Comparison of analgesic and tissue effects of subcutaneous perineural injection of liposomal bupivacaine and bupivacaine hydrochloride in horses with forelimb lameness induced via circumferential clamp

Kayla M. Le 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50010.

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Stephanie S. Caston 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50010.

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Jesse M. Hossetter 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50010.

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Bonnie L. Hay Kraus 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50010.

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Abstract

OBJECTIVE

To evaluate the analgesic and tissue effects of liposomal bupivacaine administered SC as an abaxial sesamoid nerve block in horses with experimentally induced lameness.

ANIMALS

6 healthy mature light-breed horses.

PROCEDURES

In a randomized crossover study, a circumferential hoof clamp was applied to a forelimb to induce reversible lameness. An abaxial sesamoid nerve block of the lame forelimb was performed by SC perineural injection of 10 mg of liposomal bupivacaine or bupivacaine HCl/site. Quantitative gait data were objectively obtained with a body-mounted inertial sensor system before (baseline) and at 30-minute intervals after treatment. Time to return to 85% of baseline lameness was determined. After a minimum 4-day washout period, procedures were repeated with the alternate limb and treatment. Lastly, the palmar digital nerves and perineural tissues were collected and examined histologically.

RESULTS

SC perineural injection of liposomal bupivacaine ameliorated forelimb lameness in 5 of 6 horses. The median duration of analgesia was not significantly different between liposomal bupivacaine (4.5 hours) and bupivacaine HCl (3.0 hours). Histologically, mild inflammation was noted in 3 of 10 sites injected with liposomal bupivacaine and in none of the sites injected with bupivacaine HCl.

CONCLUSIONS AND CLINICAL RELEVANCE

SC perineural injection of 10 mg of liposomal bupivacaine/site ameliorated experimentally induced forelimb lameness in some horses. At milligram-equivalent doses, liposomal bupivacaine had a similar duration of analgesia to that of bupivacaine HCl. Further investigation is required before recommending clinical use of liposomal bupivacaine for nerve blocks in horses.

Abstract

OBJECTIVE

To evaluate the analgesic and tissue effects of liposomal bupivacaine administered SC as an abaxial sesamoid nerve block in horses with experimentally induced lameness.

ANIMALS

6 healthy mature light-breed horses.

PROCEDURES

In a randomized crossover study, a circumferential hoof clamp was applied to a forelimb to induce reversible lameness. An abaxial sesamoid nerve block of the lame forelimb was performed by SC perineural injection of 10 mg of liposomal bupivacaine or bupivacaine HCl/site. Quantitative gait data were objectively obtained with a body-mounted inertial sensor system before (baseline) and at 30-minute intervals after treatment. Time to return to 85% of baseline lameness was determined. After a minimum 4-day washout period, procedures were repeated with the alternate limb and treatment. Lastly, the palmar digital nerves and perineural tissues were collected and examined histologically.

RESULTS

SC perineural injection of liposomal bupivacaine ameliorated forelimb lameness in 5 of 6 horses. The median duration of analgesia was not significantly different between liposomal bupivacaine (4.5 hours) and bupivacaine HCl (3.0 hours). Histologically, mild inflammation was noted in 3 of 10 sites injected with liposomal bupivacaine and in none of the sites injected with bupivacaine HCl.

CONCLUSIONS AND CLINICAL RELEVANCE

SC perineural injection of 10 mg of liposomal bupivacaine/site ameliorated experimentally induced forelimb lameness in some horses. At milligram-equivalent doses, liposomal bupivacaine had a similar duration of analgesia to that of bupivacaine HCl. Further investigation is required before recommending clinical use of liposomal bupivacaine for nerve blocks in horses.

