Effect of orally administered tramadol alone or with an intravenously administered opioid on minimum alveolar concentration of sevoflurane in cats

Jeff C. H. Ko Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Lisa A. Abbo Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Ann B. Weil Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Brenda M. Johnson Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Tomohito Inoue Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Mark E. Payton Department of Statistics, College of Arts and Sciences, Oklahoma State University, Stillwater, OK 74078.

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Abstract

Objective—To compare the effect of oral administration of tramadol alone and with IV administration of butorphanol or hydromorphone on the minimum alveolar concentration (MAC) of sevoflurane in cats.

Design—Crossover study.

Animals—8 healthy 3-year-old cats.

Procedures—Cats were anesthetized with sevoflurane in 100% oxygen. A standard tail clamp method was used to determine the MAC of sevoflurane following administration of tramadol (8.6 to 11.6 mg/kg [3.6 to 5.3 mg/lb], PO, 5 minutes before induction of anesthesia), butorphanol (0.4 mg/kg [0.18 mg/lb], IV, 30 minutes after induction), hydromorphone (0.1 mg/kg [0.04 mg/lb], IV, 30 minutes after induction), saline (0.9% NaCl) solution (0.05 mL/kg [0.023 mL/lb], IV, 30 minutes after induction), or tramadol with butorphanol or with hydromorphone (same doses and routes of administration). Naloxone (0.02 mg/kg [0.009 mg/lb], IV) was used to reverse the effects of treatments, and MACs were redetermined.

Results—Mean ± SEM MACs for sevoflurane after administration of tramadol (1.48 ± 0.20%), butorphanol (1.20 ± 0.16%), hydromorphone (1.76 ± 0.15%), tramadol and butorphanol (1.48 ± 0.20%), and tramadol and hydromorphone (1.85 ± 0.20%) were significantly less than those after administration of saline solution (2.45 ± 0.22%). Naloxone reversed the reductions in MACs.

Conclusions and Clinical Relevance—Administration of tramadol, butorphanol, or hydromorphone reduced the MAC of sevoflurane in cats, compared with that in cats treated with saline solution. The reductions detected were likely mediated by effects of the drugs on opioid receptors. An additional reduction in MAC was not detected when tramadol was administered with butorphanol or hydromorphone.

Abstract

Objective—To compare the effect of oral administration of tramadol alone and with IV administration of butorphanol or hydromorphone on the minimum alveolar concentration (MAC) of sevoflurane in cats.

Design—Crossover study.

Animals—8 healthy 3-year-old cats.

Procedures—Cats were anesthetized with sevoflurane in 100% oxygen. A standard tail clamp method was used to determine the MAC of sevoflurane following administration of tramadol (8.6 to 11.6 mg/kg [3.6 to 5.3 mg/lb], PO, 5 minutes before induction of anesthesia), butorphanol (0.4 mg/kg [0.18 mg/lb], IV, 30 minutes after induction), hydromorphone (0.1 mg/kg [0.04 mg/lb], IV, 30 minutes after induction), saline (0.9% NaCl) solution (0.05 mL/kg [0.023 mL/lb], IV, 30 minutes after induction), or tramadol with butorphanol or with hydromorphone (same doses and routes of administration). Naloxone (0.02 mg/kg [0.009 mg/lb], IV) was used to reverse the effects of treatments, and MACs were redetermined.

Results—Mean ± SEM MACs for sevoflurane after administration of tramadol (1.48 ± 0.20%), butorphanol (1.20 ± 0.16%), hydromorphone (1.76 ± 0.15%), tramadol and butorphanol (1.48 ± 0.20%), and tramadol and hydromorphone (1.85 ± 0.20%) were significantly less than those after administration of saline solution (2.45 ± 0.22%). Naloxone reversed the reductions in MACs.

Conclusions and Clinical Relevance—Administration of tramadol, butorphanol, or hydromorphone reduced the MAC of sevoflurane in cats, compared with that in cats treated with saline solution. The reductions detected were likely mediated by effects of the drugs on opioid receptors. An additional reduction in MAC was not detected when tramadol was administered with butorphanol or hydromorphone.

Opioids are effective in alleviating pain in cats.1–9 In addition to their analgesic effects, opioids decrease the amount of inhalant anesthetic required in cats as indicated by a reduction in the MAC.10–13 Because inhalant anesthetics induce dose-dependent cardiorespiratory depression, a reduction in MAC induced by administration of an opioid may result in improvement of cardiorespiratory function and be of clinical benefit in cats.

