Managing Chronic Pain in Advanced Chronic Kidney Disease
Outcome Score (POS) similarly evaluate 31 and 17 common symptoms, respectively, in CKD patients.11,12,45
Approach to Analgesics and Analgesic Choices In 2005, a modified World Health Organization (WHO) analgesic ladder (see Figure 1) for patients with CKD was proposed.46
effectively in a small cohort of dialysis patients with chronic pain. Ninety-six percent of patients obtained benefit; among those with neuropathic pain, post-treatment pain was rated mild or none, and among those with nociceptive pain, post-treatment pain was below 5 out of 10 and they expressed satisfaction with the degree of pain relief.32
Figure 1: World Health Organization Modified Analgesic Ladder Adapted for Chronic Kidney Disease
It was soon implemented
Severe Pain (7–10) Persistent moderate pain
3 Strong opioid ± non-opiod analgesics Despite a
validated approach to analgesics in patients with advanced CKD, high-quality pharmacokinetic and pharmacodynamic data for opioids in CKD are very limited. With this understanding, the recommendations proposed below (summarized in Table 1) rely heavily on expert opinion.
The therapeutic window (relation of drug efficacy to its toxicity) of opioids is particularly narrow in patients with advanced CKD. Reduced renal clearance of parent drug and active metabolites, altered drug distribution and protein binding, reduced drug absorption, potential uremic effects on hepatic enzyme function, and altered renal hemodynamics increase the risk of toxicity in CKD. Dialysis modality will impact drug removal. Lipophilic drugs with low solubility and high volume of distribution such as fentanyl, alfentanil, 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.47,48
Pain
should be monitored during and after dialysis to determine the need for supplemental analgesia, especially when an opioid is easily removed with hemodialysis. Should opioid toxicity occur, prolonged naloxone infusions may be required for lipophilic and protein-bound agents that are poorly dialyzed. Conversely, opioid toxicity that involves more water-soluble compounds may in part be managed by timely dialysis.49
Short-acting
opioid preparations are preferable until a stable and effective dose is clarified. If toxicity develops, this prudent approach limits the duration of undesirable symptoms.
Step 1
For mild pain, acetaminophen is the analgesic of choice and is safe in CKD. It is extensively metabolized by the liver with less than 5 % excreted unchanged via the kidney. Non-steroidal anti-inflammatory drugs (NSAIDs) are generally contraindicated except for acute pain with close clinical observation. Adverse effects of NSAIDs include loss of residual renal function, sodium and water retention, hypertension, hyperkalemia, and increased gastrointestinal bleeding risk when compounded by uremic-induced poor platelet function. There is no evidence that any specific NSAID class is safer for use in CKD patients.46,50
Step 2
For moderate pain, and pain inadequately controlled with step 1 analgesics, weak opioids should be considered. These agents are typically limited by toxicities that develop at doses too low for significant analgesic benefit.
Codeine
Codeine, a low-potency and naturally occurring opioid, is hepatically metabolized and active metabolites are renally cleared. A moderate volume of distribution limits efficient removal with dialysis. Codeine has a
US NEPHROLOGY Moderate pain (4–6) 2 Weak opioid ± non-opiod analgesics Mild pain (1–3) 1
Non-opioid analgesic (acetaminophen) ± adjuvants*
Acetaminophen up to 3.2 g/day. In high-risk patients (malnourished, alcoholic) limit to 2.6 g/day to avoid hepatotoxicity.
*Adjuvants include medications whose primary indication is for conditions other than pain, but that possess analgesic potential (anticonvulsants, A antidepressants). It also refers to drugs used to manage adverse effects (laxatives, anti-emetics, anti-psychotics) and drugs used to treat associated symptoms of anxiety, depression, and insomnia that accompany pain.
Weak opioids: tramadol (≤200 mg daily); hydromorphone (≤9 mg daily). Strong opioids: hydromorphone (≤9 mg daily); fentanyl; methadone; buprenorphine.
ceiling effect in advanced CKD, which limits its therapeutic index,51 including reports of hypotension, sedation, and respiratory instability.52,53 Chronic use of codeine should be avoided in CKD patients.
Oxycodone
Oxycodone is a semi-synthetic opioid, similar to morphine in both analgesic and side effect profile. After extensive hepatic metabolism, small amounts of unchanged oxycodone are found in urine. Active metabolites, however, accumulate in CKD with considerable inter-individual variation.54 Varied case reports of toxicity versus good clinical tolerance have led to a lack of consensus regarding safety in CKD patients. Cautious use starting at low doses in these patients is recommended.13 soluble and can be dialyzed.55
Oxycodone is water Tramadol
Tramadol is a synthetic, peripherally and centrally acting analgesic with relatively weak mu opioid receptor agonism and inhibition of noradrenaline and serotonin reuptake. Adverse effects are typical of opioids. The parent compound is slowly and extensively metabolized by the liver. However, 30 % of tramadol and 60 % of active metabolites are
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