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Objective To compare the effects of morphine (MOR), methadone (MET), butorphanol (BUT) and tramadol (TRA), in combination with acepromazine, on sedation, cardiorespiratory variables, body temperature and incidence of emesis in dogs.
Study design Prospective randomized, blinded, experimental trial.
Animals Six adult mixed-breed male dogs weighing 12.0 ± 4.3 kg.
Methods Dogs received intravenous administration (IV) of acepromazine (0.05 mg kg−1) and 15 minutes later, one of four opioids was randomly administered IV in a cross-over design, with at least 1-week intervals. Dogs then received MOR 0.5 mg kg−1; MET 0.5 mg kg−1; BUT 0.15 mg kg−1; or TRA 2.0 mg kg−1. Indirect systolic arterial pressure (SAP), heart rate (HR), respiratory rate (fR), rectal temperature, pedal withdrawal reflex and sedation were evaluated at regular intervals for 90 minutes.
Results Acepromazine administration decreased SAP, HR and temperature and produced mild sedation. All opioids further decreased temperature and MOR, BUT and TRA were associated with further decreases in HR. Tramadol decreased SAP whereas BUT decreased fR compared with values before opioid administration. Retching was observed in five of six dogs and vomiting occurred in one dog in MOR, but not in any dog in the remaining treatments. Sedation scores were greater in MET followed by MOR and BUT. Tramadol was associated with minor changes in sedation produced by acepromazine alone.
Conclusions and clinical relevance When used with acepromazine, MET appears to provide better sedation than MOR, BUT and TRA. If vomiting is to be avoided, MET, BUT and TRA may be better options than MOR.
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- Materials and methods
Neuroleptanalgesic combinations are commonly used in veterinary medicine to facilitate handling of small animals, as premedication and to provide analgesia for minor surgical procedures. Phenothiazine agents, α2-adrenoceptor agonists and opioid analgesics are the most commonly used drugs to produce neuroleptanalgesia. When these drugs are administered together, synergism seems to occur; sedation and analgesia being greater than that achieved with either drug given alone (Hall et al. 2001a).
Opioid analgesics are used primarily to produce analgesia without resulting in loss of consciousness. The analgesia produced by this class of drugs is mediated by stimulation of opioid receptors (μ, κ and δ) located mainly in the brain and in the dorsal horn of the spinal cord (Wagner 2002).
Morphine is the prototype opioid to which all others are compared. Morphine is assigned an analgesic potency of 1 and although other opioids are known to have greater analgesic potency, none has been shown to be more effective in relieving pain (Wagner 2002). Morphine possesses high affinity for μ receptors where it acts as an agonist, resulting in analgesia (Hall et al. 2001a). Adverse effects following MOR administration in dogs include vomiting (Blancquaert et al. 1986; Valverde et al. 2004) and release of histamine when administered intravenously (Robinson et al. 1988; Guedes et al. 2006).
Methadone is a synthetic opioid with high affinity for μ receptors and similar analgesic potency to MOR (Hall et al. 2001a). It was also reported that MET might act as an antagonist on N-methyl-d-aspartate (NMDA) receptors and this property might contribute to its analgesic effect as well as prevent development of tolerance (Wagner 2002). Methadone does not induce emesis (Blancquaert et al. 1986) and, in humans, it has a low potential for the release of histamine (Bowdle et al. 2004). In dogs, methadone alone induced mild sedation wheras the combination of methadone and acepromazine produced mild to intense sedation with minimal cardiorespiratory effects (Monteiro et al. 2008).
Tramadol is a synthetic opioid with low affinity for μ receptors and an analgesic potency of one-tenth of that of MOR (Duthie 1998). However, it has been reported in the literature that the analgesic properties of TRA result from both opioid and nonopioid mechanisms (Miranda & Pinardi 1998). This opioid was shown to inhibit the reuptake of norepinephrine and serotonin, achieving spinal modulation of pain and preventing impulses reaching the brain (Duthie 1998). In dogs, TRA produced similar analgesia to MOR in the early postoperative period following ovariohysterectomy (Mastrocinque & Fantoni 2003). The incidence of nausea and vomiting was lower than with other opioids in humans (Duthie 1998) and it does not release histamine (Barth et al. 1987). To the author’s knowledge, there are no data available about the use of TRA alone or in combination with tranquilizing/sedative drugs for premedication in dogs.