Specific interactions between opioids and inhalants have been evaluated in cats. Reduction of MACs of inhalant anesthetics appears to be affected by the dose, route, and class of opioid administered. Intravenous administration of morphine (1.0 mg/kg [0.45 mg/lb]) or butorphanol (0.08 mg/kg [0.036 mg/lb] or 0.8 mg/kg [0.36 mg/lb])11 or transdermal administration of fentanyl (20 and 50 μg/h)12 significantly decreases the volume percentage of isoflurane required to anesthetize cats. In contrast, epidural administration of morphine (0.1 mg/kg [0.05 mg/lb]) or buprenorphine (0.0125 mg/kg [0.006 mg/lb]) does not significantly affect the MAC of isoflurane.14

Sevoflurane is a commercially available inhalant anesthetic, and a generic form of sevoflurane has become available for use in humans. In veterinary practice, some clinics have replaced isoflurane with sevoflurane as the primary inhalant used. Similar to other inhalant anesthetics, sevoflurane induces dose-dependent cardiovascular depression in cats.15,16 Therefore, administration of analgesics that reduce the amount of sevoflurane required to maintain anesthesia without causing additional cardiovascular depression or other adverse effects is likely to be beneficial. To our knowledge, there are no published reports of studies that have evaluated the effects of opioids on the reduction of MACs of sevoflurane in cats.

Tramadol is a centrally acting opioid analgesic that is structurally related to morphine and codeine. It is widely used in humans for control of acute and chronic pain.17–19 Although the mechanisms of action have not been fully elucidated, tramadol is considered effective and treatment with the drug is associated with fewer adverse effects typical of other opioids.17–19 Use of tramadol in dogs has gained popularity among veterinarians because the drug is perceived to be an effective analgesic, is easily administered, and has a longer duration of action and fewer adverse effects than most other opioids. One study20 in dogs revealed that injectable tramadol is as effective as morphine when given preoperatively for control of pain immediately following surgery. Tramadol is only available in an oral tablet formulation in the United States. Published results from studies21,22 of tramadol use in cats are few in number, and to the authors' knowledge, the effect of oral administration of tramadol on the MAC of sevoflurane in cats has not been reported. Furthermore, the effect of coadministration of tramadol with other opioids on a reduction in the amount of inhalant anesthetic required is unknown in cats. The purpose of the study reported here was to compare the effect of oral administration of tramadol alone and with IV administration of butorphanol or hydromorphone on the MAC of sevoflurane in healthy cats.

Materials and Methods

Animals—Eight 3-year-old domestic shorthair purpose-bred research cats (4 female and 4 male; range of body weights, 4.3 to 5.8 kg [9.5 to 12.8 lb]) were used in a randomized, crossover study. The study protocol was approved by the Purdue University Animal Care and Use Committee.

Study design—Each cat was subjected to 6 anesthetic episodes that were separated by an interval of 1 to 2 weeks. For each anesthetic episode, cats received 1 of 6 treatments in randomized order until each cat received all 6 treatments. Treatments were saline (0.9% NaCl) solution (0.05 mL/kg [0.023 mL/lb], IV), tramadola (8.6 to 11.6 mg/kg [3.9 to 5.3 mg/lb], PO, 5 minutes before induction), butorphanolb (0.4 mg/kg [0.18 mg/lb], IV, 30 minutes after induction), hydromorphonec (0.1 mg/kg, IV, 30 minutes after induction), tramadol and butorphanol (tramadol, 8.6 to 11.6 mg/kg, PO, 5 minutes before induction; butorphanol, 0.4 mg/kg, IV, 30 minutes after induction), and tramadol and hydromorphone (tramadol, 8.6 to 11.6 mg/kg, PO, 5 minutes before induction; hydromorphone 0.1 mg/kg, IV, 30 minutes after induction). A washout period of 1 to 2 weeks was allowed between testing for each treatment.

Anesthesia with sevofluraned in 100% oxygen was induced in cats via face mask. Cats were orotracheally intubated, and anesthesia with sevoflurane was maintained. Following endotracheal intubation, cats were mechanically ventilated and maintained with sevoflurane via a nonrebreathing circuit.e A 30-minute period for equilibration of sevoflurane was allowed from endotracheal intubation to the administration of the injectable drug treatment. The initial vaporizer setting for sevoflurane administration was chosen on the basis of published MACs in cats23 and then adjusted accordingly.