One aspect of multimodal analgesia for orthopedic pain in horses is regional anesthesia, which includes perineural anesthesia. Perineural anesthesia is commonly performed for diagnostic and therapeutic purposes. The analgesic effects of several pharmacologic agents have been investigated; however, these agents were unable to maintain continuous analgesia in horses for > 24 hours without multiple additional doses.1–6,a,b

Perineural catheters have been described for continuous infusion of local anesthetics to achieve prolonged analgesia of the distal portion of the limb of horses.7 Although this technique can be effective, it has not been widely adopted in pain management of orthopedic conditions. Anesthetics administered via epidural injections and epidural catheters may also provide long-term analgesia.8 However, effective analgesia by epidural injection is limited by the location of the painful stimulus, and effective analgesia by an epidural catheter is limited by the difficulty of placing and maintaining an epidural catheter.8–10 Additionally, epidural injection of anesthetics may result in inadvertent recumbency of the patient.11

A liposomal formulation of bupivacaine sustains release of bupivacaine via slow degradation of multivesicular liposomes that encapsulate the drug.12 When the external layer of the phospholipid bilayer of a liposome is breached, the aqueous core of bupivacaine is released.13 A commercially available liposomal bupivacaine injectable solution has been approved for single-dose infiltration into the surgical site to provide local postoperative analgesia for cranial cruciate ligament surgery in dogs and regional postoperative analgesia immediately after onychectomy in cats.12 This formulation may provide up to 72 hours of pain relief.12 Subcutaneous injection of liposomal bupivacaine induces minimal to mild granulomatous inflammation of adipose tissue in dogs and rabbits.14

Recently, the pharmacokinetics and in vivo effect on cartilage of intra-articular injection of liposomal bupivacaine were reported in horses.15 Although sustained concentrations of bupivacaine were noted in the synovial fluid, researchers did not report any analgesic effects of liposomal bupivacaine.15 At the time of design and execution of the study reported here, an effective dose of liposomal bupivacaine for perineural anesthesia had not yet been reported for horses. Since then, however, 2 effective doses have been reported for a small number of horses.a,b If liposomal bupivacaine consistently provides extended analgesia in horses, it will be an important treatment for amelioration of musculoskeletal pain in this species.

The purpose of the study reported here was to investigate the use of liposomal bupivacaine for ABSNBs in horses with experimentally induced lameness, compare the duration of effect of liposomal bupivacaine with that of bupivacaine HCl, and describe the tissue effects of liposomal bupivacaine after SC perineural injection. We hypothesized that a milligram-equivalent dose of liposomal bupivacaine would ameliorate experimentally induced forelimb lameness but would not significantly increase the duration of analgesia when compared with bupivacaine HCl. Additionally, we hypothesized that liposomal bupivacaine would induce minimal gross and microscopic changes to the tissues at the injection sites.

Materials and Methods

Animals

All study procedures were reviewed and approved by the Iowa State University Institutional Animal Care and Use Committee. All horses used in the study were donated for reasons unrelated to lameness from a research herd undergoing dispersal, with the expressed condition that they be euthanized at the conclusion of the study in accordance with previous (nonorthopedic) research protocols. Six mature light-breed horses (5 Quarter Horses and 1 Appaloosa; 5 geldings and 1 mare) with a mean ± SD age of 15 ± 2 years (range, 13 to 18 years) and mean ± SD body weight of 524 ± 45 kg (range, 491 to 587 kg) were enrolled. Inclusion criteria for the study protocol included no clinically important disease as assessed by physical examination and no detectable forelimb lameness during trotting by hand on concrete as assessed objectively with a body-mounted inertial sensor system.c

Experimental design

The study had a crossover design. Horses were randomly assigned by use of a computer-generated random number table to determine forelimb and treatment order. Lameness was induced in the assigned forelimb, and gait was assessed 30 minutes later (baseline). An ABSNB was then performed in the lame forelimb by SC perineural injection of liposomal bupivacaine injectable solutiond or bupivacaine HCl.e Gait was reanalyzed at 30-minute intervals after treatment administration until a mean of at least 85% of the baseline VS was obtained for 2 consecutive time points. A minimum 4-day washout period was provided, during which horses were observed for systemic and local reaction to injection by daily physical examination and gait evaluation. After the washout period, lameness was induced in the opposite forelimb and horses received the second treatment and were similarly monitored as after the first treatment. At the end of the study, the horses were euthanized by IV administration of pentobarbital sodium (78 mg/kg) and phenytoin sodium solution (10 mg/kg) in accordance with donation requirements.

