When ESKD complicates the management of pain

Abstract

Pain is one of the most common symptoms reported by patients with end-stage kidney disease (ESKD) and negatively impacts their health-related quality of life (HRQOL), dialysis adherence, healthcare utilization, and mortality. There are a number of patient-related and health system-related barriers that make it very challenging to treat pain in these patients. Moreover, the limited availability of efficacious and safe nonopiate analgesic options has led to over-use of opioids in this population. We propose a framework for pain assessment and tailored treatment using nonpharmacological and pharmacological approaches to optimize pain management and opioid use. Additionally, we recommend system-level changes to improve care coordination and pain management in ESKD patients.

1 ∣. INTRODUCTION

Pain is one of the most common symptoms, reported by 30%-60% of patients with end-stage kidney disease (ESKD).^1-3 In fact, the prevalence of pain in this population is similar to that in patients with advanced cancer.³ Unfortunately, pain is frequently underdiagnosed and undertreated in ESKD patients. Fewer than 50% of hemodialysis (HD) patients with pain report using analgesics, and 75% have ineffective pain management.^2,4,5 Untreated pain negatively impacts patient's health-related quality of life (HRQOL), dialysis adherence, healthcare utilization, and mortality.^6-8 Moreover, the limited availability of efficacious and safe nonopiate analgesic options has led to overuse of opioids in this population. Over 20% of patients with ESKD in the United States use chronic opioids (defined as ≥90 days of use), which is three times the rate in the general Medicare population.⁹ More than 50% of HD patients on chronic opioids receive opioids that are not recommended or lack safety data in HD. Often the prescribed doses exceed recommendations of the Center for Disease Control and Prevention (CDC). Over one-third of the HD patients receive >50 morphine milligram equivalent per day (MME/d).⁹ Chronic opioid use in HD patients has been associated with increased risk of altered mental status, falls, fractures, hospitalizations, and mortality, in a dose-dependent manner.^9,10

1.1 ∣. Challenges to pain management in ESKD

1.1.1 ∣. Pain in ESKD is unique

The multiple etiologies of pain in ESKD complicate the experience of pain as well as the approach to treatment. Chronic pain in ESKD can be due to (a) underlying comorbid diseases such as diabetic neuropathy, peripheral vascular disease, amputations, rheumatological conditions, polycystic kidney disease; (b) complications of ESKD such as osteodystrophy, amyloid-related arthropathy, uremic neuropathy, calciphylaxis, fractures; and (c) causes related to the dialysis treatment itself—including muscular cramps, headaches, cannulation of arteriovenous fistula or graft, instillation or drainage of peritoneal fluid, and intestinal or cardiac ischemia precipitated by aggressive ultrafiltration during hemodialysis. These varying etiologies can result in different types of pain such as neuropathic (aching, dull, throbbing, cramping, pressure), nociceptive (tingling, burning, and numbness), or mixed.

1.1.2 ∣. Pain perception in ESKD may be altered

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential damage.¹¹ There is no “pain meter” that can verify the degree of pain, or “legitimate” pain. It is a subjective experience, and can only be known by the individual experiencing pain. What is unique about pain in this population is that it often coexists with a number of physical and/or psychological symptoms and conditions that may impair patient's pain coping or resiliency skills. As a result, patients with ESKD may experience and perceive pain at much lower thresholds than patients without ESKD. For example, depression, which affects 20%-25% of ESKD patients,¹² and anxiety, which affects 12%-52% of patients, can exacerbate the pain experience, increase pain-related disability and present barriers to pain management.^12,13 Depression and anxiety may also influence patient's motivation and/or willingness to seek treatment or comply with treatment recommendations. Maladaptive stress coping mechanisms are disproportionately common in patients with ESKD and may additionally impact pain perception and its management in ESKD.^14,15 A variety of other factors common in ESKD such as fatigue, poor sleep, sedentary behavior, deconditioning, social isolation, low socio-economic status, and poor health literacy may affect not only resiliency to pain but also access and ability to partake in therapies for pain such as physical rehabilitation.