Tramadol is only commercially available in the United States as a 50-mg unscored tablet. One 50-mg tablet was administered orally to each cat regardless of body weight; therefore, the dosage of tramadol ranged from 8.6 to 11.6 mg/kg. Initially, 2 of the cats vomited 10 to 20 minutes after tramadol was administered, so tramadol was administered orally 5 minutes prior to induction of anesthesia via face mask to prevent vomiting of the medication. Tramadol was administered to all cats when conscious, except for 2 that resisted oral administration of the drug while conscious and salivated profusely when tramadol was administered. Those 2 cats were anesthetized with sevoflurane via face mask, intubated, and maintained on sevoflurane; a 5-F polyurethane Foley catheter with stylet was passed orogastrically to administer the tramadol tablet (which was crushed and dissolved in water). This process was completed within 5 minutes after induction of anesthesia.

After tramadol was administered, cats were maintained on sevoflurane for 30 minutes to allow time for drug absorption. Heart rate; RR; esophageal temperature; ECG values; and indirect measurements of blood pressure (SBP, DBP, and MAP), SpO2, PETCO2, and endtidal concentration of sevoflurane were monitored throughout the study and recorded before each tail clamp application. End-tidal sevoflurane concentration and PETCO2 were measured by use of side-stream capnography and an inhalant anesthetic agent monitorf via a 5-F red rubber catheterg inserted through the lumen of the endotracheal tube, with the tip of the catheter positioned at the thoracic inlet. Respiratory rate and tidal volume were adjusted to maintain a PETCO2 between 35 and 45 mm Hg.

Before a tail clamp was applied, HR, RR, PETCO2, SpO2, MAP, SBP, DBP, esophageal temperature, and endtidal concentration of sevoflurane were recorded. The MAC of sevoflurane was determined by use of the tail clamp method.24 Briefly, hair was clipped from a section of the tail with a diameter approximately equivalent to that of a standard Backhaus towel clamp. A Backhaus towel clamp was then placed around the tail and closed to the third ratchet. The clamp was left in place for 60 seconds or until gross purposeful movement of the cat was evident. Gross purposeful movement was defined as substantial movement of the head or extremities but did not include coughing, chewing, swallowing, or increased respiratory effort. The clamp circumscribed the tail, did not puncture the skin, and provided blunt force as a supramaximal noxious stimulus on the tail of the cat. When gross purposeful movement in response to tail clamping was detected, the end-tidal concentration of sevoflurane was increased from 0.1% to 0.2%, a 5- to 10-minute period of equilibration was provided, and the cat was reevaluated for response to the tail clamping. When no purposeful movement in response to tail clamping was detected, the end-tidal concentration of sevoflurane was reduced 0.1% to 0.2%, a 5- to 10-minute period of equilibration was provided, and the cat was reevaluated for response to tail clamping. The MAC of sevoflurane was defined as the average of 2 successive end-tidal sevoflurane concentrations: the lowest sevoflurane concentration preventing gross purposeful movements in response to tail clamping and the highest concentration that did not prevent a response to tail clamping. The MAC value was measured in duplicate, and the averaged value was reported.

Immediately after the MAC of sevoflurane in treated cats was determined, a venous blood sample was obtained and assayed to confirm that there was a detectable concentration of tramadol in the blood of cats that received the drug. The plasma tramadol assay was performed at a laboratory at another university.h Plasma concentrations of tramadol were assessed by use of reverse-phase, high-performance liquid chromatography with fluorescence detection. Details of the assay method have been described elsewhere.25

Naloxone (0.02 mg/kg [0.009 mg/lb], IV) was then administered IV to each cat. Five minutes later, a second MAC determination was initiated in the same manner as described. After the second MAC was obtained (approx 30 minutes after naloxone was administered), anesthesia was discontinued and cats were allowed to recover. The interval from IV injection of saline solution, opioids, or naloxone to MAC determination was recorded.

Statistical analysis—Results are expressed as mean ± SEM. A commercial software programi was used for all statistical analyses. ANOVA methodsj were used to assess overall treatment effects. For the analyses, the study was treated as a 6 × 2 factorial design, with each of the 6 treatments or treatment combinations constituting 1 factor (6 categories) and the use of naloxone constituting the other factor (2 categories [yes and no]). The effect of a treatment for a given category of naloxone was assessed.j To assess the effect of the components of treatment combinations, orthogonal contrasts were conducted to evaluate the interaction of tramadol, butorphanol, and hydromorphone for each category of naloxone. All comparisons and contrasts were considered significant for values of P < 0.05.

