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Keywords:

  • Drug disposition;
  • Feeding;
  • Narcotic agonist-antagonist;
  • Pedometer;
  • Sedation

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

Background: Despite frequent clinical use, information about the pharmacokinetics (PK), clinical effects, and safety of butorphanol in foals is not available.

Objectives: The purpose of this study was to determine the PK of butorphanol in neonatal foals after IV and IM administration; to determine whether administration of butorphanol results in physiologic or behavioral changes in neonatal foals; and to describe adverse effects associated with its use in neonatal foals.

Animals: Six healthy mixed breed pony foals between 3 and 12 days of age were used.

Methods: In a 3-way crossover design, foals received butorphanol (IV and IM, at 0.05 mg/kg) and IV saline (control group). Butorphanol concentrations were determined by high-performance liquid chromatography and analyzed using a noncompartmental PK model. Physiologic data were obtained at specified intervals after drug administration. Pedometers were used to evaluate locomotor activity. Behavioral data were obtained using a 2-hour real-time video recording.

Results: The terminal half-life of butorphanol was 2.1 hours and C0 was 33.2 ± 12.1 ng/mL after IV injection. For IM injection, Cmax and Tmax were 20.1 ± 3.5 ng/mL and 5.9 ± 2.1 minutes, respectively. Bioavailability was 66.1 ± 11.9%. There were minimal effects on vital signs. Foals that received butorphanol spent significantly more time nursing than control foals and appeared sedated.

Conclusions and Clinical Importance: The disposition of butorphanol in neonatal foals differs from that in adult horses. The main behavioral effects after butorphanol administration to neonatal foals were sedation and increased feeding behavior.

Several studies have demonstrated adverse physiologic and behavioral consequences associated with untreated pain in human neonates1,2 and there is some evidence of similar consequences in adult horses.3 The most commonly used analgesic medications in foals are nonsteroidal anti-inflammatory drugs (NSAIDs) such as phenylbutazone and flunixin meglumine, which carry some risk of adverse gastrointestinal (GI) and renal events.4α-2 receptor agonists such as xylazine and detomidine are potent analgesics but they also produce negative cardiovascular, respiratory, and sedative effects that make them unsuitable for use in compromised foals.5,6 Because of the risks associated with the use of NSAIDs and α-2 receptor agonists, particularly in neonatal foals, there is interest in evaluating and using other analgesics to manage pain in foals.

In humans, opioids have remained the mainstay of the analgesic regimen in the neonatal intensive care unit.2,7 Butorphanol, a synthetic narcotic agonist-antagonist (μ-receptor antagonist and κ-receptor agonist), is commonly used in equine medicine and is considered an efficacious and safe visceral analgesic in adult horses.8–10 Because butorphanol causes minimal cardiovascular and respiratory effects in adult horses10,11 and is considered a desirable choice for patients with hypotension, this opioid appears especially suitable for use in neonatal foals. The purpose of this study was to determine the pharmacokinetics (PK) of butorphanol in neonatal foals after IV and IM administration; to determine whether administration of butorphanol results in physiologic or behavioral changes in neonatal foals; and to describe adverse effects associated with its use in neonatal foals.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

Animals

Six healthy neonatal Arabian/pony cross foals of both sexes (4 females, 2 males) were used. Foals were determined to be in good health based on a complete physical examination, CBC, and assessment of passive transfer of maternal antibody.a Mean (± standard deviation [SD]) age at day 1 of the trial was 5 ± 2.4 days (median, 4 days; range, 3–8 days). Mean (±SD) body weight at day 1 of the trial was 26.6 ± 5.2 kg (median, 25.6 kg; range, 20–33.2 kg). Foals were maintained with their dams in individual box stalls throughout the study period and allowed to acclimatize for a period of at least 24 hours before beginning the study. Foals were allowed to nurse their dams ad libitum and free access to water and mixed hay was provided at all times. Chemical restraint or other systemic drugs were not used. The study was approved by the Washington State University Institutional Animal Care and Use Committee.

