Introduction
Pain assessment and management in reptile patients has remained challenging in clinical settings. There are also significant physiological differences between reptile species and groups of reptiles, making extrapolation of analgesic efficacy trials difficult between even seemingly similar species. Of the data available, μ-opioid receptor agonists have most consistently resulted in analgesic efficacy in lizards and chelonians, compared with other opioid agonists.1–3
Regional anesthesia and analgesia show promise in reptile medicine, allowing for anesthetic and analgesic drug delivery that may reduce the requirement for systemically administered drugs and, therefore, may reduce the risk of adverse effects, ranging from cardiorespiratory depression to death.4–6 Additionally, regional analgesia has been reported to result in improved analgesia with less adverse effects in women in labor and people undergoing surgical procedures.7–9
Recently, a neuraxial injection technique has been described in bearded dragons (Pogona vitticeps).6,10 Neuraxial administration of lidocaine and bupivacaine resulted in motor and sensory blockade of the pelvic limbs, cloaca, and midcaudal trunk, with minimal adverse effects.6,10 These local anesthetics have a brief onset of action (within 5 minutes), but the blockade provided is also brief.6,10 For instance, pelvic limb motor blockade lasted a mean ± SD of 48 ± 25 minutes for lidocaine (2 mg/kg, 10 mg/mL) and a median of 68 minutes (range, 30 to 105 minutes) for bupivacaine (1 mg/kg, 5 mg/mL). Neuraxial morphine administration can result in a delayed onset of action but long-lasting duration due to poor lipid solubility and slow clearance from the intrathecal space.11,12 To date, no studies have been reported that evaluate the effects of neuraxial morphine administration in any lizard species. Therefore, the objective of the present study was to evaluate the efficacy and safety of neuraxial morphine administration in bearded dragons. We hypothesized that neuraxial morphine administration would result in antinociceptive effects without clinically relevant adverse effects in healthy bearded dragons.
Materials and Methods
Animals
This study was approved by the Institutional Animal Care and Use Committee of the School of Veterinary Medicine, University of Wisconsin-Madison. Ten (8 males and 2 females) healthy adult (1 to 6 years) intact inland bearded dragons with a mean ± SD body weight of 0.3 ± 0.1 kg were used in this study. Animals were deemed healthy by physical examinations and monitoring of food intake, fecal output, and body weight performed before and throughout the study.
The animals were obtained from a commercial breeder and housed at our research animal housing facility individually in glass tanks in a climate-controlled room with a 12-hour light cycle. Artificial ultraviolet B light was provided to each enclosure for 12 h/d, resulting in a temperature gradient from approximately 27 °C at one end of the tanks up to approximately 32 to 34 °C at the basking spot provided at the other end of the tanks. The animals were offered gut-loaded feeder insects dusted with calcium carbonate powder or mixed leafy greens once a day, 6 d/wk. Fresh water was provided to all animals in a bowl at all times, and all animals were soaked in a shallow warm water bath twice weekly. All animals were acclimatized to the housing conditions for at least 8 weeks prior to the start of the experiments.
Study design
In a randomized, blinded, complete crossover design with a washout period of at least 7 days between treatments, neuraxial administration of morphine combined with lidocaine was compared with neuraxial administration of lidocaine alone. Lidocaine was included in both treatment sessions to confirm the correct neuraxial delivery of the drugs by induction of a temporary regional motor block of the pelvic limbs.
Animals were randomly assigned by means of a randomizer software program (Research Randomizer version 4.0; Randomizer.org) to first receive a neuraxial injection of preservative-free lidocaine (2 mg/kg) diluted with saline solution to a total volume of 0.3 mL/kg (control treatment) or preservative-free lidocaine (2 mg/kg) combined with preservative-free morphine (0.5 mg/kg) diluted with saline solution to a total volume of 0.3 mL/kg (test treatment). If the first injection did not result in motor blockade (ie, loss of cloacal tonus or loss of motor function in response to mechanical stimulation of the pelvic limbs) within 10 minutes, a second injection with the same dose and volume was performed as previously reported.6,10
The 0.5 mg/kg dose of morphine was chosen on the basis of a preliminary study in which neuraxial morphine administration was evaluated at 0.1, 0.2, and 0.5 mg/kg combined with lidocaine (2 mg/kg) in 4 bearded dragons/dose. No adverse effects were noted at any of the doses evaluated. At 0.1 and 0.2 mg/kg, the antinociceptive effects were inconsistent and lasted for < 8 hours in all animals. Therefore, the 0.5-mg/kg dose was chosen for the present study. A sample size of 10 was chosen on the basis of the withdrawal latency difference detected during preliminary studies.