Butorphanol is a synthetic opioid with agonist–antagonist properties. Its analgesic effect results from activation of κ receptors. Conversely, BUT was also shown to have affinity for μ receptors where it acts as an antagonist. The analgesic potency of BUT is 3–5 times that of MOR. However, a ceiling effect was reported with no further increase in analgesia after 0.8–1.0 mg kg−1 (Wagner 2002). In dogs, BUT alone or in combination with acepromazine was associated with minimal cardiopulmonary depression (Trim 1983; Cornick & Hartsfield 1992) and it was also shown to have an antiemetic effect (Moore et al. 1994).
The purpose of the present study was to compare the sedative effects of MOR, MET, BUT and TRA, in combination with acepromazine, in dogs. It was also aimed to evaluate the cardiorespiratory effects and adverse effects of each of the combinations.
We hypothesized that the degree of sedation provided by administration of acepromazine/opiod combinations to dogs would vary depending on the opioid chosen.
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A limitation of the present study was that not all the opioids used were employed in equipotent doses for analgesia. Morphine is the prototype opioid to which all others are compared with a relative potency of 1. Methadone was reported to have 1 to 1.5 the potency of MOR whereas BUT is 3–5 times more potent than MOR (Wagner 2002). Tramadol is said to have 1/10 the potency of MOR (Duthie 1998). Thus, the doses of MOR, MET and BUT employed in the present study (0.5, 0.5 and 0.15 mg kg−1 respectively) may be considered to be equipotent whereas the dose of TRA (2.0 mg kg−1) may not. The equipotent dose of TRA to 0.5 mg kg−1 of MOR would be 5 mg kg−1. However, this dose is higher than the dose commonly used in clinical practice (Gaynor 2002; Mastrocinque & Fantoni 2003). All the doses employed in the present study are within reported clinical ranges for dogs (Hall et al. 2001b; Gaynor 2002; Wagner 2002; Mastrocinque & Fantoni 2003).
Phenothiazine agents produce mild to moderate sedation. Peak sedation occurs within 20 minutes following IV administration of acepromazine. Although other drugs, such as alpha2-adrenoceptor agonists, produce dose related sedation, increasing the dose of a phenothiazine does not result in enhancement of the degree of sedation and it may actually intensify the adverse effects (Hall et al. 2001a). When moderate to intense sedation is desired, phenothiazine derivatives should be administered in combination with other drugs with sedative properties such as opioid analgesics. The degree of sedation is greater with the combination than with either agent alone (Smith et al. 2001). In the present study, acepromazine alone produced mild sedation. However, when an opioid was administered 15 minutes after the phenothiazine, sedation was greater than that achieved with acepromazine alone as judged by our visual analog scale.
The sedative effect of opioids results from their interaction with μ and κ receptors (Muir 2002). However, other factors may influence sedation produced by opioid administration. In addition to the type of receptor activated, the dose, differences in pharmacokinetics, the number of observers assessing sedation and individual variation may affect the sedation score. In the present study, we aimed to minimize the influence of all these factors in the assessment of sedation by using equipotent doses, by administering the drugs intravenously, to minimize differences in the absorption times and bioavailability, by using a single blinded observer and by using a randomized cross-over design to minimize individual variation.
It has been reported in the literature that administration of μ-opioids alone results in mild to moderate sedation whereas κ-agonists produce mild sedation (Muir 2002). In a previous study, greater sedation was achieved when the μ-opioid oxymorphone was administered in combination with acepromazine than the combination of the κ-agonist BUT with acepromazine (Cornick & Hartsfield 1992). In the present study, a trend for better sedation was also observed when acepromazine was administered in combination with the μ opioids agonists (MOR and MET). The degree of sedation produced by the combination acepromazine/BUT varied with the scoring system used. Greater sedation was recorded with the VAS than with NDS. This finding is not unexpected as sedation is a subjective variable.