Lameness induction

Lameness was induced through a modification of a previously described circumferential hoof clamp.16 The hooves were trimmed, and the horses were shod by a certified journeyman farrier according to the standards of the American Farrier Association. A 1.25-cm-wide (vs 1.9-cm-wide) stainless steel pipe clamp was fastened around the hoof of the assigned forelimb distal to the coronary band, and 2 wood screws (vs zip ties) were directed into the insensitive dorsal hoof wall dorsomedially and dorsolaterally just proximal to the clamp to prevent proximal migration of the clamp (Figure 1). The clamp was tightened to induce lameness, and gait was assessed 30 minutes later to ensure lameness was present. The clamps and wood screws were removed between treatments, and the hooves were wrapped with an elastic bandage. The clamps were placed by a single farrier and replaced and tightened by a single investigator (KML).

Figure 1—
Figure 1—

Photograph of a portion of the distal aspect of the forelimb of a horse to which a hoof clamp consisting of a stainless steel, circumferential band and 2 wood screws was applied to induce forelimb lameness.

Citation: American Journal of Veterinary Research 81, 7; 10.2460/ajvr.81.7.551

ABSNB technique

Each horse was restrained in a standing position with a halter and lead rope. The 2 injection sites were cleaned with chlorohexidine and then with isopropyl alcohol, ensuring that chlorhexidine was completely removed, and the site was air-dried. Medial and lateral palmar digital nerves at the level of the base of the abaxial surface of the proximal sesamoid bones of the lame forelimb were then injected with 10 mg (0.75 mL) of liposomal bupivacaine injectable solutiond or 10 mg (2 mL) of bupivacaine HCle by use of a 22-gauge, 2.54-cm needle that was directed toward the foot.17 The primary investigator (KML) performed all injections. The 10-mg dose of liposomal bupivacaine/site had been demonstrated to effectively ameliorate natural forelimb lameness in 2 donated horses that were not included in this study. Liposomal bupivacaine injectable solution was mixed by inverting the vial several times and withdrawn aseptically from the vial with a 22-gauge needle as per the manufacturer's recommendations.15 However, some vials were punctured multiple times over the course of several days (against manufacturer's recommendations).15

The effectiveness of the ABSNB was subjectively tested by applying pressure with a ballpoint pen to the skin just proximal to the coronary band dorsally and at the medial and lateral heel bulbs. The ABSNB was considered effective if the horse did not withdraw the treated forelimb. The ABSNB was considered ineffective if the horse did withdraw the treated forelimb, and subsequently, the horse received the same treatment again after the minimum 4-day washout period.

Gait analysis

Gait was quantitatively analyzed with a body-mounted inertial sensor systemc consisting of accelerometers attached at the poll and sacrum and a gyroscope attached to the pastern region of the right forelimb, as previously described.3,18,19 All gait data were collected as horses were trotted by hand on concrete in a straight line. However, only forelimb data containing at least 25 strides with a stride rate variation of < 15% were included in the statistical analysis.

The sensors quantified movement asymmetries of the head and pelvis. Data from the sensors were processed and analyzed by computerized motion analysis algorithms, as detailed in a validation study.18 Outputs and their importance have also been reported.3 Forelimb lameness was defined in accordance with the parameters provided by the manufacturer of the sensor system,20 but we included only the VS in the statistical analysis. A VS > 8.5 mm indicated the presence of forelimb lameness. Differences between liposomal bupivacaine and bupivacaine HCl in the amelioration of experimentally induced forelimb lameness were determined with VS data.

Histologic examination

Immediately after the horses were euthanized, the palmar digital nerves and surrounding tissues at the level of the base of the proximal sesamoid bones were collected from both treated forelimbs and an untreated hind limb for histologic examination. Tissues were preserved in neutral-buffered 10% formalin solution and routinely processed and stained with H&E stain. Ten 200X fields/prepared tissue slide were reviewed by means of light microscopy. A single veterinary pathologist (JMH) blinded to treatment identified and recorded histologic changes, including the type of inflammatory cells when inflammation was identified.

