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Pain assessment and management in hemodialysis patients.

LEARNING OBJECTIVES

After reading this article, the reader will be able to:

* Describe the epidemiology and pathophysiology of pain in patients on hemodialysis

* Identify barriers to optimal pain management in this population

* Discuss analgesic considerations when choosing therapy for patients on hemodialysis

* Compare and contrast the strengths and limitations of the renal adaptation of the World Health Organization (WHO) analgesic ladder

INTRODUCTION

The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (Menkey, 1994)." Chronic pain is highly prevalent in hemodialysis patients, yet is under-diagnosed and under-treated. Several studies have described the impact and severity of pain in these patients, yet there is still a paucity of data regarding optimal management. The aims of this article are to review the studies that have explored pain assessment and management in patients on hemodialysis, and to propose quality improvement strategies that can be implemented in daily practice to address the problem of pain.

EPIDEMIOLOGY OF PAIN

Pain is one of the most common symptoms in patients with end stage renal disease (ESRD) (Cohen, 2007; Mercadante, 2005; Bailie, 2004). At least 50% of hemodialysis patients experience pain, and up to 82% of these patients report pain of moderate to severe intensity (Davison, 2003). Despite this high prevalence, a growing body of literature has shown that pain in the dialysis population is inadequately managed. In a cohort of Canadian hemodialysis patients, 75% were found to have a negative Pain Management Index, a score that is indicative of ineffective pain control (Davison, 2003). The Dialysis Outcomes and Practice Patterns Study (DOPPS) found that despite an increasing prevalence of chronic pain, analgesic use decreased, suggesting possible under-prescribing (Bailie, 2004). Furthermore, a recent systematic review reported rates of effective pain control in ESRD patients varying from 17% to 38%, and up to 84% of patients with significant pain receiving no analgesia (Wyne, 2011). Overall, this evidence highlights a lack of effective pain management strategies in dialysis facilities. There is a clear need for programs to ensure the timely identification, assessment, and provision of appropriate analgesia in these under-treated patients.

PATHOPHYSIOLOGY

Pain experienced by dialysis patients is often multifactorial, and includes nociceptive, somatic, visceral, neuropathic, and complex regional pain syndromes (Davison, 2003). The etiology of pain may be secondary to co-morbidities (e.g., diabetes, vascular disease), the primary renal disease (e.g., polycystic kidney disease), consequences of renal failure (e.g., calciphylaxis, renal osteodystrophy), or the dialysis treatment itself (e.g., recurrent needle insertion, arteriovenous fistulas). Dialysis may also induce severe headaches as a result of a large amount of water and electrolyte shifts (Goksan, 2004). In a prospective cohort study of 205 Canadian hemodialysis patients, musculoskeletal pain was reported as the most common (65%) cause of pain, followed by dialysis procedure-related pain (14%), peripheral neuropathy (15%), and peripheral vascular disease (10%) (Davison, 2003). Distinguishing between the different types of pain and their potential causes is important in determining optimal management strategies.

IMPACT OF PAIN ON OUTCOMES

Pain impacts multiple aspects of the patient's well-being, and is associated with psychological distress, impairment of interpersonal relationships, significant functional limitations, and excessive use of health care (Sanders, 1985; Von Korff 1988). Dialysis patients experience a tremendous symptom burden, yet pain alone accounts for up to 32% of the variability in health-related quality of life (Davison, 2010). Several studies have confirmed an inverse relationship between the existence of pain and dialysis patients' self-reported quality of life (Weisbord, 2005; Kimmel, 2003).

Observational studies suggest that under-managed pain has the potential to induce or exacerbate co-morbid conditions in ESRD, which may adversely affect dialysis treatment (Weisbord, 2005). In a cross-sectional study of Canadian hemodialysis patients by Davison et al. from 2001 to 2002, there was a significantly higher prevalence of depression, anxiety, severe irritability, inability to cope with stress, and insomnia in patients with moderate or severe chronic pain compared to patients with mild or no pain. In addition, patients with moderate or severe pain were found to be more likely to consider withdrawal from dialysis (Davison, 2005).

These findings emphasize that the ramifications of under-treated pain are extensive. Optimizing pain management in the hemodialysis population is essential to prevent the progression of psychiatric co-morbidities, optimize the use of health care resources and, ultimately, improve the patients' quality of life.

BARRIERS TO ADEQUATE PAIN MANAGEMENT

Common barriers to adequate pain management include patient under-reporting of pain, fear of addiction and adverse effects, lack of staff time and training, and inadequate pain assessment (Anderson, 2000). Dialysis patients are frequently assessed by nephrologists due to the repetitive nature of the schedule, yet pain assessments are not routinely performed. Health care professionals should adopt a more active approach to screening pain, as patients often do not report pain unless asked explicitly (Barakzoy, 2006). Language is also a major barrier to optimal pain management, as a high proportion (up to 42%) of dialysis patients do not speak English (Salisbury, 2009).

