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

For other opiates, e.g., morphine, propoxyphene, and meperidine rely heavily on kidney function to efficiently excrete their metabolites. In the context of renal dysfunction, accumulation of active metabolites is likely to present the greatest concern regarding toxicity. Thus, the accumulation of morphine-6-glucu-ronide (from morphine) can contribute significantly to excess sedation¹⁹; norm-eperidine (from meperidine) can lead to central nervous system neurotoxicity, predisposing patients to seizure and delirium; and N-desmethylpropoxyphene (along with its parent compound propoxy-phene) increase the risk of cardiotoxicity, seizures and ataxia.

“Fentanyl is a very potent opiate that is highly protein bound; less than 10% undergoes renal excretion unchanged... Thus, in the context of RI, fentanyl does not, therefore, present significant challenges in terms of accumulation and potential toxicity.”

By contrast, agents such as buprenorphine and methadone appear to be safe in patients with ESRD. Metabolites of buprenophine include norbuprenophine and buprenorphine-3-glucuronide; both of which are analgesically far less active. While both metabolites can accumulate in the renally-impaired patient, pharmacokinetics of buprenorphine are un-changed.²⁰ Specifically, serum concentrations of bupenorphine and norbu-prenorhpine did not differ significantly before and after dialysis treatment in patients administered trasndermal buprenorphine.²¹ One limitation to the use of buprenorphine, however, is that because of its partal mu opiate receptor agonist effects, there is an analgesic ceiling-effect. No further anal-gesic effects are appreciable beyond an optimal dosing, perhaps limiting its utility for some patients.

Methadone is metabolized to a pyrrolidine and then to a pyrroline, both of which may be hydroxylated and renally cleared. Normally, 20-50% of methadone is excreted in urine as methadone or its metabolites, while an additional 10-45% is excreted in the feces as a pyrroline metabolite. In the context of RI, the amount of metabolites excreted through fecal elimination increases so as to maintain serum levels in normal (i.e., in the absence of renal dysfunction) levels. It is noteworthy however, that methadone has been increasingly associated with death related to respiratory depression and cardiac arrhythmias, prompting an FDA health advisory endorsing conservative prescribing strategies.²² Because of the potential for life-threatening complications, it may be prudent to initiate pharmacotherapy with methadone at low doses, with slow, gradual increases as necessitated by analgesic requirements or until side effects supervene.

Fentanyl is a very potent opiate that is highly protein bound; less than 10% undergoes renal excretion unchanged. Although it is extensively hepatically metabolized, its metabolites are inactive. Thus, in the context of RI, fentanyl does not, therefore, present significant challenges in terms of accumulation and potential toxicity. It is noteworthy that hepatic metabolism of fentanyl may be modified in the context of extremes of uremia, i.e., when BUN levels are two or more times normal. In such cases, the initial fentanyl dose may need to be reduced by one-half to one-third.

Tramadol is a weak analgesic, with a low binding affinity for the µ-opiate receptor. It is unique in that in addition to its opiate effects, tramadol may contribute to analgesia by inhibiting re-uptake of serotonin (5-HT) and norepinephrine (NE) influencing descending pain inhibition. Tramadol is hepatically metabolized, leading to production of N- and O-desmethyl tramadol. Only the O-desmethyl variant is pharmacologically active, possessing 6 times the potency of the parent compound. Both tramadol (30%) and the active metabolite (60%) are dependent on renal clearance. Therefore, renal impairment decreases the extent of clearance. The levels of the O-desmethyl metabolite increase 20-40% in patients with increased severity of renal dysfunction. The medication is not suggested for use in patients with severe renal dysfunction (CLcr < 30 ml/min), but for patients with milder degrees of RI, lower doses and longer intervals between doses may be sufficient to allow for pain relief without producing adverse effects.²³ Seizures and respiratory depression have rarely been described in CKD patients; to avoid potential toxicity, doses of tramadol should not exceed 200 mg/day for patients with GFR less than 30 ml/min.²⁴ It is important to note that uremia can likewise lower the seizure threshold, thus, in the case of uremic patients treated with tramadol, the risk of seizure may be increased.¹⁷