The neuraxial injections were performed 30 minutes after administration of alfaxalone (15 mg/kg, SC, axillary region) with the sedated animal in sternal recumbency with thoracic and pelvic limbs in a normal position. The sacrococcygeal region was identified by means of moving the tail side to side to identify the space between the sacrum (immobile) and the coccygeal vertebrae. The point of needle insertion was at midline, in an imaginary line drawn between the caudal borders of the ilia. The skin of the sacrococcygeal area was prepared with 2% chlorhexidine and 70% isopropyl alcohol. A 0.5-mL syringe with 28-gauge, 13-mm needle (Beckton, Dickinson and Co) was inserted at approximately 75° with skin and bevel facing cranially. The needle was advanced cranially slowly until a twitch of the tail or pelvic limbs was observed or until the needle was inserted to approximately two-thirds of the needle length. The needle was withdrawn, and its angle was readjusted if bone was contacted at approximately less than half of the needle length. Prior to each injection, aspiration was performed and, if no blood was observed, the injection was completed.
All neuraxial injections and measurements were performed by the same person (THF and DMF, respectively), who was unaware of treatments administered. A third investigator (CM) was responsible for providing prefilled, unlabeled syringes for the injections. The sedation, neuraxial injections, and subsequent monitoring and measurements were performed in a room maintained at 23 to 25 °C.
Measurements
Measurements were obtained before alfaxalone administration, immediately before neuraxial injection (baseline), and every 5 minutes thereafter until complete recovery, which was defined as return of righting reflex and mechanical stimulation responses equivalent to presedation values. Heart rate (HR), respiratory rate (RR), cloacal tonus, sedation score, and response to mechanical stimulation of the limbs and trunk were recorded.
A Doppler probe was used to determine HR. Respiratory rate was determined by means of observing coelomic excursions. Sedation was scored on the basis of righting reflex (0, present and normal; 1, legs moving but righting reflex not present or slow and present; 2, absent) and position of the head and body (0, head and front of the body up; 1, head low and front of the body down; 2, head and body flat on the table). Cloacal tonus was assessed by means of stimulating the cloaca with the cotton tip portion of a cotton swab. Curved mosquito forceps with the tips covered with medical tape were used to perform mechanical stimulation of the limbs and trunk. Mechanical stimulation of the limbs, cloaca, and trunk was used to assess the extent of sensory and motor block. The trunk was measured from axilla to base of the pelvic limbs and divided into 4 sections by means of drawing 3 lines corresponding to 25%, 50%, and 75% of the trunk length.6 A mechanical noxious stimulus was applied bilaterally to the limbs and trunk by means of pinching the skin with the mosquito forceps until just prior to engagement of the first ratchet, and the order was always from caudal to cranial direction, as follows: pelvic limbs; 25%, 50%, and 75% of the trunk’s length; and thoracic limbs. Motor blockade was considered successful if there was no withdrawal of the stimulated limb or movement of other body parts during stimulation or lack of contraction of the cloacal sphincter following stimulation with a cotton-tipped applicator. Successful sensory block of the trunk was considered as lack of twitching or sudden movement of other parts of the body during stimulation.
