Pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs

Erica M. O'Donnell 1Veterinary Specialty Hospital, San Diego, CA 92121.

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Saya A. Press 1Veterinary Specialty Hospital, San Diego, CA 92121.

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Margo J. Karriker 2University of California Veterinary Medical Center-San Diego, San Diego, CA 92121.

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Stephanie A. Istvan 1Veterinary Specialty Hospital, San Diego, CA 92121.

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Abstract

OBJECTIVE

To determine the pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs.

ANIMALS

6 healthy adult dogs.

PROCEDURES

Each dog received a single dose of trazodone (approx 8 mg/kg) per rectum. Trazodone tablets were crushed into a powder, mixed with 5 mL of tap water, and injected into the rectum via a red rubber catheter. Sedation scores were assigned, and blood samples were collected for determination of plasma trazodone concentration at predetermined times before and after drug administration. Pharmacokinetic parameters were estimated by noncompartmental analysis.

RESULTS

Plasma trazodone concentration remained below the detection limit for 1 dog even though it became moderately sedate. Median (interquartile [25th to 75th percentile] range [IQR]) maximum plasma trazodone concentration and volume of distribution and clearance corrected for bioavailability were 1.00 μg/mL (0.66 to 1.40 μg/mL), 10.3 L/kg (7.37 to 14.4 L/kg), and 639 mL/kg/h (594 to 719 mL/kg/h), respectively. Median time to maximum plasma trazodone concentration and elimination half-life were 15 minutes (range, 15 to 30 minutes) and 12 hours (IQR, 7.99 to 12.7 hours), respectively. All dogs became mildly or moderately sedate, and the extent of sedation was maximal at a median of 30 minutes (IQR, 30 to 60 minutes) after trazodone administration. No adverse effects were observed.

CONCLUSIONS AND CLINICAL RELEVANCE

Rectal administration of trazodone may be a viable option for sedation and treatment of anxiety in dogs for which administration of sedatives and anxiolytics by other routes is contraindicated. Further research is necessary to better elucidate the pharmacokinetics and efficacy of trazodone following rectal administration and determine optimal dosing.

Abstract

OBJECTIVE

To determine the pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs.

ANIMALS

6 healthy adult dogs.

PROCEDURES

Each dog received a single dose of trazodone (approx 8 mg/kg) per rectum. Trazodone tablets were crushed into a powder, mixed with 5 mL of tap water, and injected into the rectum via a red rubber catheter. Sedation scores were assigned, and blood samples were collected for determination of plasma trazodone concentration at predetermined times before and after drug administration. Pharmacokinetic parameters were estimated by noncompartmental analysis.

RESULTS

Plasma trazodone concentration remained below the detection limit for 1 dog even though it became moderately sedate. Median (interquartile [25th to 75th percentile] range [IQR]) maximum plasma trazodone concentration and volume of distribution and clearance corrected for bioavailability were 1.00 μg/mL (0.66 to 1.40 μg/mL), 10.3 L/kg (7.37 to 14.4 L/kg), and 639 mL/kg/h (594 to 719 mL/kg/h), respectively. Median time to maximum plasma trazodone concentration and elimination half-life were 15 minutes (range, 15 to 30 minutes) and 12 hours (IQR, 7.99 to 12.7 hours), respectively. All dogs became mildly or moderately sedate, and the extent of sedation was maximal at a median of 30 minutes (IQR, 30 to 60 minutes) after trazodone administration. No adverse effects were observed.

CONCLUSIONS AND CLINICAL RELEVANCE

Rectal administration of trazodone may be a viable option for sedation and treatment of anxiety in dogs for which administration of sedatives and anxiolytics by other routes is contraindicated. Further research is necessary to better elucidate the pharmacokinetics and efficacy of trazodone following rectal administration and determine optimal dosing.

Management of dogs with anxiety with minimal short-term and long-term adverse effects is an important aspect of small animal practice. The primary goals for anxiety management are to minimize stress and stress-associated morbidity. Several psychoactive medications have been used to treat anxiety in dogs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, α2-adrenergic receptor agonists, and benzodiazepines. Unfortunately, use of those drugs has been associated with dubious efficacy and adverse effects and hemodynamic alterations, which have precluded their use in several patient populations.1–7

Trazodone hydrochloride has been used as an antidepressant and anxiolytic in human medicine for many years.8–10 It is a triazolopyridine derivative that is classified as a serotonin 2A receptor antagonist and reuptake inhibitor on the basis of its primary and secondary mechanisms of action.11–13 Trazodone may also increase serotonin concentration by lowering the inhibitory tone of γ-aminobutyric acid neurotransmitters in the cerebral cortex and thereby acts as an antidepressant and anxiolytic by mechanisms distinct from those of selective serotonin reuptake inhibitors, tricyclic antidepressants, and benzodiazepines.12,14 In human patients, the incidence of serious adverse effects associated with trazodone is low over a wide range of doses.15 Adverse effects associated with trazodone administration in human patients include hepatotoxicosis and hepatonecrosis, but the incidence of those conditions is rare, idiosyncratic, and generally unrelated to drug dosage.16

In dogs, trazodone is administered orally or IV, alone or in combination with other medications, for anxiolysis, behavioral calming, confinement tolerance, and mild sedation with minimal adverse cardiovascular or clinicopathologic effects at dosages of 4 to 10 mg/kg every 8 to 12 hours.8,11,17–22,a Adverse effects associated with trazodone administration in dogs include vomiting, gagging, constipation, colitis, hyperexcitability, excessive sedation, an increase in appetite, panting, aggression, and perceived behavioral disinhibition; however, those effects are generally transient and self-limiting and have not required additional treatment or trazodone dosage adjustment or discontinuation in published reports.8,11,21

