Pain and Chronic Kidney Disease

C H A P T E R

78 Pain and Chronic Kidney Disease Scott D. Cohena, Sara N. Davisonb, Paul L. Kimmela a

Division of Kidney Diseases and Hypertension, Department of Medicine, George Washington University, Washington, DC, United States; bDepartment of Medicine, University of Alberta, Edmonton, AB, Canada worse clinical outcomes, including increased mortality, higher rates of hospitalizations, and decreased compliance with prescriptions in patients with CKD or endstage renal disease (ESRD).6e10 Perceived pain severity is a potentially modifiable risk factor for poor clinical outcomes in CKD patients who often have multiple comorbid conditions. This chapter reviews the literature on the epidemiology of pain in patients with CKD worldwide, options for the screening for and diagnosis of pain, and the various management approaches to ameliorate the perception of pain in patients with CKD.

Abstract Several studies evaluate the deleterious impact of pain in patients with chronic kidney disease (CKD). The prevalence of pain has been estimated at approximately 50%e70% in patients with advanced CKD. The causes of pain in CKD patients are often unrelated to the kidney disease and can be categorized as neuropathic (pain due to nerve damage) or nociceptive (pain due to tissue damage) in nature. There are a variety of validated screening tools available to determine the location, degree, and quality of a patient’s pain, and any exacerbating or alleviating factors. These tools include, but are not limited to, the McGill Pain Questionnaire, Edmonton Symptom Assessment System-revised:Renal and the Brief Pain Inventory. A thorough evaluation should be undertaken to determine the underlying etiology of a patient’s acute or chronic pain syndrome. Management of pain can be divided into nonpharmacologic and pharmacologic options. Nonpharmacologic alternatives should be considered before prescribing chronic pain medications. Pharmacologic treatment should follow specific guidelines with careful selection of appropriate analgesics and dose reduction for reduced estimated glomerular filtration rate, as most commonly used pain medications and their metabolites are renally cleared with a higher risk for adverse events in CKD. Opioids should only be used for severe pain refractory to other measures, including nonopioid and adjuvant analgesics. Greater provider awareness and a multidisciplinary approach including assessment and management of concurrent psychosocial issues are likely required to adequately address pain in CKD patients.

EPIDEMIOLOGY

INTRODUCTION Perception of pain is an often overlooked yet prevalent condition in patients with chronic kidney disease (CKD).1,2 Perception of pain in patients with advanced CKD is associated with decreased quality of life (QOL), increased depressive affect, and increased perception of illness burden.3e8 Psychosocial parameters including perception of decreased QOL and increased depressive affect have been associated with Chronic Renal Disease, Second Edition https://doi.org/10.1016/B978-0-12-815876-0.00078-4

The high prevalence of chronic pain is well documented in patients with ESRD treated with dialysis.10e14 It is estimated that approximately 30e50% of patients with ESRD have chronic pain. Many of these patients are prescribed opioids, which have many adverse effects.10e14 Based on 2010 US Renal Data System data,15 approximately two-thirds of all dialysis patients were prescribed opioids. Opioid prescriptions in dialysis patients are associated with adverse effects including increased mortality, hospitalizations, and dialysis discontinuation.15,16 In the general population, prescription opioid overdoses continue to increase across the US, leading the US Department of Health and Human Services to declare a public health emergency in 2017.17 In 2016, more than 42,000 deaths were attributed to opioid overdoses, and 40% of these were attributed to prescription opioids.17 Given the magnitude of the problem and the adverse health impacts, there is an urgent need to address proper management approaches for pain in patients with CKD.

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There are few data on the prevalence of pain in predialysis CKD patients. Cohen et al.6 studied 92 predialysis CKD patients and found 69% of the cohort reported pain. There was no difference between patients’ pain intensity scores across CKD stages. There was also no difference between CKD patients’ perception of pain when compared with pain ratings of a control group of 61 general medical patients without CKD. In contrast, another study of 130 CKD patients reported a prevalence of 72.9% for acute and chronic pain1. This compared with a pain prevalence of only 9% for 100 control non-CKD ambulatory medicine patients. The majority of CKD patients reported musculoskeletal pain. Pain intensity and duration were higher in patients with CKD stages 3e5 compared with earlier stages of CKD. Data from SPRINT show no difference in pain between hypertensive patients with and without CKD.18 The disparate results likely reflect the heterogeneity of the CKD population and differences in study design. Grams et al.19 recently evaluated the prevalence of opioid, gabapentinoids, and nonsteroidal antiinflammatory drug (NSAID) use among patients with CKD in the Geisinger and John Hopkins health systems. Patients with CKD stages 4 and 5 were significantly more likely to receive an opioid prescription compared with patients with earlier stages of CKD. Gabapentinoid prescriptions were also more commonly prescribed in those with advanced stages of CKD but were prescribed at significantly lower rates compared with opioids. The incidence of symptoms, including pain, in earlier stages of CKD, also appears high. Twenty five symptoms were assessed in a cohort of 1118 patients with stage 1e5 CKD.20 The most prevalent symptom in stages 1e3 were bone and joint pain, which was reported by 86% of patients. Muscle cramps were also reported commonly in 71% of patients. There was a slight trend toward increasing incidence of pain with stage of disease such that 97% of dialysis patients in this cohort reported bone and joint pain and 92% reported muscle cramps. There are a variety of potential causes for pain in CKD patients.7 Many causes of pain are not unique to CKD but are due to comorbidities such as osteoarthritis, inflammatory arthritis, peripheral neuropathy, peripheral vascular disease, and traumatic injuries. Pain can result from the underlying kidney disease, such as with polycystic kidney disease (PKD). PKD has its own unique pain syndromes, often related to the enlarging cysts or cyst rupture. Pain may also be due to complications of poor kidney function such as secondary or tertiary hyperparathyroidism, particularly in advanced CKD stages. Patients often have more than one cause of pain.

