INTRODUCTION — Pain is one of the most common and distressing symptoms among patients with chronic kidney disease (CKD) [1]. The prevalence of pain has been associated with substantially lower health-related quality of life and greater psychosocial distress, insomnia, and depressive symptoms [2-9]. Among hemodialysis patients, severe pain is also independently associated with shortened or missed hemodialysis treatments and increased health services utilization, such as emergency department visits and hospitalizations [10].
Many analgesics that are typically used in the non-CKD population should not be used among patients with advanced CKD (ie, estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2; including those on dialysis). This topic reviews the epidemiology, assessment of pain, and management of chronic pain among patients with advanced CKD.
The evaluation and management of pain in the general adult population and among patients with mild to moderate CKD (ie, eGFR ≥30 mL/min/1.73 m2) is reviewed elsewhere. (See "Evaluation of chronic non-cancer pain in adults" and "Approach to the management of chronic non-cancer pain in adults".)
EPIDEMIOLOGY — Pain is more prevalent among CKD patients than in the general population. Over 60 percent of hemodialysis patients describe moderate or severe chronic pain [1,11]. By contrast, according to a national survey, approximately 20 percent of adults in the United States (both with and without CKD) have reported chronic pain, and approximately 7 percent have high-impact chronic pain (ie, pain that results in limitations in major life domains) [12].
Most studies of CKD patients have included only hemodialysis patients [1]. A few small studies have suggested that pain is as common among peritoneal dialysis patients and stage 5 CKD patients who are not on dialysis as among chronic hemodialysis patients [1].
Very few studies have reported the prevalence of pain among patients with nondialysis CKD. A single, small study of 130 nondialysis CKD patients with varying severity of CKD suggested that the prevalence of pain was similar (64 to 75 percent) among all levels of CKD patients [13]. However, it is not clear that patients included in this study are representative of CKD patients in the general population, since all patients in this study were drawn from a CKD clinic; many individuals with mild declines in estimated glomerular filtration rate (eGFR; ie, 60 to 89 mL/min/1.73 m2) are not followed in CKD clinics.
Most studies in CKD patients show no association of chronic pain with sex, age, race, or ethnicity [2-8,11,14,15].
ASSESSMENT OF PAIN
Screening — Both dialysis and nondialysis CKD patients should be screened routinely for the presence of pain since pain is highly prevalent, is associated with diminished quality of life and other symptoms, and is poorly recognized and quantified by care providers [2-10,16,17]. The reason for screening is that pain may be treated successfully if it is identified and sufficiently characterized by the care provider. In addition, the routine assessment of pain often provides an opportunity for difficult discussions about appropriate palliative- and supportive-care options.
There are at least eight validated symptom assessment tools designed to identify CKD patients with chronic pain (table 1) [2,3,18-25]. Tools such as the Edmonton Symptom Assessment System Revised: Renal (ESAS-r:Renal) [2,3,26] and Palliative Care Outcome Scale-Renal (POS-renal) are particularly useful for routine clinical screening for pain in kidney programs because they are short, relatively simple to complete by the patient, and require minimal facilitation from staff [18,19].
The use of these global symptom screening tools also allows for the assessment of other bothersome symptoms that often accompany pain, such as depression, anxiety, itch, nausea and vomiting, anorexia, shortness of breath, and poor sleep.
We use the ESAS-r:Renal to screen CKD patients for pain (form 1). We integrate routine screening of hemodialysis patients during monthly assessments. We screen home dialysis patients and predialysis advanced CKD patients quarterly at the time of clinic visits.
Once pain is identified, it should be further evaluated as to cause. Depending on the cause of pain, a specific intervention or pharmacologic treatment may be indicated. As an example, the patient with vascular steal syndrome may require a surgical intervention. (See "Arteriovenous graft creation for hemodialysis and its complications", section on 'Access flow-related problems'.)
Causes — CKD patients are vulnerable to all the causes of pain that affect the general population. In addition, CKD patients may experience pain related to their primary kidney disease (eg, polycystic kidney disease), comorbid conditions (eg, diabetic neuropathy or peripheral vascular disease), or sequelae of CKD (such as calcific uremic arteriolopathy [calciphylaxis], bone pain from renal osteodystrophy, and dialysis-related amyloid arthropathy). Most studies have not shown an association of pain with the biochemical derangements common in CKD [2-8,11,14,15]. However, a single but large study of 1469 patients showed that, among dialysis patients, disturbed metabolism of calcium, phosphate, and parathyroid hormone is associated with more muscle, joint, and bone pain [27].
