Benadryl Should Be Avoided in Restless Leg Syndrome
Benadryl (diphenhydramine) should not be used to treat restless leg syndrome and will likely worsen symptoms significantly. 1
Why Antihistamines Worsen RLS
The American Academy of Sleep Medicine explicitly recommends addressing and discontinuing antihistaminergic medications as potential exacerbating factors in all patients with RLS. 1
Antihistamines like diphenhydramine are specifically identified as medications that trigger or worsen RLS symptoms through their anticholinergic and antihistaminergic properties. 1, 2
Before initiating any RLS treatment, the American Academy of Sleep Medicine recommends reviewing and discontinuing exacerbating medications, including antihistamines, along with serotonergic agents, antidopaminergics, alcohol, and caffeine. 2
Evidence-Based Treatment Algorithm for RLS
Step 1: Address Iron Status First
The American Academy of Sleep Medicine recommends checking serum iron studies (ferritin and transferrin saturation) in all patients with clinically significant RLS, ideally in the morning after avoiding iron-containing supplements for at least 24 hours. 1
Iron supplementation should be considered if serum ferritin ≤75 ng/mL or transferrin saturation <20% (note this threshold is higher than general population guidelines). 1, 2
Step 2: First-Line Pharmacological Treatment
The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line therapy for RLS with moderate certainty of evidence. 1, 3
Gabapentin enacarbil is dosed at 600 mg once daily, taken at approximately 5 PM with food (FDA-approved dosing). 2
These agents are preferred over dopamine agonists because they do not cause augmentation—a progressive worsening of RLS symptoms that occurs with long-term dopamine agonist use. 1, 2, 3
Step 3: Alternative Options for Refractory Cases
Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe cases, particularly for refractory RLS or when treating augmentation from dopaminergic agents. 1, 3, 4
IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters who don't respond to oral iron therapy. 1
Common Pitfalls to Avoid
Never use dopamine agonists (pramipexole, ropinirole, rotigotine) as standard first-line therapy due to the high risk of augmentation with long-term use. 1, 5, 3
The American Academy of Sleep Medicine suggests against the standard use of these agents, though they may be considered only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects. 1, 5
Screen for and treat untreated obstructive sleep apnea, as it can worsen RLS symptoms. 1, 2
Avoid benzodiazepines like clonazepam as monotherapy—the American Academy of Sleep Medicine explicitly recommends against using clonazepam to treat RLS (conditional recommendation, very low certainty of evidence) because it primarily improves subjective sleep quality without reducing objective disease markers. 1