SCREENING FOR AND DIAGNOSIS OF PAIN IN CKD A variety of tools have been validated to screen for pain in CKD patients. The McGill Pain Questionnaire,10,21 first developed in 1975, remains one of the foremost tools used to assess pain. The questionnaire asks participants to describe the quality and intensity of their pain. The scale is rated from 0 to 78, with higher scores reflecting worse degrees of pain. The Brief Pain Inventory22 has been used to assess the location, type, and intensity of pain in patients with chronic medical illnesses including CKD. The questionnaire also evaluates the impact of pain on parameters such as general activity, mood, walking ability, work, relationships, sleep, and enjoyment of life. The standard instrument characterizes pain based on a 32-question survey, while the short form has been condensed to nine questions. The Edmonton Symptom Assessment Systemrevised:Renal (ESAS-r:R)23e25 can be used to screen for pain and psychosocial parameters. The ESAS-r:R consists of visual analog scales with a 0e10 likert scale representing “no” to “worst possible” for pain, tiredness, drowsiness, nausea, lack of appetite, shortness of breath, depression, anxiety, well-being, sleep, itch, and restless legs. Total scores range between 0 and 130, with higher scores indicating greater symptom burden. Similar global symptom assessment tools with evidence of validity for use in CKD patients include the renal version of the Palliative (or Patient) Outcome Scale, symptom module (POSs renal)26 and the Dialysis Symptom Index.27 All three of these patient-completed symptom screening tools can be downloaded from websites. If a patient screens positive for pain, further evaluation by a pain history is required. This includes documenting location, type of pain, alleviating or exacerbating factors, effect on physical and psychosocial functioning, and associated symptoms. All these variables affect treatment strategies. It is important to differentiate between acute, chronic, and episodic pain as the management differs (Table 78.1). The patient’s experience of chronic pain is affected by psychosocial factors as well as pathology that originally caused the pain. These psychosocial factors typically need to be addressed to manage pain adequately. A further psychosocial assessment may be warranted to better determine any underlying aggravating factors.7 In a study of 92 patients with CKD, pain intensity and frequency were associated with multiple psychosocial variables including depressive affect, perception of social support, and satisfaction with life.6 These results

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MANAGEMENT OF PAIN IN CKD PATIENTS

TABLE 78.1

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Types and Categories of Pain

TYPES OF PAIN Acute pain

Occurs following tissue damage and activation of nociceptors at the site of injury, such as after surgery. Acute pain can occur over long periods with repeated injury. This is termed recurrent pain and tends to be episodic with periods without pain.

Chronic pain

Initiated by tissue injury but perpetuated by peripheral and central nervous system changes leading to continuation of pain in the absence of the original injury/pain stimulus. Chronic pain is not defined by duration but rather by the absence of persistent nociceptor damage. Chronic pain is typically present for long periods of time and is often out of proportion to the extent of the originating injury.

Episodic, incident, paroxysmal, and breakthrough pain

Pain that breaks through, i.e. occurs despite regular analgesic medication.

CATEGORIES OF PAIN Nociceptive

Pain due to tissue damage. Pain may be described as sharp or dull. Nociceptive pain typically responds well to traditional analgesics.

Neuropathic

Pain due to nerve damage. Pain is characteristically described as burning, painful, cold, or like electric shocks. Neuropathic pain may be associated with tingling, feeling pins and needles, numbness, and itching. It may also be associated with episodes of spontaneous pain, hyperalgesia, and allodynia. Neuropathic pain is typically poorly responsive to opioids and generally requires the use of adjuvant analgesics such as anticonvulsants and antidepressants.

highlight the importance of integrating a psychosocial evaluation into the management of patients’ pain syndromes. For the purpose of treatment, it is also helpful to categorize pain into nociceptive, neuropathic, or mixed nociceptive and neuropathic pain. Patients and their significant others should be educated on the nature of the pain, potential causes of pain, and on the proposed management plan. Complete relief of pain is not always possible, and it is important that patients and their families as well as their physicians have realistic expectations.