To our knowledge, only 1 study18 has been conducted to determine the pharmacokinetics of trazodone in dogs. In that study,18 oral administration of trazodone (8 mg/kg) was well tolerated (with mild hypersalivation reported as the only adverse effect) and associated with a mean ± SD t½ of 166 ± 47 minutes, tmax of 445 ± 271 minutes, and Cmax of 1.3 ± 0.5 μg/mL. Administration of the same dose by the IV route was associated with transient tachycardia and aggression.18

Rectal administration of sedatives or anxiolytics is an alternative for dogs in which drugs cannot be safely administered by the oral route, such as patients immediately after brachycephalic airway correction or arytenoid lateralization surgery; patients with laryngeal dysfunction, vomiting, or dysfunction of the upper portion of the gastrointestinal tract; patients with upper airway disease; and extremely distressed patients. Rectal administration of anxiolytics may also be beneficial for mechanically ventilated patients in preparation for return to spontaneous breathing (ie, weaning off a ventilator). Trazodone has a low molecular weight and substantial aqueous solubility and is not dependent on gastrointestinal absorption or first-pass metabolism through the liver for activation, which make it a candidate for rectal administration.23–25

To our knowledge, the pharmacokinetics and efficacy of trazodone have not been determined following rectal administration to dogs. The goals of the study reported here were to determine absorption characteristics and efficacy of trazodone following rectal administration of a single dose of the drug to healthy dogs. Our hypotheses were that rectal administration of approximately 8 mg of trazodone/kg to healthy dogs would result in substantial sedation and yield a pharmacokinetic profile similar to that achieved following oral administration of the same dose of the drug.

Materials and Methods

Animals

The study protocol was reviewed and approved by the Ethics Committee of the Veterinary Specialty Hospital in San Diego. Six employee-owned dogs that were part of the hospital's population of blood donors were enrolled in the study. All 6 dogs weighed > 25 kg and were considered healthy on the basis of history and results of a physical examination, CBC, serum biochemical panel, and infectious disease panel (Dirofilaria immitis, Ehrlichia spp, Borrelia burgdorferi, Anaplasma spp, Babesia spp, Leishmania spp, Bartonella spp, and Mycoplasma spp) that were performed within 6 months prior to study enrollment. Dogs were brought to the hospital every 6 to 8 weeks to donate blood and therefore were preconditioned to the hospital environment. Each dog was individually housed in an indoor run (1.4 × 0.9 m) and had ad libitum access to water for the duration of the sample collection period. Each dog was fed 1 hour prior to trazodone administration and again following completion of sample collection.

Experimental design and sample collection

For each dog, the modified Seldinger technique was used to aseptically place a 19-gauge single-lumen peripherally inserted central catheterb into a lateral saphenous vein to facilitate serial blood sample collection. Catheter placement was achieved with manual restraint and a local anesthetic block with 2% lidocaine solution.c

The target dose of trazodone to be administered to each dog was 8 mg/kg. The target dose was calculated for each dog and rounded to the nearest 50-mg multiple (eg, for a 30-kg dog, the calculated dose of trazodone to be administered was 250 mg [30 kg × 8 mg/kg = 240 mg, which is closer to 250 mg than to 200 mg]). A trazodone slurry for rectal administration was compounded in-house by crushing the requisite number of commercially available trazodone tabletsd (100 mg of trazodone/tablet) into powder (eg, if the calculated dose to be administered was 250 mg, 2.5 tablets were crushed into powder) and mixing it with 5 mL of tap water (pH, 7.0). The slurry was compounded immediately before administration and was administered PR via a 14F red rubber catheter.e Briefly, a permanent marker was used to mark the catheter 6 cm from its tip. The dog was manually restrained in a standing position. The catheter was gently inserted through the anus and into the rectum up to the 6-cm mark. A plastic syringe was used to inject the trazodone slurry through the catheter followed by 10 mL of room-temperature (approx 22°C) tap water. Then, the catheter was removed, and the anus was gently held closed and observed for 5 minutes by an investigator (EMO) as described26 to ensure that none of the administered drug leaked from the rectum.

A standard 3-syringe technique that involved discarding 6 mL of waste blood, collecting 6 mL of blood for analysis, and flushing the catheter with 3 mL of sterile saline (0.9% NaCl) solution was used to collect blood samples at 0 (immediately before trazodone administration; baseline), 30, 60, 120, 240, 360, 480, 720, and 1,440 minutes after trazodone administration for 1 dog (pilot subject) and at 0, 15, 30, 60, 120, 240, 360, 480, and 720 minutes after trazodone administration for the remaining 5 dogs. The 6 mL of blood collected for analysis was immediately transferred to a blood collection tube that contained EDTA as an anticoagulant. Blood samples were centrifuged at 688 × g for 5 minutes within 10 minutes after collection. Plasma from each sample was transferred to an additive-free blood collection tube and stored at −80°C until shipped to the laboratory for analysis.

Because of the expense associated with measuring plasma trazodone concentration, we decided to administer trazodone to only 1 dog initially (the pilot subject) to determine whether the drug would be absorbed from the rectum in sufficient quantity to induce sedation and generate an absorption profile before proceeding with enrollment of additional dogs into the study. This also allowed us to assess and modify the times designated for blood sample collection. Given that the plasma trazodone concentration was below the LOQ at 12 and 24 hours after drug administration in the pilot subject and 5 of the 6 dogs in a previous pharmacokinetic study18 involving trazodone, we chose to collect a blood sample at 15 minutes after drug administration and forego sample collection at 24 hours after drug administration in the remaining dogs in the hope that such a sampling scheme would provide better characterization of the pharmacokinetic parameters. For consistency, only data acquired between 0 and 12 hours (0 and 720 minutes) after drug administration were included in the pharmacokinetic analysis.

