Plasma Concentrations of Lidocaine in Dogs Following Lidocaine Patch Application

Introduction

Lidocaine patches^a have been developed and approved for treating post-herpetic neuralgia in humans.¹ Use of a lidocaine patch in dogs is a novel idea for treating pain. Lidocaine binds to neuronal membrane receptors, resulting in inhibition of sodium ion influxes and stabilization of neuronal membranes, thereby inhibiting the initiation of the action potential and conduction of nerve impulses.² These effects prevent or reduce painsignal initiation and transmission from peripheral nerve axons to the central nervous system, and pain perception is decreased.²

Studies in humans have shown that up to 5% of a 700-mg lidocaine patch is absorbed systemically and produces regional analgesia in 30 minutes, with a drug elimination half-life in plasma of 6 to 8 hours.^2–5 In humans, little of the topically applied lidocaine reaches the systemic circulation, and low steady-state plasma concentrations of approximately 130 ng/mL are produced.³ Lidocaine patches are associated with local analgesia rather than local anesthesia, as humans do not report numbness or loss of sensitivity to touch, pressure, or temperature.³ The exact mechanism of this differential effect is unknown; however, it has been suggested that the lidocaine patch delivers adequate amounts of lidocaine to block sodium channels on small, injured, or dysfunctional pain fibers— but not enough to block sodium channels on large, myelinated, A-β sensory fibers.² It is currently unknown whether transdermal lidocaine results in significant absorption of lidocaine from the skin and elevates plasma lidocaine concentrations in dogs. The objectives of this study were to investigate the transdermal absorption of lidocaine after application of a lidocaine patch on the abdominal ventral midline, and to determine if plasma lidocaine concentrations were high enough to produce adverse effects in dogs.

Materials and Methods

This study protocol was approved by the Animal Care and Use Committee at the Oklahoma State University. The dogs were induced with sevoflurane^b in 100% oxygen via face mask. After intubation, the dogs were maintained on sevoflurane (3% to 5%) for approximately 20 minutes during placement of an indwelling jugular venous catheter^c for blood sampling and placement of lidocaine patches.^a The jugular catheter was secured in place via suture and a bandage, and heparinized saline was used to maintain patency of the catheter throughout the course of blood sampling. The hair over the ventral midline was clipped, and the area was cleaned with Chlorhexidine diacetate solution^d and aseptically prepared for 5% lidocaine patch application. The site preparation simulated application of a lidocaine patch following a surgical procedure in the vicinity of the ventral abdomen. Two 5% lidocaine patches were used per dog. The selection of two patches was based on clinical evaluation of local analgesia and the intent to expose a larger surface area of canine skin to the lidocaine patch in order to maximize systemic absorption of lidocaine following transdermal application.

The lidocaine patch is constructed from an adhesive material that contains 5% lidocaine.^2,3 It is applied to a non-woven, polyester felt backing, and covered with a polyethylene terephthalate film-release liner.^2,3 The release liner must be removed prior to its application to the skin. Following removal of the liner, the lidocaine patch is self-adhesive. ³ The patch is 10 × 14 cm in size and contains 700 mg of lidocaine (50 mg of lidocaine per g of adhesive patch) in an aqueous base. The patch is clean but not sterile. One patch was applied on each side of the ventral midline. Although the lidocaine patch is self-adhesive, an adhesive, non-woven fabric retention dressing^e was used to cover and secure the lidocaine patch, maintain full contact with the skin, and prevent removal by the dog.

The first blood sample was collected from each dog after placement of the jugular venous catheter and prior to the application of lidocaine patches. The dogs were recovered from anesthesia after lidocaine patch application, and an Elizabethan collar was placed on each dog. Additional blood samples were collected into heparinized tubes at 10, 20, 30, 40, and 60 minutes and at 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60, 66, 72, 78, and 80 hours after patch application. Plasma was harvested and stored at −40° C until the lidocaine assay was performed. During the blood sampling, the dogs were observed for any clinical signs of lidocaine toxicity, such as muscle tremors, facial twitching, and seizures. Heart and respiratory rates were measured and recorded at each blood sampling point. All of the patches remained intact on the dogs until they were removed at 72 hours after application. Following removal of the lidocaine patches, the skin at the sites of the application was examined for any abnormalities.