1.1.3 ∣. Systems barriers to pain management in ESKD

A number of system-related barriers complicate pain management in patients with ESKD. Because of intense and frequent engagement with nephrologists, patients with ESKD may have limited or no relationship with primary care and their nephrologist is their PCP.¹⁶ In fact, a national survey of more than 200 nephrologists in the United States, >90% of the nephrologists reported providing primary care for their ESKD patients.¹⁶ However, nephrologists may not have the training, experience or comfort level to manage pain. In a survey of 27 renal providers, 60% believed this to be the responsibility of the primary care physician (PCP) or pain specialists.¹⁷ Moreover, pain management can be a time-consuming process and it can strain the doctor-patient relationship if there is disagreement regarding treatment plan, especially opioid use. Because of the high frequency of nephrologist-dialysis patient interactions (once weekly or more), it is possible that nephrologists may be particularly reluctant to engage in this aspect of care out of concern that it will erode their relationship. On the other hand, pain is one of most common reasons for primary care visits, and internal medicine and family medicine are the top two specialties prescribing opioids in the United States.^18,19 PCPs (who choose to manage pain) and pain specialists should have the experience to routinely manage pain and are expected to have the systems in place to ensure appropriate opioid prescribing and monitoring given stricter regulations surrounding these, but may still need additional training regarding safety, efficacy, and dialyzability of analgesic medications in ESKD.

Additionally, the traditional dialysis care model uses quality metrics that lead to misaligned priorities between the dialysis providers and patients. The Center for Medicare and Medicaid Services (CMS) ESKD Quality Incentive Program links financial reimbursements for dialysis facilities to a core set of quality measures. These quality measures are based on biochemical parameters and not on measures of patients’ functional or emotional well-being or quality of life. Thus, even if personally motivated, such system-level barriers further reduce nephrologists’ desire to manage their patients’ pain. Moreover, nephrologists usually see patients while they are being dialyzed, which offers little privacy for discussing sensitive issues such as pain or opioid use. The lack of additional staff or resources in the dialysis setting to engage in symptom assessment and care coordination adds to the challenges. A low or lack of reimbursement for nonpharmacological pain treatment options and the lack of specialized practitioners that offer such treatments present other structural barriers. Lastly, the time to attend additional visits for treatments such as physical therapy or behavioral therapy is also limited because of the 15 plus hours per week spent in hemodialysis treatments and/or transporting back and forth to dialysis unit.

1.2 ∣. Recommendations for Pain Management in ESKD

Given how prevalent and debilitating pain is in dialysis patients, managing pain should be one of the top priorities for the nephrology and pain clinical and scientific communities. There is a need to rethink and change current clinical paradigm. More emphasis on patient-centered outcomes rather than laboratory outcomes in nephrology and dialysis care is a policy change that is needed. Another clinical work flow alteration integration of a functional multidisciplinary team into overall clinical management. This team would be in addition to the existing team of nephrologist, nurses, social workers, and dietitians who currently exist in dialysis units, and would include psychologists, pain specialists, and care coordinators who would facilitate symptom management. Managing pain and symptoms should be organized within a framework of regular evaluation and monitoring, tailored pharmacological and nonpharmacological treatment approaches, and system-level solutions that optimize access to organizational and community resources for pain management (Figure 1).

FIGURE 1.

