Can pregabalin (Lyrica) cause Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) or hyponatremia in patients, particularly those with risk factors such as older age, kidney disease, or those taking other medications that affect electrolyte balance or renal function?

Pregabalin Can Cause SIADH and Hyponatremia

Yes, pregabalin can cause SIADH and hyponatremia, though it is a rare adverse effect that requires clinical vigilance, particularly in elderly patients and those with other risk factors for electrolyte disturbances. 1, 2

Evidence for Pregabalin-Induced SIADH

The association between pregabalin and SIADH is documented in case reports demonstrating that patients develop euvolemic hyponatremia meeting full SIADH criteria after initiating pregabalin therapy. 1 In reported cases, patients presented with:

• Profound hyponatremia (sodium levels as low as 117 mmol/L) 2
• Neurological symptoms including confusion, gait instability, and urinary incontinence 2
• Rapid improvement after pregabalin discontinuation and fluid restriction 1, 2

The Naranjo algorithm has established probable causality for pregabalin-induced SIADH in documented cases. 2

High-Risk Patient Populations

Elderly patients face substantially elevated risk for pregabalin-induced hyponatremia due to multiple physiological vulnerabilities. 3

Age-Related Risk Factors:

• Decreased baroreceptor sensitivity leading to impaired volume regulation and potentially inappropriate ADH secretion 4
• Reduced total body water decreasing the volume of distribution for water-soluble drugs 4
• Age-related decreases in glomerular filtration rate contributing to altered fluid regulation 4
• Elderly patients are more susceptible to adverse effects of medications affecting water balance 4

Additional Risk Factors:

• Renal impairment (pregabalin is primarily renally cleared) 5
• Concurrent use of other medications that can cause SIADH (SSRIs, SNRIs, carbamazepine, NSAIDs, thiazide diuretics) 6, 3
• Polypharmacy, particularly in patients with multimorbidity and disability 5
• Excessive fluid intake 3

Clinical Recognition and Diagnosis

Monitor for hyponatremia in any patient starting pregabalin, especially within the first few weeks of therapy. 1

Diagnostic Criteria for SIADH:

• Hyponatremia (serum sodium < 134 mEq/L) 6
• Plasma hypoosmolality (< 275 mosm/kg) 6
• Inappropriately high urine osmolality (> 500 mosm/kg) 6
• Inappropriately high urinary sodium concentration (> 20 mEq/L) 6
• Absence of hypothyroidism, adrenal insufficiency, or volume depletion 6

Clinical Manifestations:

• Severity depends on the degree of hyponatremia and rapidity of development 3
• Mild symptoms: anorexia, nausea, confusion 7
• Severe symptoms (sodium ≤ 125 mEq/L): seizures, coma, death 7
• Elderly patients may present with falls, gait instability, and delirium 4, 2

Management Algorithm

Immediate Actions:

Discontinue pregabalin immediately if symptomatic hyponatremia is present. 1, 3

Treatment Based on Severity:

For severe symptomatic hyponatremia (sodium < 120 mEq/L with neurological symptoms):

• Transfer to ICU for close monitoring 6
• Administer 3% hypertonic saline with goal to correct 6 mmol/L over 6 hours or until severe symptoms resolve 6
• Monitor serum sodium every 2 hours initially 6
• Critical safety rule: Never exceed 8 mmol/L correction in 24 hours to prevent osmotic demyelination syndrome 6, 8

For mild to moderate symptomatic hyponatremia or asymptomatic patients with sodium < 120 mEq/L:

• Discontinue pregabalin 1, 3
• Implement fluid restriction to 1 L/day 6, 3
• Consider oral sodium supplementation 9
• Monitor serum sodium levels regularly 9

For patients with malnutrition, alcoholism, or advanced liver disease:

• Use more cautious correction rates (4-6 mmol/L per day) 6

Critical Clinical Pitfalls to Avoid

• Combining pregabalin with other SIADH-inducing medications (SSRIs, carbamazepine, NSAIDs) substantially increases risk 6, 3, 9
• Overly rapid correction of hyponatremia leading to osmotic demyelination syndrome 6, 8
• Inadequate monitoring during active correction 6
• Failing to perform careful medication reconciliation in elderly patients on multiple medications 9
• Using fluid restriction in cerebral salt wasting instead of SIADH (requires volume status assessment) 6

Monitoring Recommendations

When prescribing pregabalin, particularly in elderly patients:

• Check baseline serum sodium before initiating therapy 9
• Monitor serum sodium within 1-2 weeks of starting pregabalin 1
• Recheck sodium levels if any neurological symptoms develop 2
• Initial doses and subsequent dose titration should be more gradual in elderly patients 4
• Monitor renal function, as pregabalin is renally cleared and dose adjustment is required in renal impairment 5