Experimental Design

Foals received either butorphanolb or saline in a nonrandomized 3-way crossover design so that all foals received IV butorphanol (0.05 mg/kg via IV catheter in the right jugular vein), IM butorphanol (0.05 mg/kg in the lower right semimembranosus muscle), and IV saline (5 mL via IV catheter in the left jugular vein). Upon inclusion in the study, 3 foals received IV butorphanol and 3 foals received IM butorphanol on day 1 of the study. On day 3 of the study, all foals received IV saline as a control group. On day 5 of the study, IV and IM butorphanol treatments were reversed for each foal. Blood samples for determination of plasma butorphanol concentrations were collected from an 18-G catheter aseptically placed in the left jugular vein.

Blood Collection

Blood samples (5 mL) for determination of plasma butorphanol concentrations were collected in evacuated heparinized glass tubes before, and at 5, 10, 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, and 6 hours after butorphanol or saline administration. For all groups, administration of butorphanol or saline defined time 0. Heparinized blood samples were placed on ice, and centrifuged for 10 minutes at 2,000 ×g. Plasma was transferred to plastic tubes and stored at −80 °C until analysis.

Butorphanol Assay

Plasma butorphanol concentrations were determined by high-performance liquid chromatography as previously described.12 The only change in the assay was an update in equipment to the Agilent 1000 systemc that allowed a more stable baseline and improved lower limit of quantification and detection. The assay had a lower limit of quantitation (LOQ) of 2 ng/mL.

PK Calculations

Plasma concentrations of butorphanol were analyzed using a computer program.d Plasma concentration versus time curves were plotted to aid in selection of the most appropriate model for analysis. From an initial compartmental analysis of the plasma concentration versus time data and visual examination of the curves, no consistent compartmental model appeared to be suitable for all foals. For some foals, there was an obvious distribution phase with a prolonged elimination phase, and in other foals there was not. Therefore, a noncompartmental analysis (NCA) that does not assume any compartmental structure was used for the analysis. For the NCA the area under the plasma concentration versus time curve (AUC) from time 0 to the last measured concentration, (defined by the LOQ) was calculated using the log-linear trapezoidal method. The AUC from time 0 to infinity was calculated by adding the terminal portion of the curve, estimated from the relationship Cn/λZ, to the AUC0−Cn, where ëZ is the terminal slope of the curve, and Cn is the last measured concentration. Values for the maximum plasma concentration after dosing (Cmax) and time to maximum plasma concentration (Tmax) were taken directly from the data. Half-lives were calculated from the terminal slope: inline image= ln 2.0/(terminal rate constant), where ln 2.0 is the natural logarithm of 2.0. For the IV dose, apparent volume of distribution using the area method (VD area), apparent volume of distribution at steady-state (VDss), and systemic clearance (Cl) were calculated according to previously described methods.13,14 The extent of absorption (F) was calculated from a comparison of the AUC values from IM and IV (F= AUCIM/AUCIV).

Physiologic Data

Physiologic data (heart rate, respiratory rate, temperature, and GI sounds) were recorded for each foal at the same time points that blood samples were obtained. Foals were subjectively monitored for adverse effects such as excitement, increased locomotor activity, ataxia, and sedation. Rectal temperature was recorded using a digital thermometer. Abdominal sounds were evaluated by auscultation from the dorsal and ventral flank on both sides. The number of quadrants in which intestinal motility was heard during 1 minute of abdominal auscultation was recorded and a score of 1 was assigned to each quadrant if sounds were auscultated. Thus, a GI motility score that ranged from 0 to 4 was assigned at each time point. All of the physiologic data were collected by the same investigator, unblinded to treatment.

Physical activity was measured with an electronic pedometere placed over the shoulder area of the foals. Immediately before saline or butorphanol administration, a fleece harness was fitted around the thorax and 1 pedometer was attached to the harness so that the pedometer would remain in front of the shoulder and horizontal to the ground. Pedometer-registered activity was set as number of steps. The total number of steps over a 6-hour period after administration of butorphanol or saline was recorded for each foal.

