Delivery of neostigmine and glycopyrrolate by iontophoresis: a nonrandomized study in individuals with spinal cord injury

Abstract

STUDY DESIGNPhase I Clinical TrialOBJECTIVESIn this proof-of-principle study, the effectiveness and safety of transdermal administration of neostigmine/glycopyrrolate to elicit a bowel movement was compared to intravenous administration in patients with spinal cord injury.SETTINGJames J. Peters Veterans Affairs Medical Center (Bronx, NY)METHODSIndividuals were screened for responsiveness (Physical Response) to intravenous neostigmine (0.03mg/kg)/glycopyrrolate (0.006mg/kg). Intravenous neostigmine/glycopyrrolate responders (Therapeutic Response) were administered low-dose transdermal neostigmine/glycopyrrolate [(0.05mg/kg)/(0.01mg/kg)] by iontophoresis. Non-responders to low-dose transdermal neostigmine/glycopyrrolate were administered high-dose transdermal neostigmine/glycopyrrolate [(0.07mg/kg)/(0.014mg/kg)] by iontophoresis. Bowel movement, bowel evacuation time, and cholinergic side effects were recorded. Visits were separated by 2 to 14 days.RESULTSEighteen of 25 individuals (72.0%) had a bowel movement (20±22min) after intravenous neostigmine/glycopyrrolate. Of these 18 individuals, 5 individuals experienced a bowel movement with low-dose transdermal neostigmine/glycopyrrolate. Another 5 individuals had a bowel movement after high-dose transdermal neostigmine/glycopyrrolate administration. Fewer side effects were observed in individuals who received neostigmine/glycopyrrolate transdermally compared to those who were administered intravenous neostigmine/glycopyrrolate.CONCLUSIONSTransdermal administration of neostigmine/glycopyrrolate by iontophoresis appears to be a practical, safe, and effective approach to induce bowel evacuation in individuals with spinal cord injury.

Pharmacological Management of Neurogenic Bowel Dysfunction after Spinal Cord Injury and Multiple Sclerosis: A Systematic Review and Clinical Implications

“…Though metoclopramide has been shown to be an effective drug to stimulate a one-time increase in gastric emptying in SCI [ 33 ], its role in ongoing neurogenic bowel management has not been established. Similarly, intravenous or intramuscular neostigmine has been shown to induce bowel evaluation in SCI but has not been tested in routine bowel management [ 34 , 35 ]. It is possible that metoclopramide or neostigmine may have a potential role in one-time bowel preparation procedures, such as colonoscopy in SCI.…”

The Addition of Transdermal Delivery of Neostigmine and Glycopyrrolate by Iontophoresis to Thrice Weekly Bowel Care in Persons with Spinal Cord Injury: A Pilot Study

“…Intramuscular delivery of agents, if administered above the level of lesion, would be painful and may be associated with pain and hematomas that may impair mobility and transfers and, if delivered below the level of lesion, may precipitate autonomic dysreflexia in those with higher cord lesions (e.g., above thoracic level-6). The transdermal administration of these agents by iontophoresis was identified as an alternative route of administration [ 8 ]. In three subjects with spinal cord lesions above thoracic level-6, each with a history of autonomic dysreflexia, Faaborg et al reported that performing digital rectal evacuation or transanal irrigation resulted in substantial blood pressure elevations [ 15 ].…”

“…Neostigmine may be safely administered by transcutaneous route when the ratio of neostigmine to glycopyrrolate is 5:1, which appears to antagonize the cholinergic effects of neostigmine on the heart and lungs to a clinically sufficient extent but spares the prokinetic effect of neostigmine on the bowel; our group is posed to further define the most clinically beneficial ratio of neostigmine to glycopyrrolate by transcutaneous administration to successfully induce bowel evacuation with the least adverse, albeit relatively minor, side effects. In our prior work with the intravenous administration of these agents, which had a greater frequency and intensity of minor adverse events, the major adverse cardiopulmonary manifestations of neostigmine (e.g., severe bradycardia and/or bronchoconstriction) did not occur [ 8 ].…”

“…At the placement site for the cathode patch, which was approximately 4 to 6 inches distant from the anode patch electrode on the lower extremity, the skin was cleaned with 70% alcohol preparation pads. The anode patch was loaded with neostigmine and glycopyrrolate mixed in distilled water in concentrations previously described [ 8 ]. The cathode patch was loaded with 0.5 mL 0.9% normal saline with 1.0% citric acid.…”

“…The application of this methodology may have practical utility in the treatment of certain conditions that require repetitive systemic administration in the home setting, such as that for bowel care in those with SCI or other conditions associated with neurogenic bowel disorders, as well as for those in the general population without a diagnosis of neurogenic bowel but associated with DWE. Our group has reported that a single transcutaneous administration of neostigmine and glycopyrrolate stimulates a predictable bowel movement without adverse local or systemic events [ 8 ]. The question remains, and is the subject of the work presented herein, as to whether the addition of this dual drug approach by transcutaneous route to standard of care (SOC) for the bowel management confers any clinical or patient-reported benefits over that of SOC alone.…”