Framework for designing approaches to improve pain management in patients with end-stage kidney disease

1.2.1 ∣. Pain assessment

Pain should be assessed regularly to identify the specific sources of pain and their impact on the patient's quality of life and functioning. The assessment should be repeated at frequent intervals to assess efficacy of treatments and reveal new symptoms. The Pain, Enjoyment, general Activity (PEG) scale is a three-question screening tool that measures three domains of pain- average level of pain, enjoyment of life, and interference with daily activities. Although it has not been validated in patients with ESKD, it has been shown to have excellent reliability, validity, and responsiveness in nondialysis patients with chronic pain and its brevity reduces questionnaire fatigue.²⁰ The assessment should also include screening for coexisting depression and anxiety, which may require different treatment approaches than for pain, and for fatigue and patient’s overall HRQOL, which can be tracked as part of the response to therapy. Some of the validated measures for such assessments are Patient Health Questionnaire-9 (PHQ-9) for depression.²¹ Generalized Anxiety Disorder-7 (GAD-7) for anxiety,²² and Kidney Disease Quality of Life-36 (KDQOL-36) for HRQOL.²³

1.2.2 ∣. Treatment approaches for pain—General principles

Treatment for pain should be tailored to each individual according to type and severity of pain. Realistic goals of pain management and expectations should be discussed prior to initiation of treatment with the focus being improving pain to a tolerable level to optimize patient's functional status and reduce its negative impact on patient's HRQOL. A stepped care approach should be adopted which may be defined as “the least costly, least intensive, and least restrictive treatment judged sufficient to meet the person's needs and goals.”²⁴ This approach recognizes that different treatment strategies work for different patients, as well as emphasizes the need for tailored management and shared decision-making to guide treatment decisions.²⁵

In general, nonpharmacological options should be used first, given potential for adverse side effects and limited data on the safety and efficacy of the commonly prescribed analgesic medications in the setting of ESKD. Nonpharmacological treatment options can be broadly categorized as psychosocial/behavioral interventions (cognitive behavioral therapy, mindfulness, etc) and physical interventions (exercise, physical therapy, yoga, acupuncture, electrical stimulation, etc). Although most of these have not been specifically tested in ESKD, they have been proven to be efficacious in other chronic disease states and provide a promising approach for the treatment of pain in ESKD patients, either alone or as an adjunct to pharmacological treatment.^26-29 Additionally, specific treatment directly targeting coexisting symptoms may improve an individual's experience of pain by improving their motivation to seek and comply with pain treatment recommendations, and also by building resiliency and pain coping skills.

Choice of analgesic medications should be based on character and severity of pain, and benefits of medications should be cautiously weighed against the possible side-effects, drug-drug interactions, and added pill burden. We recommend patients to be started on minimal dose of an analgesic medication and up-titrated slowly based upon response and tolerance with close monitoring of adverse effects. An opioid-sparing approach should be followed. For chronic pain, scheduled doses over 24 hours period at regular intervals should be used with “as needed doses” of breakthrough medications.

1.2.3 ∣. Nonpharmacological—Psychosocial/behavioral interventions

Table 1 summarizes evidence from select studies in ESKD population which reported effect of nonpharmacological approaches on pain. Cognitive Behavior Therapy (CBT) has become a well-established and well-accepted treatment for chronic pain in the general population. Robust evidence from a meta-analysis of 35 trials (>4700 patients) supports its efficacy for improving chronic pain and pain-related disability in the general population, although the effect may be small and not durable.²⁹ Weak data hints at the possibility that CBT may help with opioid dose reduction or discontinuation in patients on long-term opioid therapy.³⁰ In the ESKD population, CBT is effective in improving depression, but its effect on pain has not been tested.³¹ Given that CBT is efficacious in other chronic disease states with high pain and symptom burden such as advanced cancer³² and is based on conceptual models that highlight precipitating and perpetuating factors (such as poor self-management skills, coping strategies, which typically exist in ESKD patients, there is a strong rationale for hypothesizing that CBT may be a successful pain management strategy in this population.

TABLE 1.

