Microneedle-enhanced transdermal drug delivery greatly improves the subset of pharmacologically active molecules that can be transported across the skin. Formulation pH plays an important role in all drug delivery systems; however, for transdermal delivery it becomes specifically significant since a wide range of pH values can be exploited for patch formulation as long as it does not lead to skin irritation or sensitization issues. Wound healing literature has shown significant pH effects on barrier recovery. Stability and solubility of the drug, and thus transport across skin, are all affected by formulation pH. The current study examined the role of ionization state of the drug naltrexone on transdermal flux and permeability across microneedle treated skin, as compared to intact skin. Impedance spectroscopy was done in pigs in vivo to assess the role of formulation pH on the rate of micropore closure under the influence of three different pH conditions. The data indicated that while there was significant advantage of using a lower pH formulation in terms of total transport across microneedle treated skin, the pH however did not have any significant effect on the rate of micropore closure beyond the first 24 h.