Lidocaine concentrations in plasma were determined at a commercial laboratory^f by gas chromatography with a nitrogen-selective detector. In summary, internal standard (8-methoxyloxapine) was added to a 0.5-mL aliquot that was made strongly basic with ammonium hydroxide and extracted with 5% isopropanol in methylene chloride. The extracted samples were analyzed on a 15-m × 0.32-mm internal-diameter capillary column with 0.15 μ DB (Dura Bound: 50% phenyl-methylpolysiloxane)-17 film^g using a gas chromatograph^h with nitrogen-selective detection. The assay’s limit of quantitation was 50 ng/mL. The interassay coefficient of variation was 11.0% and 9.1% at 1000 and 3500 ng/mL, respectively. Elution times were approximately 4.75 and 8.58 minutes for lidocaine and the internal standard, respectively. Lidocaine metabolites were not measured in this study.

Results

Seven 2- to 2.5-year-old, female, mixed-breed, hound-type dogs were used in this study. Body weights ranged from 18 to 23 kg (20.4±1.4 kg). The dogs were research animals.

At 12 hours after application of the lidocaine patches, only two of the seven dogs had plasma lidocaine concentrations that exceeded the assay’s limit of quantitation. The mean maximal plasma concentrations of lidocaine were 72.8±65.8 ng/mL, and they occurred at 24 hours after patch application [see Figure]. Plasma lidocaine concentrations were generally low and highly variable. Plasma lidocaine concentrations increased from 18.5±29.4 ng/mL at 12 hours to 72.8±65.8 ng/mL at 24 hours after patch application, and they remained at steady state between 24 and 48 hours. The “steady state” was defined as a plasma lidocaine concentration that did not continue to accumulate or decrease over time from 24 to 48 hours in these dogs (i.e., a steady plasma concentration was achieved). The plasma lidocaine concentrations decreased (21.4±24.7 ng/mL) significantly (P<0.001) between 48 and 60 hours, and they remained at a low concentration until patch removal 72 hours after application. Following patch removal, the plasma lidocaine concentrations were still quantifiable at 78 hours (30.0±26.2 ng/mL), and then they decreased to a point below the assay’s limit of quantitation by 80 hours in all dogs. Lidocaine patches were well tolerated by all dogs, and no clinical side effects were seen. Two of the seven dogs had erythema at the application site of the lidocaine patches.

Discussion

The results of this study showed minimal systemic absorption of lidocaine from transdermal application using two lidocaine patches on the ventral midline of medium-sized dogs. Similar results have been reported in humans and dogs.^1,5 In humans, four lidocaine (5%) patches were applied to healthy volunteers for 18 hours per day for 3 consecutive days.¹ On days 1, 2, and 3, mean maximum lidocaine concentrations were 145.1 to 153.8 ng/mL, and the median times to peak plasma concentration were 16 to 18 hours.¹ In the current study, the highest plasma concentration of lidocaine was 170 ng/mL, which occurred in two dogs at 24 hours after patch application. A prior study of smaller dogs (9.4 to 14.4 kg) used two methods of hair removal prior to application of one lidocaine patch on the lateral side of the thoracic wall, which was left in place for 12 and 60 hours.⁵ In dogs with clipped hair, a mean peak plasma concentration of 62.94 ng/mL was obtained after 10.67 hours, and in a depilatory group, a mean peak plasma concentration of 103.55 ng/mL was detected after 9.27 hours.⁵ The mean peak plasma lidocaine concentrations obtained in the present study were similar to those reported by Weiland, et al., although two lidocaine patches were used.⁵ This result was not surprising, as the dogs used in the present study were also approximately twice the body weight of dogs in the prior study.⁵ The very low plasma lidocaine concentrations in the study reported here indicated that the analgesic effect bserved in clinical cases in dogs following lidocaine patch application may be a direct, local analgesic effect and not a systemic effect.

