Chronic Pain in End-Stage Renal Disease

Epidemiology and Etiology 

The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”1 Epidemiologic data of pain in ESRD are extremely limited; however, recent studies have shown that moderate to severe chronic pain is common in ESRD.2, 3, 4 The literature suggests that 37% to 50% of hemodialysis patients experience chronic pain and that for 82% of these patients pain is moderate to severe in intensity.2, 3, 4 Even in the last day of life, pain is present in 42% of patients withdrawing from dialysis.5

The etiology of pain may be from numerous causes. Pain may be caused by comorbidity, whereas dialysis sustains life, underlying systemic diseases, and painful syndromes such as ischemic limbs and neuropathies persist. Given the aging dialysis population and the increasing prevalence of comorbidites including diabetes and hypertension, it is not surprising that chronic pain is a particular problem for patients with ESRD. Pain, however, may also be caused by ESRD itself. There are numerous painful syndromes unique to ESRD such as calciphylaxis and renal osteodystrophy that may develop during a patient’s time on dialysis. Pain may be a result of the primary kidney disease itself (eg, polycystic kidney disease) or the result of the treatment of ESRD. Painful chronic infections such as osteomyelitis and discitis are complications from central lines, and arteriovenous fistulas can lead to painful ischemic neuropathies. Recurrent pain caused by needle insertion, muscle cramps, and headaches during dialysis treatments is perceived as chronic pain by some patients.2

Despite limited data, it appears that musculoskeletal pain is the most common of the chronic pain syndromes in ESRD, as in the general population.2 However, unlike the general population, musculoskeletal pain in ESRD is, on average, equal in severity to neuropathic and ischemic pain. A synergistic effect of hyperparathyroidism and osteoarthritis in the development of bone pain may contribute to the high prevalence and severity of musculoskeletal pain in this population. However, the relative roles of osteoarthritis and renal osteodystrophy in these chronic pain syndromes of ESRD patients are not clear. Given the diverse causes of pain in this population, it is not surprising that pain in dialysis patients is often multifactorial. Distinguishing between the potential causes of pain is important in determining optimal management strategies. For example, neuropathic pain is often difficult to control because it is less responsive to strong opioids and commonly management requires adjuvants such as antidepressants and anticonvulsants. The synergistic interaction of these medications with opioids is typically required for adequate pain control.

Impact of Chronic Pain on Quality of Life in Patients With ESRD 

Pain is a multidimensional phenomenon with physical, psychological, and social components. Chronic pain is associated with psychological distress; impairment of interpersonal relationships; excessive use of health care; significant activity limitations in work, family and social life; and adoption of a chronic sick role.6, 7 Recent research in ESRD suggests that patient perceptions of physical symptoms, especially pain, are associated with depression and insomnia and may be more important than objective assessments in determining the HRQOL of patients with ESRD.2, 8, 9 The term “total” pain10 refers to any unmet needs of the patient that may aggravate pain and captures the importance of all the following interactions: physical, emotional (anxiety and depression), social (isolation and abandonment), spiritual (search for meaning and purpose), and financial (fear of burdening the family).11 The pain threshold and response to pain therapy largely depend on these patient-related factors rather than the potency of analgesics. These psychosocial and spiritual issues enter into a vicious cycle of interacting with and perpetuating physical symptoms and suffering of the patient. This underlines the need to address the psychosocial and spiritual issues as well as the physical in pain management.

Current Pharmacologic Management in ESRD 

Pain in ESRD is inadequately managed, and, despite what appears to be an increasing prevalence of chronic pain, analgesic use has decreased over the last few years. The Dialysis Outcomes and Practice Patterns Study compared analgesic use from 1997 to 2000 for 3,749 patients in 142 United States facilities.12 The percentage of patients using any analgesic decreased from 30% to 24%. Narcotic use decreased from 18% to less than 15%, and acetaminophen use decreased from 11% to 6%. In this study, 74% of patients with pain that interfered with work had no analgesic prescription. These findings are consistent with other reports in which 35% of hemodialysis patients with chronic pain were not prescribed analgesics, despite the vast majority experiencing moderate or severe pain and less than 10% were prescribed strong opioids.2