Acetaminophen, NSAIDs & COX-2-Inhibitors.NSAIDs are to be used cautiously in patients with chronic kidney disease. Their use can be associated with acute renal failure (particularly with ketorolac and indomethacin), interstitial nephritis (particularly with ibuprofen and naproxen), and volume overload and worsening hypertension (secondary to sodium retention as a result of antagonism of prostaglandin influences on sodium excretion). Selective cyclo-oxygenase inhibitors do not appear to afford any benefits over nonselective NSAIDs in terms of their influence on renal vasoconstriction and resultant reductions in GFR. In low doses, aspirin does not produce renal dysfunction in patients with chronic kidney disease, however, at higher doses, e.g., above 325 mg daily, it can like the NSAIDs reduce renal the GFR and contribute to reduced renal function.

Alternatives to NSAIDs include acetaminophen and nonacetylated salicylates. Acetaminophen is effective for mild pain. However, its utility in inflammatory pain is limited because it is a weak inhibitor of both COX-1 and COX-2. It is metabolized in the liver and does not require dose adjustment in CKD. As such, the National Kidney Foundation recommends acetaminophen as the non-narcotic analgesic of choice for patients with CKD.²⁵

Antidepressants. Several meta-analyses and evidence-based reviews suggest that antidepressants are useful in mitigating pain associated with neuropathy, headache, and fibromyalgia, among other conditions.²⁶⁻²⁹ The pain-mitigating effects of antidepressants appear to be independent of the influences on mood and are thought to be primarily mediated by enhancing the inhibitory neurotransmitters (e.g., noradrenergic (NE) and serotonergic (5-HT) present within supra-spinal descending pain-mediating pathways.³⁰ The literature has focused extensively on the utility of the tricyclic antidepressants (TCAs) and more recently, the serotonin and norepinephrine re-uptake inhibitors (SNRIs), i.e., venlafaxine and duloxetine. Duloxetine is the only antidepressant which has received Food and Drug Administration (FDA) approval for treatment of diabetic neuropathy.

The greatest experience with antidepressants in renal disease has involved TCAs. Virtually, all antidepressants may be safely employed among patients with renal disease, as these agents are predominantly metabolized in the liver.31,32 However, many of the hepatic metabolites rely on renal clearance (see Table 2). Thus, in the context of RI, accumulation of the metabolites of several of the TCAs is associated with numerous adverse effects including sedation, anticholinergic effects, and orthostasis which can limit their usefulness.

As regards the SNRIs, the half-life of venlafaxine is increased among patients with renal dysfunction, requiring that doses be reduced by over 50% among patients administered this agent. No data has accumulated regarding use of duloxetine in moderate-to-severe renal insufficiency. Metabolites of duloxetine rely on renal excretion and can accumulate in severe RI. The manufacturer does not recommend duloxetine for patients with severe renal impairment, i.e., < 30ml/ min, or who are dialysis-dependent.

The selective serotonin re-uptake inhibitors (SSRIs) have likewise been safely employed in patients with renal disease. However, as a class the SSRIs have not been demonstrated to be as consistently analgesic as the TCAs or SNRIs.27,33 One SSRI, paroxetine can accumulate in RI; its dosing should be reduced in moderate-to-severe RI.

Anticonvulsants. Anticonvulsants (ACDs) have efficacy in mitigating neuropathic pain, including trigeminal neuralgia and phantom limb pain, as well as migraine.²⁷˒³⁴˒³⁵ Carbamazepine is FDA approved for the treatment of trigeminal neuralgia; gabapentin, for treatment of postherpetic neuralgia; pregabalin, for postherpetic neuralgia and diabetic neuropathy and more recently, fibromyalgia; and divalproex sodium and topiramate have both been indicated for migraine prophylaxis. Emerging evidence suggests the potential analgesic roles of newer ACDs, e.g., lamotrigine, oxcarbazepine, and tiagabine.²⁷˒³⁵ Although these agents demonstrate some promise with regard to mitigating neuropathic states, their substantive and comparative analgesic utility requires further investigation. Adverse effects common to ACDs include sedation, fatigue, gastrointestinal ,and motor side effects (tremor, ataxia, and nystagmus). Rash and Stevens-Johnson syndrome are possible with carbamazepine and lamotrogine.