Video Observations and Behavioral Data

Behavioral data were obtained from analysis of videotaped recordings. Video recording occurred continuously during the 2 hours immediately after butorphanol or saline administration. The video camera was set above the stall or in front of the stall door so that it would provide an adequate visual field of the stall. Four behaviors were defined: nursing, active, inactive, and recumbent (Table 1). The behavior definitions were refined by the investigators until the definitions were mutually exclusive. Behavior budget was defined as time spent exhibiting defined mutually exclusive behaviors. Each videotape was evaluated independently by 4 trained observers, blinded to treatment. Time budgets of behavior were calculated by dividing the total duration of each behavior category by the total duration of that recording, to yield the percent of time spent in each behavior category. Time in which investigators were in the stall obtaining samples and data from the foals (data collection time) and time in which the foal was not visible within the recording field (stop time) were excluded from the time budget analysis. The mean remaining time for each data collection period was 1.41 hours (range, 0.61–1.62 hours).

Table 1.   Description of specific behaviors for analysis of video recordings of neonatal foals.
BehaviorDescription
NursingFoal is actively nursing or trying to nurse (searching the udder, following the udder when dam moves away, head tossing the udder)
ActiveChewing/eating hay, shavings, manure
Licking the walls, dam, feeder, other objects
Investigating the walls, floor, feeder, or water bucket while taking strides or standing
Rubbing any part of the body against the side of the stall/dam/ front leg or raising the hind leg to scratch the head/neck
A shake that involves the whole body
A visible urinary stream
Lifting the tail and evacuating feces
Stretching (hyperextension of the hind legs and/or hyperflexion of the head/neck)
Walking forward or backward
Jumping or trotting
InactiveStanding with head above, at, or below withers performing none of the previously defined activities
Walking slowly, forward or backward, with partial loss of body balance (staggering) performing none of the previously defined activities
Standing and having cyclic periods of doze (progressive body relaxation with lowering of the head and partial or total loss of body balance)
RecumbentFoal is in sternal or lateral recumbency
StopFoal is completely out of the camera's visual field or is partially out so that its behavior cannot be characterized accurately
Data collectionInvestigators are in the stall collecting data

Each video recording contained 8 data collection times lasting on average 3 minutes. Behavior during these data collection times was separately evaluated using a composite numerical rating scale of data collection compliance to evaluate the foals' response to human interaction (Table 2). The total score at each time point was calculated as the sum of scores given to 3 different observations: response to human approach, response to human contact or restraint, and response to release. Higher data collection compliance scores indicated greater compliance and less reactivity to human interaction. The observers who calculated behavior time budgets calculated a data collection compliance score at each data collection time point.

Table 2.   Data collection compliance scoring system.
Foal's ResponseScore
1234S
To human approachWhen foal is standing
Moves away fast or hides behind damMoves away slowlyLooks at person, does not walkDoes not react to personFoal is out of view; unable to assess
When foal is recumbent
Gets up fast and moves awayWakes up and moves the head and change body position; does not get upWakes up and moves the head but does not change body position; does not get upDoes not react to person; does not get upFoal is out of view; unable to assess
To human contact or restraintStruggles, tries to escape several times; gets up if lying downOccasional struggling or attempts to escape; gets up if lying downMinimal struggling or attempts to escape; requires minimal restraint; does not get up if lying down Foal is out of view; unable to assess
To releaseWalks away fast or jumping or kick ing; gets up and walks away fastWalks away slowly; gets up and walks away slowlyBarely moves Foal is out of view; unable to assess

Statistical Analyses

The significance of observed differences in physiologic data in the different treatment groups over time was assessed by 2-way, repeated measures analysis of variance (ANOVA) with Huyhn-Feldt correction to degrees of freedom. When appropriate, the analysis was followed by post hoc multiple comparison testing (Bonferroni's corrected paired t-test). Friedman's nonparametric test was used to investigate potential group-related changes in GI scores and pedometer readings followed, when required, by Bonferroni-corrected Wilcoxon's signed-rank test post hoc analysis.

Because the behavioral data were represented as percent of time and percentage data are not normally distributed, Friedman's nonparametric 1-way repeated measures analysis was used for this data, followed if necessary by Bonferroni-corrected Wilcoxon's signed-rank tests for multiple comparisons. Similar methodology was used to evaluate data collection compliance scores.