Measurement of plasma trazodone concentration

Plasma samples were shipped frozen to a commercial laboratory,f where the trazodone concentration in each sample was measured in triplicate by use of 2-D high-performance liquid chromatography with positive-ion electrospray liquid chromatography-tandem mass spectrometry. Briefly, 25 μL of pimozide (internal standard) was added to each 0.25-mL test aliquot of plasma, and the resulting mixture underwent protein precipitation extraction. Matrix-matching experiments for measurement of trazodone concentrations in canine plasma were performed as described,18 with the exception of a transition in laboratory protocol from use of an ultrahigh-performance liquid chromatography method to use of a high-performance liquid chromatography-tandem mass spectrometry method. That transition necessitated the addition of a 1 + 9 dilution step to the previous protocol and resulted in a higher LOQ (500 ng/mL [0.5 μg/mL]) for trazodone than that (0.050 μg/mL) reported in the other study.18 In the protocol used for the present study samples, plasma obtained from EDTA-anticoagulated blood samples was matrix matched to serum. To create calibration curves for the present study samples, 25 blank (baseline) 0.25-mL aliquots of plasma were spiked with known concentrations of trazodone (5, 20, and 400 ng/mL) and analyzed as described. The assay had an overall bias of −0.6%. The respective intra-assay CVs for precision and accuracy were 8.6% and −10.9% for samples with a known trazodone concentration of 5 ng/mL, 4.7% and 6.2% for samples with a known trazodone concentration of 20 ng/mL, and 3.3% and 8.2% for samples with a known trazodone concentration of 400 ng/mL. The respective interassay CVs for precision and accuracy were 5.7% and −6.7% for samples with a known trazodone concentration of 5 ng/mL, 3.9% and 3.5% for samples with a known trazodone concentration of 20 ng/mL, and 2.6% and 5.6% for samples with a known trazodone concentration of 400 ng/mL.

Pharmacokinetic analysis

For plasma samples with trazodone concentrations below the assay LOQ (500 ng/mL), the trazodone concentration was recorded as 0 ng/mL. For each dog, the plasma trazodone concentration over time was plotted on linear and semilogarithmic scales. The Cmax and tmax were determined by visual examination of the concentration-time plots. Other pharmacokinetic parameters (t½, AUC from time 0 to the last measured concentration, AUC from time 0 to 24 hours after drug administration, AUC from time 0 extrapolated to infinity, and AUC from the last measured time extrapolated to infinity and expressed as a percentage of the total AUC, Vd/F, CL/F, and MRT) were estimated by noncompartmental analysisg assuming extravascular drug administration and linear-up-log-down integration. Pharmacokinetic data estimated for trazodone following IV administration of a single dose (8 mg/kg; the same target dose used for the dogs of this study) of the drug to dogs of another study18 were used to facilitate calculation of the t1/2, CL/F, MRT, F, and Vd/F for trazodone following rectal administration to the dogs of the present study.

To compare pharmacokinetic parameters for trazodone following PR administration with those following PO administration, we extracted data from another study18 in which dogs were orally administered a single dose (8 mg/kg) of the drug and entered that data into a noncompartmental analysis. The relative F was calculated as ([AUCPR × DosePO]/[AUCPO × DosePR]) × 100%, where AUCPO is the AUC for trazodone following PO administration, AUCPR is the AUC for trazodone following PR administration, and DosePO and DosePR are the doses of trazodone administered by the PO and PR routes, respectively.

Adverse events and sedation scoring

All adverse events were recorded. A previously described27 and validated28 scoring system for assessing sedation in dogs was used to evaluate the extent of sedation in each dog immediately before collection of each blood sample. Briefly, each of 7 clinical variables was scored on a 3- (eye position), 4- (palpebral reflex, jaw tone and gag reflex, response to noise, resistance to being positioned in lateral recumbency, and general appearance and attitude), or 5-point (posture) scale where the extent of an abnormal response (ie, sedation) increased as the score increased. The scores for all variables were summed to calculate the sedation score. The sedation score at any assessment could range from 0 to 21, and a sedation score ≤ 3 was defined as no to mild sedation, 4 to 11 was defined as moderate sedation, and ≥ 12 was defined as extreme sedation. All sedation scores were assigned by the same investigator (EMO). The SSmax and SS-tmax were calculated directly from examination of the data.

Results

Dogs

Six healthy dogs were enrolled in the study, including 2 American Staffordshire Terriers, 1 Doberman Pinscher, 1 Great Dane, and 2 mixed-breed dogs (a shepherd mix and a Golden Retriever-Poodle mix). Median age was 5.8 years (range, 4.0 to 7.8 years), and median body weight was 33 kg (range, 25.1 to 44.5 kg). The median dose of trazodone administered was 8 mg/kg (range, 7.8 to 8.8 mg/kg), and the median total amount of trazodone administered was 275 mg (range, 200 to 350 mg). The plasma trazodone concentration was below the LOQ (ie, was recorded as 0 ng/mL) at all sample times for the Golden Retriever-Poodle mix even though the dog became clinically sedate; therefore, data for that dog were excluded from all other analyses. For the 5 dogs included in the analyses, the median age was 6.5 years (range, 4.0 to 7.8 years) and median body weight was 32 kg (range, 25.1 to 44.5 kg). The median dose of trazodone administered was 8 mg/kg (range, 7.8 to 8.8 mg/kg), and the median total amount of trazodone administered was 250 mg (range, 200 to 350 mg).

