Pain is a Problem in Chronic Kidney Disease
Pain is a significant component of the multitude of problems faced by CKD patients. The prevalence increases further in ESKD, with a prevalence of more than 50%, mostly musculoskeletal, but with ineffective pain control, and rare NSAID use. The concern with NSAID use in CKD has lead to greater dependence on non-NSAID pharmacotherapy, which include opioids, and other agents such as gabapentin and pregabalin. However, are these agents safe and effective in CKD?
Opioids may be perceived as analgesic of choice in CKD, however are associated with toxic effects including severe oversedation, seizures, myoclonus, respiratory depression and even death. However, their use in ESKD patients on hemodialysis is astonishingly high, with over 60% receiving at least one prescription every year, and more than 20% with chronic (>90 days) usage every year, as reported in a large cohort study of over 270 000 ESKD patients in United States. In addition, short-term or chronic use was associated with a significantly higher hazard (from 20 to over 50% for each individual agent) of hospitalization and death. Lest one explain away this increased hazard as an association, or from end-of-life opioid use, a subsequent analysis drills down to possible mechanisms. In a study of 140 899 Medicare-covered adults receiving hemodialysis in 2011, opioid use was associated with increased risk of altered mental status, falls and fractures. Most importantly, this study used time-varying analysis to report on these adverse events, and a biological gradient was observed with a greater risk seen with higher doses. A higher risk of hip and other fractures with narcotic analgesics has been reported in the dialysis outcomes and practice patterns survey also, and this study provides a mechanism to explain these. Even short-term opioid use can lead to dependence and chronic use, thus prolonging the exposure and possibility of adverse effects.
Tramadol is often considered a safer option in such circumstances. However, tramadol has a dual mechanism of action, acting both as a central opioid agonist (via its metabolite) and central nervous system reuptake inhibitor of serotonin and norepinephrine. The O-demethylation product of tramadol is 300 times more potent for the opioid mu-receptor when compared with the parent compound, and there is variability in this conversion between slow, fast and ultra-fast metabolizers. Thus, giving tramadol is like giving an unknown combination of an opioid and a serotonin-norepinephrine reuptake inhibitor. Unsurprisingly, tramadol is associated with seizures, hypoglycemia, the serotonin syndrome, as well as all the baggage that comes with an opioid (dependence and death). Its use is unsafe in the general population overall, not just in CKD.
Gabapentin, Pregabalin and Baclofen
Another class of agents with increasing uptake are the agonists of the central inhibitory neurotransmitter gamma-amino butyric acid (GABA), that is gabapentin, and pregabalin. Approved for restless legs syndrome, certain neuropathies and certain seizure disorders, off-label use is a particular feature of these drugs. On the contrary, these agents are mostly not effective for chronic pain, and their use in restless legs, where there is a proven small improvement in sleep quality for the general population, is also associated with increased somnolence and dizziness.[44,45] Their effect on restless legs in CKD is uncertain. Moreover, their concomitant use with opioids, which is common, increases the risk for opioid-related death significantly.
Baclofen is a synthetic derivative of GABA, and at usual doses it acts mostly on spinal motor neurons and serve to relieve muscle spasticity. However, baclofen depends on the kidneys for 85–90% of its elimination, and distributes quickly in the vascular space and the liver and kidney, but penetrates more slowly in the central nervous system. Hence, in severe CKD and more importantly in ESKD patients, baclofen use causes effects ranging from transient drowsiness, lethargy to much more severe somnolence and respiratory depression. Several case reports and series document these, including coma and death.[49,50] Their use should be avoided in severe CKD (GFR < 30 or on dialysis).
Thus, avoiding NSAIDs in severe CKD is easier said than done – the alternatives such as opioids and gabapentin, are not without their drawbacks, and some such as tramadol and baclofen are best avoided.
Curr Opin Nephrol Hypertens. 2019;28(2):163-170. © 2019 Lippincott Williams & Wilkins