Results

Intervals between administration of treatments and determinations of MACs of sevoflurane did not vary significantly among experiments (Table 1). Mean ± SEM MACs for sevoflurane were significantly lower when butorphanol (1.20 ± 0.16%), tramadol (1.48 ± 0.20%), hydromorphone (1.76 ± 0.15%), tramadol and butorphanol (1.48 ± 0.20%), and tramadol and hydromorphone (1.85 ± 0.20%) were administered, compared with the MAC of sevoflurane when saline solution was administered (2.45 ± 0.22%; Figure 1; Table 2).

Table 1—

Mean ± SEM interval until determination of the MAC of sevoflurane in 8 cats after IV injection of an opioid (butorphanol or hydromorphone) or saline (0.9% NaCl) solution and subsequent IV injection of naloxone.

TreatmentInterval after opioid injection (min)Interval after naloxone injection (min)
Butorphanol alone30.0 ± 3.722.4 ± 4.0
Hydromorphone alone31.3 ± 3.626.5 ± 5.0
Butorphanol preceded by tramadol*31.1 ± 3.824.1 ± 3.2
Hydromorphone preceded by tramadol*42.8 ± 8.337.4 ± 7.3
Saline solution32.5 ± 5.325.0 ± 4.2

Tramadol (8.6 to 11.6 mg/kg [3.9 to 5.3 mg/lb], PO) was administered to cats 5 minutes prior to induction with sevofurane and 35 minutes prior to IV administration of butorphanol (0.4 mg/kg [0.18 mg/lb], IV) or hydromorphone (0.1 mg/kg [0.04 mg/lb], IV).

Table 2—

Mean ± SEM MAC of sevoflurane and respiratory values measured in 8 healthy adult cats after administration of various treatments* in a crossover study design.

TreatmentMAC (%)RR (breaths/min)Spo2 (%)Petco2 (mm Hg)
Saline solution2.45 ± 0.22a,A12.8 ± 2.4A99.5 ± 0.336.1 ± 2.0
Saline solution and naloxone2.53 ± 0.32a,A18.1 ± 3.0A99.8 ± 0.235.8 ± 1.7
Tramadol1.48 ± 0.20b,c,B10.5 ± 2.3A99.1 ± 0.536.8 ± 0.9
Tramadol and naloxone2.35 ± 0.15a,A12.5 ± 2.8A99.6 ± 0.337.4 ± 0.6
Hydromorphone1.76 ± 0.15b,B11.4 ± 2.6B99.5 ± 0.335.3 ± 1.8
Hydromorphone and naloxone2.58 ± 0.32a,A19.3 ± 3.4A99.1 ± 0.434.6 ± 2.1
Tramadol and hydromorphone1.85 ± 0.20b,B7.0 ± 0.5A99.8 ± 0.235.6 ± 1.4
Tramadol, hydromorphone, and naloxone2.45 ± 0.28a,A12.8 ± 3.0A99.9 ± 0.137.8 ± 3.6
Butorphanol1.20 ± 0.16c,B14.0 ± 1.9A99.0 ± 0.937.5 ± 1.1
Butorphanol and naloxone1.90 ± 0.21a,A13.6 ± 2.3A99.8 ± 0.335.5 ± 1.5
Tramadol and butorphanol1.48 ± 0.20b,c,B9.8 ± 1.7A99.1 ± 0.438.1 ± 1.5
Tramadol, butorphanol, and naloxone2.16 ± 0.19a,A14.1 ± 2.6A99.3 ± 0.536.4 ± 1.7

Dosages and routes of drug administrations were as follows: saline solution: 0.05 mL/kg (0.023 mL/lb), IV; and naloxone: 0.02 mg/kg (0.009 mg/lb), IV.

Within a column, different lowercase superscript letters indicate a signifcant (P < 0.05) difference between treatments before naloxone was administered.

Within a column, different uppercase superscript letters indicate a signifcant (P < 0.05) difference between treatments after naloxone was administered.

See Table 1 for remainder of key.

