Table 4.

Analgesics to avoid in patients with advanced CKD

Analgesic	Details
NSAIDS (for chronic pain) (20)	The major limitation is gastrointestinal toxicity due to inhibition of cytoprotective mucus secretion and impaired platelet aggregation resulting in ulceration and bleeding. Risk increases in severity and frequency with increasing age: NSAID use increases the risk of gastrointestinal bleeding in the elderly four-fold. Concomitant use of antiplatelet drugs such as aspirin, anticoagulants, and SSRIs further increases bleeding risk.
	Although the gastrointestinal safety profile of COX-2 inhibitors is superior to nonselective NSAIDs, nephrotoxic and cardiovascular adverse effects (myocardial infarction, thrombotic events, and stroke) remain significant. It has been shown that the long-term use of all NSAIDs increases the risk of stroke by 64% at 2 yr. COX-2 selectivity may not play a role in the increased cardiovascular risk of NSAIDs because rofecoxib was the only drug in meta-analyses to demonstrate excessive harm and skewed the data of COX-2 selective NSAIDs (35). There is insufficient evidence to confirm any NSAID to be safe in terms of cardiovascular risk.
	In patients with residual kidney function, NSAIDs may also cause: a reduction in GFR that can be severe and irreversible if the patient has decreased effective circulating volume; sodium and water retention, which may aggravate hypertension and hyperkalemia.
	The elderly may be at increased risk for NSAIDs-associated psychiatric events such as agitation, depression, anxiety, paranoia, delirium, and hallucinations.
Codeine	A weak opioid that is metabolized by the enzyme CYP2D6 in the liver to its active metabolite morphine, which provides the analgesic effect. Only about 5%–10% of codeine is metabolized in this pathway, with most of the administered dose being converted to inactive metabolites.
	The percentage of codeine converted to morphine can be much higher in individuals who have three or more active copies of the CYP2D6 gene (“ultra-rapid metabolizers”), resulting in life-threatening or fatal respiratory depression due to high plasma levels of morphine, even with trivial doses. Conversely, poor analgesic response will be seen in those who carry inactive copies of CYP2D6 (“poor metabolizers”) due to low morphine levels after administration of standard doses (25).
	Up to 11% of codeine is also metabolized to hydrocodone (mechanism unknown).
	Both codeine and its metabolites are excreted by the kidneys and accumulate in patients with kidney failure.
Dextropropoxyphene	A weak opioid that has been withdrawn from the market in the United Kingdom, Europe, New Zealand, and Canada due to its weak analgesic effect, addictiveness, and its association with deaths and possible arrhythmias. In the United States it has a Black Box warning and is on the High-Risk Medications in the Elderly list.
	Decreased elimination of dextropropoxyphene and its major active metabolite, norpropoxyphene, occurs in patients with kidney failure (36).
Tramadol	A weak synthetic opioid related to codeine.
	Extensively metabolized in the liver with one main active metabolite, M1. Both the parent drug and M1 contribute to the analgesic effect through u-opioid receptors and two nonopioid mechanisms, inhibition of serotonin and norepinephrine reuptake (37). M1 has a significantly higher affinity for opioid receptors than tramadol, whereas tramadol is a more potent inhibitor of serotonin and norepinephrine reuptake (38).
	The enzyme CYP2D6 catalyzes the production of M1 and other CYP enzymes (CYP2B6 and CYP3A4) catalyze the production of M2, an inactive metabolite (Figure 1).
	Unpredictable risk of serious overdosing or under dosing after administration of standard doses. The concentrations of tramadol may be 20% higher in “poor metabolizers” versus individuals who have multiple functional copies of the CYP2D6 gene (“ultra-rapid metabolizers”), whereas M1 concentrations may be up to 40% lower. Factors such as the concurrent use of CYP2D6 inhibitors (Figure 2) could also result in increased tramadol concentration and decreased M1 concentration.
	Induction of CYP3A4 may pose an added risk of seizures, even when tramadol is administered in accepted doses. This is particularly problematic in the context of neuropathic pain where several of the adjuvants are CYP3A4 inducers (Figure 2).
	Serotonin syndrome is a potentially life-threatening syndrome that may occur with the use of tramadol, especially if other medications such as antidepressants or other drugs that impair the metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors) are used concurrently. Symptoms include changes in mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Morphine	Metabolized primarily to the active metabolite M3G and small amounts (approximately 10%) of M6G. M3G lacks analgesic effect but may have neuroexcitatory effects contributing to adverse effects such as allodynia, myoclonus, and seizures. M6G has potent analgesic effect, more so than morphine. Although M6G is dialyzed, it diffuses out of the central nervous system slowly so may not be completely removed during dialysis.
