Can high doses of neostigmine (acetylcholinesterase inhibitor) cause leg twitching?

Can High Doses of Neostigmine Cause Leg Twitching?

Yes, high doses of neostigmine can cause muscle twitching and fasciculations in the legs and throughout the body, but this represents a paradoxical depolarizing neuromuscular blockade rather than simple muscle twitching—a dangerous side effect that indicates excessive dosing.

Mechanism of Neostigmine-Induced Muscle Weakness and Fasciculations

• Neostigmine functions as a reversible acetylcholinesterase inhibitor that increases acetylcholine concentration in the synaptic cleft 1
• When given in excessive doses or when residual neuromuscular blockade is absent, neostigmine causes a depolarizing neuromuscular blockade that manifests as muscle weakness, fasciculations, and twitching 2, 3
• This paradoxical effect occurs because excessive acetylcholine at the neuromuscular junction leads to persistent depolarization of the muscle membrane, preventing normal repolarization and muscle contraction 3

Evidence of Muscle Twitching and Weakness from High-Dose Neostigmine

• In healthy volunteers receiving therapeutic doses of neostigmine (35 μg/kg), grip strength decreased by 20% and single twitch height decreased by 14% within 5 minutes 2
• A second dose of neostigmine further decreased grip strength by 41% and single twitch height by 25%, demonstrating dose-dependent muscle weakness and depolarizing blockade 2
• Neostigmine 2.5-5 mg in patients without neuromuscular blocking drugs caused substantial reduction in peak tetanic contraction and severe tetanic fade persisting for approximately 20 minutes 3
• The neostigmine-induced block resembles depolarizing blockade and can be potentiated by succinylcholine 3

Critical Dosing Thresholds and Safety Considerations

• The standard dose of neostigmine is 40-50 mcg/kg, and increasing above 50 mcg/kg is not recommended due to a "ceiling effect" where additional benefit is minimal but side effects increase 1, 4
• Neostigmine should never be administered when TOF ratio is already ≥0.9, as this causes paradoxical muscle weakness and respiratory impairment lasting 17-53 minutes 4
• Administering neostigmine at 40 mcg/kg when TOF >0.9 may impair upper airway patency and induce TOF fade 4

Clinical Manifestations Beyond Simple Twitching

• The muscle effects are not limited to benign fasciculations but include:
  • Decreased grip strength (up to 41% reduction) 2
  • Restrictive spirometry pattern with decreased forced vital capacity (up to 27% reduction) 2
  • Depolarizing neuromuscular blockade affecting all skeletal muscles including respiratory muscles 2, 3
  • Tonic responses in the mechanomyogram 5

Special Populations at Higher Risk

• Patients with neuromuscular disorders (dystrophia myotonica, progressive muscle dystrophy) exhibit unpredictable and potentially severe reactions to neostigmine, including long-lasting muscle weakness and tonic responses 5
• In these patients, even standard doses can produce prolonged muscle weakness that resembles depolarizing blockade 5

Key Clinical Pitfalls to Avoid

• Never administer neostigmine without quantitative neuromuscular monitoring showing at least 4 responses to TOF stimulation 1, 4
• Avoid giving neostigmine when TOF ratio is already >0.9, as this paradoxically worsens neuromuscular transmission 1, 4
• Do not exceed 50 mcg/kg dosing due to ceiling effect and increased side effects 1, 4
• Always co-administer an anticholinergic agent (atropine 0.02 mg/kg or glycopyrrolate) to prevent bradycardia and other cholinergic side effects 1, 4