Pharmacokinetic parameters

The median plasma trazodone concentration over time was plotted for the 5 dogs retained in the analysis (Figure 1). Variability in exposure across dogs was moderate (CV, 46%). Rectal administration of trazodone was associated with rapid absorption, resulting in a median Cmax of 1 μg/mL (IQR, 0.66 to 1.4 μg/mL) at a median tmax of 15 minutes (range, 15 to 30 minutes). Other pharmacokinetic parameters were summarized (Table 1). The plasma trazodone concentration remained greater than the median Cmax at 1 and 3 hours after drug administration in 2 dogs and 1 dog, respectively. Plasma trazodone concentration remained measurable (≥ 0.5 μg/mL) for 2 hours after drug administration in all 5 dogs, for 6 hours in 3 dogs, and for 8 hours in 2 dogs. The plasma trazodone concentration was below the LOQ for all 5 dogs at 12 hours after drug administration, which made extrapolation of data for the terminal portion of the concentration-time curve challenging.

Figure 1—
Figure 1—

Median plasma trazodone concentration (solid line) and sedation score (dashed line) over time for 5 healthy adult dogs that received a single dose of the drug (approx 8 mg/kg, PR). The sedation score could range from 0 to 21, and a sedation score ≤ 3 was defined as no to mild sedation, 4 to 11 was defined as moderate sedation, and ≥ 12 was defined as extreme sedation. Bars indicate the IQR.

Citation: American Journal of Veterinary Research 81, 9; 10.2460/ajvr.81.9.739

Table 1—

Summary of pharmacokinetic parameters for trazodone following rectal administration of a single dose of the drug (approx 8 mg/kg) to 5 healthy adult dogs.

ParameterMean (SD)Median (range; IQR)Geometric mean (SD)
Cmax (μg/mL)1.02 (0.429)1.00 (0.540–1.50; 0.660–1.40)0.944 (1.57)
tmax (h)0.300 (0.112)0.25 (0.25–0.50; 0.25–0.25)0.287 (1.36)
tlast (h)5.20 (3.03)6 (2–8; 2–8)4.34 (2.05)
t½ (h)24.3 (33.5)12.0 (4.67–83.8; 7.99–12.7)13.7 (2.97)
Cl/F (mL/kg/h)573 (261)639 (125–786; 594–719)485 (2.15)
Vd/F (L/kg)10.4 (4.44)10.3 (4.84–15.2; 7.37–14.4)9.57 (1.62)
MRT (h)35.2 (48.2)17.2 (7.51–121; 11.7–18.4)20.2 (2.89)
AUC0–last (h·μg/mL)4.00 (3.02)4.03 (0.960–7.26; 0.996–6.73)2.85 (2.73)
AUC0–24 (h·μg/mL)5.77 (2.65)5.73 (2.39–8.64; 4.00–8.07)5.21 (1.71)
AUC%extrap (%)68.9 (26.5)70.1 (34.7–98.5; 51.1–90.1)64.3 (1.54)
AUC0–∞ (h·μg/mL)22.1 (22.5)13.5 (10.1–62.2; 11.1–13.8)16.7 (2.11)

Parameters were estimated by noncompartmental analysis.

AUC0-∞ = AUC from time 0 to infinity. AUC0-last = AUC from time 0 to the last measurable concentration. AUC0-24 = AUC from time 0 to 24 hours after administration. AUC%extrap = AUC from the last measured time extrapolated to infinity and expressed as a percentage of the total AUC. tlast = Time to the last measured concentration.

Sedation scores

No adverse effects were observed following rectal administration of trazodone. The median sedation score over time was plotted for the 5 dogs retained in the analysis (Figure 1). The median SSmax was 7 (range, 2 to 11; IQR, 6 to 9), and the median SS-tmax was 30 minutes (range, 15 to 240 minutes; IQR, 30 to 60 minutes). Moderate sedation was achieved in 4 of the 5 dogs (SSmax range, 6 to 11), and only mild sedation was achieved in the remaining dog (SSmax, 2). The SS-tmax was 240 minutes for the dog with an SSmax of 11. Only 3 of the 5 dogs remained moderately sedate at 6 hours after trazodone administration, and all 5 dogs were classified as not sedate or only mildly sedate at 12 hours after drug administration. The median SSmax (rS, 0.71; P = 0.18) and median SS-tmax (rS, 0.3; P = 0.17) were both positively correlated with the tmax for trazodone, although neither of those correlations were significant owing to the small sample size (n = 5). Neither SSmax nor SS-tmax was strongly correlated (rS, < 0.60 for all comparisons) with other pharmacokinetic parameters (Cmax, t½, AUC, Vd/F, Cl/F, and MRT).

Discussion

Results of the present study indicated that, in healthy dogs, rectal administration of trazodone resulted in rapid absorption of the drug and the onset of mild or moderate sedation within 15 to 30 minutes. One of the 6 study dogs never developed measurable plasma trazodone concentrations (≥ 0.5 μg/mL) following rectal administration of the drug, although it did become clinically sedate. Three of the 5 study dogs that developed measurable plasma trazodone concentrations remained moderately sedate at 6 hours after drug administration, but the sedative effects of the drug had worn off by 12 hours after administration in all 5 dogs. Thus, we accepted (ie, failed to reject) our hypothesis that rectal administration of a single dose of trazodone (8 mg/kg) to healthy dogs would result in substantial sedation.

