The MAC of inhalant anesthesia is defined as the lowest concentration of a given inhalant anesthetic required to prevent gross purposeful movement in 50% of patients in response to a supramaximal stimulus. It can be used to guide the administration of inhalant anesthesia, such as the commonly used drug isoflurane.1,2 Inhalant anesthetics have multiple expected adverse effects that are typically dose dependent. These include hypotension, hypoventilation, and arrhythmias. The use of premedication can be beneficial to decrease patient and staff stress, ease handling, and lower the required doses of induction and maintenance anesthetics, thus limiting the adverse effects of anesthetics.1–3 Studies4–10 evaluating the effects of specific premedications, including the oral administration of drugs like clonidine, gabapentin, and trazodone, have demonstrated that their administration can decrease the MAC of a given inhalant in human and veterinary patients. The oral premedications gabapentin and trazodone individually reduce the MAC of isoflurane (MACISO) anesthesia in dogs by 20% and 17%, respectively.11,12
Gabapentin is labeled for postherpetic neuralgia and adjunctive seizure therapy for epileptic humans older than 3 years of age, but clinically, it is also often used for analgesia and sedation.13 Gabapentin’s mechanism of action is not completely understood. Gabapentin is structurally similar to GABA and is thought to decrease the release of excitatory neurotransmitters by binding to N-type calcium channels. The resultant inhibition of calcium transport may result in decreased central sensitization.14,15 In addition, gabapentin may act as an N-methyl-d-aspartate receptor antagonist, acting as an additional method of preventing central sensitization.16,17
In humans, gabapentin use has been evaluated for public speaking–related anxiety and for control of postoperative pain in patients undergoing a variety of surgical procedures. When given as a premedication, it has effectively reduced postoperative pain scores and the frequency of rescue analgesia administration for patients undergoing adenotonsillectomy, cholecystectomies, and hysterectomies.18–21 Gabapentin’s use as an analgesic and anxiolytic has been extrapolated to veterinary patients, despite limited evidence. Evaluation of its dosing in Greyhounds revealed a peak plasma concentration of 13.22 ng/mL at 2 hours after the oral administration of gabapentin at 20 mg/kg every 8 hours.14 Gabapentin reduces signs of veterinary visit–related anxiety in dogs.22 Reports of the use of gabapentin as a premedication and the effect on postoperative pain management have contradicting results in veterinary patients; however, the doses and frequency of administration used in those studies23–25 were lower and less frequent than the described dose and interval for maintenance of steady-state plasma concentrations of gabapentin.
Trazodone is an antidepressant medication that acts as both a serotonin receptor antagonist and a serotonin reuptake inhibitor. At lower doses, it antagonizes hydroxytryptamine receptors, leading to hypnosis or calming. Higher doses lead to serotonin transporter inhibition, providing an antidepressive effect.26,27 In dogs, trazodone has adequate oral bioavailability. Oral administration of trazodone at a dosage of 8 mg/kg is well tolerated by dogs, but IV administration at the same dose is associated with higher rates of adverse effects.28
Trazodone’s calming effects have been used in both human and veterinary medicine to aid in the management of insomnia, anxiety, and postsurgical confinement.29–32 Administration of oral trazodone (doses ranging from 9 to 12 mg/kg) to dogs 90 minutes before transport to the veterinary hospitals has been shown to be effective in reducing signs of stress during the visit.33 In dogs undergoing anesthesia, lower doses of propofol were needed in dogs who received oral trazodone 2 hours before anesthesia than in those who received a placebo medication.34
Gabapentin and trazodone are both commonly used in veterinary medicine to reduce signs of fear and anxiety.35 Although they are commonly used in tandem for these effects, literature regarding their use together is limited. The objective of this study was to evaluate the effect of premedication with the combination of gabapentin (20 mg/kg orally) and trazodone (8 mg/kg orally) on MACISO anesthesia in dogs. We hypothesized that this premedication protocol would decrease MACISO anesthesia in dogs by a greater percentage than if the drugs were used individually.
