Cascading Prescriptions
Why does gabapentin cause edema?
The medication lists of many older adults require some scrolling to get from top to bottom. In fact, the lists are often so lengthy and complicated that it's difficult to discern what conditions a patient doesn't have. One reason for this unwieldiness is a phenomenon known as the "prescribing cascade," in which the side effects of one medication require treatment with another, and so on. Some of these cascades, even if cumbersome to the patient, make a certain amount of physiological sense. For example, patients getting chemotherapy also get anti-emetics, or patients on opioids for pain receive a bowel regimen for constipation. However, one cascade is a little less obvious. Why are patients on gabapentin more likely to be prescribed a loop diuretic?
A recent study using data from the Department of Veteran Affairs showed that in older veterans (≥66 years old) taking both a gabapentinoid and a loop diuretic, they were significantly more likely to have been prescribed the gabapentinoid first. More specifically, the adjusted sequence ratio (ASR) of 1.23 means the diuretic was 23% more likely to be prescribed after rather than before initiating gabapentin. Veterans who were slightly older ( ≥85 years old) were less likely to have this suspected cascade, but veterans who were on ≥10 medications were actually more likely to have it.
The real question, though: What side effect of gabapentin necessitates a loop diuretic? In some of the earliest clinical trials of gabapentin for treatment of post-herpetic neuralgia, edema was noted in 3x more of those treated compared to control. Meta-analyses have confirmed this association, with Cochrane reporting edema in 7% of patients on gabapentin versus 2% for placebo. The same has been shown for other gabapentinoids, including pregabalin.
Gabapentin seems to cause edema through a decrease in myogenic tone. An increase in blood pressure causes an initial, sharp increase in blood vessel diameter. The blood vessel, sensing high pressures, contracts back down to limit excess blood flow to the capillaries. This is the myogenic response. Myogenic tone is a steady-state of contraction that then maintains the diameter that the myogenic response created.
Gabapentinoids are high-affinity ligands for the α2δ subunit of voltage-gated calcium channels on blood vessels. Binding to these channels prevents the contraction necessary for the maintenance of myogenic tone. As the blood vessel diameter increases, hydrostatic pressure builds in downstream capillary beds, which forces fluid into the interstitium and eventually leads to edema.
In fact, gabapentinoids can decrease myogenic tone as much as another medication class known to cause edema: calcium channel blockers (CCBs). They decrease myogenic tone in a similar fashion (disruption of calcium channels), although as they seem to also actively dilate vessels, CCBs are associated with both more edema and significant hypotension.
The similarities don't stop there. Since the edema isn't due to excess sodium and water retention (such as in congestive heart failure), loop diuretics actually have little benefit in treating edema from gabapentinoids or CCBs. As gabapentin is so widely used (the 10th-highest number of prescriptions in the USA according to ClinCalc), and diuretics are not benign drugs, clinicians should think twice before initiating a potentially unnecessary prescription cascade.
Take Home Points
Gabapentin and pregabalin have long been known to cause edema
This leads to a common prescribing cascade in which the prescription of one of these drugs leads to the later prescription of a loop diuretic.
The mechanism of gabapentinoid-induced edema is related to the loss of myogenic tone.
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Credits & Suggested Citation
◾️Episode written by Tony Breu
◾️Show notes written by Giancarlo Buonomo and Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com
Breu AC, Abrams HR, Cooper AZ, Buonomo G. Cascading Prescriptions. The Curious Clinicians Podcast. October 2nd, 2024.
Image Credit: MedIzzy