Figure 1—
Figure 1—

Mean ± SEM MAC of sevoflurane in 8 cats treated with butorphanol (0.4 mg/kg [0.18 mg/lb], IV), hydromorphone (0.1 mg/kg [0.04 mg/lb], IV), tramadol (8.6 to 11.6 mg/kg [3.9 to 5.3 mg/lb], PO), tramadol and butorphanol (same dosages and routes), and tramadol and hydromorphone (same dosages and routes). *Mean MAC is significantly (P < 0.05) different from that for saline (0.9% NaCl) solution. †Mean MAC is significantly (P < 0.05) different from that for other drugs or drug combinations.

Citation: Journal of the American Veterinary Medical Association 232, 12; 10.2460/javma.232.12.1834

A significant increase in HR was detected in cats when treated with hydromorphone after naloxone was administered (from 134.9 ± 6.2 beats/min to 150.8 ± 9.8 beats/min; Table 3). A similar significant effect was also detected in cats when treated with tramadol and hydromorphone after naloxone was administered, compared with values obtained before naloxone was administered (from 136.8 ± 9.1 beats/min to 150.9 ± 7.7 beats/min). When cats were treated with tramadol and butorphanol, HRs were significantly lower after naloxone was administered (132.9 ± 10.6 beats/min) compared with HRs after naloxone administration when cats were treated with hydromorphone, tramadol and hydromorphone, or saline solution.

Table 3—

Mean ± SEM cardiovascular values and esophageal temperature measured in 8 healthy adult cats after administration of various treatments in a crossover study design.

Treatment*HR (beats/min)MAP (mm Hg)SBP (mm Hg)DBP (mm Hg)Temperature (°C)*
Saline solution143 ± 8.5a,A65.4 ± 5.1a,b,A91.5 ± 5.241.0 ± 5.2b,A37.2 ± 0.1 a,A
Saline solution and naloxone144 ± 8.4a,A70.9 ± 6.4a,A94.8 ± 5.845.6 ± 5.1a,A37.1 ± 0.2c,A
Tramadol133.8 ± 8.8176.8 ± 7.3a,A102.3 ± 7.855.4 ± 7.8a,A37.5 ± 0.2a,A
Tramadol and naloxone143 ± 7.3a,b,A66.5 ± 4.3a,A102.1 ± 6.642.9 ± 2.8a,B37.4 ± 0.1 a,A
Hydromorphone134.9 ± 6.2a,B59.1 ± 3.6b,c,A90.8 ± 5.137.4 ± 4.3b,A37.4 ± 0.1a,A
Hydromorphone and naloxone150.8 ± 9.8a,A64.0 ± 6.0a,A94.1 ± 6.638.3±3.1a,A37.2 ± 0.1b,c,A
Tramadol and hydromorphone136.8 ± 9.1a,A62.8 ± 5.0b,c,A96.3 ± 5.742.0 ± 4.2b,A37.4 ± 0.1a,A
Tramadol, hydromorphone, and naloxone150.9 ±7.7a,A69.3 ± 3.6a,A96.3 ± 3.342.0 ± 3.9a,A37.3 ± 0.2a,b,A
Butorphanol131.6 ± 8.1a,A61.3 ± 3.9b,c,A89.3 ± 4.340.1 ±3.1b,A37.4 ± 0.1a,A
Butorphanol and naloxone140.1 ± 9.2a,b,A60.1 ± 4.0a,A90.4 ± 6.640.1 ± 3.7a,A37.1 ± 0.1b,c,B
Tramadol and butorphanol129.9 ± 10.2a,A53.3 ± 4.0c,B84.1 ± 5.836.4 ± 3.8b,A37.5 ± 0.1a,A
Tramadol, butorphanol, and naloxone132.9 ± 10.6b,A65.1 ± 7.4a,A89.9 ± 8.738.3 ± 5.4a,A37.3 ± 0.1a,b,A

To convert to degrees Farenheit, multiply the value by 9/5 and add 32.

See Table 2 for remainder of key.

The MAP of cats when treated with tramadol and butorphanol significantly increased from 53.3 ± 4.0 mm Hg to 65.1 ± 7.4 mm Hg, and the DBP of cats when treated with tramadol significantly decreased from 55.4 ± 7.8 mm Hg to 42.9 ± 2.8 mm Hg after naloxone was administered (Table 3). When cats were treated with tramadol, they had significantly higher DBPs, compared with DBPS when cats were treated with any other compound, before but not after naloxone was administered.