Thermal withdrawal latencies (TWLs) of the pelvic limbs in response to a thermal noxious stimulus were measured using a plantar testing device (plantar test with heated base; IITC Life Science Inc). The heated glass base’s temperature was set at 29 °C. The TWL (in seconds) was measured in response to a noxious infrared radiant heat stimulus applied to the plantar surface of each hind foot. Prior to the start of the study, the bearded dragons were acclimated to the testing device for at least 15 minutes daily for 2 weeks. Animals were able to freely move in the testing chamber and were not able to see human observers or other bearded dragons. Following this, pelvic limb TWLs were measured daily, and the thermal intensity was increased daily until a targeted 8- to 12-second withdrawal for the group of bearded dragons was achieved. The radiant heat beam intensity selected was 65%. To avoid tissue damage, the cutoff time was set at 25 seconds. The TWL measurements were measured on each day of experiments prior to sedation with alfaxalone (baseline) and then again at 2 hours after neuraxial injection to ensure the animals had normal motor function and did not have residual sedation from alfaxalone. Measurements were obtained at 2, 4, 8, 12, 24, and 48 hours after neuraxial injection, in duplicate, 5 minutes apart at each time point for each foot. If the duplicate measurements differed by > 20%, a third measurement was recorded and the mean of all 3 latencies for each foot and each time point was used for data analysis.
All animals were regularly monitored for 30 days after the last injection for any adverse effects, such as skin damage (burns), pelvic limb paresis, cloacal sphincter atony, or loss of sensation of limbs, cloaca, or trunk.
Statistical analysis
Data were analyzed by use of commercial software (SigmaPlot version 13; Systat Software Inc). Thermal withdrawal latency data for both limbs were averaged, and δ values were used to evaluate differences between treatments at different time points. Thermal withdrawal latency, HR, and RR data were evaluated for normality with the Shapiro-Wilk test, and the Brown-Forsythe test was utilized to assess for equal variance.
Data were compared between treatments with a 2-way repeated-measures ANOVA. The Holm-Sidak method was utilized for post hoc pairwise comparisons if significant differences were found between treatments. Cumulative scores for head position and righting reflex were generated by means of adding all recorded scores of each parameter from baseline to return to a score of 0. The cumulative score for each of the parameters was compared between treatments using the Wilcoxon signed rank test. Differences were considered statistically significant at P < 0.05.
Results
The success rate after the initial injection for lidocaine alone was 90% (9/10) for both treatments. The same bearded dragon, required 2 injections with both treatments, and the second injection was successful both times, increasing the overall success rate to 100%. For those 2 failed initial injections, no twitch of the pelvic limbs or tail was noted and the needle was inserted to approximately two-thirds of the needle length into the animal. However, not all successful injections were associated with a twitch. A twitch of the pelvic limbs or tail was observed in 17 of 20 successful injections. For those 3 successful injections without a resultant twitch, the needle was inserted to approximately two-thirds of the needle length into the animal. Blood was aspirated on 4 occasions: 2 happened in the same animal (both treatments), and the other 2 were in different animals (1 in each treatment).
Time to onset of motor blockade of the pelvic limbs for both treatments was 5 minutes. There was no difference in the measured sedation parameters (righting reflex and head position) or duration of motor block between treatments (Table 1). Most bearded dragons had sensory blockade up to 25% of the trunk (9/10 animals for both treatments), but there was also a moderate incidence of cranial spread up to 75% of the trunk with both treatments (5 and 4 animals for lidocaine and lidocaine-morphine, respectively).
Summary data for 10 bearded dragons (Pogona vitticeps) following neuraxial administration of lidocaine (2 mg/kg) or lidocaine (2 mg/kg) and morphine (0.5 mg/kg).
| Lidocaine | Lidocaine-morphine | |||||||
|---|---|---|---|---|---|---|---|---|
| Variable | n | Median | IQR | Range | n | Median | IQR | Range |
| Duration (min) | ||||||||
| Pelvic limb motor blockade | 10 | 20 | 20–27.5 | 15–45 | 8 | 30 | 20–45 | 15–60 |
| Cloacal tone loss | 10 | 30 | 30–45.0 | 20–75 | 9 | 30 | 20–45 | 10–220 |
| 25% trunk sensory blockade | 9 | 25 | 15–30.0 | 10–45 | 9 | 30 | 15–45 | 5–75 |
| 50% trunk sensory blockade | 5 | 15 | 10–20.0 | 5–25 | 7 | 10 | 8–13 | 5–30 |
| 75% trunk sensory blockade | 5 | 5 | 5–15.0 | 5–20 | 4 | 5 | 5–6 | 5–10 |
| Forelimb motor blockade | 2 | 10 | 8–13 | 5–15 | 0 | – | – | – |
| Loss of righting reflex | 8 | 25 | 19–30 | 10–45 | 8 | 18 | 14–30 | 5–30 |
| Cumulative righting reflex score | 10 | 13.5 | 11.3–15.0 | 8.0–17.0 | 10 | 13 | 11.3–14.0 | 7.0–16.0 |
| Cumulative head position score | 10 | 10.0 | 7.2–13.0 | 4.0–19.0 | 10 | 10.5 | 8.0–16.3 | 6.0–25.0 |
No significant (P ≥ 0.16) differences were identified between treatments for any of these variables.