Nonpharmacological approaches for pain management in ESKD population: evidence from selected studies

Author, year	Patient population	Study design	Duration of intervention	Results
Behavioral therapy
Ramezanzadeh et al, 201633	30 HD patients, age range: 20-55 y, 65% males	RCT: 8 sessions of Acceptance and Commitment Therapy (ACT) (each 1 h) vs usual care	Not available	Significantly improvement in pain catastrophizing scale (P < .05)
Mindfulness
Heidari Gorji et al, 201435	80 HD patients, mean age 48 y, 55% males	RCT: Benson relaxation training for 15 min twice daily vs usual care	4 wk	19% decrease in pain postintervention (P < .001) (compared to preintervention levels) but no significant difference between the 2 arms
Rambod et al, 201436	86 HD patients, mean age 50 y, 60% males	RCT: audiotape of Benson relaxation technique twice a day each time for 20 min	8 wk	Significantly improvement in pain intensity
Physical therapy/exercise
Painter et al, 200042	180 HD patients, mean age 54 y, 55% males	two-parallel arm: 8-week of individually prescribed home exercise followed by 8 wk of cycling during HD vs control arm	16 wk	15% improvement in bodily pain (P = .003)
Rhee et al, 201943	22 HD patients, Mean age 57 y, 41% male	Single arm cohort study—Combination of aerobic exercise with bicycle ergometer and anaerobic exercise with elastic bands during HD	6 mo	10% improvement in bodily pain (P = .014)
Yoga
Yurtkuran et al, 200748	37 HD patients, mean age 40 y, 40% males	RCT: Modified yoga-based exercise, 30 min/d, twice a week during HD, Group sessions directed by certified yoga teacher vs usual care	3 mo	37% in pain intensity (P = .03)
Music therapy
Burrai et al, 201939	24 patients on HD (mean HD vintage 6.3 y), Mean age 62.3 y, 62.5% male	RCT: 15 min of live music (sung by a trained nurse) during HD	4 wk	Significant improvement in pain by about 3 points (measured on visual analog scale) (P < .001)
Burrai et al, 201440	114 patients on HD, Mean age 68.2 y, 43% male	RCT: 30 min of live saxophone music during HD vs Control (Standard care)	4 wk	Pain showed a significant reduction of 48.1% in the intervention vs control group (P < .001)
Acupuncture
Bullen et al, 201871	101 HD patients, Mean age 57.6 y, Dialysis vintage 7.5 y, 58% male	Single arm cohort study—20 min of acupuncture or massage once a week	8 wk	10.5% reduction in pain

Acceptance and Commitment Therapy (ACT), is the latest generation therapeutic approach for pain. ACT provides strategies to increase willingness to experience aspects of chronic pain that may be difficult to alter (acceptance) and allows patients to engage in valued life activities even in the face of pain (committed action). Evidence from meta-analysis in the general population shows moderate to large effect size efficacy of ACT on acceptance, psychological flexibility, pain interference, and physical functioning outcomes.²⁷ There is limited experience with ACT in dialysis patients. A small study from Iran involving 30 hemodialysis patients showed improvements in pain with eight sessions of ACT as compared to usual care.³³

Two large ongoing trials in the United States will provide more evidence on the effectiveness of such behavioral interventions on pain in ESKD population. The Technology Assisted Collaborative Care (TACcare) trial is a randomized controlled trial (RCT) testing telemedicine-delivered CBT ± pharmacotherapy versus health education attention control to treat pain, depression, and fatigue in HD patients using.³⁴ The recently funded Hemodialysis Opioid Prescription Effort (HOPE) Consortium will conduct a multisite pragmatic RCT to improve pain control and opioid use in HD, and will include a behavioral therapy-based intervention.