Management of chronic pain should first focus on nonpharmacologic options.7,28 These include topical therapies such as heating pads or ice to reduce local inflammation.7,28e31 Physical therapy programs often form an essential component of pain management. Other nonpharmacologic therapies include transcutaneous electrical stimulation (TENS) and ultrasound technology.28 Arthritis and other musculoskeletal causes of pain are felt to be the most responsive to TENS.28,32 Lifestyle modifications including diet and exercise and mind-body interventions such as cognitive behavioral therapy have been shown to be effective.33,34 Surgical options and referral to a pain subspecialist may be appropriate in certain circumstances, depending on the underlying etiology of a patient’s pain. For example, patients with inflammatory arthritis may require evaluation by a rheumatologist and patients with traumatic injuries may need orthopedic evaluation. PKD patients may require laparoscopic cyst decortications (unroofing and collapse of cysts) and marsupialization if pain is related to cyst growth.35 The World Health Organization (WHO) advocates a stepwise approach to pain management that was demonstrated to be useful and efficacious in cancer patients and is now adopted for use in nonmalignant pain (Figure 78.1). Preliminary data suggest this approach may be used effectively for patients with ESRD and CKD.36,37 Caution with prescription opioids is strongly advised given the multitude of adverse health outcomes associated with this medication class. When prescribing analgesics, five principles should be followed (Table 78.2). The choice of analgesic in stage 4 or 5 CKD is challenging because of the pharmacokinetic and pharmacodynamic consequences associated with severe diminution in glomerular filtration rate. Drug metabolism is altered significantly, and the risk of toxicity from accumulation of renally excreted drugs and their metabolites is high. In view of the potential for toxicity, short-acting rather than long-acting preparations should be used until stable pain relief has been achieved. There are a variety of analgesic options for the management of pain in CKD patients (Table 78.3). Dose adjustments are usually necessary in patients with advanced CKD.

WHO Ladder Step 1 Acetaminophen is the first-line step 1 analgesic for most CKD patients. The dose of acetaminophen does not need to be adjusted for kidney function. Recent evidence suggests that lifetime cumulative doses of

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FIGURE 78.1 World Health Organization 3 Step Analgesic Ladder, N Adjuvants include medications such as anticonvulsants for neuropathic pain. It also refers to agents administered to manage adverse effects of an opioid. This includes antiemetics or laxatives. Adapted from World Health Organization.

acetaminophen do not have an adverse effect on CKD progression. Despite its widely accepted use in CKD patients, acetaminophen may have nephrotoxic potential. Fored et al.38 found an increased risk for CKD in those patients who used acetaminophen either alone or in combination with aspirin. Patients on combination acetaminophen and aspirin therapy had 2.2 higher odds for development of CKD. Perneger et al.39 also found an increased risk of ESRD among patients who took increasing cumulative doses of acetaminophen over time. Other studies have not confirmed these findings. When patients with CKD have been prescribed therapeutic doses of acetaminophen, there is no evidence to support a risk for development of worsening renal function.40 However, patients with chronic alcoholism and malnutrition may be at increased risk for hepatotoxicity.41e43 To avoid toxicity, it is recommended to not exceed 3 g/day of acetaminophen. In high-risk

patients, such as malnourished or alcoholic patients, ingestion should be limited to 2.6 g/day.44 The renal hemodynamic effects of NSAIDs are related to inhibition of renal prostaglandin synthesis, thereby causing renal afferent arteriolar vasoconstriction and hemodynamically mediated acute kidney injury (AKI).45 Kidney injury in the setting of NSAIDs may result from acute interstitial nephritis, which rarely can be associated with minimal change disease. Other complications associated with NSAID use include hyperkalemia, edema, hypertension, and papillary necrosis.7,28,45e47 Even in dialysis-dependent patients with no residual kidney function, NSAIDs are associated with an increased risk of gastrointestinal bleeding, and studies have suggested that there might be an increased risk of myocardial infarction.48 For these reasons, chronic NSAID use, including NSAIDs with supposedly less potential for AKI, such as sulindac and

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TABLE 78.2

Principles of Pain Management

By mouth

Use the oral or transdermal route whenever possible.

By the clock

Where pain is continuous, analgesics should be given regularly. Additional breakthrough medication should be available on an “as needed” (PRN) basis.

By the ladder

Initial analgesia should be started at the lowest appropriate WHO analgesic ladder level based on severity of pain. The drug should be used to its fulltolerated dose before titrating up to the next level on the ladder. Adjuvant drugs can be added to all three steps of the ladder. There are no safe step 2 analgesics for patients with advanced CKD. Step 1 analgesics can be added to step 3 drugs.

For the individual

There is no standard dose of strong opioids. The “right dose” is that which relieves pain without causing unacceptable side effects. Sensitivity to adverse effects varies between patients and must be monitored closely.