IQR = Interquartile (25th to 75th percentile) range.
The TWLs were significantly (≤ 0.005) longer between 2 and 12 hours after neuraxial administration of lidocaine-morphine versus lidocaine (Figure 1). By 24 hours, latencies had decreased with lidocaine-morphine and were no longer significantly (P = 0.20) different from lidocaine. No skin damage was noted in the testing sites by the thermal stimulation in any of the animals.
Mean ± SEM change in thermal withdrawal latency at various points in response to a thermal noxious stimulus applied to the plantar aspect of the pelvic limbs, following neuraxial administration of lidocaine (2 mg/kg; black circles) or lidocaine (2 mg/kg) and morphine (0.5 mg/kg; white circles) in 10 bearded dragons (Pogona vitticeps). *Pairs of values at the same time point differ significantly (P < 0.05). BL = Baseline.
Citation: American Journal of Veterinary Research 83, 3; 10.2460/ajvr.21.08.0104
Heart rate was significantly (P = 0.03) higher with lidocaine versus lidocaine-morphine at 5 minutes after neuraxial injection (Figure 2). Compared with values obtained immediately prior to the neuraxial injection, HR was significantly lower between 20 and 120 minutes postinjection with lidocaine and between 5 and 120 minutes with lidocaine-morphine. Respiratory rate did not change significantly over time after neuraxial drug administration for either treatment (Figure 3).
Mean ± SEM heart rates in the bearded dragons (that were sedated with alfaxalone) at various points before (baseline) and after neuraxial administration of lidocaine or lidocaine-morphine. Values for heart rate were significantly lower than baseline values between 20 and 120 minutes with lidocaine and between 5 and 120 minutes with lidocaine-morphine. See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 83, 3; 10.2460/ajvr.21.08.0104
Mean ± SEM respiratory rates in the bearded dragons at various points. See Figures 1 and 2 for remainder of key.
Citation: American Journal of Veterinary Research 83, 3; 10.2460/ajvr.21.08.0104
Discussion
The results of this study suggested that neuraxial administration of morphine (0.5 mg/kg) combined with lidocaine (2 mg/kg) can provide at least 12 hours but less than 24 hours of regional antinociceptive effects in healthy bearded dragons. Additionally, no clinically relevant adverse effects were noted in these animals.
Neuraxial lidocaine was used in the present study during both treatment sessions to ensure a successful injection was achieved because loss of motor function of the pelvic limbs or cloaca was obvious. Therefore, separation of the antinociceptive effects of neuraxial lidocaine and morphine was not possible. However, the addition of local anesthetics can have a synergistic effect and prolong the effects of morphine and should be considered clinically.13–18 In addition, neuraxial administration of morphine alone has been associated with inconsistent efficacy in a few reports.16,17 Motor dysfunction may be a concern when local anesthetics are added; however, this can be prevented or minimized if lower doses of local anesthetics are used while still providing similar antinociception19 or even maintaining the synergistic effect of the combination.13 In most instances in clinical reptile medicine, morphine would likely be combined with a local anesthetic such as lidocaine or bupivacaine to perform a surgical procedure of the tail, cloaca, pelvic limbs, or caudal trunk.5
Onset of neuraxial morphine administration in dogs and cats has been reported to be between 30 and 60 minutes.11,20 Onset of antinociceptive effects of neuraxial morphine administration in the present study could have occurred before the 2-hour monitoring point; however, we elected to delay the TWL testing until that time point to ensure all animals had normal motor function of limbs and had returned to normal behavior, which otherwise could have affected the results. The duration of antinociceptive effects of neuraxial morphine administration in the present study was between 12 and 24 hours. This was within the range found in the literature for neuraxial morphine in dogs and cats, in which the duration of action has been reported to be between 6 and 24 hours.11,16,17,20,21
The total volume of injection can influence the cranial spread of neuraxial injections.22–24 A previous study6 involving neuraxial lidocaine administration in bearded dragons used the same dose of lidocaine (2 mg/kg) but a lower volume of administration (0.2 mL/kg) than in the present study (0.3 mL/kg). The higher volume resulted in more consistent cranial spread in the present study, where 50% (5/10) of the animals had sensory blockade up to 75% of the trunk, but only 17% (1/6) of animals had this cranial spread with lower volume of administration in the previous study.6 In addition to more consistent cranial spread, no relevant adverse effects were observed in the present study, suggesting that this dose of lidocaine (2 mg/kg) diluted to a higher volume (0.3 mL/kg) may be more clinically relevant for procedures involving the trunk in healthy bearded dragons. However, 2 of 10 animals had motor blockade up to the forelimbs, which could be excessive and potentially lead to clinically relevant complications; therefore, studies involving a larger sample size are still warranted to confirm the safety of this higher volume (0.3 mL/kg).