Other behavioral interventions such as relaxation techniques and biofeedback have shown conflicting results. A systematic review of RCTs assessing relaxation techniques among >400 patients with chronic pain in the general population found no benefit in reducing pain, however, the studies were of low quality and thus the data are insufficient to be conclusive at this time.²⁶ In hemodialysis patients, two small studies indicate such relaxation techniques may improve pain intensity and HRQOL (Table 1).^35,36 Mindfulness-based meditation, which involves focusing the mind on experiences (like emotions, thoughts, and sensations) in the present moment, has shown some promise in improving pain in the non-ESKD population.³⁷ A recent pilot study demonstrated that a brief, individualized, chairside mindfulness meditation intervention was feasible and acceptable to HD patients³⁸ and live music therapy during HD has shown some promise in improving pain in two small studies.^39,40 Larger studies are needed to evaluate feasibility and effectiveness of all of the relaxation/ mindfulness meditation-based therapies in patients with ESKD.

1.2.4 ∣. Nonpharmacological—Physical interventions

Resistance training and coordination/stabilization exercise programs have been shown to have beneficial effect in chronic low back pain in a number of trials in non-ESKD populations.²⁸ In ESKD patients, a meta-analysis of >40 RCTs of exercise or physical activity intervention demonstrated a beneficial effect on HRQOL, although most of the studies have been limited by small sample size and/or other methodological limitations.⁴¹ A few of these studies reported pain as an outcome, and the reported effect was generally small.^42,43 Other physical interventions such as yoga, acupuncture, and electrical stimulation have limited data and/or limited efficacy in both ESKD and non-ESKD patients.^44-46 For example, a meta-analysis of effect of yoga on chronic low back pain included 12 trials (>1000 patients) and concluded that yoga may have some improvement in pain at 3 and 6 months, but the effect was small and not clinically important.⁴⁶ Two RCTs have assessed yoga in HD patients, only one of which showed improvement in pain.^47,48 More research is needed to evaluate the effect of the physical interventions in improving pain outcomes in ESKD.

1.3 ∣. Pharmacological approaches

1.3.1 ∣. Nonopioid medications

The choice of analgesic medication is based on whether the pain is predominantly neuropathic or nociceptive in nature. We have summarized some of the recommended medications from a number of recent reviews focused on pharmacological management of pain in Tables 2 and 3.^49-52 Since dialysis can affect pharmacokinetics and dialyzability of these medications, special consideration should be given to the dosing and timing of these medications. Some of the medications that should be avoided in ESKD are listed in Table 4.^49,50

TABLE 2.

Neuropathic pain treatment options for dialysis patients^a

Medication	Dosing in HD	Pharmacokinetics in HD	Max dose for HD	Special considerations
Gabapentin53	Start at 100 mg qhs and increase weekly by 100 mg qhs	T ½ = 50-130 h 35% removed by HD, Supplemental dose of 100-300 mg can be given post-HD54	300 mg qhs	If ineffective at maximum tolerated dose after 2-4 wk, discontinue and start pregabalin
Pregabalin54	Start at 25 mg qhs (given post-HD)	Dialyzed (50% dialyzed in 4 h), Supplemental dose of 75-100 mg can be given post HD	75 mg qhs	If ineffective at maximum tolerated dose after 2-4 wk, discontinue
Duloxetine (SNRI)	Start with 20 mg qd	Not dialyzed	30 mg/d	Limited data
Tricyclic antidepressant Amitryptyline	Start with 25 mg qd	Not dialyzed	100 mg/d	Caution in elderly and cardiac patients May be useful in patients with pain and insomnia Can have anticholinergic side effects such as dry mouth, urinary retention, orthostatic hypotension

Abbreviation: qd, daily; qhs, every night at bedtime.

^aThe medication list is not meant to be exhaustive but provides a list of preferred choices based on available safety and efficacy data in dialysis patients.

TABLE 3.