The dose of trazodone (8 mg/kg) administered PR to the dogs of the present study was the same as that administered PO and IV to the dogs of another pharmacokinetic study.18 Trazodone doses of 4 to 10 mg/kg, PO, have been described in dogs.8,11,17–22,a It is possible that administration of higher doses of the drug may achieve higher plasma trazodone concentrations and more extensive sedation than those achieved in the present study, but administration of higher trazodone doses might also increase the risk for adverse effects. Further investigation of rectal administration of trazodone to dogs at doses > 8 mg/kg is warranted.

The plasma trazodone concentration necessary for inducing sedation in dogs (ie, therapeutic concentration) is unknown. In human patients, the therapeutic trazodone concentration ranges from 0.13 to 2.00 μg/mL,29 and there is a wide range of recommended dosing schemes (eg, 25 to 600 mg or 0.26 to 5 mg/kg for an average 70-kg adult).15 Therefore, it is difficult to make comparisons between trazodone administration in human patients and dogs. Nevertheless, the measurable plasma trazodone concentrations achieved for the dogs of the present study were generally within the therapeutic trazodone concentration reported for humans.

In dogs, trazodone is effectively absorbed following administration by the PO and IV routes.18 In that study,18 the mean ± SD Cmax for trazodone was not reported following IV administration and was 1.3 ± 0.5 μg/mL following PO administration, which was higher than the mean ± SD Cmax (0.94 ± 0.43 μg/mL; median, 1 μg/mL) achieved for the dogs of the present study. For 2 dogs of the present study, the Cmax was 1.4 and 1.5 μg/mL, and the plasma trazodone concentrations in those dogs remained above the mean Cmax for the study population for at least 60 minutes. The tmax for both of those dogs was 15 minutes, which indicated that trazodone is rapidly absorbed following rectal administration.

Comparison of the pharmacokinetic parameters for trazodone determined following rectal administration of the drug to the dogs of the present study with those determined following oral and IV administration of the drug to the dogs of another study18 had several limitations, despite administration of the same dose (8 mg/kg) of trazodone by each route (PR, PO, and IV). Perhaps the greatest limitation was that the LOQ for trazodone in the present study (0.5 μg/mL) was 10 times that for the other study18 (0.05 μg/mL). Although the same laboratory analyzed plasma samples from both studies, during the intervening period between the 2 studies, the laboratory changed its protocol for matrix-matching experiments in canine blood samples, resulting in a higher LOQ for trazodone in the present study. A lower LOQ for trazodone would have allowed more precise and prolonged pharmacokinetic profiling, which would have helped overcome limitations associated with the limited exposure range. In the present study, the AUC from the last measured time extrapolated to infinity and expressed as a percentage of the total AUC had a wide range (35% to 98%; median, 70%). The concentration-time curves were quite flat throughout the duration that plasma trazodone concentrations remained measurable (ie, ≥ 0.5 μg/mL), which necessitated substantial extrapolation for estimation of parameters during the elimination and terminal phases. It also made calculating the F of trazodone following rectal administration challenging because we estimated it by use of pharmacokinetic parameters for trazodone following IV administration estimated in the other study18 with a lower LOQ. A lower LOQ would presumably result in a larger absorption interval and a larger AUC. Thus, the AUC, F, and other parameters dependent on F (eg, Cl/F and Vd/F) were likely underestimated in the present study and should be interpreted with caution.

The F of trazodone following rectal administration (median, 30%; range, 7% to 55%) estimated in the present study was fairly low, compared with the mean ± SD F of trazodone following oral administration (84.6 ± 13.2%) estimated in the other study.18 However, as previously stated, the F of trazodone following rectal administration reported in the present study likely represented an underestimation of the true F owing to differences in methodology between the present study and study18 from which pharmacokinetic data for trazodone following IV administration were extracted for calculation of F. The lower F of trazodone when administered PR versus PO might also be a function of differences in absorption of the drug associated with administration route. For example, a portion of the drug may have leaked from the anus following rectal administration, despite the fact that the anus of each dog was held closed manually by an investigator for several minutes following drug administration to minimize leakage. Also, the presence of feces in the rectum might impair systemic absorption of a drug. Comparison of plasma trazodone concentrations in dogs when the drug is rectally administered after an enema and without an enema might provide information regarding the effect of feces on rectal absorption of trazodone. However, administration of an enema prior to rectal administration of trazodone may not be feasible in clinical patients. Regardless, a study in which trazodone is administered to dogs by the PO, PR, and IV routes and all blood and plasma samples are processed in the same manner for measurement of plasma trazodone concentration is necessary to allow for more accurate comparison of the pharmacokinetics of the drug among the different routes of administration. Also, that study would ideally involve a larger population of dogs (> 6) than the present study.

Results of the present study indicated that rectal absorption of trazodone was rapid (median tmax, 15 minutes [range, 15 to 30 minutes]), as was the onset of sedation. Although the median SS-tmax was 30 minutes (range, 15 to 240 minutes), all dogs had an increase in sedation score (ie, were more sedate) between baseline (immediately before) and 15 minutes after trazodone administration and were classified as mildly or moderately sedate at 1 hour after trazodone administration. This profile is ideal for perioperative dosing of trazodone because most surgical procedures for which postoperative oral administration of drugs is contraindicated (eg, brachycephalic airway surgery and arytenoid lateralization surgery) typically require < 2 hours to complete. Trazodone could be rectally administered soon after anesthesia induction such that its clinical effects would peak during anesthesia recovery and last for several hours thereafter until drugs could be safely administered orally. Plasma trazodone concentration was not measured between baseline and 15 minutes after trazodone administration in the present study. It is possible that the true tmax of trazodone following rectal administration is < 15 minutes. Another study in which plasma trazodone concentration is measured at shorter intervals during the first 15 minutes after rectal administration of the drug would allow the tmax to be more precisely defined.