For heart rate, respiratory rate, and temperature after rejection of the global hypothesis, planned comparisons were made between control versus IV groups and control versus IM groups. For the behavioral data, GI scores, pedometer readings, and data collection compliance scores, comparison between IV and IM group were made. Statistical analyses were conducted using NCSS 2004 software.f If not indicated otherwise, data are presented as mean ± SD. Significance was set at P < .05.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

PK Analysis

Mean values for PK parameters after IV and IM butorphanol are shown in Table 3. Plots of plasma concentration versus time for each injection are shown in Figure 1. The mean bioavailability was 66.1%. The sampling strategy and assay sensitivity were suitable for this study because the terminal portion AUC left to be extrapolated was only 12% for the IV administration and 9% for the IM injection.

Table 3.   Noncompartmental analysis of butorphanol in neonatal foals after IV and IM injection at 0.05 mg/kg.
ParameterUnitsMean (IV)SD (IV)ParameterUnitsMean (IM)SD (IM)
  1. Tmax, time of peak concentration; Cmax, peak concentration; C0, y-axis intercept of concentration after IV injection; AUC0Cn, area under the curve extrapolated from 0 to the last measured concentration; AUC0∞, area under the curve extrapolated from 0 to infinite; VD (area), apparent volume of distribution area method; Cl, clearance; MRT, mean residence time; VDss, apparent volume of distribution at steady state; F, bioavailability.

Terminal rate1/hour0.470.29Terminal rate1/hour0.800.27
Terminal half-lifeHours2.131.39Terminal half-lifeHours0.940.28
C0ng/mL33.2212.19TmaxHours0.100.04
AUC0CnHours ng/mL23.482.66Cmaxng/mL20.063.55
AUC0∞Hours ng/mL26.983.64AUC0[RIGHTWARDS ARROW]CnHour ng/mL16.364.59
AUC % extrapolated%12.488.34AUC0[RIGHTWARDS ARROW]Hour ng/mL17.944.70
VD (area)mL/kg5,467.393,025.37MRTHours1.150.20
ClmL/h/kg1,882.49260.99F%66.1011.92
MRTHours2.161.30    
VDssL/kg3.861.94    
image

Figure 1.  (Top and bottom). Plasma concentration profile (mean ± SEM) of butorphanol after administration of 0.05 mg/kg IM or IV to neonatal foals. Top panel is graphed on a linear y axis, the bottom panel on a semilogarithmic y axis.

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Physiologic Data

There was no significant treatment-time interaction for heart rate (P= .63) (Fig 2). Although there was a significant treatment-time interaction for respiratory rate (P < .001), visual evaluation of the plot (Fig 3) revealed that there was not a consistent treatment-related-respiratory pattern. Both treatment groups had a respiratory rate significantly lower than the control group at 15 minutes. The respiratory rate for the IV group was significantly higher than the respiratory rate for the control group at 90 minutes. Compared with the control group, foals that received IM butorphanol had a significantly lower respiratory rate at 10 and 45 minutes after drug administration. Rectal temperature in the IV group was significantly higher than that in the control group at 10, 15, 30, 45, 60, and 90 minutes after butorphanol administration (Fig 4). Compared with the control group, rectal temperature was significantly higher in the IM group at 30, 45, 60, 90, 120, and 180 minutes after drug administration. Foals that received IV butorphanol had significantly lower GI motility scores than those in the IM (P= .004) and control groups (P= .004). The GI scores between the IM and control groups were not statistically different.

image

Figure 2.  Heart rate (mean ± SEM) of foals after saline (control) or butorphanol administration (IM or IV). Closed circles, IV butorphanol; open circles, IM butorphanol; closed triangles, control.

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image

Figure 3.  Respiratory rate (mean ± SEM) of foals after saline (control) or butorphanol administration (IM or IV). Closed circles, IV butorphanol; open circles, IM butorphanol; closed triangles, control. *Significant difference between IM and control. #Significant difference between IV and control.