Nociceptive pain treatment options for dialysis patients^a

Medication	Dosing in HD	Pharmacokinetics in HD	Max dose for HD	Special considerations
Stage 1: Mild pain
Acetaminophen	650 mg every 8 h, no dose adjustment for HD, Dialyzed by HD but supplemental dose not necessary	T ½ = 1-4 h		4000 mg/d; 2000 mg/d (or not at all) if liver disease or daily alcohol
Topical analgesic (Capsaicin, lidocaine, or menthol-containing creams)72	No dose adjustment for HD	Peripherally absorbed and used		Topical NSAIDs are considered safer although data in ESKD is limited. Avoid use over extensive surface area use.
NSAIDs (Naproxen and Celecoxib—Preferred NSAIDs because of potentially less cardiovascular risk)	No dose adjustment for HD			Use for short term as time limited trial with careful monitoring for adverse events—worsening of hypertension, hyperkalemia, volume retention, gastrointestinal bleed, and loss of residual renal function60,73,74
Stage 2: Moderate to severe pain
Oxycodone (short acting)68	Start with 2.5 mg q 12 hr, Only 10% Dialyzed by HD	T ½ = 3-5 h		Use caution if requiring more than 30 mg (~50 MME) per day, may need referral to pain specialist
Stage 3: Severe pain
Hydromorphone (short acting)	Start at 0.5-1 mg po q 6 hrs, About 50% is dialyzed by HD, thus limiting risk of accumulation in HD pts	T ½ = 3-6 h		Use caution if requiring more than 12.5 mg (~50 MME) per day, may need referral to pain specialist
Buprenorphine69 (transdermal or sublingual)	Transdermal start at 5 mcg every week; For opioid tolerant patients, on MME > 30 mg/d can start at sublingual 1 mg every 6 h	T½ =20-73 h, analgesic effect is 6 h; elimination is through bile secretion, not dialyzed		Buprenorphine/naloxone combination medication indicated for sublingual dosing to use in opioid-tolerant patients using at least 30 MME per day. This formulation would be off-label use for pain.
Methadone75	Start 1-2 mg po q12-24 hrs	T1/2 = May be up to 60 h due to slow release from tissue reservoirs, not dialyzed		Monitor for Q-T prolongation
Fentanyl (transdermal)	Dose equivalent dose of patient's oral narcotics, wean oral opioids after 1-2 d	Not dialyzed		Do not start in opioid naïve patient

Abbreviations: MME, Morphine Milligram Equivalent.

^aThe medication list is not meant to be exhaustive but provides a list of preferred choices based on available safety and efficacy data in dialysis patients.

TABLE 4.

Medications to be avoided in ESKD

Medications	Side effects
NSAIDs (for chronic pain)	Cardiotoxicity, GI Bleed, loss of residual kidney function
Codeine	Respiratory and CNS depression, hypotension
Morphine	Respiratory and CNS depression, myoclonus, seizures
Hydrocodone	Limited data
Tapentadol	Limited data
Meperidine	Seizures, altered mental status
Tramadol	Limited data, variable metabolism, seizures, serotonin syndrome

For neuropathic pain (Table 2), the most commonly prescribed medication is gabapentin, which was prescribed in 19% of US dialysis patients with Medicare (per review of Medicare Part D records), while pregabalin was used in 4%. Both are readily dialyzable, with 35% of gabapentin and 50% of pregabalin removed by HD treatment; thus these medications should be given post HD.^53,54 These medications are associated with an increased risk of falls and altered mental status in a dose-response fashion, and their effects may be pronounced in the elderly.⁵⁵ They should be used judiciously, starting with the lowest possible dose, with careful monitoring for side effects. Alternative neuropathic analgesics such as serotonin-norepinephrine reuptake inhibitors (SNRI) or tricyclic antidepressants (TCA) have been extensively studied and efficacious in non-ESKD population, and are in fact recommended as first- or second-line treatments for diabetic neuropathy in a number of international guidelines, including from the American Diabetes Association.⁵⁶ However, data in ESKD is almost nonexistent. These medications are not removed by dialysis, and the anticholinergic and serotonergic effects of these medications may be exacerbated in patients with ESKD. Thus, they should be used cautiously.