Methods
Study population
Six, healthy, mixed-breed dogs were studied in this project. The population included 3 neutered males and 3 neutered females, aged 13.3 ± 1.5 months and weighing 36.8 ± 3.4 kg (mean ± SD). The study was approved by the IACUC of The Ohio State University (2017A00000039). The dogs were deemed to be healthy based on physical examination, CBC, and chemistry panel analysis. All dogs had food, but not water, withheld for at least 12 hours before anesthesia.
Experimental design
A randomized, single-observer, blinded, crossover format was used for data collection. Each of the 6 dogs underwent 2 anesthetic events with a minimum of 7 days between the 2 events. Dogs were randomly assigned via closed envelope selection to the control (no premedication) or experimental (gabapentin and trazodone premedication) group for the first anesthetic event, with 3 falling into each group. If indicated, gabapentin (20 mg/kg) and trazodone (8 mg/kg) were administered orally in the hospital by another member of the research team 2 hours before induction of anesthesia. Doses were approximated using patient body weights and available gabapentin capsules and trazodone tablets. No placebo was used for the control group. The observer was not present for or aware of premedication administration. The opposite treatment was used for the second anesthetic event.
Anesthesia and instrumentation
A 20-gauge catheter was placed aseptically in a cephalic vein, and propofol (6 mg/kg) was administered IV to induce anesthesia. A cuffed endotracheal tube (12-mm inner diameter for 5 dogs; 14-mm inner diameter for 1 dog) was used to intubate the airway, and the dog was attached to a circle breathing system with a gas analyzer in place. Isoflurane was administered with an oxygen flow rate of 1 L/min via an out-of-circuit vaporizer adjusted to achieve an end-tidal concentration of isoflurane (ETISO) of 1.6% for maintenance anesthesia. Dogs were placed in left lateral recumbency for the remainder of instrumentation and anesthesia.
Ventilation was mechanically volume controlled to 6 breaths/min at a tidal volume of 10 to 15 mL/kg. The rate and volume of ventilation were adjusted throughout anesthesia to keep end-tidal CO2 between 30 and 45 mm Hg. Monitoring of ventilation, capnography, and spirometry was accomplished using an integrated anesthesia machine (A5 Anesthesia System with Passport 12 Multiparameter Monitor; Mindray). An infrared gas analyzer was used to continuously monitor inspired and expired gases. This device was calibrated daily as specified by the manufacturer’s instruction using a gas cylinder (Airgas Therapeutics; Air Liquide) with known concentrations of gases (2% desflurane, 5% CO2, 33% N2O, and 55% O2, balance N2). Body temperature was monitored using a calibrated esophageal temperature probe and was maintained between 37.5 and 38.0 °C with the aid of a warm water circulating blanket and forced air warming blanket (Bair Hugger; 3M). Heart rate and rhythm were monitored continuously with lead II ECG, and oxygen saturation levels were assessed via pulse oximetry. A 20-gauge catheter was aseptically placed in a dorsal pedal artery, connected to a pressure transducer, and used for direct blood pressure monitoring. The transducer was placed at the level of the dog’s sternum with laser-level assistance and zeroed to atmospheric pressure.
Determination of MAC
Following a 60-minute equilibration period at an ETISO of 1.6%, the below iterative bracketing technique was used to determine MAC, as described in previous studies.9,11,12,36 The blinded observer was responsible for the determination of a positive response to stimulation and MAC calculation. Two 24-gauge, 10-mm, platinum, subdermal, needle electrodes were placed 2 cm apart in the maxillary buccal mucosa, caudal and dorsal to the maxillary incisors. These electrodes were connected to an electrical stimulator (Grass SD9 Stimulator; Grass Instruments). The stimulator was set to deliver a stimulus of 50 V at 5 Hz for a 10-ms pulse for 1 minute. The dogs were monitored for purposeful movement (positive response), including lifting of the head or repeated limb movement. Responses that were not considered positive included arching of the back, blinking, nystagmus, chewing, or swallowing. If a positive response was noted, the stimulation was stopped.