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image

Figure 4.  Rectal temperature (mean ± SEM) of foals after saline (control) or butorphanol administration (IM or IV). Closed circles, IV butorphanol; open circles, IM butorphanol; closed triangles, control. *Significant difference between IM and control. #Significant difference between IV and control.

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Pedometer readings (total number of steps) at the end of each trial were significantly different between groups (P= .03). Although the post hoc test was not significant for any of the comparisons, there was a tendency for those foals that did not receive butorphanol to take more steps. The number of steps taken by one of the foals in the control group was an outlier (6,590 steps/6 hours). This value increased the mean number of steps for that group and may have caused the differences between groups to be significant in the global analysis. When we repeated the analysis replacing this value for the lowest pedometer reading in the control group (701 steps/6 hours), the differences were still statistically significant (same P value). When the data from this foal were eliminated from the analysis, the differences between groups were statistically significant (P= .041). In either case, post hoc comparisons were not significant.

Behavioral Data

Time budgets of behavior obtained from the different groups are summarized in Figure 5. The total amount of time that the foals spent nursing was significantly different between groups (P= .011). Compared with foals in the control group, foals that received butorphanol, either IV or IM, spent significantly more time nursing (P < .001). The differences between the IV group and IM group were not significant. The total amount of time that foals were active, inactive, and recumbent was not significantly different between groups.

image

Figure 5.  Percentage of total time spent during the 2 hours of observation in each of 4 categories of behavior (nursing, active, inactive, and recumbent) by foals receiving saline (control) or butorphanol (IV or IM). The height of the box indicates the interquartile range (IQR), which contains 50% of values. Horizontal lines represent median of the distribution. The upper whisker is the largest observation that less than or equal to the 75th percentile plus 1.5 times IQR. Values outside the upper and lower whiskers are outliers. Values that are <3 IQRs from the 25th and 75th percentiles are designated mild outliers by the open circle symbol; values outside 3 IQRs are designated severe outliers by the open triangle symbol. *Significant difference from control group.

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Because clinical observations revealed that the sedative effects of butorphanol were no longer evident in most foals by 45 minutes after administration, statistical analysis of each hour of recording was performed independently (Figs 6 and 7). For the 1st hour after saline or butorphanol administration, there were no statistically significant differences between groups in the amount of time that foals spent nursing. During the 2nd hour, foals that received butorphanol, either IV or IM, spent more time nursing than those that did not (P < .001) and foals that received IV butorphanol spent more time nursing than foals that received IM butorphanol (P < .001). There were no statistically significant differences in the amount of time that foals were active or inactive for either hour. The amount of time that foals spent in a recumbent position was statistically different between groups during the 2nd hour of observation; control foals spent more time recumbent than those that received butorphanol, either IV (P < .001) or IM (P= .047). When compared with the IM group, foals that received IV butorphanol spent less time recumbent (P= .011).

image

Figure 6.  Percentage of time spent during the 1st hour of observation in each of 4 categories of behavior (nursing, active, inactive, and recumbent) by foals receiving saline (control) or butorphanol (IV or IM). See legend for Figure 5 for detailed explanation of box plots.

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image

Figure 7.  Percentage of time spent during the 2nd hour of observation in each of 4 categories of behavior (nursing, active, inactive, and recumbent) by foals receiving saline (control) or butorphanol (IV or IM). See legend for Figure 5 for detailed explanation of box plots. *Significant difference from control group; Significant difference from IM group.

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Clinical observations indicated that administration of butorphanol to the foals was associated with behavioral effects characterized mostly by sedation, ataxia, and increased feeding behavior. Subjectively, the sedative effects were characterized by inactivity, progressive lowering of the head, front limb relaxation, decreased response to external stimuli, and occasional recumbency. Based on the investigators' observations, sedative effects were considered moderate in the majority of the foals and they were most evident within 3–15 minutes after butorphanol administration and lasted for 20–40 minutes. In general, foals that received IM butorphanol appeared less sedated than those that received IV butorphanol. No foals appeared excited. One foal that received IV butorphanol showed a strong nursing response and mild ataxia, but no overt signs of sedation.