Analgesic use is complicated by altered pharmacokinetics and pharmacodynamics in dialysis. This may be a perceived barrier by clinicians to optimize pain management. Effective prescribing of analgesics must be balanced with safety considerations, particularly in this fragile population. Advanced age, multiple co-morbidities, and polypharmacy further increase the potential risk for analgesic toxicities (Nayak-Rao, 2011). Other safety concerns must also be weighed for each patient when considering selected analgesics, including potential risks of delirium, falls, and misuse or abuse, particularly with opioid therapy (O'Neil, 2012). Routine screening for risk before prescribing and ongoing reassessment are necessary (Glick, 2011).

PAIN ASSESSMENT

Pain assessment involves an organized and detailed history to elucidate the cause of pain, its location, quality, severity and, finally, the impact on physical, social, and emotional functioning (Glick, 2011). Clinical trials have used several general pain assessment tools in the dialysis population, including the Brief Pain Inventory (Calero, 2009; Gamondi, 2013; Golan, 2009), McGill Pain Questionnaire (Davison, 2003; Barakzoy, 2006; Calero, 2009; Harris, 2012; Masajtis-Zagajewska, 2011; Binik, 1982), and the Pain Management Index (Davison, 2003; Calero, 2009). The BC Renal Agency has developed a nephrology-specific pain measurement tool, accounting for different pain types, patient goals, medications, and effects on quality of life in chronic kidney disease patients. However, none of these tools have been validated specifically in the dialysis population, and it may be unrealistic to rely on multiple tools in a clinical setting. There remains a need for simple, validated screening and assessment tools for pain in the dialysis population.

Implementing routine pain screening is the first step to developing effective pain management strategies. Frequent measurement of pain intensity, quality, and impact on function is critical to identify patients with inadequate pain management and guide appropriate interventions. For example, symptoms of neuropathic pain likely have poor response to opioid therapy; adjuvants such as antidepressants or anti-convulsants may be required (Nayak-Rao, 2011).

ANALGESIC CONSIDERATIONS IN DIALYSIS

The role of dialysis in the clearance of a drug and/or its metabolites is very complex. The properties of the parent drug and its metabolites have to be considered, as well as technical factors related to the dialysis procedure (Dean, 2004). Within the opioid class, lipophilic drugs with low solubility and high volume of distribution such as fentanyl and methadone are less likely to be removed with dialysis compared with less protein-avid and more water-soluble molecules like oxycodone, morphine, hydromorphone, and their metabolites (Glick, 2011). The extent of renal and non-renal clearances of the drug is also an important factor. For example, acetaminophen is mostly cleared by the liver, and so dialysis will have little effect upon its clearance. The pharmacokinetics of analgesics in ESRD is beyond the scope of this article, but is described in several nephrology review articles (Kurella, 2003; Dean, 2004; Launay-Vacher, 2005; Glick, 2011; Nayak-Rao, 2011).

Analgesic use involves a small margin between relieving pain and causing unwanted effects, especially in ESRD (Daines, 2004). Opioids can accumulate in the body and cause significant adverse effects such as respiratory depression, sedation and myoclonus (Davison, 2003; Kurella, 2003; Rehm, 2003). Conversely, effective pain control may be compromised if the analgesic is easily removed with hemodialysis. Routine monitoring during and after dialysis is essential to determine the need for supplemental analgesia and to identify signs and symptoms of toxicity (Salisbury, 2009). In general, analgesics should be started at low doses and titrated carefully in hemodialysis patients.

GUIDELINES FOR ANALGESIC USE IN DIALYSIS

Although pharmacological reviews of analgesic use in renal failure have been published, there are no consensus guidelines for pain management specific to the renal context. The World Health Organization (WHO) three-step analgesic ladder has been recommended to guide treatment of patients with end stage renal disease in several review articles in nephrology literature (Kurella, 2003; Rehm, 2003; Davison, 2003; Davison, 2005). Recent prospective validation studies (Barakzoy, 2006; Salisbury, 2009) have demonstrated that implementation of a renal adaptation of the WHO analgesic ladder can significantly reduce pain scores in hemodialysis patients.

Details on the renal adaptation of the WHO analgesic ladder can be found in Table 1. In ESRD patients, acetaminophen, tramadol, and fentanyl are the most appropriate medications for mild (step 1), moderate (step 2) and severe (step 3) pain respectively. There is limited evidence on the use of buprenorphine, oxycodone and hydromorphone. Methadone is safe, but should only be prescribed by a clinician experienced in its use. Morphine and codeine are not recommended because of metabolite accumulation (Murtagh, 2007). Adjuvants such as anticonvulsants and antidepressants may be co-administered at any stage of the WHO ladder for neuropathic pain (Glick, 2011).
Table 1: Renal adaptation of the WHO Analgesic Ladder
(Barakzoy, 2006; Murtagh, 2006; Salisbury, 2009; Glick, 2011)

WHO            Analgesic        Recommendation      Adverse Effects
Ladder

Step 1:    Acetaminophen      The National        Hepatotoxicity has
Mild Pain                     Kidney Foundation   been reported in
                              recommends          persons with
                              acetaminophen as    underlying liver
                              the non-narcotic    disease or
                              analgesic of        long-term alcohol
                              choice for          use with doses
                              mild-to-moderate    exceeding 4,000
                              pain in ESRD.       mg/day.