	M3G and M6G (more so than the parent drug morphine) accumulate in patients with advanced CKD.
	There is poor, inconsistent correlation between plasma levels of morphine, M3G, and M6G and clinical efficacy or adverse effects (39). The best correlation appears to be between higher levels of morphine and constipation and high levels of M3G and cognitive impairment (26). There are many reports in the literature of profound toxicity in patients with advanced CKD.
Oxycodone	A semisynthetic opioid metabolized primarily by CYP3A4 to the active metabolite noroxyodone with a small amount metabolized by CYP2D6 to the active metabolite oxymorphone, the clinical relevance of which is not clear. The potential for drug interaction and unpredictable pharmacodynamic response therefore is relatively high (Figure 1).
	Less than 10% is excreted unchanged in the urine. Despite this, both the parent drug and the active metabolites appear to accumulate in patients on dialysis (40) with reports of toxicity (41). The central opioid effects are governed by the parent drug.
	A recent systematic review of opioid use in patients with cancer with some degree of kidney failure found two studies that evaluated oxycodone use: higher oxycodone levels were associated with increased fatigue but the metabolite noroxycodone was not associated with any of the evaluated adverse effects (26).
	A single study assessed the pharmacokinetics after a single 20-mg oral dose of an abuse-deterrent formulation of extended release oxycodone in patients with mild (n=6), moderate (n=5), and severe (n=6) kidney failure (42). Cmax and AUC continued to increase with increasing severity of kidney failure and patients with severe kidney failure had a Cmax (31.6 ng/ml versus 17.6 ng/ml) and AUC (493.5 ng.h/ml versus 210.7 ng.h/ml) more than double that of those with normal kidney function. Adverse effects were experienced by 50% of patients with severe kidney failure versus 14.3% in those with normal kidney function.
	In a case study of a single patient on HD, oxycodone and its metabolites were reduced by dialysis, yet there was no loss of analgesia (43). More recently, knowledge about the dialyzability of oxycodone comes from a study of 20 patients on HD on stable doses of oxycodone CR (44). Dialyzability of oxycodone and noroxycodone was possible but very limited. Not surprisingly, therefore, there was no significant increase in postdialysis pain with no need for additional opioid dosing. This is not surprising because oxycodone has a relatively high volume of distribution (greater than hydromorphone), is nearly 50% protein bound, and is only moderately water soluble.
Hydrocodone	A semisynthetic strong opioid synthesized from codeine: 99% of the world’s supply is consumed in the United States where it is the most commonly prescribed opioid, including for patients with CKD.
	Primarily metabolized in the liver into several metabolites, including hydromorphone, via CYP2D6. Therefore, it might be expected to have a similar unpredictable risk of serious overdosing or under dosing after administration of standard doses as seen with codeine and tramadol (Figure 1). In clinical practice this is less clear. The production of the active metabolite of hydrocodone (hydromorphone) is reduced in CYP2D6 “poor metabolizers” but there is little evidence of a difference in analgesic effect. Ultra-rapid CYP2D6 metabolizers may have an increased response to hydrocodone with an increased risk of overdose.
	Approximately 26% is excreted in the urine either unchanged or as a metabolite; therefore, kidney failure is hoped to have only a minimal effect on drug clearance. However, data are extremely limited as described below.
	There is only a single study that has assessed the extent to which varying degrees of kidney failure can affect the pharmacokinetics of hydrocodone and this involved a single 45-mg dose of extended-release formulation over 144 h (45). All subjects received naloxone at 15 and 3 h before and 9 and 21 h post dose to minimize opioid-related adverse effects. There were eight patients with mild kidney failure (>50–80 ml/min), nine with moderate (30–50 ml/min), nine with severe (<30 ml/min), and nine on HD ≥6 mo. Systemic exposure was up to 70% greater in patients with moderate-to-severe kidney failure compared with patients with mild kidney failure but appeared to be unchanged in patients on HD. There was no consistent trend toward an increase in maximum concentration of hydrocodone with increasing severity of kidney failure. However, the incidence of adverse effects in patients on dialysis was similar to those with normal kidney function despite the concurrent use of naltrexone.
	Without any data to support its use and the high potential for unpredictable toxicity risk, it remains unclear the role that hydrocodone should or should not have in the pharmacologic management of pain for patients with advanced CKD.

NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors; COX, cyclooxygenase; CYP, cytochrome P450; M1, O-desmethyltramadol; M3G, morphine-3-glucuronide; M6G, morphine-6-glucuronide; HD, hemodialysis; Cmax, maximum concentration; AUC, area under the curve; HD, hemodialysis; CR, controlled release.