Data Collection Compliance Scoring System

Foals that received butorphanol, either IV or IM, had higher data compliance scores than those foals that received saline (Table 4). The difference between the IV and IM groups was not significant. Data collection compliance scores obtained from the 8 data collection time points recorded during the 2-hour video footage were divided in 2 groups and analyzed independently. The 1st group included the median scores obtained from the 1st 4 data collection times corresponding to approximately 5, 10, 15, and 30 minutes, postbutorphanol or saline administration. The 2nd group included the median scores obtained from the last 4 data collection times corresponding to approximately 45, 60, 90, and 120 minutes, postbutorphanol or saline administration. Data collection compliance scores from the 1st 4 data collection times, but not the last 4 times, were significantly different (P= .039) and scores for foals that received butorphanol, either IV or IM, were higher than scores for foals receiving saline. The difference in scores between the IV and IM groups was not significant.

Table 4.   Data collection compliance scores (median and interquartile range).
 ControlIV ButorphanolIM Butorphanol
  • *

    Significant difference between treatment groups (P < .05)

All time points6 (4.5–7.6)*7.5 (6.1–8.5)*8 (6.5–9)*
5–30 minutes6 (4.5–9)*8.5 (6.3–9.3)*8.8 (7.8–10)*
45–120 minutes6 (5–7.5)7 (6–7.5)7.5 (6–8.5)

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

Results of this study indicate that butorphanol can be administered safely to neonatal foals at a dosage of 0.05 mg/kg IV or IM. The marked difference in disposition and behavioral effects of butorphanol in neonatal foals as compared with reported effects in adult horses emphasizes the importance of establishing dosing regimens for foals based on age-specific PK and pharmacodynamic studies. Butorphanol administration in neonatal foals resulted in sedation and increased nursing behavior with no increase in locomotor activity.

The manufacturer's recommended dosage of butorphanol for adult horses for treatment of abdominal pain is 0.1 mg/kg body weight IV.12 Information on the use of butorphanol in neonatal foals is largely anecdotal. Based on clinical experience with butorphanol in neonatal foals that suggests sedative effects, we chose a dosage of 0.05 mg/kg butorphanol for this study. In adult horses, a plasma concentration between 20 and 30 ng/mL has been proposed to provide adequate visceral analgesia without adverse effects.12 Although analgesia was not tested in this study, IV and IM administration of butorphanol resulted in plasma concentrations generally below the targeted plasma butorphanol concentration for visceral analgesia in adult horses. When butorphanol was administered IV, mean plasma butorphanol concentration fell below 20 ng/mL after 5 minutes and mean plasma butorphanol concentrations did not reach 20 ng/mL at any time after IM administration. Assuming that the therapeutic range of plasma butorphanol concentration in adult horses could be extrapolated to equine neonates, our study would indicate that higher doses of butorphanol would be required in order to provide foals with analgesia. However, analgesia is likely determined by the concentration of drug at the receptor site, the population of receptors in the central nervous system (CNS), and by the affinity of the drug for the receptor, and caution should be used when considering plasma concentration alone to predict analgesia. Recent studies in humans have highlighted age as the most important factor affecting morphine requirements in neonates and infants postoperatively.15 In 1 study, human neonates aged 7 days or younger required significantly less morphine postoperatively than older neonates, and morphine plasma concentrations were not correlated with analgesia.16 The dosage of butorphanol necessary to produce analgesia in neonatal foals remains to be determined.

There are several differences between the PK results of this study and previous studies of PK of butorphanol in adult horses.12,17 The VDss of butorphanol was greater in neonatal foals (3.86 L/kg) than in adult horses (1–1.13 L/kg).12,17 Ordinarily, a larger apparent volume of distribution in young animals is associated with a higher percentage of body water. However, when the apparent volume of distribution is greater than physiologic volume ( 1 L/kg), other explanations are needed. If VDSS is larger than physiologic volume, it indicates high tissue binding.18 There may be higher binding affinity in some tissues in foals as compared with adult horses. A consequence of the larger volume of distribution in neonatal foals is that plasma concentrations will be proportionately lower at a given dose of butorphanol compared with adult horses. Depending on receptor location, a higher volume of distribution also may increase the amount of drug available at its receptor, enhancing drug-induced clinical effects.19