Plasma trazodone concentrations and sedation scores varied greatly among the dogs of the present study following rectal administration of the drug. Detectable plasma trazodone concentrations were never achieved in 1 dog even though it became moderately sedate. Compared with the mean Cmax (0.94 μg/mL) for the study population, the Cmax was higher for 3 dogs (1.0, 1.4, and 1.5 μg/mL) and lower for 2 dogs (0.5 and 0.6 μg/mL). One of the dogs with a Cmax greater than the mean became only mildly sedate during the sampling period. We do not believe that the discrepancies in plasma trazodone concentrations among dogs were caused by analytic error because each sample was analyzed in triplicate per the laboratory's protocol. Rather, we believe the discrepancies observed among dogs in regard to plasma trazodone concentration and sedation score were the result of intersubject variation in the absorption and metabolism of and response to trazodone. Evaluation of a larger study population is necessary to develop a more robust pharmacokinetic profile for trazodone following rectal administration.

Aside from sedation, no clinical effects attributable to trazodone administration were observed in the dogs of the present study. In dogs, adverse effects associated with trazodone administration include vomiting, gagging, constipation, colitis, hyperexcitability, excessive sedation, panting, aggression, and perceived behavioral disinhibition.8,11,21 Although cardiovascular variables were not monitored for the dogs of the present study, proxies for those variables such as general attitude and signs of anxiety and mentation were evaluated as part of the sedation score. Nevertheless, cardiovascular variables should be monitored in conjunction with sedation score assignment in future studies involving trazodone administration to dogs.

For the dogs of the present study, the Cmax did not appear to correspond to the SSmax. To eliminate interobserver variability, all sedation scores were assigned by 1 investigator, who used a scoring system that was designed27 and validated28 for use in dogs. All dogs of the present study were individually housed in a hospital setting throughout the period during which sedation scores were assigned. Dogs unfamiliar with a hospital setting may become anxious, which could affect the sedation score. The dogs evaluated in the present study were blood donors for our hospital and were preconditioned to the hospital environment. Therefore, we do not believe that the sedation scores were affected by the dogs being exposed to a novel environment. All dogs were healthy and did not have any evidence of gastrointestinal tract disease that could alter absorption of a rectally administered drug.

The present study had several limitations. The study population was small, and a more comprehensive pharmacokinetic profile for trazodone following rectal administration could have been developed had a larger number of dogs been evaluated. Cardiovascular variables were not monitored, so it is possible adverse effects such as tachycardia, hypertension, and hypotension went undetected. All evaluated dogs were healthy, and the estimated pharmacokinetic parameters may differ in dogs with systemic illnesses that might affect absorption and F of the drug. Also, pharmacokinetic profiling was limited owing to changes in the laboratory protocol used to measure plasma trazodone concentration, which increased the LOQ of trazodone for this study (0.5 μg/mL) 10 times relative to that for a previous pharmacokinetic study18 (0.05 μg/mL). The ability to measure lower concentrations of trazodone would have improved the precision and accuracy of the estimated pharmacokinetic parameters. Finally, although all sedation scores were assigned by the same investigator, thereby eliminating interobserver variability, the study did not include an untreated control group against which the perceived clinical efficacy of trazodone could be compared.

Findings of the present study suggested that rectal administration of a single dose (8 mg/kg) of trazodone was well tolerated in healthy dogs and associated with rapid absorption and mild to moderate sedation that lasted for several hours. No adverse effects were observed, and the trazodone-induced sedative effects were worn off by 12 hours after drug administration. Rectal administration of trazodone may be a viable option for sedation and treatment of anxiety in dogs for which administration of sedatives and anxiolytics by other routes (eg, PO or IV) is contraindicated or associated with undesired adverse effects. Further research involving a larger number of dogs than that evaluated in the present study and rectal administration of trazodone at various doses after administration of an enema and without an enema is warranted to better elucidate the pharmacokinetics and clinical efficacy of trazodone following rectal administration.

Acknowledgments

The authors thank Dr. Gary Clark for assistance with statistical analysis and Eric Alexy for assistance with performing the drug assays.

ABBREVIATIONS

AUC

Area under the concentration-time curve

Cl/F

Clearance corrected for bioavailability

Cmax

Maximum plasma drug concentration

CV

Coefficient of variation

F

Bioavailability

IQR

Interquartile (25th to 75th percentile) range

LOQ

Lower limit of quantification

MRT

Mean residence time

PR

Per rectum

SSmax

Maximum sedation score

SS-tmax

Time to maximum sedation score

t½

Apparent elimination half-life

tmax

Time to maximum plasma drug concentration

Vd/F

Volume of distribution corrected for bioavailability

Footnotes

a.

Gomoll AW, Byrne JE. Cardiovascular effects of trazodone in animals (abstr). J Clin Pharmacol 1981;1:70S-75S.

b.

Small animal long term venous catheterization set, Mila International Inc, Florence, Ky.

c.

Sparhawk Laboratories, Lexington, Ky.

d.

Teva Laboratories-Pliva, Zagreb, Croatia.

e.

Cardinal Health, Dublin, Ohio.

f.

NMS Labs, Willow Grove, Pa.

g.

Phoenix WinNonlin, version 8.0, Certara, Princeton, NJ.

References

  • 1. Väisänen M, Raekallio M, Kuusela E, et al. Evaluation of the perioperative stress response in dogs administered medetomidine or acepromazine as part of the preanesthetic medication. Am J Vet Res 2002;63:969975.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Plumb DC. Plumb's veterinary drug handbook. 7th ed. Ames, Iowa: John Wiley and Son Inc, 2011;13451348.