Pain may also be directly or indirectly related to dialysis. Painful conditions may be related to the dialysis access. As examples, arteriovenous fistulas can lead to painful ischemic neuropathies, and tunneled catheters may result in painful, chronic infections such as osteomyelitis and discitis. (See "Arteriovenous graft creation for hemodialysis and its complications", section on 'Access flow-related problems'.)
Pain may also be directly related to the dialysis treatment; hemodialysis patients often experience recurrent cramps or headaches during their dialysis treatments [28], and peritoneal dialysis patients may have pain due to abdominal distension, recurrent peritonitis, and lower back strain [28].
Pain is generally classified as either nociceptive or neuropathic. Nociceptive pain is usually due to tissue injury. Causes of nociceptive pain common among advanced CKD patients include (but are not limited to) osteoarthritis, renal osteodystrophy, dialysis-related amyloid arthropathy, and kidney or liver capsule distension from autosomal dominant polycystic kidney disease (ADPKD). All can cause mild, moderate, or severe pain. (See 'Nociceptive pain' below.)
Neuropathic pain arises from abnormal neural activity secondary to disease, injury, or dysfunction of the nervous system (see 'Neuropathic pain' below). Common examples of neuropathic pain among patients with CKD include but are not limited to diabetic neuropathy, phantom limb pain, and carpel tunnel syndrome.
Among CKD patients, the pain is often mixed nociceptive/neuropathic in nature. (See 'Mixed nociceptive and neuropathic pain' below.)
TREATMENT OVERVIEW — In the general adult population, treatment options for chronic pain fall into six major categories: pharmacologic, physical medicine, behavioral medicine, neuromodulation, interventional, and surgical approaches. Optimal patient outcomes often result from multiple approaches utilized in concert and coordinated by a multidisciplinary team that includes pain specialists. Medication is not the sole focus of treatment but is used when nonpharmacologic interventions have been insufficient to adequately control pain. Medication is best used in conjunction with other treatment modalities to meet treatment goals [29]. (See "Approach to the management of chronic non-cancer pain in adults".)
Nonpharmacologic treatment — Nonpharmacologic modalities are generally the same among CKD patients as in the general population and are discussed elsewhere (see "Approach to the management of chronic non-cancer pain in adults", section on 'Nonpharmacologic therapies'). However, frailty or general disability may prevent some patients from benefiting fully from physical interventions. In addition, behavioral approaches such as cognitive-behavioral therapy (CBT) may be challenging and possibly less effective for some CKD patients, especially those already on dialysis, because of the time and cognitive ability required. Regardless, where available, these modalities should be tried as first-line therapy.
Pharmacologic treatment of mild to moderate CKD (eGFR ≥30 mL/min/1.73 m2) — With the exception of nonsteroidal antiinflammatory drugs (NSAIDs), the pharmacologic treatment of chronic pain in patients with mild to moderate CKD is similar to the general population without CKD. However, NSAIDs should typically be avoided. (See "Pharmacologic management of chronic non-cancer pain in adults".)
Occasionally, NSAIDs provide greater pain control and potentially fewer side effects than other medications, particularly among patients with mild reductions in eGFR (ie, >45 mL/min/1.73 m2). For such patients, many clinicians will use low doses of NSAIDs after a careful discussion of the potential risks versus benefits of the medication. NSAIDs are best reserved for specific indications of acute, rather than chronic pain, limiting their use to the lowest effective dose and shortest duration [30,31]. All CKD patients who are being chronically treated with NSAIDs should have close monitoring of eGFR (ie, every three months), with discontinuation of NSAIDs if the eGFR declines faster than expected. However, we stress that there is no dose of NSAID that is considered "safe" for individuals with reduced eGFR.