Compared with adult horses, the Cl of butorphanol was faster in foals (31 mL/kg/min in this study versus 21 mL/kg/min in adult horses).17 This clearance rate approaches the rate of hepatic blood flow for animals of this size, suggesting high hepatic clearance. The high Cl in foals, compared with adults, was an unexpected finding. Usually Cl is reduced in neonates and increases with age,20–24 but allometry also may be a factor causing a higher Cl owing to lower body weight. Allometric scaling shows that, for some drugs, Cl increases inversely with body weight.25

After either IV or IM administration, the terminal elimination half-life of butorphanol was shorter in adult horses (IV = 0.74 hour; IM = 0.57 hour) than in neonatal foals (IV = 2.1 hour; IM = 0.94 hour).12,17 The terminal half-life is a PK parameter dependent upon Cl and VDss. Slower Cl, or larger volume of distribution will increase half-life. In these foals, volume of distribution was proportionately higher than the change in Cl, therefore the half-life was longer. IV administration was associated with a longer half-life than IM injection, but an examination of the plasma concentration graphs shows that this is a reflection of the steepness of the terminal slope (Fig 1). It was possible to detect a longer terminal slope after IV than IM administration but this difference was minimal and the terminal slope after IM injection may have been below the limit of detection for the assay. Concentrations could be detected longer after IV administration because of higher plasma concentrations and because the assay used for this current study is more sensitive than previously used assays.12

As shown previously in adult horses, IM butorphanol is not completely absorbed (66% in foals and 37% in adults).17 Higher IM absorption of drugs has been observed previously in young animals of many species, including foals. Higher IM absorption may be a result of higher body water composition resulting in better uptake of an injection. More efficient drug absorption after IM injection in human neonates is attributed to a higher density of skeletal muscle capillaries.26 Examination of the plasma profile (Fig 1 and Table 3) shows that although absorption rate was fast, a fraction of the dose (34%) was not bioavailable. A rapid absorption rate does not necessarily imply a high extent of bioavailability because the absorption rate actually represents the disappearance of drug from the site of injection, rather than the appearance of drug in the systemic circulation.27 From a clinical point of view, when an IV catheter is not available for drug administration in neonatal foals, the IM route is able to provide blood concentrations close to those obtained after IV injection within 6 minutes of administration, offering a practical alternative to the IV route.

Although some changes in vital signs were observed after administration of butorphanol, these changes generally were of too low a magnitude to be of clinical relevance. As in adult horses, butorphanol produced no significant changes in heart rate over time.9,11,12,17 This may be especially relevant in foals, in which cardiac output is primarily dependent on heart rate.

Butorphanol-treated foals had mild decreases in respiratory rates as compared with the control group for the 1st 15 minutes after drug administration (Fig 3), possibly as a result of butorphanol-induced respiratory depression. However, studies in adult horses have failed to demonstrate such an effect.10,11,17,28,29 A more likely explanation for the transient mild decrease in respiratory rate in foals is that it occurs as a consequence of a general sedative effect. When administered IV or IM, butorphanol caused a mild but significant increase in temperature. This drug-related increase in body temperature has been an inconsistent finding in studies of adult horses receiving butorphanol.10,28–30

In adult horses, decreased GI motility associated with the use of opioids, especially with the use of μ-receptor agonists, may predispose to impactions and colic.30–32 Although butorphanol decreases GI motility in horses,3,12,30 it appears to do so to a much lesser degree than μ-agonists33,34 and its use at recommended dosages has not been associated with an increased risk of colic.12,32 In this study, we found that the administration of butorphanol IV to neonatal foals produced a significant decrease in GI motility score. One limitation of our study is that, although all GI scores were obtained by the same investigator (which adds consistency from 1 measurement to the next) the investigator was not blinded to the treatment group.