  • 3. Simon BT, Scallan EM, Siracusa C, et al. Effects of acepromazine or methadone on midazolam-induced behavioral reactions in dogs. Can Vet J 2014;55:875885.

    • Search Google Scholar
    • Export Citation
  • 4. Rankin DC. Sedatives and tranquilizers. In: Grimm KA, Lamont LA, Tranquilli WJ, et al, eds. Veterinary anesthesia and analgesia. 5th ed. Ames, Iowa: Wiley Blackwell, 2015;196206.

    • Search Google Scholar
    • Export Citation
  • 5. Congdon JM, Marquez M, Niyom S, et al. Evaluation of the sedative and cardiovascular effects of intramuscular administration of dexmedetomidine with and without concurrent atropine administration in dogs. J Am Vet Med Assoc 2011;239:8189.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Hayashi K, Nishimura R, Yamaki A, et al. Comparison of sedative effects induced by medetomidine, medetomidine-midazolam and medetomidine-butorphanol in dogs. J Vet Med Sci 1994;56:951956.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Court MH, Greenblatt DJ. Pharmacokinetics and preliminary observations of behavioral changes following administration of midazolam to dogs. J Vet Pharmacol Ther 1992;15:343350.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Gruen ME, Roe SC, Griffith E, et al. Use of trazodone to facilitate postsurgical confinement in dogs. J Am Vet Med Assoc 2014;245:296301.

  • 9. DeBattista C, Sofuoglu M, Schatzberg AF. Serotonergic synergism: the risks and benefits of combining the selective serotonin reuptake inhibitors with other serotonergic drugs. Biol Psychiatry 1998;44:341347.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Bossini L, Casolaro I, Koukouna D, et al. Off-label uses of trazodone: a review. Expert Opin Pharmacother 2012;13:17071717.

  • 11. Gruen ME, Sherman BL. Use of trazodone as an adjunctive agent in the treatment of canine anxiety disorders: 56 cases (1995–2007). J Am Vet Med Assoc 2008;233:19021907.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge, England: Cambridge University Press, 2008;322326.

    • Search Google Scholar
    • Export Citation
  • 13. Ankier SI, Martin BK, Rogers MS. Trazodone—a new assay procedure and some pharmacokinetic parameters. Br J Clin Pharmacol 1981;11:505509.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Luparini MR, Garrone B, Pazzagli M, et al. A cortical GABA-5HT interaction in the mechanism of action of the antidepressant trazodone. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:11171127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Bryant SG, Ereshofsky L. Antidepressant properties of trazodone. Clin Pharm 1982;1:406417.

  • 16. Voican CS, Corruble E, Naveau S, et al. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 2014;171:404415.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Gruen ME, Sherman BL. Animal Behavior Case of the Month: thunderstorm phobia. J Am Vet Med Assoc 2012;241:12931295.

  • 18. Jay AR, Krotscheck U, Parsley E, et al. Pharmacokinetics, bioavailability, and hemodynamic effects of trazodone after intravenous and oral administration of a single dose to dogs. Am J Vet Res 2013;74:14501456.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Gomoll AW, Byrne JE, Deitchman D. Hemodynamic and cardiac actions of trazodone and imipramine in the anesthetized dog. Life Sci 1979;24:18411847.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Seksel K. Use of trazodone as an anxiolytic for surgical cases, in Proceedings. Vet Behav Chapt Sci Week 2013;121124.

  • 21. Gilbert-Gregory SE, Stull JW, Rice MR, et al. Effects of trazodone on behavioral signs of stress in hospitalized dogs. J Am Vet Med Assoc 2016;249:12811291.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Murphy LA, Barletta M, Graham LF, et al. Effects of acepromazine and trazodone on anesthetic induction dose of propofol and cardiovascular variables in dogs undergoing general anesthesia for orthopedic surgery. J Am Vet Med Assoc 2017;250:408416.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Mirassou MM. Rectal antidepressant medication in the treatment of depression. J Clin Psychiatry 1998;59:29.

  • 24. De Boer AG, De Leede LG, Breimer DD. Drug absorption by sublingual and rectal routes. Br J Anaesth 1984;56:6982.

  • 25. National Center for Biotechnology Information. Trazodone monograph. Available at: pubchem.ncbi.nlm.nih.gov/compound/5533. Accessed Feb 7, 2018.

    • Search Google Scholar
    • Export Citation
  • 26. Brewer DM, Cerda-Gonzalez S, Dewey CW, et al. Pharmacokinetics of a single-dose rectal zonisamide administration in normal dogs. J Vet Intern Med 2015;29:603606.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27. Grint NJ, Burford J, Dugdale AH. Does pethidine affect the cardiovascular and sedative effects of dexmedetomidine in dogs? J Small Anim Pract 2009;50:6266.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Wagner MC, Hecker KG, Pang DSJ. Sedation levels in dogs: a validation study. BMC Vet Res 2017;13:110.

  • 29. Mercolini L, Colliva C, Amore M, et al. HPLC analysis of the antidepressant trazodone and its main metabolite m-CPP in human plasma. J Pharm Biomed Anal 2008;47:882887.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figure 1—

    Median plasma trazodone concentration (solid line) and sedation score (dashed line) over time for 5 healthy adult dogs that received a single dose of the drug (approx 8 mg/kg, PR). The sedation score could range from 0 to 21, and a sedation score ≤ 3 was defined as no to mild sedation, 4 to 11 was defined as moderate sedation, and ≥ 12 was defined as extreme sedation. Bars indicate the IQR.