When no positive response was detected, the vaporizer was adjusted to achieve a 20% reduction in ETISO. Stimulation was repeated following a 15-minute equilibration period at the new ETISO. This process was repeated until a positive response was noted. Following a positive response, the ETISO was increased by 10%, and a 15-minute equilibration period was used before reapplication of the above stimulus. This was repeated until a positive response was no longer seen. The MACISO was considered to be the mean of the ETISO values at which a positive response was detected and the lowest ETISO at which a positive response was no longer seen. This process of MAC determination was repeated, starting at an ETISO 0.3% higher than the lowest ETISO at which a positive response was seen. If the 2 MAC values differed by > 10%, a third was determined. The mean of the MAC values collected was considered the MACISO for that anesthetic episode. Before each stimulation, heart rate, rhythm, systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, oxygen saturation, ETISO, and end-tidal CO2, were recorded.
Once MAC was determined for the anesthetic even, the isoflurane vaporizer was turned off and all monitoring except for the gas analyzer was discontinued. Mechanical ventilation was continued until the dog swallowed without stimulation. At this time, the ETISO was recorded, and the dog was extubated. The time from discontinuing isoflurane administration to extubation was also recorded. Adverse events associated with anesthetic recovery or buccal stimulation were recorded.
Statistical analysis
Data were tested for normality using the Kolmogorv-Smirnoff test. Normally distributed data (MAC, heart rate, ETISO, and time to extubation) were reported as mean ± SD and tested using a paired t test. Nonnormally distributed data (systolic arterial pressure, mean arterial pressure, diastolic arterial pressure, and time to first MAC determination) were reported as median (range) and tested using Wilcoxon signed-rank test. Significance was set at values of P < .05.
Results
Six dogs were anesthetized twice, once with gabapentin and trazodone premedication and once without. One of the 6 dogs had to be anesthetized a third time due to miscalculation of the MACISO during initial data collection. The third anesthetic episode in this dog was separated from the second by at least 7 days. The same premedication protocol used for the miscalculated episode was used for the third episode to maintain an equal number of episodes in each group. Arterial catheter placement was unsuccessful in 1 dog in each group, so blood pressure data were only available from 5 dogs in each group.
Data were reported using either mean ± SD or median and range (Table 1). The MACISO was 34.7% significantly lower (P = .008) with gabapentin and trazodone premedication (0.62 ± 0.18%) than without gabapentin and trazodone premedication (0.95 ± 0.14%). In addition, heart rate at the time of stimulation (P = .033) and ETISO at the time of extubation (P = .013) were significantly decreased with gabapentin and trazodone premedication (heart rate, 64 ± 10 beats/min; ETISO, 0.38 ± 0.12%) than without (heart rate, 82 ± 11 beats/min; ETISO, 0.52 ± 0.08%). There were no noted adverse effects secondary to the decreased heart rate.
Mean ± SD or median (range) values for MAC, cardiovascular, and recovery data for 6 dogs anesthetized with isoflurane alone or after oral administration of gabapentin (20 mg/kg) and trazodone (8 mg/kg).
| Variable | Gabapentin and trazodone with isoflurane | Isoflurane |
|---|---|---|
| MACISO (%)a | 0.62 ± 0.18 | 0.95 ± 0.14 |
| HR (beats/min)a | 64 ± 10 | 82 ± 11 |
| SAP (mm Hg)b | 110 (86–131) | 100 (93–128) |
| MAP (mm Hg)b | 77 (70–90) | 71 (63–99) |
| DAP (mm Hg)b | 65 (54–75) | 59 (57–85) |
| Time MACISO determination (min) | 196 (163–234) | 153 (138–320) |
| ETISO immediately before extubation (%)a | 0.38 ± 0.12 | 0.52 ± 0.08 |
| Time to extubation (min) | 20 ± 15 | 20 ± 7 |
Cardiovascular values were obtained after equilibration at the lowest end-tidal concentration of isoflurane (ETISO) at which gross purposeful movement did not occur.