For certain ACDs, e.g., carbamazepine and valproic acid, the kidneys have a negligible role in the clearance of the drug.³⁶ However, being an acidic agent, valproate is highly bound to albumin. In RI, hypoalbuminemia may result in increased unbounded (active) serum levels. In such cases, free drug levels should be monitored to avoid untoward effects. Dosing may need to be lowered so as to avoid excessive/toxic levels. By contrast, for gabapentin, pregabalin, topiramate and oxcarbazepine, there is significant reliance on renal clearance necessitating dose adjustments in the setting of RI³⁶ (see Table 3).

Both gabapentin and pregabalin are devoid of significant protein binding and have no active metabolites. Neither agent requires hepatic metabolism and both are freely filtered at the glomerulus, i.e., with 80% of gabapentin and 90% of pregabalin doses excreted in urine. Impaired renal functioning, therefore, produces significant reductions in drug clearance and leads to higher plasma concentrations and a substantially longer half-life of either drug. Dose adjustments are required in patients with RI, otherwise adverse effects, e.g., somnolence, ataxia, tremor and nystagmus, are likely to occur. Adverse effects of pregabalin can include peripheral edema, especially when combined with thiazolidinediones.³⁷ Caution is advised for its use in patients with congestive heart failure and may be particularly problematic in patients with underlying RI.

Topiramate is unique in that its dependence on renal clearance is dependent upon whether it is administered as monotherapy or in conjunction with other agents. Topiramate undergoes extensive renal clearance (approximately 80% clearance), and as with gabapentin and pregabalin, plasma concentrations increase significantly in patients with RI. If used as neuropathic pain or migraine related monotherapy, dose adjustments appear to be warranted when topiramate is employed in patients with compromised renal function. However, the renal clearance of topiramate is reduced when it is co-administered with other anticonvulsants. For example, when co-administered with carbamazepine, the latter agent will induce hepatic metabolism of the topiramate.³⁸ Less of the topiramate clearance therefore is reliant upon intact renal function in such circumstances, e.g., only 40% is excreted in urine unchanged. Hence, in the context of co-administration of topiramate with other anticonvulsants, e.g., carbamazepine, less of a dose reduction in renal failure is required.

Unlike its a structural variant of carbamazepine, oxcarbazepine and its active metabolites are extensively reliant on renal clearance. As a result, dose adjustment is required for patients with severe RI and kidney failure.

The pharmacokinetics of lamotrigine, e.g., volume of distribution and peak concentration, are unchanged in renal dysfunction. However, data is limited as to pharmacokinetic changes and half-life in patients with severe renal dysfunction, i.e., GFR < 15 ml/min. As such, caution is advised, and lower doses recommended in this population.

Several ACDs have been associated with electrolyte disturbances and potential renal toxicities that can potentially complicate their use in patients with RI. For example, hyponatremia has been associated with carbamazepine, oxcarbazepine and to a lesser extent, valproic acid use. Valproic acid has rarely, although potentially, been associated with tubulo-interstitial nephritis while topiramate has been linked with the development of kidney stones.

Dopamine Agonists. Dopamine agonists, e.g., levodopa, pramipexole, ropinirole, have been advocated for the treatment of restless legs syndrome. However, seldom have long-term safety and efficacy studies been conducted among uremic patients.9 At present, it does not appear that doses of levodopa or ropinirole need to be reduced in the context of kidney disease. However, for pramipexole, doses should not exceed 0.75 mg daily among patients requiring dialysis, but the optimum dose requirements and dose restrictions in the context of kidney disease and dialysis have, as yet, to be determined systematically.