In contrast to the relatively low plasma lidocaine concentrations obtained in dogs following transdermal lidocaine administration, lidocaine plasma concentration was reported to be at least 10 times higher (1465 to 1537 ng/mL) when lidocaine was given at 2 mg/kg as an intravenous (IV) bolus, followed by a 30-minute constant rate of infusion at 50 μg/kg per minute in dogs.⁶ The mean plasma lidocaine concentration that induces seizure-like activity in dogs is 8210±1690 ng/mL.⁷ Based on this plasma lidocaine concentration, the transdermal lidocaine patch may be considered to be relatively safe when administered to dogs.

Although a prior study reported that application of a depilatory agent led to a more rapid and higher absorption of lidocaine, the current study was designed to mimic the normal preoperative method of hair removal and skin preparation for sterile surgery, in order to evaluate the systemic uptake of lidocaine under common clinical conditions. Lidocaine is not well absorbed across normal, unbroken skin.³ It is not known how much systemic absorption might occur if the lidocaine patch was inadvertently placed over broken skin or surgical wounds.

In the current study, the plasma lidocaine concentrations decreased significantly from maximal, steady concentrations (between 24 and 48 hours) to a lower concentration at 60 hours. Concentrations remained at this lower level until after patch removal. The exact reason for this decrease was unknown. All patches remained in place on the dogs, so it was unlikely that poor contact between the patch and skin accounted for the decline. It is possible that a refractory period of dermal absorption may occur with prolonged contact with a lidocaine patch. Other studies have also reported a similar drop in plasma lidocaine concentration.⁵

The significant variability that occurs with transdermal absorption of drugs may arise from many different factors.⁸ Differences in skin structure and function between humans and dogs may play a significant role in transdermal lidocaine absorption. The efficacy of transdermal drug delivery is primarily dependent upon skin barrier properties, the ratio of the area of the transdermal patch to the total body mass, and the drug’s lipid solubility, which affects its ability to traverse the epidermal barrier.⁸ Individual variability in systemic absorption of lidocaine in dogs from patches has also been reported.⁵ It was proposed that individual variations, such as gender differences, cutaneous vasoactivity, skin damage, body temperature, and hydration are potential factors that influence the uptake of lidocaine from a transdermal patch.⁵ The current study confirmed a high degree of individual variability in systemic absorption of lidocaine from patches applied to the ventral midline of dogs.

Humans have reported no loss of sensitivity to touch, pressure, or temperature at the site of lidocaine patch application. ⁹ It has been suggested that a lidocaine patch delivers adequate amounts of lidocaine to block sodium channels on small, injured, or dysfunctional pain fibers, but not a high enough concentration to block sodium channels on large, myelinated, A-ß sensory fibers.² This limitation may result in analgesia without blocking all of the sensory and motor inputs, and it may account for the lack of numbness and maintenance of sensitivity to touch in humans.³ Further studies in animals are needed to document the role of lidocaine patches in pain management, as well as to explore the concentration of lidocaine in tissues at the site of application.

The current study differs from previous reports in several ways. This study evaluated two lidocaine patches on each dog, and patches were placed on the abdominal ventral midline. The skin was prepared aseptically prior to lidocaine patch application, and the patches were left in place for 72 hours. In this study, the transdermal absorption of lidocaine was extremely variable and produced only low plasma lidocaine concentrations; however, a steady-state plasma lidocaine concentration was achieved 24 to 48 hours after lidocaine patch application. Furthermore, the plasma lidocaine concentration appeared to linger for an additional 6 hours after the patch removal. Based on the low plasma lidocaine concentrations obtained in this study, use of a lidocaine patch should be relatively safe in dogs, and any analgesic effect observed may arise from a direct, local effect rather than a systemic effect.

Conclusion

Two 5% lidocaine patches were applied to the ventral mid-line of seven dogs for 72 hours, with plasma concentrations of lidocaine measured for 80 hours. Lidocaine was detectable in plasma 12 hours after patch application, and it reached steady-state concentrations 24 to 48 hours after application. Plasma lidocaine levels decreased dramatically at 60 hours post-application. Low plasma lidocaine concentrations persisted for 6 hours after patch removal. Transdermal absorption of lidocaine was highly variable and produced very low plasma lidocaine concentrations in dogs.