The growing use of gabapentinoids in the treatment of neuropathic pain has brought with it a silent but clinically serious problem: the blurring of causal links between the drug and side effects. When swelling of the lower legs or feet – which can be directly caused by gabapentin or pregabalin – is misinterpreted as heart failure, a “prescribing cascade” is triggered, a chain of additional prescriptions that often brings no benefit and may create new risks. In the elderly population, where polypharmacy and multimorbidity are common, such cascades are particularly dangerous because they increase the likelihood of falls, metabolic disorders, and hospitalizations.

Why gabapentinoids have become the “standard” – and where their limits lie

Gabapentinoids (gabapentin and pregabalin) have become the most common non-opioid pharmacological option for various forms of neuropathic pain in recent years, including postherpetic neuralgia and diabetic peripheral neuropathy, and as adjunctive treatment for partial epilepsies. They have also expanded to “off-label” indications such as radicular pain and some chronic pain syndromes. Their popularity is largely due to the desire of health systems to reduce exposure to opioids. However, a neuro-destructive or “soft” profile does not mean an absence of side effects: among the most common are drowsiness, dizziness, and peripheral edema. Precisely this edema – without breathlessness, without chest pain, but with visible swelling of the ankles – is often the clinical trigger for the cascade.

How the cascade occurs: from leg swelling to a diuretic prescription

A typical sequence looks like this: a patient aged 70+ started therapy with gabapentin or pregabalin; after two to four weeks, they notice swelling of the feet and lower legs. In the office, without a systematic “time-out” and check of recent therapy changes, the edema is attributed to potential heart failure or venous insufficiency. With the best intentions, the doctor introduces a loop diuretic (most commonly furosemide) “as a trial” – and thereby, inadvertently, replaces the cause (the drug) with symptomatic treatment (the diuretic). The new drug then opens up a whole new domain of risks: hyponatremia, hypokalemia, hypovolemia with dizziness and falls, renal function disorders, and a requirement for frequent laboratory controls. In a short time, the patient goes from one pill to a whole series of interventions, without evidence that they truly needed any of it.

What recent studies show

In the last few years, several analyses of large populations have been published that consistently reveal the same pattern: after starting gabapentinoids, the likelihood of introducing a loop diuretic increases compared to the period before their start. This is a so-called “sequence symmetry analysis” design, which compares the order of prescribing drugs to detect possible cascades. Signals have been confirmed in American and European databases and in veteran cohorts older than 65. In practice, this means that a portion of edema “treated” with diuretics is actually a side effect of gabapentinoids, and not a manifestation of heart failure or kidney disease. Some newer research additionally points to a possible difference within the class – namely, in a large cohort of older users with chronic, non-cancer pain, the start of pregabalin was associated with a higher incidence of heart failure compared to gabapentin. Such findings do not forbid the use of pregabalin but reinforce the need for caution in cardiovascularly at-risk patients and when titrating doses.

Guidelines and the geriatric perspective

Updated criteria from the American Geriatrics Society (Beers Criteria 2023) remind us that drugs causing sedation, dizziness, and orthostatic hypotension – clinically relevant effects for gabapentinoids as well – increase the risk of falls and injuries in older persons. The recommendation is not to “ban” but to individualize: clearly define the goal of treatment (e.g., pain reduction and function improvement), determine a trial period, monitor utility and side effects, and regularly review the benefit-risk ratio. The latest additions with lists of alternatives further encourage the application of non-pharmacological strategies (physiotherapy, cognitive-behavioral techniques, pain education), especially when evidence of pharmacological benefit is modest.

What regulatory documents say

In official summaries of product characteristics for gabapentin, peripheral edema is listed among the most common side effects in adults, along with dizziness and drowsiness. Similarly applies to pregabalin. At the same time, instructions for furosemide and other loop diuretics emphasize the risk of fluid and electrolyte disturbances – hyponatremia, hypokalemia, hypovolemia – and worsening of renal function and hypotension, whereby older patients are particularly vulnerable. If a diuretic is introduced “on a wrong assumption,” the patient becomes exposed to all these dangers without any proof that they will truly treat the cause of the problem.

How to recognize that edema is likely drug-induced

Distinguishing drug-induced edema from congestive heart failure is not trivial, but there are useful clinical clues. First, temporal coincidence: edema often appears within a few weeks of introducing gabapentin/pregabalin or increasing the dose. Second, morphology: swelling is typically symmetrical and distal (feet, ankles), without clear signs of pulmonary congestion (orthopnea, paroxysmal nocturnal dyspnea, crackles). Third, findings: natriuretic peptides and chest X-rays may be normal, and cardiac function stable compared to previous findings. Fourth, dose and dynamics: an increase in gabapentinoid dose sometimes accompanies the progression of edema, and dose reduction or discontinuation leads to symptom alleviation within a few days to a few weeks.

