Table 3.

Systemic Pharmacotherapy for Neuropathic Corneal Pain

Medication (class)	Mechanism of action	Starting dosage	Maximum dosage	Side Effects	Precaution and contraindications
First-Line Agents
(Tricyclic Antidepressants) Nortriptyline, Desipramine Use a tertiary amine TCAs only if a secondary are not available Ref. 112–119 Nortriptyline/Desipramine are FDA-approved for treatment of symptoms of depression	Monoamine reuptake inhibition, sodium channel blockade and anticholinergic effects	10–25 mg at bedtime	100 mg at bedtime	Dry mouth, constipation, somnolence, anticholinergic effects, weight gain	Cardiac disease, prostatic adenoma and seizure disorder High doses should be avoid in adults>65 years of age
Carbamazepine (Anticonvulsant) Ref. 120,121 FDA-approved for epilepsy, trigeminal neuralgia, and manic and mixed episodes of bipolar disorder	Sodium channel– blocker	200mg daily	400–800mg/day, divided in 2–3 doses	Hyponatremia, Drowsiness, headache, Dizziness, rash and nausea	Concomitant use of MAO inhibitors Cardiac or hepatic disease Renal failure Prostatic hyperplasia
Second-Line Agents
Low-Dose Naltrexone (Opioid Antagonist) Ref. 122–124 FDA-approved at higher doses (50 mg to 300 mg) for treatment of drug and alcohol addiction	At low doses has an antiinflammatory effect, reducing the proinflammatory cytokines Modulating microglial activity Opioid antagonist - μ-opioid and κ-opioid receptors	1.5 mg at bed time	4.5 mg/bedtime	Headache, vivid dreams, nightmares, tachycardia and anxiety	Past organ transplant and use of immunosuppressive drugs
Tramadol (Opioid Agonist) Ref. 110,111,125 FDA-approved for treatment of moderate to moderately severe pain	μ-receptor agonist and monoamine reuptake inhibitor	50mg/day	100 mg/day in divided doses every 3–7 days as tolerated	Nausea, vomiting, constipation, dizziness, and somnolence	History of substance abuse, suicide risk and antidepressant in elderly patients
Third-Line Agents
Calcium channel α 2-δ ligands - Gabapentin (Anticonvulsants) FDA-approved for treatment of post-herpetic neuralgia Pregabalin (Anticonvulsant) Ref. 113, 126–136 FDA-approved for treatment of neuropathic pain and fibromyalgia	Act on the α2δ subunit of voltage-gated calcium channels, which decrease central sensitization	100–300 mg three times/day 50mg three times/day or 75mg twice a daily	2400 mg/day 300 mg/day	Sedation, dizziness, peripheral edema	Reduced dose in renal insufficiency
(Serotonin-noradrenaline reuptake inhibitors) Duloxetine Ref. 137–139 FDA-approved for treatment of diabetic peripheral neuropathic pain and fibromyalgia	Serotoninnoradrenaline reuptake inhibitors	30 mg/day	60 mg twice/day	Nausea, abdominal pain, constipation	Hepatic disorders Use of tramadol hypertension
Mexiletine (Sodium Channel Blocker) Ref. 140 FDA approved for treatment of cardiac arrhythmia	Voltage-gated sodium channel blocker Lidocaine analogue Class IB anti-arrhythmic	225–675 mg/day	675 mg/day	Nausea, headache, sleep disturbances, tiredness, Gastritis is the most common side effect	Hepatic impairment Severe heart failure Sinus node dysfunction or intraventricular conduction defect