Naloxone reversed the reduction in the MAC of sevoflurane that was detected when tramadol, butorphanol, hydromorphone, tramadol, and one of the other opioids were administered and restored MACs to those attained when saline solution was administered (Figure 2). Saline solution alone did not affect the MAC of sevoflurane, and administration of naloxone did not affect the MAC in cats when treated with saline solution. Calculation of orthogonal contrasts and subsequent analysis indicated that the MAC of sevoflurane increased when tramadol and hydromorphone were administered together, compared with the MACs obtained when the drugs were administered alone (Table 4). No additional reduction in the MAC was detected when tramadol and butorphanol were administered together, compared with when the drugs were administered alone.

Table 4—

Mean ± SEM MACs obtained by use of orthogonal contrast analysis for the assessment of drug interactions in 8 cats treated with tramadol, butorphanol, hydromorphone, and combinations before and after subsequent naloxone administration.

Treatment combinationMAC before naloxone administered (%)MAC after naloxone administered (%)
Tramadol, butorphanol, and tramadol and butorphanol versus saline solution*
Tramadol1.48 ± 0.202.35 ± 0.15
Butorphanol1.20 ± 0.161.90 ± 0.21
Tramadol and butorphanol1.48 ± 0.202.16 ± 0.19
Saline solution2.45 ± 0.222.53 ± 0.32
Tramadol, hydromorphone, and tramadol and hydromorphone versus saline solution
Tramadol1.48 ± 0.202.35 ± 0.15
Hydromorphone1.76 ± 0.152.58 ± 0.32
Tramadol and hydromorphone1.85 ± 0.202.45 ± 0.28
Saline solution2.45 ± 0.222.53 ± 0.32

Values differed signifcantly (*P = 0.001; †P = 0.005) before naloxone administration, but not significantly (*P = 0.234; †P = 0.893) after naloxone administration.

Figure 2—
Figure 2—

Mean ± SEM MAC of sevoflurane after naloxone administration (0.02 mg/kg [0.009 mg/lb], IV) in 8 cats treated with butorphanol, hydromorphone, tramadol, tramadol and butorphanol, and tramadol and hydromorphone. Differences between treatment effects were not significant. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 232, 12; 10.2460/javma.232.12.1834

Plasma concentrations of tramadol obtained when MAC determinations were made ranged widely from lower than the detectable limit of quantification in 2 cats to as high as 5,143 ng/mL in 1 cat. The M-1 metabolite was also detected at various concentrations in plasma of these cats.

Discussion

Reported MACs for sevoflurane in cats are variable and include 2.58 ± 0.30%,23 3.3 ± 0.2%,26 and 3.41 ± 0.65%.27 This range of values is not surprising and may be attributable to variation in sensitivity to inhalants among cats.27 In the study reported here, the mean ± SEM MAC of sevoflurane was 2.45 ± 0.22%, which is similar to the published values. Administration of naloxone did not significantly change the MAC of sevoflurane in cats treated with saline solution (2.53 ± 0.32%), which indicated a lack of effect of naloxone on the MAC.

Opioid μ-receptor full agonists (eg, morphine11 and alfentanil10), κ-receptor agonists (eg, butorphanol11), or μ-receptor partial agonists (eg, buprenorphine11) significantly reduce the MAC of isoflurane in cats. In the present study, butorphanol (0.4 mg/kg, IV) had a more profound effect in reducing the MAC of sevoflurane (1.2 ± 0.2%) than did hydromorphone (0.1 mg/kg, IV; MAC, 1.8 ± 0.2%), compared with the MAC achieved when cats were treated with saline solution (2.5 ± 0.2%). In another study11 in which investigators evaluated the effects of various opioids on reducing the MAC of isoflurane in cats, morphine had a more profound effect than did butorphanol or buprenorphine. The difference between results of that study and those of the study reported here may be attributable to differences in inhalant anesthetics evaluated, drugs used, or doses administered.

In the present study, although administration of naloxone to cats subsequent to administration of saline solution did not significantly change the MAC of sevoflurane from that obtained without naloxone, administration of naloxone to cats after treatment with butorphanol or hydromorphone reversed the opioid-induced reduction in MAC that was detected previously. This reversal effect of naloxone was confirmed by use of statistical analyses that clearly indicated the MACs achieved after naloxone was administered were no longer significantly different from those when cats were treated with saline solution (Table 2 and Figure 2). Analysis of these results suggested that the reduction in the MAC of sevoflurane that was detected after IV administration of butorphanol and hydromorphone is associated with activity of the 2 drugs at opioid receptors.