           Non-Steroidal      Topical gels        Loss of residual
           Anti-Inflammatory  acceptable. Oral    renal function,
           Drugs (NSAIDs)     agents discouraged  sodium and water
           (e.g., Ibuprofen,  in patients with    retention,
           Naproxen)          residual urine      hypertension,
                              output, advanced    hyperkalemia, and
                              age, or multiple    increased
                              co-morbidities.     gastrointestinal
                                                  bleeding risk when
                                                  compounded by
                                                  uremic-induced
                                                  poor platelet
                                                  function.

Step 2:    Tramadol           Recommended. Safer  Side effects are
Moderate                      than oxycodone,     similar to those
Pain                          although dose       of opioids:
                              adjustment may be   nausea, central
                              necessary due to    nervous system
                              renal clearance.    (CNS) depression,
                                                  and constipation.
                                                  Tramadol may cause
                                                  seizures in
                                                  conditions
                                                  associated with a
                                                  lowered seizure
                                                  threshold. Risk
                                                  for serotonin
                                                  syndrome with
                                                  concomitant
                                                  serotonergic
                                                  medications.

           Oxycodone          Use cautiously. No  Nausea, CNS
                              data available on   depression, and
                              dialysis of         constipation.
                              oxycodone.

Step 3:    Hydromorphone      Use cautiously.     Nausea, CNS
Severe                        Hydromorphone has   depression, and
Pain                          been used without   constipation.
                              adverse effects in  Metabolite
                              dialysis patients,  accumulation may
                              but there are no    cause
                              data concerning     neuro-excitation
                              dialysis of the     with agitation,
                              metabolites, and    confusion, and
                              metabolite          hallucinations.
                              accumulation is a
                              risk.

           Fentanyl           Recommended.        Nausea, CNS
                              Appears safe, at    depression, and
                              least over short    constipation.
                              periods. It is
                              largely cleared by
                              the liver, and
                              metabolites are
                              inactive.

           Methadone          Recommended.        Nausea, CNS
                              Appears safe, at    depression, and
                              least over short    constipation. High
                              periods. It is      potential for drug
                              largely cleared by  interactions.
                              the liver, and
                              metabolites are
                              inactive.

Unsafe: Codeine, Morphine, Meperidine, and Propoxyphene are not
recommended in hemodialysis patients due to case reports of
accumulation and toxicity in renal failure.


The use of the WHO ladder in dialysis has several limitations. First, the algorithm was originally devised for patients with cancer and may not directly apply to patients with chronic kidney disease (Williams, 2008). Second, it does not provide guidance on specific dosing of analgesics in hemodialysis. Lastly, long-term efficacy and the development of tolerance over time remains unknown, as only short-term studies have been conducted (Nayak-Rao, 2011). However, until further research is conducted, the WHO ladder is the only validated clinical tool available for use in hemodialysis patients.

Non-pharmacological options such as the use of ice, heat, or massage should also be considered as part of a multimodal approach to pain management. However, there is a lack of research on the use of complementary therapies for pain in patients with ESRD. Although they have not been studied in dialysis patients in particular, strategies such as transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS), and acupuncture can be helpful in the treatment of neuropathic pain (Innis, 2006).

CONCLUSION

Chronic pain is a common and disabling symptom for hemodialysis patients and adds significantly to their burden of disease (Nayak-Rao, 2011). Effective pain management can enhance patient outcomes such as patient comfort, safety, and satisfaction of care that will improve overall quality of life (Williams, 2008). Routine pain assessments and the use of clinical guidelines are evidence-based strategies that should be implemented in all dialysis facilities to improve the quality of patient care. There is a need for additional research to validate assessment tools, update pharmacokinetic studies and inform more detailed guidelines and clinical decision tools.

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Charisse De Castro, PharmD Student, Laura Murphy, PharmD, and Marisa Battistella, BScPhm, PharmD, ACPR

Charisse De Castro, PharmD Student, University Health Network, Toronto, ON

Laura Murphy, PharmD, University Health Network, Toronto, ON

Marisa Battistella, BScPhm, PharmD, ACPR, Clinician Scientist, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto ON. Clinical Pharmacist--Nephrology, University Health Network, Toronto, ON

Address correspondence to: Marisa Battistella, BScPhm, PharmD, ACPR, Clinical Pharmacist--Nephrology, University Health Network, 200 Elizabeth Street, EB 214, Toronto, ON M5G 2C4

Email: marisa.battistella@uhn.ca
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Title Annotation:CONTINUING EDUCATION SERIES
Author:De Castro, Charisse; Student, PharmD; Murphy, Laura; PharmD; Battistella, Marisa; BScPhm
Publication:CANNT Journal
Geographic Code:1CANA
Date:Jul 1, 2013
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