Pharmacologic treatment of advanced CKD (eGFR <30 mL/min/1.73 m2) — Our pharmacologic approach is adapted from the World Health Organization (WHO) analgesic ladder, which involves a cautious, stepwise approach to prescribing analgesic agents according to pain severity (figure 1) [31-33]. According to the WHO analgesic ladder, mild pain is treated with nonopioid analgesic agents (tier 1), moderate pain is treated with a weak opioid with or without a nonopioid agent (tier 2), and severe pain is treated with a strong opioid (tier 3) (table 2 and figure 1) [34]. The WHO ladder is modified for patients with CKD since many specific agents (such as codeine and tramadol) should not be used for individuals with a severely reduced estimated glomerular filtration rate (eGFR) (table 2) [31,35]. Systematic reviews for nonmalignant chronic pain have supported use of the WHO analgesic ladder approach in the general [29,36-43] and geriatric [44] populations. Most palliative care consensus groups with expertise in caring for CKD patients advocate for this approach [14,28,31,33,45-56].
We deviate somewhat from the recommendations of the WHO; specifically, we do not use a weaker opioid prior to a stronger opioid, due to lack of clear advantages with this approach. Weaker opioids have a variable response among patients with advanced CKD, with an unpredictable risk of fatal overdosing with trivial doses or a poor analgesic effect after administration of standard doses [31]. In addition, weaker opioids have a similar rate of dose-dependent adverse effects as low-dose strong opioids. There is no evidence that weaker opioids have a lower addiction potential compared with low-dose strong opioids. Instead, we favor treatment with a strong opioid initiated at a low dose with slow titration to desired effect, especially among patients with an estimated glomerular filtration rate of <30 mL/min/1.73 m2 [31]. (See 'Drugs that should be avoided' below.)
However, no good studies have examined the effect of treatment algorithms on clinically important outcomes such as pain, overall symptom burden, and quality of life of patients with CKD [11,32].
Principles for dosing and administration — The general principles of the pharmacologic treatment of pain are the same for patients with advanced CKD as for the general population.
These include the following principles (table 3):
●By mouth – The safest route of administration is oral. However, consideration should also be given to effectiveness, patient comfort, and patient control. For example, if ingestion or absorption of the medication is uncertain, analgesia needs to be given by an alternative route such as transdermal, subcutaneous, or rectal routes. Although hemodialysis patients have easy intravenous access, intravenous administration should be avoided as the route of administration of analgesic agents for chronic pain in order to optimize safety and minimize the risk of addiction and abuse.
●By the clock – Analgesics given for moderate to severe pain are given on a fixed-dose schedule around the clock and not only on an "as needed" or "prn" basis. This allows for more consistent pain relief. Patients given scheduled analgesics are more comfortable and use less medication overall. Some patients with mild pain may achieve adequate pain relief with analgesic dosing posthemodialysis only. An example is CKD patients with mild neuropathic pain, which may be adequately controlled with gabapentin postdialysis. (See 'Neuropathic pain' below.)
●By the ladder – A stepwise approach is recommended, in which medications are added sequentially. For CKD patients, it is important to select analgesic agents carefully, depending on the eGFR.
●For the individual – There is a great deal of interpatient variability in the response to analgesic agents. The maximal dose varies by patient and is identified by the amount needed to relieve the pain without producing intolerable side effects. Since there are no studies on the long-term use of analgesics in patients with CKD, careful attention must be paid to issues of efficacy and safety, and close monitoring is essential.
By using this approach, pain can be controlled safely in most patients with advanced CKD and those on dialysis.
Drug selection — The analgesic choice for individual patients with advanced CKD depends on at least three variables:
●The nature of the pain – For all patients, the choice of analgesic agent for individual patients depends in part on the nature of the pain. Pain is generally classified as either nociceptive or neuropathic. Nociceptive pain is usually due to tissue injury (see 'Nociceptive pain' below). Neuropathic pain arises from abnormal neural activity secondary to disease, injury, or dysfunction of the nervous system (see 'Neuropathic pain' below). Among patients with advanced CKD, the pain is often mixed nociceptive/neuropathic in nature. (See 'Mixed nociceptive and neuropathic pain' below.)
●The severity of pain – Patients who present with severe pain may require the initiation of stronger agents at the outset.
●The severity of kidney dysfunction – Many analgesic agents should have dose reductions or should not be used among individuals with advanced CKD. This is because the pharmacokinetics and pharmacodynamics of many analgesics and most opioids are altered among such patients, and the risk of toxicity from accumulation of renally excreted drugs and their metabolites is high. (See 'Drugs that should be avoided' below.)
