulnerable population.
Pain patients suffering from chronic conditions can be notoriously persistent and demand that prescribers intervene.5,6 Considering the pitfalls of nonsteroidal anti-inflammatory drug (NSAID) therapy for a CKD patient in whom comorbid conditions are expected, providers often feel enormous pressure to prescribe opioids to alleviate suffering. Unfortunately, time constraints and patient demands likely contribute to practitioners ignoring certain minimum recommended standards from published pain guidelines, which can be disastrous. At a minimum, providers should perform a combined physical and pain assessment, attempting to determine the cause and mechanism of the patient’s pain complaint (neuropathic or musculoskeletal) to guide therapy.
It also is crucial to obtain a patient’s previous medical history to identify a history of substance abuse, serious mental illness, previous medication trials, documented pharmacy records from all sources, and/or an established pain care plan, if it exists. Any of these considerations can impact a provider’s decision to initiate medication management. Prior to issuing a prescription for opioids, providers need to explain to patients appropriate expectations and risk versus potential benefit, as well as discuss the goals of care.7,8
In clinical practice, it often is presumed that increased half-life of opioids in dialysis patients translates into increased analgesia or, in other words, “short-acting agents become long-acting” in this setting. This idea has become so pervasive that, in the authors’ experience, it is rare to see an extended-release opioid prescribed to dialysis patients. However, there is not a shred of scientific evidence on which to base this presumption. The half-life referenced here is elimination half-life, which is increased because of the body’s inability to excrete the more hydrophilic metabolized drug products that accumulate with renal dysfunction and failure. In most cases, however, the metabolites that have accumulated are inactive and no longer contribute to analgesia or toxicity in any meaningful way.9
Only delayed hepatic metabolism of the active parent drug, theoretically, would lead to increased duration of action for opioid analgesics, which appears only marginally increased in dialysis patients.9-11 While studies have shown that there is a marginal delay of hepatic metabolism in dialysis patients, mostly affecting cytochrome P 450 (CYP450) metabolism, it is unclear if this is some compensatory mechanism to divert drug metabolism to an unobstructed pathway (similar to methadone in dialysis patients) or whether this may have any tangible effect on duration of analgesia. Clearly, this is an area where additional studies would be useful in guiding appropriate drug therapy.
Recently, debates surrounding the use of opioids for chronic noncancer pain have highlighted research indicating correlations between morphine equivalent daily dose (MEDD) and adverse outcomes.12-15 Although, there is a strong correlation between daily dose and adverse outcomes, it is plausible that patients requiring higher doses are sicker to begin with and that they had shorter lifespans due to chronic disease(s), regardless of the MEDD. Therefore, the exact cut-off, or threshold, where this risk is significantly increased is not yet clear.16 In fact, even if there was expert consensus on what constitutes a MEDD, it still does not account for polymorphic variations in metabolism (which affect metabolite concentrations), drug-drug or drug-disease interactions, and various pharmacokinetic patient variables.