Tramadol is a synthetic opioid with a chemical structure related to that of morphine and codeine.18 The effects of tramadol, including induction of analgesia, are brought about via 2 mechanisms. One mechanism involves inhibition of norepinephrine and serotonin reuptake in the CNS; the other involves weak agonistic effects of tramadol at opioid μ-receptors.18,25,28 It has been suggested that tramadol increases CNS activity, which results in a potential reduction of depth of inhalant anesthesia.28 However, a study29 of the effects of tramadol in rats revealed that IV administration of tramadol at 10 mg/kg (4.5 mg/lb) significantly reduces the MAC of isoflurane on a magnitude similar to that of IV administration of morphine at 1 mg/kg (0.45 mg/lb). In the present study, oral administration of tramadol to cats significantly reduced the MAC of sevoflurane, compared with MACs when saline solution was administered. Our study also revealed that the magnitude of the reduction in the MAC of sevoflurane induced by tramadol was intermediate between that of butorphanol and hydromorphone in cats.

The MAC is a measurement of the anesthetic potency of an inhalant anesthetic and degree of consciousness, and it reflects the degree of analgesia.29 It has been suggested that approximately a third of the analgesic activity of tramadol is attributable to activity at opioid receptors and that the remaining analgesic activity is attributable to inhibition of reuptake mechanisms involving norepinephrine and serotonin.29 In rats, treatment with naloxone before tramadol is administered abolishes the reduction in the MAC of isoflurane induced by tramadol. In contrast, administration of yohimbine, an α2-receptor antagonist, does not result in a reversal of the tramadol-induced reduction of the MAC of isoflurane. Investigators in that study29 suggested that morphine and tramadol reduce isoflurane MAC in rats as a result of the action of these drugs at opioid receptors. In the present study in cats, the reduction in the MAC of sevoflurane induced by administration of tramadol alone, another opioid alone, or tramadol and another opioid was reversed by naloxone, which supports the supposition of direct involvement of opioid receptors in reducing the MAC of sevoflurane.

Tramadol improves the efficacy of analgesia when used together with morphine for patient-controlled analgesia in human patients after abdominal surgery, compared with patient-controlled analgesia by use of morphine alone.30 It follows that when tramadol is used concurrently with another opioid, the reduction of the MAC of sevoflurane would be enhanced. However, in the study reported here, administration of tramadol with butorphanol or hydromorphone did not enhance the reduction of the MAC of sevoflurane. More specifically, there was no additional reduction of the MAC of sevoflurane in cats when they were treated with a combination of tramadol and butorphanol, and there appeared to be less reduction in the MAC of sevoflurane in cats when they were treated with tramadol and hydromorphone, compared with the reduction detected in cats when treated with tramadol alone. The reason for the lack of an enhancement effect on the MAC of sevoflurane when tramadol was administered with another opioid in cats is unknown.

Review of the literature reveals conflicting evidence of the effect of tramadol on the depth of anesthesia in humans.31–35 Results of some studies indicate that tramadol causes a 65% incidence of awareness in human patients anesthetized with enflurane and nitrous oxide.31,32 A bolus injection of tramadol in patients anesthetized with isoflurane and nitrous oxide induces dose-dependent activation of changes in electroencephalograms, the clinical importance of which is unknown.33 Other studies that used electroencephalograms or bispectral indices to indicate depth of anesthesia revealed that administration of tramadol during a stable plane of anesthesia does not cause patient awareness nor change the depth of anesthesia.34,35 In a sibling studyk that involved dogs, we evaluated the effect of tramadol, butorphanol, and hydromorphone on the reduction of the MAC of sevoflurane. Results of that study indicated that oral administration of tramadol enhances the reduction of the MAC of sevoflurane when combined with hydromorphone or butorphanol. Furthermore, the effect was more pronounced in dogs treated with tramadol and hydromorphone than in dogs treated with tramadol and butorphanol, which suggests that interspecies variation may result in differences in the responses detected in patients treated with tramadol and other opioids and anesthetized with sevoflurane. Regardless of the lack of an additional enhancement of reduction of the MAC of sevoflurane in cats treated with tramadol and an opioid, administration of naloxone to cats treated with tramadol and butorphanol or tramadol and hydromorphone reversed the reduction of the MAC of sevoflurane induced by these drug combinations. Additional research is required to explore the mechanism of interaction between opioids and tramadol in cats.