DAP = Diastolic arterial pressure. HR = Heart rate. MACISO = Minimum alveolar concentration of isoflurane. MAP = Mean arterial pressure. SAP = Systolic arterial pressure.
Time to first MAC determination, systolic arterial pressure, mean arterial pressure, diastolic arterial pressure (at the time of stimulation), and time to extubation did not differ significantly between the 2 groups. No ECG changes were noted during anesthesia or with stimulation. One dog did regurgitate under anesthesia during an episode in which no premedications were given. No adverse effects secondary to the regurgitation were noted. All dogs recovered uneventfully from anesthesia.
Discussion
The results of this study showed a significant decrease in MACISO in dogs undergoing anesthesia with isoflurane following premedication with the combination of oral trazodone (8 mg/kg orally) and gabapentin (20 mg/kg orally), compared to dogs undergoing anesthesia with isoflurane without premedication. With the above premedication, MACISO was decreased by 0.33 ± 0.04%, supporting the hypothesis that these medications, in combination, would have a greater MAC-sparing effect than when used individually.
The MAC has been found to be affected by physiologic, pathologic, and pharmacologic factors, such as sedative or analgesic drugs.1,2 Gabapentin’s effectiveness in decreasing postoperative pain and anxiety in humans has been extrapolated to veterinary species.18–21 Definitive conclusions regarding gabapentin’s efficacy as a veterinary pain medication are difficult to determine due to contradictory results and the protocols used in previous studies.23–25 Its efficacy as an anxiolytic in rats, and more recently in dogs, has been supported.22,37 The MACISO reduction from gabapentin may be secondary to the proposed analgesic effects of N-methyl-d-aspartate receptor blocking and reduced wind-up pain or its sedative effects.
Trazodone acts as a 5-hydroxytryptamine (5HT) antagonist and 5HT reuptake inhibitor. It also increases the release of 5HT, also known as serotonin, by blocking inhibitory signaling pathways within the brain.26,27 The 5HT effect, as well as antagonism of both histamine and α1-adrenergic receptors, is believed to be the mechanism by which trazodone has its hypnotic, or calming, effect.26 Trazodone has primarily been used in veterinary medicine due to its efficacy in managing canine anxiety or assisting with postsurgical restriction.30,32,33 The hypnotic effects may explain trazodone’s contribution to MAC reduction.
Several anxiolytic medications administered to dogs or cats before veterinary visits have been evaluated, and their individual use has been supported.35 The commonly used medications gabapentin and trazodone have been found to individually decrease the minimal alveolar concentration of isoflurane.11,12 To our knowledge, this study is the first to evaluate the use of oral premedication with a combination of gabapentin and trazodone on MACISO, although this combination is frequently used in clinical practice. In this study, the heart rate at the time of MAC determination in dogs who received the premedication (64 ± 10 beats/min) was decreased compared to those that did not (82 ± 11 beats/min). This change was not noted in previous studies.11,12 No adverse effects were noted related to the cardiovascular effects, and the heart rate was maintained within clinically relevant reference ranges throughout all anesthetic episodes. This change in heart rate could have more clinical impact in patients with comorbidities. Further studies would be needed to evaluate the impact on such patients and to determine definitive causation as bradycardia is not a listed described adverse effect of gabapentin or trazodone.13,14,26,27
Previous pharmacodynamic studies14,28 of gabapentin and trazodone suggest that plasma concentrations of both medications are at therapeutic levels 2 hours after administration at the doses used in this study. This suggests that these medications could be given orally by owners before presentation to limit the stress of handling and, based on this study, decrease the MACISO. Although it is recommended to avoid oral administration of food or medications before anesthesia to limit the risk of vomiting/regurgitation and aspiration,3 only 1 dog in the current study regurgitated. This dog did not receive oral premedication the day it regurgitated, so a correlation can be established to the administration of oral medication in this study. No adverse effects were noted related to this regurgitation, and no gastrointestinal effects were seen in the 2 related studies11,12 evaluating these medications individually.