Barriers to Pain Assessment and Management in ESRD 

Inadequate pain management is not unique to nephrology. Despite the availability of effective pain management interventions13 and published guidelines14 for the management of malignant and nonmalignant pain, many patients continue to receive inadequate analgesia.15 Patient-related factors are a major issue. Patients fail to seek medical attention until pain becomes severe. They think they need analgesics, especially strong opioids, only “when absolutely necessary.” Fear of addiction is also common. Some patients stop taking opioids because adverse effects such as nausea and vomiting are mistaken for an allergic reaction. Inadequate pain assessment and lack of staff time and training in the basic principles of pain management have also been identified as barriers to adequate pain management in cancer patients.16 These barriers also apply to ESRD; however, there are unique barriers that must be overcome in patients with ESRD. There is a lack of recognition by the nephrology community concerning the extent and severity of the problem and hence a lack of clinical and research focus in this area. This has led to a lack of a discrete medical literature that synthesizes pain management and nephrology. Probably one of the largest obstacles is the altered pharmacokinetics and pharmacodynamics of analgesics in ESRD. This will be addressed in more detail later. The high incidence of comorbidity, polypharmacy, and an elderly population also complicate pain management because of increased risk of toxicity and adverse effects of analgesics. In addition, the adverse effects of analgesics may be mimicked by uremic symptoms resulting in the withdrawal of analgesia. Finally, there is a distinct lack of training in pain assessment and management in nephrology training programs.

Pharmacokinetics of Opioids in ESRD 

Poor management of pain in ESRD is in large part because of the reluctance to use analgesics and, in particular, opioids. The absorption, metabolism, and clearance of analgesics are more complex in ESRD with patients being more likely to experience opioid toxicity. Unfortunately, the pharmacokinetics and pharmacodynamics of opioids have yet to be studied in patients with ESRD; therefore, the appropriate dosing of opioids in ESRD remains unknown. Effective treatment of pain in ESRD requires a clear understanding of the pharmacology, potential impact, and adverse effects associated with each of the analgesics used. Until the pharmacokinetics and pharmacodynamics of analgesics in ESRD are studied, their use will likely remain limited in this population with inadequate pain control.

Most of the information about opioid use in ESRD patients comes from experience with morphine. Clinical data suggest that patients with kidney failure are particularly susceptible to the toxic effects of morphine. Nausea, vomiting, myoclonus, and seizures as well as prolonged and profound analgesia, sedation, and respiratory depression have been reported with morphine in patients suffering from kidney failure.17, 18, 19, 20, 21 There are several hypotheses for this including increased enterohepatic circulation of morphine and accumulation of large quantities of the active metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G).22 Because of these difficulties, alternative strong opioids are typically recommended to manage severe pain in patients with ESRD. It has been suggested that other opioids such hydromorphone, methadone, and fentanyl are better tolerated with safer profiles in this patient population. Data, however, remain limited with these opioids and the evidence is anecdotal at best.

Hydromorphone 

Hydromorphone may potentially be an underused opioid in treating severe pain in ESRD patients. It is a hydrogenated ketone of morphine with approximately 7 times the narcotic analgesic effect of morphine and produces significant and rapid pain relief after oral administration.23, 24, 25 It has a similar side effect profile to morphine,26 although it may cause less pruritus, sedation, and nausea.27 What few data are available on oral hydromorphone come from single dose studies in healthy subjects. It has a short half-life and is extensively metabolized to hydromorphone-3-glucuronide (H3G) in the liver with the conjugates excreted in the urine. In addition, small amounts of hydromorphone-6-glucuronide (H6G) are produced. Given the structural similarity of H3G and H6G to M3G and M6G respectively, one could expect these metabolites to accumulate in patients with kidney failure. There is a single report in the literature in which 1 patient with chronic kidney failure (Cr 327 μmol/L) who had received hydromorphone 24 mg daily had a 4-fold increase in the molar ratio of H3G to hydromorphone.28 This is supported by the occasional clinical observation in the literature resulting in neuroexcitation29 and cognitive impairment.30 Despite theoretical concerns, a recent retrospective audit31 and our own clinical experience suggest that hydromorphone may be better tolerated than morphine by patients with ESRD.