In the study reported here, some changes in cardiorespiratory variables were associated with the drug treatments. A significant increase in HR in cats when treated with hydromorphone alone or with tramadol was detected after naloxone was administered. These changes may have reflected the antagonistic action of naloxone on HR induced by hydromorphone. However, the detected increases in HR were not considered clinically important. A change in MAP was detected when cats were treated with tramadol and butorphanol (from 53 to 65 mm Hg), and the DBP when cats were treated with tramadol alone decreased from 55 to 43 mm Hg after naloxone was administered. The aforementioned effects on blood pressure may have indicated that naloxone antagonized the action of tramadol and the other opioids.

To make the results of our study applicable to clinical practice, commercially available tramadol was used to determine the effect of tramadol on reducing the MAC of sevoflurane in cats. Several practical challenges were encountered as a result of this choice. First, tramadol was only available as a 50-mg unscored tablet; therefore, it was difficult to administer a precise dose to each cat. Second, although most cats tolerated oral administration of tramadol, 2 cats had difficulty ingesting the tablet, presumably because it was unpalatable. Unpalatability was also reported in a pharmacokinetic studyl of tramadol in cats. For a tablet form of tramadol to be useful clinically, development of a more palatable formulation is recommended to minimize rejection by cats.

In the study reported here, there was a wide range of plasma concentrations of tramadol. However, results of plasma tramadol assays indicated that tramadol and its metabolite, M-1, were circulating in the blood of most cats when the MAC of sevoflurane was determined. The highly variable oral absorption rates for the dose of tramadol (8.6 to 11.6 mg/kg) were consistent with those reported in another studyl in which another dose of tramadol (4 mg/kg [1.8 mg/lb]) was orally administered to cats. Although plasma concentrations of tramadol were inconsistent in the cats in our study, the effect of tramadol on the reduction in the MAC of sevoflurane was significant and was abolished when naloxone was administered. The reported terminal half-life of tramadol is 2.5 hours in cats, and the M-1 metabolite circulates much longer.l The exact mechanism of tramadol and its metabolite on reducing the MAC of inhalant anesthetics in cats is unknown and requires additional investigation.

The results of the study reported here indicated that oral administration of tramadol reduced the MAC of sevoflurane in cats and that the magnitude of this effect was intermediate between that of butorphanol and hydromorphone. The reduction in the MAC of sevoflurane induced by administration of tramadol, butorphanol, or hydromorphone in cats was related to the action of these drugs at opioid receptors and was reversible with administration of naloxone. There was no advantage to administering tramadol with another opioid to reduce the MAC of sevoflurane, compared with the use of each drug alone.

ABBREVIATIONS

DBP

Diastolic blood pressure

HR

Heart rate

MAC

Minimum alveolar concentration

MAP

Mean arterial blood pressure

PETCO2

End-tidal partial pressure of carbon dioxide

RR

Respiratory rate

SBP

Systolic blood pressure

SpO2

Oxygen saturation as measured by pulse oximetry

a.

Caraco Pharmaceutical Laboratory Ltd, Detroit, Mich.

b.

Torbugesic, Fort Dodge Animal Health, Overland Park, Kan.

c.

Baxter Healthcare Corp, Deerfield, Ill.

d.

SevoFlo, Abbott Animal Health, Abbott Park, Ill.

e.

Modified Jackson Rees, Smiths Medical PM, Waukesha, Wis.

f.

Passport, Gas module II, Datascope Corp, Paramus, NJ.

g.

Kendall, Mansfield, Mass.

h.

Pharmacology Analytical Laboratory, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC.

i.

PROC MIXED, SAS, version 9.1, SAS Institute Inc, Cary, NC.

j.

PROC MIXED (LSMEANS, SLICE option), SAS, version 9.1, SAS Institute Inc, Cary, NC.

k.

Ko JCH, Abbo LA, Johnson BM. The effect of oral tramadol alone or concurrent with opioid administration on sevoflurane minimum alveolar concentration in dogs. School of Veterinary Medicine, Purdue University, West Lafayette, Ind: Unpublished data, 2007.

l.

Papich MG, Bledsoe DL. Tramadol pharmacokinetics in cats after oral administration of an immediate release tablet (abstr). J Vet Intern Med 2007;21:616.

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