Tramadol is an opioid with low affinity for μ receptors, which also acts by inhibiting the reuptake of norepinephrine and serotonin (Gaynor 2002). This mixed mechanism of action might explain the analgesic effect produced by TRA administration in spite of its low affinity for opioid receptors. In addition to its ability to block these reuptake mechanisms, TRA is metabolized in the liver to O-desmethyltramadol (M1), which is a pharmacologically active metabolite. M1 was reported to have greater affinity for μ receptors than TRA itself (Poulsen et al. 1996) and it is thought that this metabolite contributes to the analgesic effect of TRA (Poulsen et al. 1996; Shipton 2000). M1 also appears to play a role in sedation produced by TRA as its IV administration resulted in sedation in dogs whereas IV (4 mg kg−1) or oral (11 mg kg−1) administration of the parent drug TRA did not (Kukanich & Papich 2004). In the present study, the degree of sedation produced by acepromazine/TRA was lower than that achieved with the other combinations. It might be hypothesized that the low affinity of TRA for μ receptors or the production of insufficiently high concentrations of M1 during the course of observation, or both, may be responsible for these results.
Results of the present investigation indicate that acepromazine in combination with MET, MOR or BUT results in good sedation; this effect being apparently greater with acepromazine/MET. Tramadol has little influence on sedation achieved with acepromazine alone. Thus, the combination acepromazine/TRA is not recommended when moderate to intense sedation is required. Peak sedative effect appears to occur within 30–45 minutes after administration of all combinations.
Pedal withdrawal reflex was used in the present study to assess acute somatic pain subjectively. However, the results of the present study should be interpreted carefully because drugs that influence vigilance, motor responses and autonomic reflexes, such as neuroleptanalgesic combinations, are thought to affect the subjective experience of pain making it difficult to differentiate sedative and analgesic effects of drugs (Ansah et al. 1998). Thus, one could not ascertain, based on the results of our study, that better analgesia was provided by the combination acepromazine/MET.
The effects of acepromazine on HR and arterial blood pressure of dogs have been previously reported. Acepromazine causes a decrease in arterial pressure (Popovic et al. 1972; Turner et al. 1974; Stepien et al. 1995), which is mediated through peripheral alpha-1 adrenoceptor block and depression of the vasomotor centre within the hypothalamus, resulting in vasodilation (Thurmon et al. 1996). However, hypotension (SAP < 90 or MAP < 70 mmHg) was not reported following acepromazine administration in healthy animals. The effects of acepromazine on PR in dogs are variable. Tachycardia in response to a decrease in arterial blood pressure (Turner et al. 1974), a slight decrease (Popovic et al. 1972) or no change (Stepien et al. 1995) have been reported. In the study reported here, a 15% decrease in SAP and a 17% decrease in PR were observed after acepromazine administration. Hypotension was not observed in any of the dogs treated with acepromazine and only one dog developed bradycardia (PR = 56 beats minute−1).
The cardiovascular effects of opioids are quite variable and may be influenced by the drug, its dose and species involved (Hall et al. 2001a). This class of drugs seems to affect myocardial contractility minimally or not at all. However, increased vagal tone may result in bradycardia (Hall et al. 2001a; Wagner 2002). A decrease in HR was reported in dogs treated with MET, oxymorphone and hydromorphone alone (Smith et al. 2001; Monteiro et al. 2008) and following administration of MET, buprenorphine, oxymorphone, hydromorphone or BUT in combination with acepromazine (Cornick & Hartsfield 1992; Stepien et al. 1995; Smith et al. 2001; Monteiro et al. 2008). The present study was in agreement with previous reports. A decrease in PR was observed after administration of acepromazine with MOR, BUT or TRA. However, PR did not change significantly after the combination acepromazine/MET and this finding is in contrast with previous studies. In a previous study performed in our laboratory, PR decreased after intramuscular administration of 0.5 mg kg−1 of MET alone or in combination with acepromazine (0.05 mg kg−1, IM) (Monteiro et al. 2008). The differences between the two studies may be due to the routes of administration employed (IV versus IM). In another study in conscious dogs, IV MET (1 mg kg−1) also decreased HR (Hellebrekers et al. 1989). In the latter study, the authors suggested that bradycardia was mediated, at least partially, through vasopressin release after MET administration in doses of 1 mg kg−1 or higher. Vasoconstriction and increased systemic vascular resistance occurs as a result of vasopressin release and induces a compensatory decrease in HR and cardiac output. These findings suggest that another mechanism might be involved in the decrease in PR after MET administration, in addition to the centrally mediated increase in vagal tone reported before. It is possible that, at the dose used in the present study (0.5 mg kg−1, IV), MET did not induce significantly high concentrations of vasopressin release and consequently, systemic vascular resistance did not increase. Therefore, a compensatory bradycardia was not observed. Another hypothesis is that the alpha-adrenergic blocking properties of acepromazine overwhelmed the vasoconstriction induced by vasopressin.