  • 1. Väisänen M, Raekallio M, Kuusela E, et al. Evaluation of the perioperative stress response in dogs administered medetomidine or acepromazine as part of the preanesthetic medication. Am J Vet Res 2002;63:969975.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Plumb DC. Plumb's veterinary drug handbook. 7th ed. Ames, Iowa: John Wiley and Son Inc, 2011;13451348.

  • 3. Simon BT, Scallan EM, Siracusa C, et al. Effects of acepromazine or methadone on midazolam-induced behavioral reactions in dogs. Can Vet J 2014;55:875885.

    • Search Google Scholar
    • Export Citation
  • 4. Rankin DC. Sedatives and tranquilizers. In: Grimm KA, Lamont LA, Tranquilli WJ, et al, eds. Veterinary anesthesia and analgesia. 5th ed. Ames, Iowa: Wiley Blackwell, 2015;196206.

    • Search Google Scholar
    • Export Citation
  • 5. Congdon JM, Marquez M, Niyom S, et al. Evaluation of the sedative and cardiovascular effects of intramuscular administration of dexmedetomidine with and without concurrent atropine administration in dogs. J Am Vet Med Assoc 2011;239:8189.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Hayashi K, Nishimura R, Yamaki A, et al. Comparison of sedative effects induced by medetomidine, medetomidine-midazolam and medetomidine-butorphanol in dogs. J Vet Med Sci 1994;56:951956.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Court MH, Greenblatt DJ. Pharmacokinetics and preliminary observations of behavioral changes following administration of midazolam to dogs. J Vet Pharmacol Ther 1992;15:343350.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Gruen ME, Roe SC, Griffith E, et al. Use of trazodone to facilitate postsurgical confinement in dogs. J Am Vet Med Assoc 2014;245:296301.

  • 9. DeBattista C, Sofuoglu M, Schatzberg AF. Serotonergic synergism: the risks and benefits of combining the selective serotonin reuptake inhibitors with other serotonergic drugs. Biol Psychiatry 1998;44:341347.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Bossini L, Casolaro I, Koukouna D, et al. Off-label uses of trazodone: a review. Expert Opin Pharmacother 2012;13:17071717.

  • 11. Gruen ME, Sherman BL. Use of trazodone as an adjunctive agent in the treatment of canine anxiety disorders: 56 cases (1995–2007). J Am Vet Med Assoc 2008;233:19021907.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge, England: Cambridge University Press, 2008;322326.

    • Search Google Scholar
    • Export Citation
  • 13. Ankier SI, Martin BK, Rogers MS. Trazodone—a new assay procedure and some pharmacokinetic parameters. Br J Clin Pharmacol 1981;11:505509.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Luparini MR, Garrone B, Pazzagli M, et al. A cortical GABA-5HT interaction in the mechanism of action of the antidepressant trazodone. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:11171127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Bryant SG, Ereshofsky L. Antidepressant properties of trazodone. Clin Pharm 1982;1:406417.

  • 16. Voican CS, Corruble E, Naveau S, et al. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 2014;171:404415.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Gruen ME, Sherman BL. Animal Behavior Case of the Month: thunderstorm phobia. J Am Vet Med Assoc 2012;241:12931295.

  • 18. Jay AR, Krotscheck U, Parsley E, et al. Pharmacokinetics, bioavailability, and hemodynamic effects of trazodone after intravenous and oral administration of a single dose to dogs. Am J Vet Res 2013;74:14501456.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Gomoll AW, Byrne JE, Deitchman D. Hemodynamic and cardiac actions of trazodone and imipramine in the anesthetized dog. Life Sci 1979;24:18411847.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Seksel K. Use of trazodone as an anxiolytic for surgical cases, in Proceedings. Vet Behav Chapt Sci Week 2013;121124.

  • 21. Gilbert-Gregory SE, Stull JW, Rice MR, et al. Effects of trazodone on behavioral signs of stress in hospitalized dogs. J Am Vet Med Assoc 2016;249:12811291.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Murphy LA, Barletta M, Graham LF, et al. Effects of acepromazine and trazodone on anesthetic induction dose of propofol and cardiovascular variables in dogs undergoing general anesthesia for orthopedic surgery. J Am Vet Med Assoc 2017;250:408416.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Mirassou MM. Rectal antidepressant medication in the treatment of depression. J Clin Psychiatry 1998;59:29.

  • 24. De Boer AG, De Leede LG, Breimer DD. Drug absorption by sublingual and rectal routes. Br J Anaesth 1984;56:6982.

  • 25. National Center for Biotechnology Information. Trazodone monograph. Available at: pubchem.ncbi.nlm.nih.gov/compound/5533. Accessed Feb 7, 2018.

    • Search Google Scholar
    • Export Citation
  • 26. Brewer DM, Cerda-Gonzalez S, Dewey CW, et al. Pharmacokinetics of a single-dose rectal zonisamide administration in normal dogs. J Vet Intern Med 2015;29:603606.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27. Grint NJ, Burford J, Dugdale AH. Does pethidine affect the cardiovascular and sedative effects of dexmedetomidine in dogs? J Small Anim Pract 2009;50:6266.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Wagner MC, Hecker KG, Pang DSJ. Sedation levels in dogs: a validation study. BMC Vet Res 2017;13:110.

  • 29. Mercolini L, Colliva C, Amore M, et al. HPLC analysis of the antidepressant trazodone and its main metabolite m-CPP in human plasma. J Pharm Biomed Anal 2008;47:882887.

    • Crossref
    • Search Google Scholar
    • Export Citation

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