What is the best course of treatment for a 21-year-old female patient with a history of chronic exertional compartment syndrome (CECS) versus shin splints, presenting with symptoms concerning for restless leg syndrome (RLS), iron deficiency anemia (IDA) with laboratory findings of low hemoglobin, microcytic anemia, and pending ferritin level, and how to manage her condition if she is unable to tolerate gabapentin (Neurontin)?

Management of Iron Deficiency Anemia and Restless Legs Syndrome in a 21-Year-Old Female

Laboratory Interpretation

Your patient has clear iron deficiency anemia (IDA) that requires immediate treatment, and her RLS symptoms are likely secondary to this iron deficiency. The new labs confirm microcytic anemia (hemoglobin 10.7 g/dL, MCV 77.5 fL, RDW 18.3%) with severely low transferrin saturation (8%) and high TIBC (419 µg/dL), which are diagnostic of IDA 1, 2. The initial iron of 34 µg/dL with TSAT 8% represents functional iron deficiency with inadequate iron delivery to support erythropoiesis 1.

While awaiting the ferritin result, the constellation of microcytic anemia, low TSAT (<20%), and elevated TIBC is sufficient to diagnose IDA and initiate treatment 1, 3. The ferritin will help quantify iron stores, but treatment should not be delayed 1.

Iron Deficiency Anemia Treatment

Start oral iron supplementation immediately with ferrous sulfate 325 mg daily or every other day. 1, 4. Alternate-day dosing may improve absorption and reduce gastrointestinal side effects 1.

• Administer iron on an empty stomach when possible, or with vitamin C (250-500 mg) to enhance absorption 1
• Avoid taking iron within 2 hours of antacids containing aluminum or magnesium 5
• Expect hemoglobin to rise by approximately 1-2 g/dL after 3-4 weeks of therapy 1, 3
• Continue iron supplementation for 3-6 months after hemoglobin normalizes to replenish iron stores 1

If oral iron is not tolerated or ineffective after 3 months, consider IV ferric carboxymaltose 1000 mg in one or two infusions 1, 6.

Additional Workup Required

Obtain the following labs immediately:

• Ferritin level (already pending) - essential for quantifying iron stores and guiding RLS treatment 1, 6
• Celiac serology (tissue transglutaminase antibody) - mandatory in all premenopausal women with IDA to exclude celiac disease, which is present in up to 4% of cases 1
• Reticulocyte count - to assess bone marrow response and exclude other causes of microcytic anemia 1, 2

Do not proceed with invasive GI investigation (endoscopy/colonoscopy) at this time. In asymptomatic premenopausal women under age 50, GI malignancy is extremely uncommon (0-6.5% yield), and her presentation is consistent with inadequate dietary intake or menstrual losses 1. Reserve GI investigation for: persistent IDA after iron supplementation, GI symptoms, strong family history of colorectal cancer, or age ≥50 years 1.

Restless Legs Syndrome Management

Iron Supplementation as Primary RLS Treatment

For RLS, iron supplementation is indicated when ferritin ≤75 ng/mL or transferrin saturation <20%. 1, 6, 4. Your patient's TSAT of 8% already meets this threshold 6. The American Academy of Sleep Medicine uses different iron thresholds for RLS than for general anemia management because brain iron deficiency plays a critical role in RLS pathophysiology 6, 4.

• Iron deficiency is strongly associated with RLS, and correcting it may resolve symptoms entirely 1, 4
• Continue iron supplementation indefinitely with monitoring every 6-12 months, as RLS symptoms may recur if iron stores decline 6

When to Start Pharmacologic RLS Treatment

Wait to initiate pharmacologic RLS therapy until after assessing response to iron supplementation, especially if symptoms are intermittent and not impairing sleep. 6, 7. The decision to start medication depends on symptom severity and impact on quality of life 4, 8.

If symptoms are intermittent and not impairing sleep:

• Address iron deficiency first with oral supplementation 6, 7
• Eliminate exacerbating factors: caffeine (especially evening), alcohol within 3 hours of bedtime, antihistamines (diphenhydramine), and ensure adequate sleep hygiene 1, 7, 9
• Reassess symptoms after 3 months of iron therapy 6

If symptoms are chronic and impairing sleep, or if iron supplementation alone is insufficient after 3 months:

First-Line Pharmacologic Treatment (If Gabapentin Cannot Be Used)

Pregabalin is the preferred alternative to gabapentin, starting at 75 mg once daily 1-2 hours before bedtime, titrating to 150-300 mg daily as needed. 1, 6, 7, 4. Pregabalin is an alpha-2-delta ligand with the same mechanism as gabapentin but offers twice-daily dosing and potentially superior bioavailability 6, 8.

Alternative first-line option: Gabapentin enacarbil (prodrug of gabapentin) 600 mg once daily at 5 PM. 6, 7, 4. This formulation may be better tolerated if standard gabapentin caused specific side effects 6.

Medications to Avoid

Do NOT use dopamine agonists (ropinirole, pramipexole, rotigotine) as first-line therapy. 6, 7, 10, 4. The American Academy of Sleep Medicine now recommends against standard use of these agents due to augmentation risk—a paradoxical worsening of symptoms with earlier onset, increased intensity, and spread to other body parts, occurring in 7-10% annually 6, 4, 8. While ropinirole is FDA-approved for RLS 10, guidelines have shifted away from dopamine agonists since these approvals 6, 7.

Avoid clonazepam - insufficient evidence of efficacy, does not reduce objective RLS markers, and carries risks of sedation and falls 6.

Clinical Algorithm Summary

1. Start oral ferrous sulfate 325 mg daily/every other day immediately 1, 4
2. Obtain pending ferritin, add celiac serology and reticulocyte count 1
3. Eliminate RLS exacerbating factors (caffeine, alcohol, antihistamines) 7, 9
4. Reassess in 3 months:
   • If hemoglobin normalizes and RLS symptoms resolve → continue iron for 3-6 months total 1, 6
   • If anemia persists → consider IV iron or investigate for malabsorption/ongoing losses 1
   • If RLS symptoms persist despite corrected iron and are impairing sleep → start pregabalin 75 mg at bedtime 6, 7, 4
5. Monitor iron studies every 6-12 months long-term to prevent RLS recurrence 6

Critical Pitfalls to Avoid

• Do not delay iron supplementation waiting for ferritin results—the diagnosis is already established 1, 2
• Do not start dopamine agonists despite FDA approval—current guidelines prioritize alpha-2-delta ligands due to augmentation risk 6, 7, 4
• Do not pursue invasive GI workup in an asymptomatic 21-year-old woman without first treating iron deficiency and checking celiac serology 1
• Do not use RLS-specific iron thresholds (ferritin ≤75 ng/mL) to guide anemia treatment—treat the anemia regardless of ferritin level given the clear IDA picture 1, 6
• Do not assume RLS requires immediate pharmacologic treatment if symptoms are intermittent and not impairing sleep—iron correction alone may suffice 6, 7