Intravenous administration of MOR and meperidine results in histamine release; which causes vasodilation and decreases arterial blood pressure, this effect being prevented when the drugs are administered intramuscularly (IM) (Hall et al. 2001a). In addition to the route, the rate of administration also influences the release of histamine and this effect appears to be attenuated by slow IV administration (Moss & Rosow 1983). In the present study, we minimized the release of histamine by administering the opioids slowly over 5 minutes. Hence, it is not likely that arterial blood pressure was influenced by histamine release after administration of MOR or any other treatments.
A decrease in arterial blood pressure has been reported after administration of acepromazine in combination with buprenorphine, hydromorphone, oxymorphone or BUT in dogs, although severe hypotension was not reported following any of the combinations (Cornick & Hartsfield 1992; Stepien et al. 1995; Smith et al. 2001). The reduction in blood pressure seems to be more pronounced when higher doses of the phenothiazine (0.22 mg kg−1, IV) were used (Cornick & Hartsfield 1992) and less likely to be influenced by increasing doses of opioids (Stepien et al. 1995). These findings are supported by a previous study which reported that the alpha-adrenergic block induced by acepromazine is dose related (Ludders et al. 1983). In the present study, a further decrease in SAP compared with mean values at time ACP was observed only after TRA administration, but TRA has not yet been reported to reduce cardiac output or to decrease systemic vascular resistance in dogs. Additionally, histamine release, which could result in decreased systemic vascular resistance, was not observed following TRA administration in people (Barth et al. 1987). Further research is required to evaluate the haemodynamic effects of TRA in dogs.
Acepromazine has little effect on respiratory function. Although fR may decrease, blood-gases are not significantly changed (Popovic et al. 1972; Turner et al. 1974). Conversely, opioid administration may result in respiratory depression by decreasing ventilatory response to hypercapnia (Wagner 2002); this effect being more pronounced with the μ agonists than with the κ agonists (Hall et al. 2001a). When opioids are used alone and within clinical dose ranges in dogs, respiratory depression is unlikely to occur. This effect becomes more important when opioids are administered in combination with other respiratory depressant drugs such as injectable or inhaled general anaesthetics (Wagner 2002). However, when opioids were used in conjunction with acepromazine in healthy dogs, respiratory depression did not occur. Minimal changes were observed in pH, bicarbonate concentration, PaCO2 and PaO2 in dogs treated with acepromazine and buprenorphine, oxymorphone or BUT (Cornick & Hartsfield 1992; Stepien et al. 1995). In the present study, no dog had apnoea or obvious cyanosis. However, as blood-gases were not measured, it cannot be ascertained that respiratory depression did not occur.
The decrease in temperature after administration of all treatments in the present study was due to the effects of acepromazine and opioids on thermoregulatory mechanisms (Thurmon et al. 1996; Hall et al. 2001a; Wagner 2002). Rectal temperature decreased more in MOR and MET than in other treatments. It has been reported that opioids that cause panting may increase heat loss through airways (Wagner 2002). However, in the present study, only one of six dogs in MOR and MET were panting during the study and panting in these dogs was not related to the lowest temperatures observed.
Vomition is an adverse effect that may occur after administration of low lipid soluble opioids such as MOR, hydromorphone and oxymorphone (Valverde et al. 2004). This effect is thought to result from stimulation of δ receptors in the chemoreceptor trigger zone (CTZ) (Blancquaert et al. 1986). The incidence of vomition after IM administration of MOR (0.5 mg kg−1) was 75% (Valverde et al. 2004). In the present study, premedication with acepromazine masked the true emetic effect of the opioids employed. One of six dogs (17%) vomited after MOR administration whereas none of the dogs vomited after MET, BUT and TRA, demonstrating a higher potential for MOR to induce vomiting in nonpainful, healthy dogs than for the other opioids tested, probably because of its lower lipid solubility. A previous study, using the same doses as the present one, reported a similar incidence of vomiting (25%) after acepromazine followed by MOR (Valverde et al. 2004).
Results of the present study suggest that, in the doses used, all combinations used are well-tolerated by healthy dogs. The major side effect observed was bradycardia. Good sedation was achieved with acepromazine in combination with MET, MOR or BUT, but not TRA. If vomiting is to be avoided, MET, BUT and TRA may be better options.