Statistical analysis

Data for time to return to 85% of the baseline VS were tested for normality by use of the Shapiro-Wilk test. Normally distributed data were compared between treatment groups with a 2-tailed, paired t test. Nonnormally distributed data were compared between treatment groups with the Wilcoxon signed rank test. All data were analyzed by use of statistical software.f Values of P < 0.05 were considered significant.

Results

The modified circumferential hoof clamp method induced lameness in all 6 horses prior to treatment (baseline), with a mean ± SD VS of 20.0 ± 8.6 mm (range, 12.3 to 32.7 mm). No significant differences were noted in baseline VS between treatments (P = 0.68), forelimbs (P = 0.49), or treatment orders (P = 0.09). One horse had mild residual lameness 1 day after the first treatment (liposomal bupivacaine) that resolved without intervention on day 2.

Horses had no signs of local or systemic reaction to liposomal bupivacaine or bupivacaine HCl. Liposomal bupivacaine and bupivacaine HCl ameliorated forelimb lameness at a dose of 10 mg/injection site in 5 of 6 horses and in all 6 horses, respectively. Initially, however, the ABSNB was ineffective in 2 horses 30 minutes after injection of liposomal bupivacaine from the manufacturer-supplied vial that was first punctured 96 hours beforehand. After the ABSNB was ineffective for a second horse, both horses were trotted once again > 30 minutes after injection. Neither horse had a decrease from the baseline VS. After a 4-day washout period, these 2 horses were reinjected with 10 mg of liposomal bupivacaine/site from a yet-unpunctured vial. After 30 minutes, the ABSNB had effectively eliminated skin sensation and lameness. The ABSNB was ineffective for a third horse, the single mare enrolled in this study, despite multiple attempts on different days with different vials of liposomal bupivacaine. Lameness was subsequently ameliorated at a dose of 27 mg/site. Because of the higher dose needed to ameliorate lameness in this horse, data from this horse were excluded from the statistical analyses.

The median (range) time to return to 85% of the baseline VS with liposomal bupivacaine and bupivacaine HCl was 4.5 hours (range, 2 to 4.5 hours) and 3 hours (range, 2.5 to 4 hours), respectively. Results were not significantly (P = 0.06) different.

Histologically, only 1 nerve had a mild peripheral change characterized as proliferation of fibrocytes in the perineurium, which disrupted the axons in the fascicles, yet without inflammation of the surrounding tissues. This nerve was from the forelimb in which lameness was ameliorated by means of injection with liposomal bupivacaine. The other neurovascular bundle from the same limb did not have any histologic changes.

Tissues surrounding the nerves from 3 forelimbs of 3 horses had mild inflammation, characterized by lymphocytes, macrophages, and polymorphonuclear cells in the collagen bundles. The nerves of these forelimbs had been blocked with liposomal bupivacaine. Of the injection sites with inflammation, 2 were present in the first treated forelimb and 1 was present in the second treated forelimb. No inflammation was noted in the examined tissues of the hind limbs or forelimbs for which nerves were injected with bupivacaine HCl.

Each of 3 sites had a chronic recanalizing thrombus in the palmar or plantar digital arteries of 1 side of a limb. The thrombus was noted for a forelimb injected with bupivacaine HCl as the first assigned treatment (1/3 sites) and for the control hind limbs (2/3 sites). Vascular expansion of the tunica intima, which narrowed the lumen of the large muscular arteries (palmar digital arteries), was noted at the injection site of 1 forelimb with liposomal bupivacaine as the first assigned treatment and was also noted for 1 control limb. Vascular expansion was accompanied by a mild degree of inflammation for the forelimb injected with liposomal bupivacaine and by a chronic recanalizing thrombus on the opposite side of the control limb.

Discussion

The modified circumferential hoof clamp used in the present study induced forelimb lameness in each horse. One horse had residual lameness after removal of the clamp. This contrasts with other reports2,16 in which lameness did not persist after removal of the circumferential hoof clamp. Lameness may have persisted for this horse owing to the use of a thinner clamp or because of repetitive trotting on a concrete surface. Additionally, underlying musculoskeletal disease may have been present despite the subjective lack of forelimb lameness prior to the start of the study. Although underlying musculoskeletal disease may have affected the degree of lameness produced by the clamp, the confounding effect of any disease would have been negated because each treated forelimb served as its own control.