Attention to detail

Pain changes over time, thus there is a need for ongoing reassessment.

TABLE 78.3

salsalate,26,47e49 should be avoided in patients with advanced CKD. Low-dose aspirin for cardioprotection can be used safely in CKD patients.50

WHO Ladder Step 2 There are no weak opioids considered safe for use in patients with advanced CKD. For example, tramadol, a weak synthetic opioid related to codeine, is extensively metabolized in the liver. Both the parent drug and the main active metabolite O-desmethyltramadol (M1) are renally cleared. There is an unpredictable risk of serious overdosing or underdosing after administration of standard doses.51 In addition, patients with advanced CKD are at an increased risk for seizures and respiratory depression with increased levels of M1.52e54 There is no evidence that weak opioids are less risky than strong opioids if the strong opioid is used at its lowest effective dose.55 There is also no evidence that at equivalent analgesic efficacy, weak opioids carry a lower risk of addiction than low-dose strong opioids. A recent study of 140,899 hemodialysis patients in the US showed the risk for altered mental status, falls, and fractures were greater with codeine rather than with strong opioids.2,51

Analgesic Options for Chronic Pain Management in CKD Patients

Pain Category

Recommend

Recommend with Caution and Adjust Dose for Renal Function

Avoid

WHO STEP I (MILD PAIN) Acetaminophen

X

NSAIDs

X

WHO STEP II (MODERATE PAIN) Tramadol

X

Codeine

X

Hydrocodone

X

WHO STEP III (SEVERE PAIN) Morphine sulfate

X

Hydromorphone

X

Methadone

X

Fentanyl

X

Oxycodone

X

ADJUVANTS Gabapentin

X

Duloxetine

X

Pregabalin

X

Tricyclic antidepressants

X

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Adjuvant Therapy Adjuvant drugs are those that have a primary indication other than pain but are analgesic in some situations. Adjuvant therapy is the first pharmacological step for people with a neuropathic component to their pain. Anticonvulsants and tricyclic antidepressants (TCAs) are the two classes of drugs for which there is the most evidence of efficacy in neuropathic pain. In patients with normal kidney function, TCAs are considered first-line treatment options for the treatment of neuropathic pain. However, due to the increased potential for anticholinergic and cardiac adverse events in CKD patients, this class of medications is considered second-line in patients with CKD. Anticonvulsants are considered first line for the pharmacologic treatment of chronic neuropathic pain in patients with advanced CKD. There is no evidence that they are effective for acute pain. Gabapentin, an analog of the neurotransmitter gamma-aminobutyric acid, is increasingly being used for the management of chronic neuropathic pain and fibromyalgia.56 The drug undergoes renal clearance and elimination is reduced markedly in patients with advanced CKD.57,58 Therefore, patients are at increased risk for adverse effects such as neurotoxicity and AKI.57,58 Caution must be used and appropriate dose reduction applied. A recent study in ESRD patients demonstrated an association between prescription of gabapentin and adverse events such as falls.59 In patients with an estimated glomerular filtration rate (eGFR) between 15 and 30 mL/min/ 1.73 m2, the suggested maximum daily dose is 600 mg, and for patients with an eGFR <15 mL/min/1.73 m2, the suggested maximum daily dose is 300 mg. Neuropathic pain often tends to be worse at night. Because of a delayed onset of action, the drug should be taken two to three hours before going to bed. Pregabalin is another anticonvulsant that can be used to treat refractory neuropathic pain. There have been case reports of neurotoxicity when using pregabalin in CKD patients.60,61 Pregabalin has also been associated with peripheral edema. A recent study in ESRD patients found an association between pregabalin use and increased risk for falls and altered mental status.59 Dose reduction is required based on GFR. The maximum recommended dose for eGFR 30e60 mL/ min/1.73 m2 is 150 mg twice per day. For eGFR 15e30 mL/min/1.73 m2, the maximum recommended dose is 150 mg once per day, and for eGFR <15 mL/ min/1.73 m2, the maximum daily dose is 75 mg daily. Carbamazepine appears as effective as both gabapentin and pregabalin. Although carbamazepine may have more adverse effects, it requires no dose adjustment in CKD.

Duloxetine, a selective norepinephrine and serotonin reuptake inhibitor, is increasingly being used for the treatment of neuropathic pain in a variety of clinical scenarios including diabetic and chemotherapy-associated neuropathy, fibromyalgia, and chronic musculoskeletal pain in the general population.62e64 Serotonin and norepinephrine play an essential role in mediating chronic pain signals. Similar to gabapentin and pregabalin, duloxetine and its metabolites are renally cleared.65 There is very limited experience with its use in patients with advanced CKD. Duloxetine is not recommended in patients with eGFR less than 30 mL/min/1.73 m2. For patients with lower stages of CKD, duloxetine may be started at a reduced dose of 30 mg daily with cautious upward titration based on the patient’s tolerance and symptoms. Lidocaine patches are another option for the management of neuropathic pain, because they have less systemic absorption. This topical analgesic is particularly effective for the treatment of postherpetic neuralgia.66,67 Caution is advised in patients with severe renal impairment who use lidocaine patches due to concern for toxicity.