The optimal analgesic agents for CKD patients are indicated in the table (table 2). Suggested dose reductions are based on both clinical experience and available data. Pharmacokinetic data on analgesic medications in the context of advanced CKD may differ from that in the general population (table 4).
However, the pharmacokinetic and pharmacodynamic data of analgesics in CKD remain limited, and the level of evidence for use of individual analgesics varies considerably. Most pharmacokinetic studies have not been designed to evaluate efficacy and safety and are typically small, single-dose studies or studies over very short periods of time of patients with varying degrees of kidney function. Only a few studies have provided information regarding clinically relevant outcomes such as analgesic effect or adverse effects.
Specific pain syndromes
Nociceptive pain — Causes of nociceptive pain common to patients with advanced CKD include (but are not limited to) osteoarthritis, renal osteodystrophy, dialysis-related amyloid arthropathy, and kidney or liver capsule distension from autosomal dominant polycystic kidney disease (ADPKD). All can cause mild, moderate, or severe pain. Below is presented an approach to mild, moderate, and severe nociceptive pain, based upon the WHO analgesic ladder and modified or reduced eGFR (algorithm 1).
Acetaminophen — Acetaminophen, prescribed in standard doses, is the first-line analgesic for patients with advanced CKD who have nociceptive pain. Acetaminophen is extensively metabolized in the liver, and only 2 to 5 percent of the therapeutic dose is excreted unchanged in the urine. Acetaminophen elimination is not significantly reduced among patients with decreased eGFR [57]. Cumulative doses of acetaminophen likely do not affect CKD progression [58]. Thus, in the presence of pain, it is relatively safe to give up to a full dose of acetaminophen to patients with advanced CKD.
Opioids — For patients who do not respond to acetaminophen alone, we treat with acetaminophen plus a strong opioid. Preferred opioids include hydromorphone, fentanyl, methadone, or buprenorphine. We usually start with hydromorphone at 0.5 to 1 mg orally every four to six hours. We do not use codeine, tramadol, morphine, meperidine/pethidine, hydrocodone, or propoxyphene among patients with advanced CKD [31]. Oxycodone may be used among patients with CKD but is considered a second-line agent compared with other opioids discussed above. (See 'Drugs that should be avoided' below.)
The choice of specific agent is generally determined by drug metabolism and availability, clinician comfort and experience with particular agents, and patient preference. As an example, patients may prefer a drug such as fentanyl or buprenorphine, which is administered via a transdermal route, rather than oral preparations. Side effects such as sedation may also influence the selection of specific agent.
Opioids should be used with caution among patients with advanced CKD since such patients are at higher risk for toxic side effects compared with patients with normal kidney function. There is a poor understanding of the pharmacokinetics and pharmacodynamics of opioids among patients with severely reduced eGFR. In view of the potential for severe toxicity, normal-release (short-acting), not modified-release (long-acting), preparations are preferred when available (table 2).
Oral or transdermal agents, rather than parenteral routes, should be used. Patients should be evaluated closely for evidence of benefit and/or toxicity. The onset of adverse side effects should trigger a reassessment of analgesic strategy and choice of opioid.
●Hydromorphone – Hydromorphone appears to be better tolerated than morphine when immediate-release preparations are used for pain relief [59]. One study that examined the pharmacokinetics and pharmacodynamics and efficacy of hydromorphone among 12 anuric hemodialysis patients found that hydromorphone use resulted in greater than a 65 percent reduction in pain over dosing intervals, with no clinically significant opioid toxicity [60]. Furthermore, hydromorphone did not accumulate in these patients over a mean duration of nine months.
Hydromorphone should be used with caution among all CKD patients, with close observation for side effects. Hydromorphone has a high potential for respiratory depression and addiction.
Hydromorphone is metabolized primarily in the liver to conjugates, hydromorphone-3-glucuronide (H3G), which are excreted in the urine and accumulate in patients with reduced eGFR [61]. Case reports have suggested that the accumulation of H3G conjugate may lead to myoclonus and delirium among patients with severely reduced eGFR [62]. These patients were taking higher doses of hydromorphone than is common in routine practice (equivalent to approximately 3000 mg and 500 to 1000 mg oral morphine per 24 hours, respectively).
