Muscle tremors observed in white rhinoceroses immobilised with either etorphine-azaperone or etorphine-midazolam: An initial study.

Etorphine-azaperone is the most commonly used drug combination for chemical immobilisation of free-ranging white rhinoceroses, but causes several profound physiological disturbances, including muscle tremors. The addition of benzodiazepine sedatives, such as midazolam, has been proposed to reduce the muscular rigidity and tremors in immobilised rhinoceroses. Twenty-three free-ranging, sub-adult white rhinoceros bulls were darted and captured using a combination of etorphine plus either azaperone or midazolam. Skeletal muscle tremors were visually evaluated and scored by an experienced veterinarian, and tremor scores and distance run were compared between groups using the Wilcoxon rank sum test. No statistical differences were observed in tremor scores (p = 0.435) or distance run (p = 0.711) between the two groups, and no correlation between these variables was detected (r = -0.628; p = 0.807). Etorphine-midazolam was as effective as etorphine-azaperone at immobilising rhinoceroses, with animals running similar distances. Although the addition of midazolam to the etorphine did not reduce tremor scores compared to azaperone, it might have other beneficial immobilising effects in rhinoceroses, and further investigation is necessary to elucidate possible methods of reducing muscle tremoring during chemical immobilisation of rhinoceroses.

Investigation of cardiorespiratory effects of the selective 5-HT4 agonist BIMU-8 in etorphine-immobilised goats (Capra aegagrus hircus) in a randomized, blinded and controlled trial.

BACKGROUND: Opioid-induced respiratory compromise remains a significant challenge in etorphine-immobilised wildlife. Serotonergic agonists offer a potential avenue for preventing or treating opioid-induced respiratory compromise. We therefore aimed to determine whether the selective 5-hydroxytryptamine receptor 4 (5-HT4) agonist, BIMU-8, reverses opioid-induced respiratory compromise in etorphine-immobilised goats. METHODS: Seven healthy adult goats were immobilised with etorphine, then treated with BIMU-8 or sterile water 5 minutes later in a randomised, prospective cross-over study. Cardiorespiratory variables were measured at 1-minute intervals from 4 minutes before etorphine to 15 minutes after its administration. Arterial blood gas analyses were also performed before and after etorphine administration and the respective treatments. RESULTS: Intravenous injection of BIMU-8 attenuated etorphine-induced respiratory compromise, as indicated by improvements, compared to baseline and between treatments, in respiratory rate (fR ), peripheral arterial blood oxygen saturation (SpO2 ), partial pressure of arterial oxygen (PaO2 ) and the alveolar-arterial oxygen partial pressure gradient (P(A-a)O2 ). BIMU-8 caused an increase in heart rate and a temporary decrease in arterial blood pressure. Mild movements and slight muscle spasm occurred but BIMU-8 did not reverse immobilisation. CONCLUSION: Our results indicate that BIMU-8 may be a potential drug candidate for the treatment, or prevention, of etorphine-induced respiratory compromise in immobilised ungulates.

Dose-effect study of the serotonin agonist R-8-OH-DPAT on opioid-induced respiratory depression in blesbok (Damaliscus pygargus philipsi) and impala (Aepyceros melampus).

OBJECTIVE: To determine whether the R-enantiomer of 8-hydroxy-2-(di-n-propylamino) tetralin (R-8-OH-DPAT) alleviates respiratory depression in antelope species immobilized with etorphine. The experiment also aimed to establish the most clinically effective dose of this serotonin 5- HT1A receptor agonist. ANIMALS: A group of six female blesbok and six female impala. STUDY DESIGN: Each animal was subjected to four immobilization treatments in a prospective four-way crossover design-control treatment consisting of only etorphine at 0.09 mg kg-1 and three treatments consisting of etorphine at 0.09 mg kg-1 combined with 0.005, 0.02 and 0.07 mg kg-1 of R-8-OH-DPAT, respectively. Induction, quality of immobilization and recovery were monitored in each treatment. Physiological variables including heart rate, respiratory rate, arterial blood pressure and blood gases were measured for 35 minutes during immobilization. A linear mixed model was used to assess the effects of treatments over the recumbency period. RESULTS: R-8-OH-DPAT did not influence induction, immobilization or recovery scores. Respiratory rate in blesbok was increased in the medium- and high-dosage R-8-OH-DPAT treatment group. However, this increased respiratory rate did not translate into improvements of arterial partial pressure of oxygen (PaO2) values in the blesbok. The medium and higher dosages of R-8-OH-DPAT in impala led to an improved PaO2 as well as to decreased opioid-induced tachycardia during the first 10 minutes of immobilization. CONCLUSIONS AND CLINICAL RELEVANCE: Previous reports indicated that the racemic mixture of 8-OH-DPAT injected intravenously had a positive effect on blood-gas values in etorphine-treated hypoxemic goats. In this experiment, similar effects could be seen in impala at the higher dosage rates of R-8-OH-DPAT. However, failure to achieve an improvement of blood-gas values in blesbok was an unexpected result. It could be speculated that the dosage, species-specific differences of serotonin receptors or the use of the R-enantiomer of 8-OH-DPAT might play a role.