The predominant behavioral response described after butorphanol administration to adult horses is an excitatory effect manifested as an increase in locomotor activity.3,8,11,12,28,35,36 Other behavioral effects observed in adult horses include ataxia,8,9,11,12,35–37 tossing and jerking of the head,11 sedation,11,28,37 indifference to surroundings,11 and shivering.8,28,36 In the foals in this study, the main behavioral effects after butorphanol administration were sedation and mild ataxia. These effects were more prominent when butorphanol was given IV and they were usually no longer evident after 30–40 minutes. There was individual variation in the degree of sedation observed with quite pronounced sedation in some foals after IV administration. The sedative effects of opioids are thought to occur through a κ mechanism. After the administration of high doses of a κ-agonist to adult horses, they appear to be drowsy and uncoordinated.29 In adult horses, butorphanol does not typically produce sedation,29,38 but in this study all but 1 foal became sedated. This may indicate an increased sensitivity to butorphanol in neonatal foals, possibly via increased drug accumulation in the CNS of neonates due to immaturity of the blood-brain barrier19,39,40 or abnormal expression of P-glycoprotein in neonates compared with adults. Alternatively, age-related differences in κ- and μ-receptor populations, distribution, or physiologic role may exist.39,41,42 Because butorphanol is a weak μ-antagonist, it can cause locomotor excitement in horses although not to the same degree as strong μ-agonists.12,29,35 In this study, pedometers were used to measure physical activity in a manner similar to that used in research with a variety of other species.43–45 The pedometer readings at the end of each trial (6 hours after butorphanol or saline administration) showed that control foals were physically more active than butorphanol-treated foals. Because there was considerable variability among readings within the same group, only the global analysis showed a statistically significant difference between groups. The higher pedometer readings in control foals can be explained by the nursing behavior and sedative effects induced by butorphanol.

Foals that received butorphanol spent more time nursing than control foals. For the 1st hour, foals in the IV group were more sedated than the IM group and therefore they nursed less. During the 2nd hour, foals in the IM group nursed less than the previous hour because the feeding response started to fade away, while this response dominated in the IV group during the 2nd hour. These observations suggest that butorphanol administration induces the same intensity of feeding response whether the IV or IM route is used but the onset of action is delayed when the IV route is used. Also, the orexigenic response induced by butorphanol is likely of short duration.

After administration of low doses of opioids to adult horses, increased eating behavior may be the principal behavioral effect observed.46 In particular, pentazocine, a synthetic agonist-antagonist opioid similar to butorphanol, increases feeding behavior in horses.46 A number of other studies have demonstrated that opioid peptides (enkephalins, β-endorphin and dynorphins), peptide analogs, and opiate drugs activating μ-, δ-, and κ-receptors may stimulate food intake in humans and experimental animals.47,48 Several studies in rats have shown that butorphanol and other κ-opioid receptor agonists induce a vigorous orexigenic response and increase short-term food intake more effectively than other opioid agonists.47–50

Butorphanol-treated foals spent less time recumbent than control foals. This may be a result of the feeding response induced by butorphanol and because, despite obvious sedation, most foals remained standing after butorphanol administration. During the 2nd hour, control foals spent more time recumbent than butorphanol-treated foals. All foals had more undisturbed time during the 2nd hour of the study and control foals, which were not experiencing the orexigenic effect induced by butorphanol, spent more time recumbent than the other foals.

Butorphanol decreases foal responsiveness to human interaction and physical activity as indicated by compliance scores and pedometer readings. Butorphanol results in a significant decrease in respiratory rate, increase in body temperature, and decrease in intestinal sounds in neonatal foals. However, these changes are mild and their clinical relevance, if any, remains to be determined.

Footnotes

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

aSNAP Foal IgG test, IDEXX Laboratories Inc, Westbrook, ME

bTorbugesic, Fort Dodge Animal Health, Fort Dodge, IA

cAgilent Technologies Inc, Palo Alto, CA

dWinNonlin version 5.0, Pharsight, Mountain View, CA

ePedometer Step Counter with Calorie Counter, Oregon Scientific, Portland OR

fNCSS, Kaysville, UT

Acknowledgment

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References

The authors thank Dr Bryan K. Slinker for his assistance with the statistical analysis. This study was generously funded by Mary V. Schindler through a Washington State University intramural grant program and by Fort Dodge Animal Health Inc.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgment
  8. References
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