Hydromorphone may not be as well tolerated among patients with severely reduced GFR (ie, <10 mL/min/1.73 m2), either during the final days of life following withdrawal from dialysis or if being managed conservatively without dialysis. In one study of anuric hemodialysis patients, H3G accumulated between dialysis treatments but appeared to be removed effectively during hemodialysis [60]. Among such patients, the clinician should be especially vigilant for toxic side effects. For such patients who develop side effects, other opioids (such as fentanyl, methadone, or buprenorphine) may be preferred. Fentanyl is particularly effective among patients who have withdrawn from dialysis in the last days of life since it is transdermally administered.
●Methadone – Methadone may be particularly useful for the management of severe chronic pain in patients with advanced CKD. It is excreted mainly in the feces, although approximately 20 percent is excreted unchanged in the urine [63]. In anuric patients, it is excreted exclusively in feces, with no accumulation in plasma. The parent drug and metabolites do not seem to be removed substantially by hemodialysis, so supplemental methadone is not required postdialysis treatment [64,65]. These factors would suggest that methadone may be a safe, effective analgesic for use in patients with advanced CKD by those familiar with its use as careful monitoring is essential, including monitoring for prolongation of the QT interval [65]. In addition, it may be more effective for neuropathic pain than other opioids because of its activity against the N-methyl-D-aspartate (NMDA) receptor antagonism. (See 'Neuropathic pain' below.)
●Fentanyl – Fentanyl is rapidly metabolized in the liver, with only 5 to 10 percent excreted unchanged in the urine [66]. Its metabolites are considered to be inactive. There does not appear to be any clinically significant accumulation of fentanyl when administered to patients with advanced CKD [67-69]. Similarly, alfentanil is extensively metabolized in the liver to inactive compounds, and its pharmacodynamics and pharmacokinetics in advanced CKD appear relatively unchanged.
●Buprenorphine – Buprenorphine is an effective, long-acting opioid analgesic with an apparent ceiling effect on respiration. It can be administered sublingually or via a transdermal patch. Buprenorphine is a particularly useful analgesic for patients with severely reduced eGFR. Buprenorphine is completely metabolized by the liver, with little unchanged drug found in the urine [70]. Its two major metabolites, buprenorphine-3-glucuronide (B3G) and norbuprenorphine, are primarily excreted via the fecal route, and only 10 to 30 percent of these are excreted in the urine [71]. B3G is inactive, with no analgesic properties, whereas norbuprenorphine has an analgesic effect without the ability to cross the blood-brain barrier and produce toxic neurological side effects [72].
Neuropathic pain — Common examples of neuropathic pain among patients with advanced CKD include, but are not limited to, diabetic neuropathy, phantom limb pain, and carpel tunnel syndrome. Below is our pharmacologic approach to neuropathic pain, which uses adjuvant therapies such as gabapentin or pregabalin as first-line agents (algorithm 2).
Gabapentin and pregabalin — We treat patients with chronic neuropathic pain with antiseizure medications, including gabapentin and pregabalin. We usually use gabapentin because it is generally the less expensive agent; efficacy and toxicity profiles appear to be similar.
Gabapentin is an analog of the neurotransmitter gamma-aminobutyric acid (GABA). Gabapentin is cleared by the kidney, and elimination is markedly reduced in patients with low GFR [73]. As a result, patients with advanced CKD are at an increased risk for side effects such as neurotoxicity and acute kidney injury secondary to rhabdomyolysis [74,75]. Doses should be reduced based on eGFR (table 4). In addition, among older patients or those with only mild neuropathic pain, it is reasonable to start at an even lower dose than permissible by eGFR (eg, 100 mg postdialysis in hemodialysis patients and 100 mg every second night in nondialysis CKD patients with eGFR <15 mL/min/1.73 m2 who are not on dialysis).
Pregabalin is also an antiseizure medication that is used to treat refractory neuropathic pain. There have been case reports of neurotoxicity when using pregabalin in CKD patients [76]. Caution must be used and appropriate dose reduction applied (table 4). Among patients with eGFR <15 mL/min/1.73 m2 who have mild or moderate pain, pregabalin may be effective at doses as low as 25 mg after each dialysis session or 25 mg every second night among patients with eGFR <15 mL/min/1.73 m2 who are not on dialysis.