Compared to etorphine-azaperone, the ketamine-butorphanol-medetomidine combination is also effective at immobilizing zebra (Equus zebra).

OBJECTIVE: To compare immobilization efficacy of a nonpotent opioid drug combination, ketamine-butorphanol-medetomidine (KBM) to the preferred etorphine-azaperone (EA) combination in zebras. STUDY DESIGN: Randomized crossover trial. ANIMALS: A group of ten adult zebra (six females and four male). METHODS: KBM and EA were administered once to the zebras in random order by dart, 3 weeks apart. Once a zebra was recumbent and instrumented, physiological parameters were measured and recorded at 5-minute intervals until 20 minutes. Antagonist drugs were administered at 25 minutes. KBM was antagonised using atipamezole (7.5 mg mg-1 medetomidine dose) and naltrexone (2 mg mg-1 butorphanol dose). EA was antagonized using naltrexone (20 mg mg-1 etorphine dose). Induction and recovery (following antagonist administration) times were recorded. Physiological parameters, including invasive blood pressure and blood gas analysis, were compared between combinations using a general linear mixed model. Data are reported as mean ± standard deviation or median (interquartile range). RESULTS: The doses of KBM and EA administered were 3.30 ± 0.18, 0.40 ± 0.02 and 0.16 ± 0.01 mg kg-1; and 0.02 ± 0.001 and 0.20 ± 0.01 mg kg-1, respectively. KBM and EA induction times were 420 (282-564) and 240 (204-294) seconds, respectively (p = 0.03). Zebras remained recumbent throughout the study procedures. Systolic blood pressure (226 ± 42 and 167 ± 42 mmHg) and oxygen partial pressure (64 ± 12 and 47 ± 13 mmHg) were higher for KBM compared to EA (p < 0.01). Recovery time, after administering antagonists, was 92 (34-1337) and 26 (22-32) seconds for KBM and EA, respectively (p = 0.03). CONCLUSIONS AND CLINICAL RELEVANCE: Compared to EA, KBM also immobilized zebras effectively. Systemic hypertension and moderate hypoxaemia are clinical concerns of KBM and severe hypoxaemia is a concern of EA. This occurrence of hypoxaemia highlights the importance of oxygen administration during immobilization.

Tremors in white rhinoceroses (Ceratotherium simum) during etorphine-azaperone immobilisation.

Little is known about the mechanisms causing tremors during immobilisation of rhinoceros and whether cardiorespiratory supportive interventions alter their intensity. Therefore, we set out to determine the possible mechanisms that lead to muscle tremors and ascertain whether cardiorespiratory supportive interventions affect tremor intensity. We studied tremors and physiological responses during etorphine-azaperone immobilisation in eight boma-held and 14 free-living white rhinoceroses. Repeated measures analysis of variance and a Friedman test were used to determine differences in variables over time and between interventions. Spearman and Pearson correlations were used to test for associations between variables. Tremor intensity measured objectively by activity loggers correlated well (p < 0.0001; r2 = 0.9) with visual observations. Tremor intensity was greatest when animals were severely hypoxaemic and acidaemic. Tremor intensity correlated strongly and negatively with partial pressure of oxygen (PaO2 ) (p = 0.0003; r2 = 0.9995) and potential of hydrogen (pH) (p = 0.02, r2 = 0.97). It correlated strongly and positively with adrenaline concentrations (p = 0.003; r2 = 0.96), and adrenaline correlated strongly and negatively with PaO2 (p = 0.03; r2 = 0.95) and pH (p = 0.03; r2 = 0.94). Therefore, hypoxaemia and acidaemia were likely associated with the intensity of tremors through their activation of the release of tremorgenic levels of adrenaline. Tremors can be reduced if circulating adrenaline is reduced, and this can be achieved by the administration of butorphanol plus oxygen insufflation. Furthermore, to assist with reducing the risks associated with rhinoceros immobilisation, tremor intensity could be used as a clinical indicator of respiratory and metabolic compromise.

Severe Hypoxemia in Muskoxen ( Ovibos moschatus ) Immobilized with Etorphine and Xylazine Corrected with Supplemental Nasal Oxygen.