Methadone 

Methadone, a synthetic opioid derivative, is a powerful mu-delta opioid agonist.32 The molecule also blocks N-methyl-D-aspartate receptor sites.33 This has been shown to decrease the formation of opioid tolerance and prevent glutamate excitotoxicity, which has been implicated in the pathogenesis of chronic pain.34 Clinically, its main use has been as a substitute opioid in the management of dependence. However, methadone is increasingly being used as an effective opioid in the management of nonmalignant and cancer pain,35 where some clinicians believe it may be more effective for neuropathic pain than other strong opioids because of its N-methyl-D-aspartate receptor antagonism.36, 37 Methadone has high oral bioavailability and is extensively distributed in the tissues where it accumulates with repeated dosing. Thus, although it has a plasma half-life of 2 to 3 hours, it has prolonged pharmacological action because of slow release from the reservoirs in the tissues of up to 60 hours.38 Methadone is excreted mainly in the feces with metabolism into pharmacologically inactive metabolites primarily in the liver, although about 20% is excreted unchanged in the urine.39 It does not appear to be removed by dialysis,40, 41 and, in anuric patients, methadone excretion in the feces may be enhanced with limited accumulation in plasma.41 These factors suggest that methadone may be an effective analgesic for use in patients with kidney impairment if carefully monitored, although extensive pharmacokinetic and pharmacologic data are not yet available.

Fentanyl 

Fentanyl is a rapid-onset, potent, synthetic opioid commonly given to produce analgesia during anesthesia.42 Fentanyl is 50 to 100 times more potent and 1,000 times more lipophilic than morphine.43 These properties make it suitable for use in a transdermal delivery system.44 Fentanyl causes less histamine release, a lower incidence of constipation and affords greater cardiovascular stability than morphine and can thus be a useful alternative when the side effects of morphine hamper effective pain management.43 Fentanyl is rapidly metabolized in the liver with only 5% to 10% excreted unchanged in the urine.45 Its metabolites are considered to be inactive. It is often assumed that because fentanyl is metabolized and eliminated almost exclusively by the liver, its kinetics would be minimally altered by kidney failure. However, the hepatic clearance and extraction of drugs with high hepatic extraction ratios like fentanyl can be inhibited by uremia.46, 47 There are very few pharmacokinetic data on fentanyl in ESRD, and these are limited to intravenous use during anesthesia.46, 47, 48, 49, 50 These studies have conflicting data about the effect of kidney failure on the elimination and distribution of fentanyl. One study showed a strong inverse correlation between the clearance of fentanyl and the blood urea nitrogen.46 However, this was not duplicated in 2 small studies and a case study.48, 49, 50

These conflicting and limited data make dosing of opioids difficult in ESRD and have reduced significantly their potential use in this population. An expanded understanding of the pharmacokinetics and pharmacodynamics of opioids in ESRD will be required to develop effective clinical approaches to pain syndromes in ESRD.

Pharmacologic Management of Chronic Pain in ESRD 

Given the lack of pharmacokinetic and pharmacodynamic data, it is difficult to confidently advocate for specific treatment algorithms for pain management in ESRD. However, there are principles of pain assessment and management that can be adapted and integrated into the care of ESRD patients while further research tests the effectiveness of various pharmacological and nonpharmacological interventions. These basic principles of pain management are summarized in Figure 1 with some points expanded on later.

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Figure 1. Fast facts on pain assessment and management.

One of the first principles of pain management is to believe the patient’s report of pain and initiate discussions about their pain. Clinically, it is important to differentiate patients with recurrent or persistent pain who remain functional from those whose pain produces significant disability and suffering. Many people function quite effectively with a background of mild pain that does not seriously impair or distract them. As pain severity increases to moderate intensity, pain passes a threshold beyond which it is hard for the patient to ignore. At this point, it becomes disruptive to many aspects of the patient’s life.51 This severity-interference relationship can be defined on a 0- to 10-point numerical scale where 1 to 4 represents mild pain, 5 to 6 represents moderate pain, and 7 to 10 represents severe pain. The World Health Organization analgesic ladder for pain management (Fig 2) is predicated on classifying pain into one of these severity categories. It is not always possible to completely eliminate pain. A more realistic goal of pain management may be to optimize pain relief while focusing on disability issues to make patients more functional in their daily activities. The reduction of pain severity across the severity boundaries might be thought of as clinically significant goals of therapy that could help achieve this aim.

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Figure 2. The World Health Organization ladder.