Among patients with severely reduced GFR, gabapentin and pregabalin may have a beneficial effect on other common symptoms among patients with advanced CKD, including pruritus, restless legs syndrome, and poor sleep.
Tricyclic antidepressants — For patients with neuropathic pain that is unrelieved by the maximum safe dose of gabapentin or pregabalin, we switch to a tricyclic antidepressant (TCA). Although TCAs are considered first line for the pharmacologic treatment of neuropathic pain in patients with normal kidney function, we only use TCAs among patients with advanced CKD if gabapentin or pregabalin is not effective. This is because side effects of TCAs are more common among CKD patients. Side effects include dry mouth, orthostatic hypotension, and somnolence due to anticholinergic, histaminergic, and adrenergic activity. TCA-induced tachyarrhythmias are also a concern among CKD patients, given the high burden of cardiovascular disease in CKD. For these reasons, TCAs are considered second-line therapy for neuropathic pain in advanced CKD.
Amitriptyline has been the most widely studied TCA in chronic pain [77,78], although a number of others, including doxepin, imipramine, nortriptyline, and desipramine, also have been used with success.
We generally start amitriptyline at 10 mg daily. It can take up to six weeks, including two weeks at the highest dose tolerated, for an adequate trial of treatment with TCA, although the onset of analgesia may be after one week [79,80].
TCAs (mainly those with greater anticholinergic effects) are relatively contraindicated in patients with severe cardiac disease, particularly conduction disturbances.
Carbamazepine is a tricyclic compound chemically related to TCAs. It is used for treatment of seizure disorders and as a mood stabilizer. Carbamazepine may be as effective as gabapentin for treating neuropathic pain with fewer adverse effects. Unlike gabapentin and pregabalin, it requires no dose adjustment in patients with advanced CKD. We generally start carbamazepine at 100 mg once or twice daily and slowly increase the dose by 100 mg per day to a maximum of 1200 mg per day.
For patients with neuropathic pain who are unresponsive to gabapentin, pregabalin, TCAs, or carbamazepine, we add traditional analgesics in a stepwise manner, starting with acetaminophen. (See 'Acetaminophen' above.)
For patients who do not respond to adding acetaminophen, an opioid may be added to acetaminophen. (See 'Opioids' above.)
Methadone may be effective for severe neuropathic pain because of its activity against the NMDA receptor antagonism.
We do not use codeine, tramadol, morphine, meperidine/pethidine, or propoxyphene among patients with advanced CKD. Oxycodone may be used among patients with advanced CKD but is considered a second-line agent compared with other opioids discussed above. (See 'Drugs that should be avoided' below.)
Mixed nociceptive and neuropathic pain — Ischemic pain is usually mixed nociceptive and neuropathic. Among patients with advanced CKD, this commonly includes pain from peripheral vascular disease, calciphylaxis, and vascular steal syndrome.
We treat patients with mixed nociceptive and neuropathic pain with acetaminophen and gabapentin or pregabalin (or another adjuvant agent) (algorithm 3). We titrate the dose of gabapentin or pregabalin as required, treating the neuropathic component of the pain before adding other analgesics. For patients who do not respond to acetaminophen plus one of these two drugs, we add an opioid. As noted above, tier 2 agents on the WHO analgesic ladder for the non-CKD population include weak opioids such as codeine and non-opioids such as tramadol. However, there is no good weak opioid for patients with advanced CKD. Codeine and tramadol should not be used among patients with advanced CKD. (See 'Opioids' above.)
Thus, for CKD patients with significantly reduced eGFR, most clinicians add a low dose of a strong opioid. (See 'Opioids' above.)
The preferred opioid for mixed nociceptive/neuropathic pain is methadone. Methadone may be effective for severe neuropathic pain because of its activity against the NMDA receptor antagonism.
We generally do not use NSAIDs, codeine, tramadol, morphine, meperidine, propoxyphene, or pethidine among patients with advanced CKD for the treatment of chronic pain. (See 'Drugs that should be avoided' below.)
