Safe Analgesic Use in Patients With Renal Dysfunction
The ubiquity of chronic pain conditions and associated disability impair the quality of life of many patients, prompting initiatives to make pain management a priority. However, effective pain management can sometimes be undermined when clinicians are uncomfortable with treatment strategies for patients with significant medical comorbidities. Among these, clinicians are likely to be particularly unfamiliar with the appropriate use of analgesics and co-analgesic adjuvants in the treatment of patients with pain and co-existing renal insufficiency (RI), i.e., suboptimal renal function and end-stage renal disease (ESRD).
It is likely that clinicians will encounter pain management needs among patients with RI. Chronic kidney disease (CKD) is highly prevalent; estimated to affect over 19 million people in the United States.1 Based upon trends in the growth of the aging sector of the population, as well as rates of hypertension and diabetes mellitus, it is anticipated that rates of renal dysfunction in the general population will continue to rise.2 Elderly patients, i.e., those over age 65 years, constitute the majority of patients on dialysis and are the fastest growing cohort in end-stage renal disease.3
In addition, pain constitutes a significant symptom accompanying renal dysfunction interfering with adaptive functioning and quality of life. Patients with CKD are specifically at risk for pain, and available evidence suggests that such patients are especially vulnerable to ineffective pain management.4-7 A prospective chart review of dialysis patients revealed that 50% reported problems with pain.5 The most common pain complaints encountered suggested a musculoskeletal etiology, e.g., osteoarthritis, muscle cramps, inflammatory arthritis, and osteomyelitis. Metabolic bone disease accompanying renal dysfunction can produce pain associated with moderate-to-severe bone pain, e.g., carpal-tunnel syndrome, arthralgias, fractures, and bone cysts. Other common pain-related conditions were related to the dialysis procedure directly, peripheral vascular disease, trauma, or malignancy.5 Restless legs syndrome (RLS) contributed significantly to the morbidity of pre-dialysis CKD patients8 as well as among dialysis-dependent patients.9 Because of advanced age, many patients with CKD have other medical comorbidities that contribute to the experience of chronic pain, e.g., diabetes mellitus, giving rise to kidney disease, can likewise predispose patients to painful polyneuropathies.
Both the co-occurrence of pain and renal disorders and the trend toward increasing rates of RI in the general population invite the need for familiarity with the safety, pharmacokinetic profile, and efficacy of analgesics and adjuvants in individuals with RI. Unfortunately, the evidentiary base informing the selection, dosing, and monitoring of analgesic and co-analgesic adjuvant agents in RI is limited. There is a dearth of literature on effective analgesic use in patients with renal dysfunction. Additionally, studies of the use of such agents in patients with renal impairment are often confined to a few participants for each medication. Despite the lack of extensive empiric investigation, attempts are made in this paper to provide a pragmatic review of analgesic pharmacologic approaches in the context of RI.
Defining Renal Insufficiency
RI involves a functional loss of nephrons10; associated with the accumulation of waste products such as blood urea nitrogen (BUN) and creatinine in the body. Although serum levels will reflect this accumulation, they are poorly correlated with degree of renal dysfunction because of confounding variables such as rate of creatinine production from muscle tissue. The degree of RI is provided by the glomerular filtration rate (GFR), which is approximated by the creatinine clearance (Clcr). The latter value is best measured using a 24-hour urine collection but, where this is not feasible, the Clcr may be calculated using the Cockcroft-Gault equation11:
Clcr=[(140 – age) x (ideal body weight kg)] / 72 x serum creatinine level (mg/dL) For women, this value is multiplied by a correction factor of 0.85.
The Cockcroft-Gault formula may not be universally applicable. It becomes increasingly inaccurate at the extremes of weight and serum creatinine and in the setting of an unstable creatinine. Some patients (e.g., children, burn patients, or elderly patients with muscle wasting) may require the use of other formulas.12 Nephrology consultation is advised in these cases.
The National Kidney Foundation Kidney Disease Outcomes Quality Initiative13 has classified degree of renal dysfunction on the basis of diminished GFR. These categories include mild RI (60-89mL/minute/1.73m2), moderate RI (30-59mL/minute/ 1.73m2), severe RI (15-29mL/minute/1.73m2), and kidney failure (< 15mL/minute/1.73m2).
General Issues Related to Pharmacology in Renal Disease
The selection and dosing recommendations for many analgesics which follow are based upon the degree of RI as estimated by the GFR. RI can result in the accumulation of medications or their metabolites producing significant untoward effects. The renal excretion of a drug is a function of both the fraction of that drug that is normally removed by the kidneys and the degree of RI. For drugs cleared primarily by renal excretion (e.g., gabapentin and pregabalin), even a mild degree of renal insufficiency can be problematic if administered using conventional doses and schedules. Similarly, RI can delay the clearance of active metabolites of selected drugs, resulting in significant accumulations and potential adverse effects.12
Pharmacology in Renal Disease: Specific Agents Opioids.
Opioids have been the mainstay of treatment in moderate-to-severe acute pain states and terminal disorders, and have been increasingly employed in the management of chronic pain. Most opioids can be safely employed in RI, with a few precautions.14-17 The half-lives of several hydrophilic opiate analgesics, e.g., codeine, oxycodone, and hydromorphone, are prolonged in the context of renal dysfunction (see Table 1). Customary analgesic dosing can result in such prolongations and drug accumulation pre-disposing patients to significant adverse effects, including constipation, nausea, vomiting, excess sedation, pruritus, and respiratory depression. In extreme cases, narcosis can occur with resultant CNS depression, seizures, myoclonus, and delirium.14-17