What to do instead of automatically prescribing diuretics

The first step is “clinic before automatism”: check if a gabapentinoid was introduced or increased in the last 4–8 weeks. If so, consider dose reduction or gradual discontinuation in agreement with the patient and clear instructions on symptom monitoring. In many cases, mild edema does not require pharmacological intervention; non-pharmacological measures like elastic compression stockings, occasional leg elevation, and short-term salt restriction help. If the analgesic effect is not measurably beneficial, deprescribing is a more rational choice than “masking” symptoms with a diuretic. In patients with severe edema that impairs function, before diuretics, it is worth trying a temporary dose reduction or discontinuation of gabapentinoids and close supervision. In case of suspicion of cardiac etiology, perform a targeted minimal set of diagnostics (physical exam, saturation, auscultation, NT-proBNP as needed) – but still do not skip the simple question: “Could this have been caused by the drug?”

Risks of the cascade in numbers and outcomes

Once the cascade is triggered, the consequences are measurable: within a few weeks after introducing a loop diuretic, electrolyte disturbances (hyponatremia, hypokalemia), worsening of renal function, symptoms like dizziness and blurred vision, and falls are frequent. In the elderly, this translates into emergency department admissions and hospitalizations. Additional diagnostics (heart ultrasound, venous Doppler, labs) and consultative assessments increase the cost and complexity of care – while the patient is kept away from the simplest and most logical intervention: adjustment or discontinuation of the drug that is the likely cause.

Practical algorithm for the clinic

1) Confirm the symptom. Objectify swelling (bilaterality, pitting, circumference), measure body mass, assess dyspnea and orthopnea. 2) Check the timing. Review all therapy changes in the last 2 months; if the gabapentinoid is new or the dose increased, note the coincidence. 3) Perform a trial intervention. Reduce the dose or introduce planned discontinuation with a check-up in 7–14 days; add non-pharmacological measures if needed. 4) Delay the diuretic. Do not introduce a loop diuretic until you assess the response to the intervention, unless there are clear signs of congestion and hemodynamic burden. 5) If a diuretic is nevertheless unavoidable, plan early control of electrolytes (Na, K, creatinine) and actively look for symptoms of hypovolemia. 6) Document and report. Record suspicion of a side effect and report it to the pharmacovigilance system; this raises collective awareness and improves prescribing safety.

Differential within the class: are all gabapentinoids the same?

Not necessarily. Comparative cohort analyses in the elderly population with chronic pain showed that pregabalin was associated with a higher incidence of heart failure compared to gabapentin. Potential explanations include pharmacodynamic differences (higher affinity binding to the α₂δ subunit and faster achievement of peak concentrations) and prescribing patterns (higher starting doses, faster titration). The clinical implication is pragmatic: in cardiovascularly at-risk patients, carefully titrated gabapentin may have an advantage, with the narrowest possible duration of therapy and a plan for regular review of benefits.

Alternative strategies: fewer pills, more function

The best prevention of cascades is a prudent start to therapy. For syndromes with limited evidence of benefit (e.g., non-specific low back pain without radiculopathy), non-pharmacological interventions should be preferred: structured exercise and stabilization programs, pain education, cognitive-behavioral techniques, perineural approaches where indicated. If a gabapentinoid is started anyway, set measurable goals (e.g., ≥30% reduction in pain intensity and functional improvement), define a trial period (4–6 weeks), and agree on an exact evaluation plan. Without achieved benefit – deprescribe, instead of the “automatism” of increasing the dose.

Role of the patient and family

Patients should be empowered to ask four questions with every new drug: Why? (indication and expected benefit), How long? (trial period), How do we know it works? (measure of success), and What side effects to look for? (edema, drowsiness, dizziness). If edema occurs, it is important to first contact the doctor who introduced the gabapentinoid for therapy adjustment – and not seek a “second opinion” that could result in yet another prescription and a new risk.

Digital tools and care organization

Electronic health records and prescribing modules can reduce the risk of cascades. Simple decision rules – for example, a pop-up warning “new edema + recent gabapentinoid initiation” – remind of the possibility of drug-induced etiology. Similarly, standardized checklists for deprescribing in a geriatric profile clinic can include a question about edema for every patient on a gabapentinoid, with a recommendation for a trial dose reduction before any diuretic.

What this means for the system and costs

The cumulative effect of “small” prescribing errors becomes large when summed up at the population level: additional lab controls, specialist assessments, diagnostics, falls, and hospitalizations. At the same time, interventions to prevent cascades are relatively cheap: education of doctors and pharmacists, short checklists in offices, reminders in IT systems, and regular review of therapy in older patients. This not only improves safety but also reduces unnecessary costs.

Summary for quick application in practice

• Think of the drug. Edema 2–6 weeks after introduction or dose increase of gabapentin/pregabalin – suspect the drug first, not the heart.


• Check values. If there are no clear signs of congestion, delay the diuretic and assess the gabapentinoid (dose, need, benefit).


• Try deprescribing. Reduce the dose or plan discontinuation; check-up in 7–14 days, non-pharmacological measures as needed.


• If you introduce a diuretic anyway, check electrolytes and renal function early and actively ask about dizziness/falls.


• Document and report. Report side effects; by doing so, you help the next patient and colleagues.

End of automatism: clinic first

The simplest question in medicine – “Could this have been caused by the drug?” – often prevents the most expensive mistakes. With gabapentinoids, this means starting thoughtfully, titrating slowly, measuring effect, and looking for early signs of edema. If edema appears, intervene at the source first, not on the symptom. Thus, a cascade of prescriptions that exposes the older patient to risks without real benefit and burdens a system already working at capacity limits is prevented.