WHO Ladder Step 3 Strong opioids should only be reserved for severe pain that is refractory to other measures. Opioids should be prescribed in close consultation with the patient and with the patient’s primary care provider. In the setting of CKD, opioids carry an increased risk for adverse events including hypotension, depression of the central nervous and respiratory systems, seizures, and myoclonus.68e70 As with other medications, appropriate dose reduction should be applied when prescribing to patients with advanced CKD. Morphine undergoes hepatic metabolism and its metabolites are renally cleared.71 Therefore, CKD patients are at higher risk for morphine toxicity. Morphine should be avoided in patients with advanced CKD stages.71 Methadone, hydromorphone, fentanyl, and buprenorphine may have more favorable pharmacokinetic characteristics (Table 78.3).72e74 Hydromorphone has a shorter half-life, lower volume of distribution, and lower molecular weight compared with morphine.71 Hydromorphone may also cause less nausea, pruritus, and sedation compared with morphine.71 Methadone may be preferable to other opioids in the setting of CKD, because its metabolites undergo both gastrointestinal and renal clearance.72 There is believed to be increased gastrointestinal clearance of methadone in CKD patients.72 The metabolites of fentanyl are reportedly “inactive” and less toxic. The drug can be given topically via a transdermal

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REFERENCES

patch.74 Compared with morphine, fentanyl may cause less constipation, hemodynamic instability, and histamine release.71 Fentanyl undergoes predominately hepatic metabolism, with only 5e10% of it undergoing renal clearance. Caution must be exercised with prescription of fentanyl because of its potential for abuse and its therapeutic/toxic ratio. Strong opioids should be considered a last resort option due to risk of addiction and adverse effects. A complete history and physical examination should be performed before prescribing to determine the underlying cause of the patient’s pain, and to ascertain if the patient may be at increased risk for adverse events. A thorough social history should be documented to determine if patients have a previous history of drug-seeking behaviors, which places them at a higher risk for addiction. Once opioids are prescribed, close medical followup and monitoring is indicated to screen for signs of aberrant use or addiction such as inappropriate or escalating doses.

CONCLUSION Pain is prevalent in CKD patients and can be associated with psychosocial variables including poorer QOL and increased depressive affect. There are a variety of screening tools available to determine the severity and impact of a patient’s pain. Management of pain in CKD patients should follow specific guidelines and appropriate dose reduction for reduced eGFR. Many of the commonly used pain medications and their metabolites are renally cleared, with a higher risk for adverse events in CKD. Nonpharmacologic alternatives should be considered before prescribing chronic pain medications for CKD patients. Patients’ psychosocial needs should be addressed, as treatment of depression and anxiety may be associated with decreased perception of pain. In the midst of the opioid epidemic and increasing data regarding the multiple deleterious health consequences of prescription of opioids, additional studies are urgently needed to determine the optimal management approach for the treatment of pain in patients with CKD. With more provider awareness and using multidisciplinary approaches, the pain epidemic in CKD patients may be more effectively managed.

References 1. Pham PC, Dewar K, Hashmi S, et al. Pain prevalence in patients with chronic kidney disease. Clin Nephrol 2010;73:294e9. 2. Raj R, Ahuja KD, Frandsen M, Jose M. Symptoms and their recognition in adult haemodialysis patients: interactions with quality of life. Nephrology 2017;22(3):228e33.