When prescribing analgesic medications for nociceptive pain (Table 3), consideration should be given to the severity, chronicity, and location of pain. Acetaminophen is safe and does not require dose adjustment for HD. Although its efficacy in patients with osteoarthritis and low back pain is limited,^57,58 it may be worth a trial for other pain etiologies in patients with ESKD and may provide benefit when taken on a scheduled basis rather than on an “as needed” basis. For localized pain, such as that due to osteoarthritis, or due to cannulation of arteriovenous dialysis access, topical analgesics such as lidocaine can provide effective short-term relief. One of the most commonly used over-the-counter analgesics—nonsteroidal anti-inflammatory drugs (NSAIDs) warrant careful use in patients with ESKD. Potential toxicities include cardiotoxicity (myocardial infarction, stroke, thrombotic events, etc), gastrointestinal bleeding, and loss of residual kidney function if taken over prolonged periods.^59,60 A recent observational study showed an association of NSAID use with mortality in ESKD patients, however, the results are likely confounded by comorbid illnesses.⁶¹ Given these concerns, NSAIDs should be used cautiously under the physician's supervision. Their use should be limited to short periods such as a gout flare or postsurgical pain. Long-term use is not recommended. Topical NSAIDs such as diclofenac or salicylate gel may be safer as there is limited systemic absorption, but prolonged or high-dose use on a large body surface area should be avoided.⁵¹ Cannabinoids have shown promise in improving pain in the general population.⁶² Although medical cannabis has no specific safety profile for patients with ESKD, substances that stimulate the cannabinoid receptors may have a theoretical basis for potential efficacy without compromising renal or other function. Some cannabinoids can cause confusion and sedation, which would increase risk for falls and the other risks associated with altered mental status. Those that are less sedating would be preferred, but clearly more research is needed in this area.

1.3.2 ∣. Opioid medications

Because of the limitation of other classes of medications in patients with ESKD on dialysis, opioids may be useful in individual cases. Based on the Center for Disease Control guidelines, some of the general principles of opioid use are outlined below.⁶³ These include using an opioid sparing approach, that is, maximizing nonopioid analgesics and nonpharmacological options first, weighing risks and benefits at initiation and then every 3 months or more frequently as needed. Before starting opioids, clinicians should establish realistic treatment goals with patients and administer an opioid agreement which outlines goals and monitoring procedures, responsibilities of the patient (eg, how to get refills, single opiate prescriber) and how opioids will be discontinued if benefits do not outweigh risks. Opioids should be started with the lowest possible dose and considered to be a “test”, using immediate-release formulations (instead of extended-release). If the pain is not responsive with a low dose, the pain may not be opioid responsive pain. If the pain responds slightly, for either shorter periods than desired or to a lower degree than desired, it may be reasonable to increase the dose or the frequency. Prescribers should be exceedingly cautious with opioids at morphine milligram equivalent daily dose (MME) above 50 mg. Concurrent benzodiazepines and other sedatives should be avoided.

Opioid use should be monitored by reviewing prescription drug monitoring program data and using drug screens, pill counts, or self-reported questionnaires [such as the Current Opioid Misuse Measure (COMM)⁶⁴]. Monitoring with drug testing, a staple of guideline concordant care in patients on chronic opioid therapy, requires testing using oral fluid in patients with ESKD. It generally has good sensitivity and specificity, but the window of detection is shorter than for urine drug testing.⁶⁵ It should capture the use of chronic opioid but the shortened detection may miss use of illicit opioids that are taken intermittently. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone.