DRUGS THAT SHOULD BE AVOIDED — We generally do not use nonsteroidal antiinflammatory agents (NSAIDs), codeine, tramadol, dextropropoxyphene, morphine, meperidine/pethidine, or propoxyphene among patients with advanced CKD.
●Nonsteroidal antiinflammatory agents – NSAIDs may cause an acute reduction in glomerular filtration rate (GFR), sodium and water retention, hypertension, and hyperkalemia and potentially contribute to the progression of CKD (see "NSAIDs: Acute kidney injury", section on 'Kidney prostaglandin expression and function' and "NSAIDs: Acute kidney injury", section on 'Mechanism of acute kidney injury' and "Epidemiology and pathogenesis of analgesic-related chronic kidney disease", section on 'Nonsteroidal antiinflammatory drugs').
NSAIDs also compromise the gastrointestinal mucosa, inhibit platelet function, and are associated with increased risk of cardiovascular morbidity and mortality. All of these potential adverse effects have serious implications for patients with advanced CKD, who are already at high risk for gastrointestinal bleeding and cardiovascular incidents. We avoid NSAIDs, if possible, among patients with estimated GFR (eGFR) <60 mL/min/1.73 m2, especially in older adults >75 years.
When applied topically, NSAIDs do not appear to be associated with serious side effects. Where pain is present in joints or nonulcerated skin, this may be a useful alternative to oral administration for patients with advanced CKD.
●Morphine – We do not use morphine for patients with advanced CKD, although it is considered by many to be the drug of choice for the treatment of severe pain in patients with normal kidney function. Only a small percentage is excreted unchanged in the urine (5 to 10 percent of the dose). The active metabolites, however, accumulate rapidly in patients with GFR <30 mL/min/1.73 m2 [81-86], potentially causing life-threatening or fatal respiratory depression, and chronic use is associated with significant toxicity. Alternative strong opioids such as hydromorphone, alfentanil and fentanyl, methadone, and buprenorphine are generally more appropriate, especially for patients with eGFR <30 mL/min/1.73 m2.
●Codeine – Codeine is metabolized in the liver by the enzyme CYP2D6 to its active metabolite morphine, which provides the analgesic effect. Morphine is renally excreted and accumulates in patients with kidney failure [87-89]. The percentage conversion of codeine to morphine in individual patients is highly variable due to the genetic polymorphism of the CYP2D6 gene. Such variable conversion to morphine can result in life-threatening or fatal respiratory depression due to high plasma levels of morphine, even with trivial doses in some and poor analgesic response in others with standard or higher doses [31]. There have been several case reports of prolonged narcosis in patients with CKD following ingestion of codeine, mostly among patients with eGFR <30 mL/min/1.73 m2 [89,90]. For this reason, codeine should be avoided among patients with advanced kidney disease, if possible, even though some CKD patients are able to tolerate regular doses of codeine for a prolonged period without experiencing toxicity.
●Tramadol – Tramadol is metabolized in the liver by the enzyme CYP2D6 with unpredictable bioavailability due to the genetic polymorphism of the CYP2D6 gene. Ninety percent of tramadol and its metabolites are excreted in the urine [91]. Even low doses of tramadol among patients with advanced CKD may cause significant side effects, including central nervous system depression. In addition, serotonin syndrome, a potentially life-threatening condition, may occur with the concurrent use of tramadol and drugs such as antidepressants, which alter the metabolism of tramadol. (See "Serotonin syndrome (serotonin toxicity)".)
●Dextropropoxyphene – Dextropropoxyphene is an opioid for mild to moderate pain, usually prescribed in combination with acetaminophen. Dextropropoxyphene is not available in the United States or in European Union countries, because of a high fatality risk related to overdose. However, it appears to be available in Asia, and South America. Dextropropoxyphene is contraindicated in patients with eGFR <30 mL/min/1.73 m2. Decreased elimination of dextropropoxyphene and its major pharmacologically active metabolite, norpropoxyphene, has been reported in such patients [92], and its use has been associated with central nervous system (CNS) toxicity, respiratory depression, and cardiotoxicity [93].