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3. Skevington SM. Investigating the relationship between pain and discomfort and quality of life, using the WHO-QOL. Pain 1998; 76:395e406. 4. Perlman RL, Finkelstein FO, Liu L, et al. Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study. Am J Kidney Dis 2005;45:658e66. 5. Unruh M, Weisbord SD, Kimmel PL. Health-related quality of life in nephrology research and clinical practice. Semin Dial 2005;18: 82e90. 6. Cohen SD, Patel SS, Khetpal P, Peterson RA, Kimmel PL. Pain, sleep disturbance, and quality of life in patients with chronic kidney disease. Clin J Am Soc Nephrol 2007;2:919e25. 7. Davison SN. Chronic kidney disease: psychosocial impact of chronic pain. Geriatrics 2007;62:17e23. 8. Davison SN, Jhangri GS. The impact of pain and symptom burden on the health-related quality of life of hemodialysis patients. J Pain Symptom Manag 2010;39(3):477e85. 9. Mapes DL, Lopes AA, Satayathum S, et al. Health-related quality of life as a predictor of mortality and hospitalization. The dialysis outcomes and practice patterns study (DOPPS). Kidney Int 2003;64: 339e49. 10. Patel SS, Kimmel PL. Quality of life in patients with chronic kidney disease: focus on end-stage renal disease treated with hemodialysis. Semin Nephrol 2005;26:68e79. 11. Davison SN. Chronic pain in end-stage renal disease. Adv Chron Kidney Dis 2005;12:326e34. 12. Harris TJ, Nazir R, Khetpal P, et al. Pain, sleep disturbance, and survival in hemodialysis patients. Nephrol Dial Transplant 2012;27: 758e65. 13. Almutary H, Bonner A, Douglas C. Symptom burden in chronic kidney disease: a review of recent literature. J Ren Care 2013; 39(3):140e50. 14. Almutary H, Bonner A, Douglas C. Which patients with chronic kidney disease have the greatest symptom burden? A comparative study of advanced CKD stage and dialysis modality. J Ren Care 2016;42(2):73e82. 15. Kimmel PL, Fwu CW, Abbott KC, et al. Opioid prescription, morbidity, and mortality in United States Dialysis Patients. J Am Soc Nephrol 2017;28:3658e70. 16. Ishida JH, McCulloch CE, Steinman MA, Grimes BA, Johansen KL. Opioid analgesics and adverse outcomes among hemodialysis patients. Clin J Am Soc Nephrol 2018;13:746e53. 17. https://www.hhs.gov/opioids/about-the-epidemic/index.html. 18. The Sprint Research Group. Randomized trial of intensive versus standard blood pressure control. N Engl J Med 2015;373:2103e16. 19. Novick TK, Surapaneni A, Shin JI, et al. Prevalence of opioid, gabapentinoid and NSAID use in patients with CKD. Clin J Am Soc Nephrol 2018;13(12):1886e8. 20. Senanayake S, Gunawardena N, Palihawadana P, Bandara P, Haniffa R, Karunarathna R, et al. Symptom burden in chronic kidney disease; a population based cross sectional study. BMC Nephrol 2017;18:228. 21. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975;1:277e99. 22. Cleeland C. Research in cancer pain. What we know and what we need to know. Cancer 1991;67(3 Suppl.):823e7. 23. Davison SN, Jhangri GS, Johnson JA. Cross sectional validity of a modified Edmonton Symptom Assessment System (ESAS) in dialysis patients: a simple assessment of symptom burden. Kidney Int 2006;69:1621e5. 24. Davison SN, Jhangri G, Johnson J. Longitudinal validation of a modified Edmonton symptom assessment system (ESAS) in hemodialysis patients. Nephrol Dial Transplant 2006;21:3189e95. 25. Edmonton Zone Palliative Care Program and Northern Alberta Renal Program. Available from: http://www.palliative.org/tools. html.

IX. SPECIAL CONSIDERATIONS

1286

78. PAIN AND CHRONIC KIDNEY DISEASE

26. Murphy EL, Murtagh FE, Carey I, Sheerin NS. Understanding symptoms in patients with advanced chronic kidney disease managed without dialysis: use of a short patient-completed assessment tool. Nephron Clin Pract 2009;111(1):c74e80. 27. Weisbord SD, Fried LF, Arnold RM, Rotondi AJ, Fine MJ, Levenson DJ, et al. Development of a symptom assessment instrument for chronic hemodialysis patients: the Dialysis Symptom Index. J Pain Symptom Manag 2004;27(3):226e40. 28. Pham PT, Toscano E, Pham PT, et al. Pain management in patients with chronic kidney disease. Nephrol Dial Transplant 2009;2:111e8. 29. Ciolek JJ. Cryotherapy. Review of physiological effects and clinical application. Clevel Clin Q 1985;52:193e201. 30. Collins NC. Is ice right? Does cryotherapy improve outcome for acute soft tissue injury? Emerg Med J 2008;25:65e8. 31. Adams ML, Arminio GJ. Non-pharmacologic pain management intervention. Clin Podiatr Med Surg 2008;25:409e29. 32. Johnson M, Martinson M. Efficacy of electrical nerve stimulation for chronic musculoskeletal pain: a meta-analysis of randomized controlled trials. Pain 2006;130:157e65. 33. National Center for Complementary and Alternative Medicine. http://nccam.nih.gov. 34. Gilpin HR, Keyes A, Stahl DR, Greig R, McCracken LM. Predictors of treatment outcome in contextual cognitive and behavioural therapies for chronic pain: a systematic review. J Pain 2017;18(10): 1153e64. 35. Bajwa ZH, Gupta S, Warfield CA, et al. Pain management in polycystic kidney disease. Kidney Int 2001;60:1631e44. 36. Barakzoy AS, Moss AH. Efficacy of the World Health Organization analgesic ladder to treat pain in end-stage renal disease. J Am Soc Nephrol 2006;17:3198e203. 37. Launay-Vacher V, Karie S, Fau JB, Izzedine H, Deray G. Treatment of pain in patients with renal insufficiency: the World Health Organization three-step ladder adapted. J Pain 2006;6:137e48. 38. Fored CM, Ejerblad E, Lindblad P, et al. Acetaminophen, aspirin, and chronic renal failure. N Engl J Med 2001;345:1801e8. 39. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med 1994;331:1675e9. 40. Evans M, Fored CM, Bellocco R, et al. Acetaminophen, aspirin and progression of advanced chronic kidney disease. Nephrol Dial Transplant 2009;24:1908e18. 41. Mazer M, Perrone J. Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management. J Med Toxicol 2008;4:2e6. 42. Khandkar MA, Parmar DV, Das M, Katyare SS. Is activation of lysosomal enzymes responsible for paracetamol-induced hepatotoxicity and nephrotoxicity? J Pharm Pharmacol 1996;48:437e40. 43. Eguia L, Materson BJ. Acetaminophen-related acute renal failure without fulminant liver failure. Pharmacotherapy 1997;17:363e70. 44. Chandok N, Watt KD. Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin Proc 2010;85:451e8. 45. Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: effects on kidney function. J Clin Pharmacol 1991;31:588e98. 46. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med 1984;310:563e72. 47. Patrono C, Dunn MJ. The clinical significance of inhibition of renal prostaglandin synthesis. Kidney Int 1987;32:1e12. 48. Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib, and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess 2008;12:278.