For 5 of 6 horses, liposomal bupivacaine ameliorated lameness at a dose of 10 mg/injection site. Its duration of analgesia was not significantly longer than that of bupivacaine HCl at a milligram-equivalent dose. We decided to use time to return to 85% of the baseline VS as our study end point because this is similar to that in a previous report,3 and we believed time to return to 100% of the baseline VS would have unnecessarily prolonged lameness and resulted in inadvertent injury. However, the duration of analgesia would have likely increased if time to return to 100% of the baseline VS was chosen as our study end point.

Authors of a recent abstracta reported that liposomal bupivacaine, versus saline solution, results in a significantly decreased response to mechanical pressure to the digit for 4 hours after SC injection of liposomal bupivacaine near the palmar digital nerve at the level of the proximal sesamoid bones. However, the authors injected more than twice the dose (26.6 vs 10 mg) and volume (2 vs 0.75 mL) of liposomal bupivacaine per site that we injected per site. However, lameness was not reported, and gait was not analyzed to determine the effectiveness of liposomal bupivacaine. Instead, the effectiveness of liposomal bupivacaine was quantified with mechanical nociceptive thresholds as measured by use of an algometer. Therefore, a direct comparison between studies cannot be made.

Yet, as in our study, authors of another recent abstractb similarly induced lameness and compared the analgesic effect of liposomal bupivacaine and bupivacaine HCl through quantitative analysis of the gait with the body-mounted inertial sensor system. The VS was determined at 0, 1, 6, and 24 hours after lameness induction and again prior to injection and at 1, 6, 24, 48, and 72 hours after injection. Compared with the VSs of untreated lame horses, the VSs for lame horses were significantly different at 1, 6, and 24 hours after injection of liposomal bupivacaine and at 1 hour after injection of bupivacaine HCl. However, the authors injected more than 3 times the dose (39.9 vs 10 mg) and volume (3 vs 0.75 mL) of liposomal bupivacaine per siteg that we injected per site. The varied durations of analgesia of liposomal bupivacaine suggest duration is likely dose dependent.

Although the manufacturer12 of liposomal bupivacaine recommends puncturing the vial of drug with a needle only once to withdraw all doses and discarding any drug that is remaining in the vial after 4 hours, we punctured the vial multiple times at 24-hour intervals because of the expense of purchasing the necessary number of vials to complete our study. The manufacturer likely recommends discarding the drug remaining in a vial after 4 hours of its puncture because of the lack of preservative and concerns about microbial contamination. Interestingly, an ABSNB performed with liposomal bupivacaine from a vial first punctured > 72 hours previously was ineffective by 30 minutes in 2 horses. However, loss of skin (superficial) sensation does not directly equate to loss of sensation of deeper structures.3 Although we chose skin sensation to determine the success of the ABSNB, amelioration of lameness is theoretically possible without concomitant loss of skin sensation. Yet, these 2 horses did not have decreases from their baseline VS after the initial injections but did have decreases from their baseline VS after injection with liposomal bupivacaine aspirated from a new vial. Lameness was successfully ameliorated in another horse injected with liposomal bupivacaine aspirated from a vial first punctured 72 hours previously. Because of these collective findings, the study protocol was revised such that no horse was injected with liposomal bupivacaine from a vial punctured > 72 hours previously. Overall, lameness was successfully ameliorated in 4 horses with liposomal bupivacaine aspirated from a vial within 24 hours of its first needle puncture and in 1 horse each with liposomal bupivacaine aspirated from a vial within 48 or 72 hours of its first needle puncture.

Lack of preservative within a vial of liposomal bupivacaine may have permitted degradation of the liposomes by inadvertent introduction of microbes. Also, multiple needle punctures may have caused physical, premature rupture of liposome vesicles. Information regarding stability of this liposomal bupivacaine injectable solution is proprietary and, therefore, unavailable. Yet, the researchers of a recent study21 did not report bacterial growth from aliquots of liposomal bupivacaine that had been withdrawn with an aseptic technique from a single vial over 5 consecutive days, and concentrations of free (unencapsulated) bupivacaine did not differ from baseline through day 4.