Dialysis Dependent Patients

Dialysis methods in current use include hemodialysis, peritoneal dialysis and continuous replacement therapy. Unfortunately, little is known from systematic study about drug removal by peritoneal dialysis and continuous replacement therapy. During hemodialysis, a drug is more likely to be removed if it is water-soluble, has a low molecular weight and has a low plasma protein binding value.³⁹ Analgesics, or their metabolites, that are highly fat-soluble (lipophilic), or which are highly protein bound are not effectively removed by dialysis could theoretically accumulate in the body to extremely high levels. These agents will require dose restriction, if they are to be used at all. By contrast, other agents that are water-soluble, or which have glucuronide and polar metabolites, are effectively removed by hemodialysis. In such cases, supplemental medication dosing are likely to be required post-dialysis. Common anal-gesic medication dosing guidelines for hemodialysis-dependent patients are shown in Table 4.

During a dialysis session, the equilibrium in drug concentration between the systemic circulation and the periphery is disrupted, so that there may be an initial lowering of the plasma drug level, followed by a rebound rise after dialysis as the drug redistributes from the periphery to the circulation.¹⁸ This phenomenon has been reported with valproic acid, for example. In addition, dialysis patients experience significant fluid shifts and frequently become dehydrated. Immedately post-dialysis, patients commonly experience hypotension, especially orth-ostasis. Various analgesic and co-analgesic agents with significant orthostatic side effects, e.g., TCAs, may be intolerable, and therefore, should be avoided in dialysis patients.

Recommended Analgesic Medication Options in RI

Pain management strategies, e.g., the World Health Organization Analgesic Ladder, have been advocated for patients with malignant pain, and increasingly utilized to assist in the management of chronic non-malignant pain. However, the utility and efficacy of the WHO Ladder in the treatment of pain among patients with end-stage renal disease has only recently been empirically evaluated in a small, prospective study of hemodialysis patients. Adjusting medication selection and dosing based upon type of pain (neuropathic versus nociceptive) and pain severity, it was possible to effectively reduce pain in 96% of patients.⁴² More extensive and longer-term investigations into the utility of the WHO Ladder in patients with RI appear warranted.

Some elements of the WHO Ladder may be inappropriate when one considers the implications of co-existing renal dysfunction in patients with multiple medical conditions. Careful attention to analgesic selection, dosing and dose titration in patients with renal impairment and end-stage renal disease can help avoid adverse drug events, which are commonly seen in these populations.

Summary

The following general guidelines summarize pain management strategies for patients with renal insufficiency:

Mild Pain

• Use acetaminophen for mild pain.

• For inflammatory pain, nonacetylated salicylates are advocated. If NSAIDs are invoked under such circumstances, their use should be restricted to only brief periods.

Moderate Pain

• Use of tramadol, oxycodone, hydrocodone are reasonable options. However, these agents require prolonged dosing intervals, greater than those normally employed for the non-renal compromised patient, to avoid accumulation and potential for adverse drug effects.

• Avoid codeine and propoxyphene use.

Severe Pain

• Use of buprenorphine, fentanyl and methadone appear to be safest in the patient with renal compromise, although the clinician should bear in mind that fentanyl dosing may need to be reduced in extremes of uremia

• Use of other opiate analgesics, e.g., oxycodone and hydromorphone may require prolonged dosing intervals.

• Avoid use of meperidine and morphine. However, morphine may be acceptable for short term use, e.g., acute pain, but with protracted use, may result in accumulation of metabolites which can be problematic.

Other issues

• Antidepressants may be easier to invoke in the treatment of neuropathic pain. The tolerability of TCAs may be limiting. Dose adjustments of venlafaxine and duloxetine may be required in RI.

• Anticonvulsants such as gabapentin and pregabalin require dose restrictions in neuropathy; other alternatives, e.g., carbamazepine and lamotrigine, may be viable alternatives, particularly if antidepressants are poorly tolerated and/or ineffective.

• Levodopa or ropinirole are safe dopamine agonists to employ in the treatment of restless legs syndrome associated with RI. n