49. Laffi G, Daskalopoulos G, Kronborg I, et al. Effects of sulindac and ibuprofen in patients with cirrhosis and ascites: an explanation for the renal-sparing effect of sulindac. Gastroenterology 1986;90:182e7. 50. McCullough PA, Sandberg KR, Borzak S, et al. Benefits of aspirin and beta-blockade after myocardial infarction in patients with chronic kidney disease. Am Heart J 2002;144:226e32. 51. Davison SN. Clinical pharmacology considerations in pain management in patients with advanced kidney failure. Clin J Am Soc Nephrol 2019;14(6):917e31. 52. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993;46:313e40. 53. Raffa RB, Friderichs E, Reimann W, et al. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 1992;260:275e85. 54. Gardner JS, Blough D, Drinkard CR, et al. Tramadol and seizures: a surveillance study in a managed care population. Pharmacotherapy 2000;20:1423e31. 55. “Weak” opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine. Prescrire Int 2016;25(168):45e50. 56. Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011;3:CD007938. 57. Torregrosa-de Juan E, Olague-Diaz P, Royo-Maicas P, et al. Acute renal failure due to gabapentin: a case report and literature. Nefrologia 2012;32:130e1. 58. Bassilios N, Launay-Vacher V, Khoury N, et al. Gabapentin neurotoxicity in a chronic hemodialysis patient. Nephrol Dial Transplant 2001;16:2112e3. 59. Ishida JH, McCulloch CE, Steinman MA, et al. Gabapentin and pregabalin use and association with adverse outcomes among hemodialysis patients. J Am Soc Nephrol 2018;29:1970e8. 60. Randinitis EJ, Posvar EL, Alvey CW, et al. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol 2003;43:277e83. 61. Healy DG, Ingle GT, Brown P. Pregabalin- and gabapentinassociated myoclonus in patient with chronic renal failure. Mov Disord 2009;24:2028e9. 62. Boyle J, Eriksson ME, Gribble L, et al. Randomized, placebocontrolled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: impact on pain, polysomonographic sleep, daytime functioning, and quality of life. Diabetes Care 2012;35:2451e8. 63. Pergolizzi Jr JV, Raffa RB, Taylor Jr R, et al. A review of duloxetine 60 mg once-daily dosing for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis pain and low back pain. Pain Pract 2013;13:239e52. 64. Takenaka M, Iida H, Matsumoto S, et al. Successful treatment by adding duloxetine to pregabalin for peripheral neuropathy induced by paclitaxel. Am J Hosp Palliat Care 2013;30:734e6. 65. Lobo ED, Heathman M, Kuan HY, et al. Effects of varying degrees of renal impairment on the pharmacokinetics of duloxetine: analysis of a single-dose phase I study and pooled steady-state data from phase II/III trials. Clin Pharmacokinet 2010;49:311e21. 66. Argoff CE. New analgesics for neuropathic pain: the lidocaine patch. Clin J Pain 2000;16:S62e6. 67. Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain 1999;80:533e8.

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REFERENCES

68. Murtagh FEM, Chai MO, Donohoe P, et al. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. J Pain Palliat Care Pharmacother 2007; 21:5e16. 69. Kurella M, Bennett WM, Chertow GM. Analgesia in patients with ESRD: a review of available evidence. Am J Kidney Dis 2003;42: 217e28. 70. Saboory E, Derchansky M, Ismaili M, et al. Mechanisms of morphine enhancement of spontaneous seizure activity. Anesth Analog 2007;105:1729e35. 71. Nayak-Rao S. Achieving effective pain relief in patients with chronic kidney disease: a review of analgesics in renal failure. J Nephrol 2011;24:35e40.