The MACISO without premedication in this study (0.95 ± 0.14%) is lower than previously determined MACISO levels ranging from 1.36% to 1.38%.36,38 The current study design was based on a previously established bracketing technique used to determine MAC in several veterinary studies,9,36,39–41 including the studies of Hoffman et al12 and Johnson et al11 that inspired this study. The MACISO in the studies of Hoffman et al12 and Johnson et al11 (1.02% and 0.91%, respectively) was more similar to, but still higher than, the value determined in the current study. Eger et al42 evaluated the use of various stimuli in the determination of MAC with halothane and found that the intensity of stimulation does alter the calculated MAC value. The MAC can also be decreased due to several variables such as hypothermia, hypercapnia, hypoxemia, drug administration, individual variation, and the definition of a positive response to stimulation.1 These variables were controlled for via consistent anesthetic protocols and anesthetic monitoring and the use of equilibration periods, the same population as its own control group, a consistent stimulus, and a single researcher determining a positive response as described in previous studies.11,12,39–42 The relatively lower MAC in this study may be due to the use of a lower frequency stimulus leading to a detectable response at lower anesthetic planes or a slight variation in the definition of a positive response between studies.
The end-tidal concentration of isoflurane at the time of extubation in this study was lower in the experimental group (0.38 ± 0.12%) than in the control (0.52 ± 0.08%). This change was not noted in the previous studies11,12 evaluating the individual effect of these medications on MACISO in dogs. There is limited literature in veterinary medicine regarding the end-tidal concentration of inhalants at the time of extubation. Studies in human medicine have evaluated this topic via the determination of MAC fractions at the time of extubation for multiple inhalants. The MAC fraction at the time of extubation using isoflurane in humans is 0.72, but this has not been evaluated in veterinary medicine.43,44 The MAC fraction may provide a way to predict inhalant concentrations at extubation and could explain the lower end-tidal isoflurane concentration in the experimental group, as they had a lower MACISO. However, the MAC fraction at extubation for isoflurane has not been evaluated in veterinary medicine and further studies are needed to determine a cause for the variation seen in the current study.
Limitations of this study include the small study population, variability in exact dosing due to available capsule or tablet sizes, as well as the lack of determination of plasma concentrations of the administered premedications at the time of MAC determination. The protocol used in the current study was determined based on previous studies14,28 of plasma concentrations of gabapentin and trazodone. It is possible that drug metabolism throughout the anesthetic episodes led to plasma concentrations of gabapentin and trazodone below peak or effective levels at the time of MAC determination. Future studies utilizing exact, compounded doses with the determination of plasma concentrations of each drug at the time of each MAC determination could help better determine the appropriate dosage and timing of administration of these oral premedications before anesthetic episodes.
In conclusion, this study determined that the combined use of gabapentin (20 mg/kg orally) and trazodone (8 mg/kg orally) as a premedication protocol decreased MACISO by 0.33 ± 0.04%. Further studies may be warranted to determine the cardiovascular effects of these medications when used together.
Acknowledgments
None reported.
Disclosures
Dr. Aarnes is a member of the AJVR Scientific Review Board but was not involved in the editorial evaluation of or decision to accept this article for publication.
No AI-assisted technologies were used in the generation of this manuscript.
Funding
This study was funded by Canine Research Funds of The Ohio State University.
ORCID
J. Aiello https://orcid.org/0009-0007-9875-970X
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