In the study reported here, 1 nerve that had been blocked with liposomal bupivacaine had proliferation of fibrocytes within the perineurium, and 3 sites that had been injected with liposomal bupivacaine had mild inflammation of perineural tissues. Likewise, SC perineural injection of liposomal bupivacaine produced minimal to mild granulomatous inflammation of perineural adipose tissue of rabbits and dogs examined 3 and 15 days after injection.14 Liposomes likely induced these changes. Because of randomization of treatment order and variable timing of euthanasia and histologic examination in our study, identification of inflammation after injection with liposomal bupivacaine or bupivacaine HCl may have been hindered. Randomization of the forelimb to be treated but not the order of treatments may have allowed a clearer comparison of histologic results. Alternatively, the nerve and surrounding fascia without the associated artery and vein could have been excised (high palmar digital neurectomy) from a live, anesthetized horse immediately after the washout period for the first treatment. Both would have ensured consistent timing to detect histologic changes after injection, but excision of the nerves and surrounding fascia would have added a more invasive procedure to our study. The importance of the histologic vascular changes noted in both treated and untreated limbs is unknown.

The present study was limited by its small sample size. Because the results of the abstracted studiesa,b had not yet been reported at the time our study was conducted, we had chosen to enroll only a small number of horses to establish proof of concept, safety, and effectiveness of an ABSNB with liposomal bupivacaine. Additionally, we did not use this liposomal bupivacaine injectable solution according to the manufacturer's recommendations (ie, the study involved multiple needle punctures of each vial), which may have contributed to its shorter duration of analgesia, compared with durations previously reported.a,b

Subcutaneous perineural injection of liposomal bupivacaine ameliorated experimentally induced lameness in the horses of the study reported here. At milligram-equivalent doses, liposomal bupivacaine did not significantly increase the duration of analgesia, compared with that of bupivacaine HCl. Given the ability of liposomal bupivacaine to ameliorate lameness in horses and to produce an extended duration of analgesia at higher doses, further investigations of higher doses in horses are warranted. If a dose of liposomal bupivacaine is identified that can provide longer-term analgesia than that achieved with bupivacaine HCl and other local anesthetics, liposomal bupivacaine may be of benefit for use in horses. As such, further studies to establish pharmacokinetics and guidelines for administration of liposomal bupivacaine are needed before its clinical use can be recommended. Also, its effectiveness should be evaluated after aspiration from a vial that had been previously punctured with multiple needles or that had been first punctured > 4 hours beforehand. This product is intended to be used before 4 hours after a single needle puncture of its vial, and deviation from this may decrease its efficacy.

Acknowledgments

Funded by the Research Incentive Seed Grant, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University.

The authors declare that there were no conflicts of interest.

Presented in abstract form at the Annual Conference of the Veterinary Orthopedic Society Conference, Breckenridge, Colo, February 2019.

ABBREVIATIONS

ABSNB

Abaxial sesamoid nerve block

VS

Vector sum

Footnotes

a.

McCracken MJ, Schumacher J, Doherty T, et al. The duration of effect and efficacy of liposomal bupivacaine administered adjacent to the palmar digital nerves of the horse (abstr). Vet Surg 2019;48:1137.

b.

Pezzanite LM, Griffenhagen G, Hendrickson D, et al. Comparison of two bupivacaine formulations using an experimental model of equine sole pain (abstr). Vet Surg 2019;48:1148.

c.

The Equinosis Q with Lameness Locator, Equinosis LLC, Columbia, Mo.

d.

Nocita, Aratana Therapeutics Inc, Leawood, Kan.

e.

Hospira, Lake Forest, Ill.

f.

GraphPad Prism, version 8.0.1 for Windows, GraphPad Software, San Diego, Calif.

g.

Pezzanite L, Colorado State University, Fort Collins, Colo: Personal communication, 2019.

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