The therapeutic window for opioid medications is narrow. In meta-analysis of randomized clinical trials in the general population, the efficacy of opioid on improved pain relief and function has been modest, with less than 1 point improvement on a 10-point Likert pain scale and 2 points improvement on a 100-point physical function scale.⁶⁶ Individuals with CKD or ESKD have not been included in these trials, so the specific analgesic impact is not known in this population. However, it is likely that individuals with ESKD experience the many known side effects of opioids, including sedation, confusion, constipation, and injuries associated with falls.⁶⁷ While the literature on these specific effects is limited in populations with ESKD, this is well documented in the elderly, which represents a high proportion of the individuals with ESKD. The constipation from opioid use may increase the risk of peritonitis for patients on peritoneal dialysis. Even low dose opioids are associated with increased morbidity and mortality in the context of ESKD.^9,10

ESKD and dialysis induces an additional complication regarding metabolism and dialyzability of opioids. The naturally occurring opioids (eg, morphine, codeine) have active metabolites, which may increase their toxicity in ESKD. The semi-synthetic opioids such as hydromorphone (Dilaudid™), the synthetic opioids (fentanyl, methadone), and the semisynthetic (from thebaine, not morphine) opioid buprenorphine do not have active metabolites and are safer in patients with ESKD. Thus, naturally occurring opioids should be avoided and only semi-synthetic or synthetic opioids should be prescribed. Although oxycodone is metabolized by the liver into active metabolites which may accumulate in ESKD, it may be used cautiously in these patients; however, sustained-release formulations should be avoided due to the risk of accumulation and toxicity.⁶⁸ Buprenorphine has a lower risk profile and could be substituted, using split dosing every 6 hours or a continuous transdermal patch.⁶⁹

When prescribing opioids, providers should educate patients on risks of opioid overdose and incorporate strategies to mitigate risk into the management plan. This includes considering offering naloxone, an opioid antagonist, when risk factors for opioid overdose such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/d), or concurrent benzodiazepine use, are present.⁶³ Naloxone is not dialyzed out and does not need dose adjustment in ESKD.⁶⁸ Dialysis units should stock naloxone and dialysis staff should be trained how and when to use it.

Tramadol belongs to a class of medication with dual mode of action—both as an agonist of the mu-opioid receptor and as a serotonin-norepinephrine uptake inhibitor (SNRI). Because its metabolism depends on an individual's cytochrome P450 genetic profile, its opioid potency is highly variable and unpredictable.⁷⁰ It may act either as an SNRI or as a strong opioid depending on the individual's metabolism. Additionally, it has multiple interactions with other medications and may result in serotonin syndrome or seizures. It is generally felt to be safe, and listed on the WHO step ladder of analgesia for moderate pain. However, given the variability in effect (with potential potency of a strong opioid), it should be used cautiously, starting with the very smallest dose in patients with ESKD.

1.3.3 ∣. System-level changes

Apart from the individual patient-level recommendations for pain management, we would advocate for system-level changes to prioritize and incentivize symptom management as a key part of overall clinical care in patients with ESKD. Dialysis care team have the unique opportunity to assess patients’ pain and monitor for benefits or side-effects from pain treatments because of frequent contacts with the patient, much more than PCPs. Nephrologists who intend to prescribe meds need training. There also needs to be greater care coordination between the PCP and other pain specialists, with involvement of palliative care if needed. Pain management should be the combined responsibility of all providers. Adding symptom assessment, management, and care coordination will require additional resources and expertise support for the dialysis team.

Lastly, changes at the level of organizational infrastructure and support are needed to improve the access and affordability of nonpharmacological options. Reimbursement for nonpharmacological pain interventions that are efficacious (which remains to be proven) is needed. Testing novel telemedicine-based delivery options for behavioral therapy especially in the dialysis unit, and increasing patient and provider awareness on the availability of such nonpharmacological options may increase their uptake.

2 ∣. CONCLUSION

Pain should be assessed regularly and tailored treatment options provided according to the type of pain. Analgesic medications should be prescribed based on their safety profile in ESKD with special consideration to dialyzability and timing of medications. Opioids may be appropriate in some cases with adequate safety monitoring. More research is needed on the effectiveness of nonpharmacological options and nonopioid analgesic medications for pain treatment in ESKD. Lastly, system-level changes are needed to improve care coordination and pain management in ESKD patients.