●Oxycodone – We avoid use of oxycodone among patients with advanced CKD, whenever possible, due to the risk of respiratory depression [94]. Oxycodone may be used among patients with CKD as a second-line agent after hydromorphone, fentanyl, methadone, or buprenorphine has been attempted. Oxycodone is eliminated mainly by metabolism in the liver to noroxycodone and oxymorphone, both of which were shown to accumulate in patients with advanced CKD [95]. Less than 10 percent of oxycodone is excreted unchanged in the urine [96].
●Meperidine/pethidine – Meperidine or pethidine is contraindicated in all patients with CKD. Meperidine/pethidine is metabolized in the liver mainly to active metabolites with proconvulsive activity, which accumulate in patients with kidney impairment [97].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Pain is a common and distressing symptom among patients with chronic kidney disease (CKD). Many analgesics that are typically used in the non-CKD population should not be used among patients with advanced CKD (ie, estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2; including those on dialysis). (See 'Introduction' above and 'Epidemiology' above.)
●Patients with advanced CKD patients are vulnerable to all the causes of pain that affect the general population. In addition, CKD patients may have pain related to their primary kidney disease or related to dialysis. (See 'Causes' above.)
●Both dialysis and nondialysis CKD patients should be routinely screened for pain. We screen patients for pain using the Edmonton Symptom Assessment System Revised: Renal (ESAS-r:Renal) (form 1). We screen hemodialysis patients monthly and home dialysis patients and predialysis CKD patients quarterly. (See 'Assessment of pain' above.)
●As for the general adult population, treatment options for chronic pain include pharmacologic and nonpharmacologic approaches. Nonpharmacologic modalities are first-line for the treatment of chronic pain in patients with CKD and are generally the same among CKD patients as in the general population. Some patients may be too frail to benefit fully from physical interventions. Behavioral approaches may be challenging and less effective for some CKD patients. (See 'Treatment overview' above.)
●Nociceptive pain is usually due to tissue injury. Causes of nociceptive pain common to patients with advanced CKD include (but are not limited to) osteoarthritis, renal osteodystrophy, dialysis-related amyloid arthropathy, and kidney or liver capsule distension from autosomal dominant polycystic kidney disease (ADPKD). We suggest the following approach, which is based upon clinical experience rather than published data (algorithm 1) (Grade 2C):
•We initiate treatment with acetaminophen.
•For patients who do not respond to acetaminophen alone, a low dose of a strong opioid may be added to acetaminophen. There is no good weak opioid for patients with advanced CKD.
•Preferred opioids include hydromorphone, fentanyl, methadone, or buprenorphine.
●Neuropathic pain arises from abnormal neural activity secondary to disease, injury, or dysfunction of the nervous system. Common examples of neuropathic pain among patients with advanced CKD include diabetic neuropathy, phantom limb pain, and carpel tunnel syndrome. We suggest the following approach, which is based upon clinical experience and expert opinion rather than well-designed clinical trials (algorithm 2) (Grade 2C):
We initiate treatment with gabapentin or pregabalin and then switch to a tricyclic antidepressant (TCA) if the gabapentin or pregabalin are not effective. If TCAs are ineffective, we add analgesics as described above. (See 'Neuropathic pain' above.)
●Mixed nociceptive/neuropathic pain is common among patients with advanced CKD and is most often caused by ischemia. We suggest the following approach, which is based upon clinical experience rather than published data (algorithm 3) (Grade 2C):
•We treat patients with mixed nociceptive and neuropathic pain with acetaminophen and gabapentin or pregabalin.
•For patients who do not respond to acetaminophen plus gabapentin/pregabalin, we add an opioid.
•The preferred opioid for mixed nociceptive/neuropathic pain is methadone.
●We generally do not use nonsteroidal antiinflammatory agents (NSAIDs) among CKD patients. When they are indicated, mostly for acute pain, low doses and close monitoring for adverse effects and the eGFR are recommended (ie, every three months), with discontinuation of the NSAID if the eGFR declines. (See 'Pharmacologic treatment of mild to moderate CKD (eGFR ≥30 mL/min/1.73 m2)' above and 'Drugs that should be avoided' above.)
●We do not use codeine, tramadol, morphine, meperidine/pethidine, or propoxyphene among patients with advanced CKD. Oxycodone may be used among patients with CKD but is considered a second-line agent compared with other opioids discussed above. (See 'Drugs that should be avoided' above.)