Twenty-three muskoxen ( Ovibos moschatus ) housed in a captive facility for rewilding in Sweden were chemically immobilized for annual health evaluations and hoof trimming. The muskoxen were darted in May to September (2012-15) in their holding pen with etorphine (0.015 mg/kg) and xylazine (0.1 mg/kg) intramuscularly. Twenty-two of the 23 animals were immobilized with a single dart injection. The mean (SD) induction time was 4 (2) min. Arterial blood gases were collected from 18 animals. All animals were severely hypoxemic with varying degrees of respiratory acidosis. The hypoxemia resolved in 17 of 18 animals with intranasal oxygen supplementation at 1 L/min per 100 kg. Relative arterial oxygen saturation (SpO2) measured by pulse oximetry was significantly higher than the arterial oxygen saturation calculated from the partial pressure of arterial oxygen (SaO2) obtained by a blood gas analyzer. Based on these findings, muskox can be immobilized successfully with etorphine (0.015 mg/kg) and xylazine (0.1 mg/kg) but should receive supplemental oxygen.

Butorphanol with oxygen insufflation improves cardiorespiratory function in field-immobilised white rhinoceros (Ceratotherium simum).

Opioid-induced immobilisation results in severe respiratory compromise in the white rhinoceros (Ceratotherium simum). The effectiveness of oxygen insufflation combined with butorphanol in alleviating respiratory depression in free-ranging chemically immobilised white rhinoceroses was investigated. In this prospective intervention study 14 free-ranging white rhinoceroses were immobilised with a combination of etorphine, azaperone and hyaluronidase. Six minutes (min) after the animals became recumbent, intravenous butorphanol was administered and oxygen insufflation was initiated. Previous boma trial results were used for comparison, using repeated measures two-way analysis of variance. The initial immobilisation-induced hypoxaemia in free-ranging rhinoceroses (arterial partial pressure of oxygen [PaO2] 35.4 mmHg ± 6.6 mmHg) was similar to that observed in boma-confined rhinoceroses (PaO2 31 mmHg ± 6 mmHg, n = 8). Although the initial hypercapnia (PaCO2 63.0 mmHg ± 7.5 mmHg) was not as severe as that in animals in the boma trial (79 mmHg ± 7 mmHg), the field-immobilised rhinoceroses were more acidaemic (pH 7.10 ± 0.14) at the beginning of the immobilisation compared with boma-immobilised rhinoceroses (pH 7.28 ± 0.04). Compared with pre-intervention values, butorphanol with oxygen insufflation improved the PaO2 (81.2 mmHg ± 23.7 mmHg, p < 0.001, 5 min vs 20 min), arterial partial pressure of carbon dioxide (55.3 mmHg ± 5.2 mmHg, p < 0.01, 5 min vs 20 min), pH (7.17 ± 0.11, p < 0.001, 5 min vs 20 min), heart rate (78 breaths/min ± 20 breaths/min, p < 0.001, 5 min vs 20 min) and mean arterial blood pressure (105 mmHg ± 14 mmHg, p < 0.01, 5 min vs 20 min). Oxygen insufflation combined with a single intravenous dose of butorphanol improved oxygenation and reduced hypercapnia and acidaemia in immobilised free-ranging white rhinoceroses.

Hypoxia following etorphine administration in goats (Capra hircus) results more from pulmonary hypertension than from hypoventilation.

BACKGROUND: Etorphine, a potent opioid agonist, causes pulmonary hypertension and respiratory depression. Whether etorphine-induced pulmonary hypertension negatively influences pulmonary gas exchange and exacerbates the effects of ventilator depression and the resultant hypoxemia is unknown. To determine if these effects occurred we instrumented twelve goats with peripheral and pulmonary arterial catheters to measure systemic and pulmonary pressures before and after etorphine administration. Concurrent cardiopulmonary and arterial blood gas variables were also measured. RESULTS: Etorphine induced hypoventilation (55% reduction to 7.6 ± 2.7 L.min(-1), F(11,44) = 15.2 P < 0.0001), hypoxia (<45 mmHg, F(11,44) = 8.6 P < 0.0001), hypercapnia (>40 mmHg, F(11,44) = 5.6 P < 0.0001) and pulmonary hypertension (mean 23 ± 6 mmHg, F(11,44) = 8.2 P < 0.0001). Within 6 min of etorphine administration hypoxia was twice (F(11,22) = 3.0 P < 0.05) as poor than that expected from etorphine-induced hypoventilation alone. This disparity appeared to result from a decrease in the movement of oxygen (gas exchange) across the alveoli membrane, as revealed by an increase in the P(A-a)O2 gradient (F(11,44) = 7.9 P < 0.0001). The P(A-a)O2 gradient was not correlated with global changes in the ventilation perfusion ratio (P = 0.28) but was correlated positively with the mean pulmonary artery pressure (P = 0.017, r(2) = 0.97), indicating that pulmonary pressure played a significant role in altering pulmonary gas exchange. CONCLUSION: Attempts to alleviate etorphine-induced hypoxia therefore should focus not only on reversing the opioid-induced respiratory depression, but also on improving gas exchange by preventing etorphine-induced pulmonary hypertension.