The selection of analgesics should take into account the type and severity of pain, anticipated duration of treatment, and potential adverse effects or interactions with concomitant medications. Reviews of the available evidence on analgesia in patients with ESRD have been recently published, including suggested dosing regimens.52, 53 The World Health Organization advocates a stepwise approach to analgesic therapy (Fig 2). The first step is to use agents such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) for mild to moderate pain. Acetaminophen is metabolized by the liver and does not require dose adjustment in the presence of ESRD. Acetaminophen is found in numerous over-the-counter medications. Inadvertent use of multiple acetaminophen-containing medications may result in hepatotoxicity. The National Kidney Foundation recommends acetaminophen as the nonnarcotic analgesic of choice for mild to moderate pain for patients with ESRD.54 NSAIDs can be used for the treatment of mild to moderate pain and can be used in conjunction with acetaminophen. NSAIDs may increase the risk of bleeding in patients with ESRD because of their effects on platelet function and gastrointestinal mucosa and may have potential cardiovascular risks. For these reasons, NSAIDs should be used for precise indications (eg, gout) and for a limited time in patients with ESRD. NSAIDs may also compromise residual kidney function; residual kidney function is associated with overall well-being and survival and should be protected as much as possible. Step 2 involves weak opioids for the initial treatment of moderate to severe pain or if pain control is inadequate with a lesser analgesic. If pain is still not relieved, or if it is severe, step 3 advocates for a stronger opioid such as hydromorphone. Opioids may be switched from one to another if adequate pain control occurs at a dose that results in troublesome adverse effects. Cross tolerance to the adverse effects of opioids may allow a switch to another opioid that can give equally good pain control but at a dose that does not cause the adverse effects. Adjuvants may be used at any step of the ladder for specific indications. Lower-level analgesics can be used for breakthrough analgesia while using regular doses of higher-level analgesics. Common adverse effects of opioids such as constipation should be anticipated and actively prevented. This is especially important in peritoneal dialysis patients in whom constipation interferes with functioning of the peritoneal dialysis catheter.

Due to altered pharmacokinetics and pharmacodynamics, there are analgesics such as meperidine and propoxyphene that should be never be used in ESRD patients. Meperidine is metabolized in the liver to the active metabolite normeperidine which is excreted by the kidneys. Meperidine and normeperidine are associated with seizures in ESRD and should not be used in this patient population. The Dialysis Outcomes and Practice Patterns Study recently reported that propoxyphene is the most commonly prescribed opioid and that it was prescribed alone or in combination with acetaminophen for 50.7% of patients.12 Propoxyphene is related to methadone, and its active metabolite norpropoxyphene is excreted by the kidney. It has properties similar to quinine and can predispose patients to cardiac conduction abnormalities. Neither propoxyphene nor norpropoxyphene are removed with dialysis, and the cardiotoxicity cannot be reversed by naloxone. It should be avoided or used with extreme caution in patients with ESRD. Opioids known to accumulate with chronic use such as morphine can still be safely and effectively used in acute pain situations; they should be switched to safer analgesics for more long-term pain management.

Understanding the cause of pain is critical in tailoring analgesic therapy. Somatic pain, such as pain associated with bone disease, responds well to NSAIDs and opioids. Control of neuropathic pain is often difficult because patients are less responsive to strong opioids. Adjuvants such as antidepressants and anticonvulsants are typically required for adequate pain control. Amitriptyline is effective in neuropathic pain; it takes less time to achieve analgesia than it does to control depression.

Summary 

Chronic pain is a common and disabling symptom for patients with ESRD that is currently being undertreated. Effective pain management is an integral component of quality care for our patients. Unless the psychosocial, spiritual, and physical attributes of pain are all addressed, pain will never be relieved adequately.

Nephrology practices are frequently dependent on protocols aimed at guiding and assuring quality assessment and improvement. These protocols have largely focused on optimizing biochemical parameters. The use of such protocols has been widely accepted as a necessity in attaining improved medical outcomes. Pain assessment and management protocols need to be developed and implemented in the dialysis units to both guide staff in the practices of pain assessment and management and to allow for routine symptom assessment and management. Because dialysis is routinely delivered in a team-based setting, it is perfectly situated to adopt the interdisciplinary team model that is common to palliative care, a model that provides excellent symptom management and quality of life assessment.55 However, for these algorithms to be developed, an increased clinical and research focus in this area is required. The pharmacokinetics and various intervention strategies will need to be systematically studied in the ESRD population.