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72. Kreek MJ, Schecter AJ, Gutjahr CL, et al. Methadone use in patients with chronic renal disease. Drug Alcohol Depend 1980;5:197e205. 73. Davies G, Kingswood C, Street M. Pharmacokinetics of opioids in renal dysfunction. Clin Pharmacol Kinet 1996;31:410e22. 74. Labroo RB, Paine MF, Thummel KE, et al. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos 1997;25:1072e80. 75. Zhang X, Donnan PT, Bell S, Guthrie B. Non-steroidal antiinflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol 2017;18: 256.

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78. PAIN AND CHRONIC KIDNEY DISEASE

QUESTIONS AND ANSWERS Question 1 A 64-year-old man with stage 4 CKD, baseline eGFR 25 mL/min, presents to his nephrologist reporting lower back pain for the past week. He reports lifting heavy objects before the onset of pain. Which of the following statements is correct? A. Pain prevalence consistently decreases as CKD stages advance B. The back pain is likely secondary to nephrolithiasis C. Pain is a common symptom reported in CKD patients D. You should immediately refer the patient to a pain specialist Answer: C Pain is prevalent in patients with CKD. Studies have estimated the prevalence of reported pain to be up to 70% in patients with CKD. The prevalence of pain did not change across the different CKD stages in one study; however, in another study pain was perceived as more intense in those with advanced stages of CKD. Immediate referral to a pain specialist is not appropriate until other measures are tried in close consultation with the patient’s primary care provider.1,6

Question 2 The patient has tried acetaminophen and heating pads with no relief and requests “something stronger” for pain. Which of the following analgesic medications would be most appropriate to treat this patient’s chronic pain? A. B. C. D. E.

Amitriptyline Morphine Sulfate Ibuprofen Tramadol None of the above

Answer: E Based on current recommendations, the analgesics listed should be avoided in CKD patients and none of the above is the correct answer.52e54

Question 3 The patient returns 2 weeks later reporting shooting pains radiating down the back of his right leg down to his foot. You recommend physical therapy and that he consult with his primary care physician for additional options. Which of the following medications would you recommend to the primary care physician as the best adjuvant to help with this patient’s pain?

A. B. C. D.

Gabapentin Ibuprofen Morphine sulfate Amitriptyline

Answer: A This patient has sciatic neuropathic pain which is best managed with an adjuvant analgesic such as the anticonvulsant gabapentin. The other medications listed are contraindicated in patients with advanced CKD. Recent studies in ESRD patients suggest more data are needed regarding results of treatment with gabapentin in patients with CKD.56,59

Question 4 A 58-year-old woman with breast cancer metastatic to the bone and stage 4 CKD, GFR 20 mL/min, reports severe diffuse bone pain. She requests stronger analgesics. She currently takes acetaminophen with no relief of her symptoms. You discuss the case with the patient’s primary care physician to develop an optimal therapeutic plan. Which of the following medications would you recommend as the next best option for this patient? A. B. C. D.

Fentanyl patch Amitriptyline Ibuprofen Morphine sulfate

Answer: A This patient has severe bone pain from metastatic disease which often requires the strongest analgesic options. Fentanyl patch is the best choice of the options listed. Fentanyl undergoes primarily hepatic clearance; however, clearance of the drug is reduced in patients with several renal failure, therefore a reduced dose should be considered. The other medications should be avoided in patients with advanced CKD.73,74

Question 5 A 64-year-old woman with a history of type 2 diabetes mellitus for 25 years and stage 4 CKD, GFR 25 mL/min, reports painful burning in both feet for the past month. She requests analgesic relief. Which of the following medications may be most effective in relieving her symptoms? A. B. C. D.

Morphine sulfate Duloxetine Ibuprofen Acetaminophen

Answer: B This patient has neuropathic pain, which is best managed with an adjuvant such as duloxetine. Other

IX. SPECIAL CONSIDERATIONS

QUESTIONS AND ANSWERS

appropriate options might include gabapentin or pregabalin which are not listed as answer choices. These medications, in light of recent data in the ESRD population, need study in the CKD population. The other medications listed are either not appropriate for patients with CKD or not shown to be effective for neuropathic pain.59,62e64

Question 6 A 53-year-old woman with stage 3a CKD, GFR 50 mL/min presents to the hospital with AKI. Her admission S[Cr] is 6.7 mg/dL. She states she has had severe back pain for the past month and recently started taking over the counter pain medication. Over the past

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week, she developed gastroenteritis with poor oral intake. Which of the following medications most likely contributed to the AKI? A. B. C. D.

Duloxetine Tramadol Ibuprofen Acetaminophen

Answer: C This patient presented to the hospital with AKI in the setting of volume depletion. Ibuprofen is a cause of AKI, especially in the setting of volume depletion and preexisting CKD. The other answer choices listed are not associated with AKI.45e47,75

IX. SPECIAL CONSIDERATIONS