The duration of effects following epidural anesthesia in dogs seems to be influenced by the concentration and total dose administered.25,26 According to Otero and Campoy,27 it appears that once a minimum volume is reached to effectively achieve epidural blockade, the concentration of the local anesthetic will directly influence the duration of effects. This could explain the difference in duration observed between the present study and the previous study6 using the same dose of lidocaine (2 mg/kg) but different volumes and, therefore, different concentrations (0.3 and 0.2 mL/kg, respectively). Mean ± SD duration of motor blockade of the pelvic limbs in the other study6 was 48 ± 25 minutes (range, 25 to 90 minutes), whereas in the present study the median was 20 minutes (range, 15 to 45 minutes) for lidocaine, demonstrating a clinically relevant decrease.
In reptiles, the onset and duration of anesthetic and sedative drugs have been shown to be temperature dependent.1 In the present study, the effect of body temperature on the duration of efficacy of neuraxial morphine or lidocaine was not evaluated and, therefore, it cannot be ruled out that at different body temperatures the duration of these drugs is different from what was reported here.
No significant respiratory depression or changes in HR have been observed in dogs receiving a morphine epidural.17,19,28,29 In the present study, HR significantly decreased following neuraxial administration of lidocaine or lidocaine-morphine. Lidocaine-morphine resulted in overall lower HRs than did lidocaine, but HRs remained within what would be considered a clinically normal range for sedated bearded dragons with both treatments. An initial transient increase in HR occurred at 5 minutes after neuraxial lidocaine administration. This finding is consistent with the results of a previous study6 that used neuraxial lidocaine administration at the same dose in bearded dragons.6 In both studies, the increase in HR was transient and resolved by 10 minutes following injection. No significant difference was noted in RR between treatments or compared with baseline after neuraxial morphine administration, but more thorough evaluation with the use of blood gas analysis is indicated for better assessment of respiratory function, which was not performed in the present study.
A limitation of the present study was the lack of systemically administered morphine as a control treatment, since it cannot be ruled out that the TWL increase was due to a systemic absorption of morphine. However, morphine has been previously evaluated3 for its antinociceptive effects in bearded dragons by use of the same thermal nociception method employed in the present study. The SC administered morphine doses evaluated in that study3 were 1, 5, 10, and 20 mg/kg. Only 10- and 20-mg/kg doses resulted in a significant increase in TWL at 2, 4, and 8 hours after administration. Therefore, it is unlikely that the antinociceptive effects of the 0.5-mg dose of morphine/kg administered via neuraxial injection in the present study were due to systemic absorption because the previous study3 demonstrated the need for a dose 20 times as high to achieve thermal nociception after SC administration in bearded dragons.
In conclusion, neuraxial administration of morphine (0.5 mg/kg) combined with lidocaine resulted in regional antinociceptive effects for at least 12 hours without clinically relevant adverse effects in healthy bearded dragons, demonstrating potential for providing regional pain management in this species.
Acknowledgments
Funded by the Companion Animal Fund, School of Veterinary Medicine, University of Wisconsin-Madison. This funding source did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript.
The authors declare that there were no conflicts of interest.
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