Butorphanol with oxygen insufflation corrects etorphine-induced hypoxaemia in chemically immobilized white rhinoceros (Ceratotherium simum).

BACKGROUND: Opioid-induced immobilization is associated with severe respiratory depression in the white rhinoceros. We evaluated the efficacy of butorphanol and oxygen insufflation in alleviating opioid-induced respiratory depression in eight boma-managed rhinoceros. RESULTS: Chemical immobilization with etorphine, azaperone and hyaluronidase, as per standard procedure for the white rhinoceros, caused severe respiratory depression with hypoxaemia (PaO2 = 27 ± 7 mmHg [mean ± SD]), hypercapnia (PaCO2 = 82 ± 6 mmHg) and acidosis (pH =7.26 ± 0.02) in the control trial at 5 min. Compared to pre-intervention values, butorphanol administration (without oxygen) improved the PaO2 (60 ± 3 mmHg, F (3,21) =151.9, p < 0.001), PaCO2 (67 ± 4 mmHg, F (3,21) =22.57, p < 0.001) and pH (7.31 ± 0.06, F (3,21) = 27.60, p < 0.001), while oxygen insufflation alone exacerbated the hypercapnia (123 ± 20 mmHg, F (3,21) = 50.13, p < 0.001) and acidosis (7.12 ± 0.07, F (3,21) = 110.6, p < 0.001). Surprisingly, butorphanol combined with oxygen fully corrected the opioid-induced hypoxaemia (PaO2 = 155 ± 53 mmHg) and reduced the hypercapnia over the whole immobilization period (p <0.05, areas under the curves) compared to the control trial. However, this intervention (butorphanol + oxygen) did not have any effect on the arterial pH. CONCLUSIONS: Oxygen insufflation combined with a single intravenous dose of butorphanol improved the immobilization quality of boma-managed white rhinoceros by correcting the opioid-induced hypoxaemia, but did not completely reverse all components of respiratory depression. The efficacy of this intervention in reducing respiratory depression in field-captured animals remains to be determined.

TH-030418: a potent long-acting opioid analgesic with low dependence liability.

Numerous efforts have been made on the chemical modification of opioid compounds, with the ultimate goal of developing new opioid analgesics that is highly potent and low/non-addictive. In a search for such compounds, TH-030418 [7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydrooripavine] was synthesized. Here, we evaluated the pharmacological activities of TH-030418, in comparison with morphine, the prototype opioid analgesic. In radioligand binding assays, TH-030418 bound potently and nonselectively to µ-, δ-, κ-, and ORL1 (opioid receptor-like 1) receptors stably expressed in CHO (Chinese hamster ovary) cells with K (i) values of 0.56, 0.73, 0.60, and 1.55 nM, respectively. When administered subcutaneously, TH-030418 was much more potent than morphine in analgesia, with the ED(50) values of 1.37 µg/kg and 1.70 µg/kg in hot plate and acetic acid writhing tests, respectively. The opioid antagonist naloxone blocked the antinociceptive effect of TH-030418, indicating that the action of TH-030418 was mediated by opioid receptors. The antinociceptive effect of s.c. TH-030418 in hot plate test lasted for more than 12 h, which is much longer than those of morphine (2.5 h) and dihydroetorphine (1.5 h). In addition, naloxone did not precipitate withdrawal syndrome in the mice treated with TH-030418 previously. Most importantly, TH-030418 did not induce conditioned place preference in mice after chronic treatment. These results indicate that TH-030418 is a potent long-acting opioid analgesic with low dependence liability and may be of some value in the development of new analgesics.

Effects of serotonin agonists and doxapram on respiratory depression and hypoxemia in etorphine-immobilized impala (Aepyceros melampus).

Respiratory depression is a common side effect when opioids are used to immobilize wildlife. Serotonergic ligands have the potential to reverse opioid-induced respiratory depression. We examined whether any of three serotonergic ligands could reverse this depression in etorphine-immobilized (0.07 mg/kg) impala (Aepyceros melampus). The study took place in September-December 2007. Impala received intravenous injections of metoclopramide (10 mg/kg, n=6), buspirone (0.05 mg/kg, n=8), pimozide (1 mg/kg, n=8), doxapram (1 mg/kg, n=6), and control solutions on separate occasions. During the immobilization, partial pressures of oxygen (PaO(2), mmHg) and carbon dioxide (PaCO(2), mmHg), respiratory rate (breaths/min), ventilation (l/min), peripheral O(2) saturation (%), tidal volume (l), and respiratory exchange ratio were measured before and after injection of the experimental drugs. Etorphine immobilization caused respiratory depression and hypoxia (mean+/-SD, PaCO(2)=51+/-2 mmHg, PaO(2)=40+/-3 mmHg). Metoclopramide and buspirone, but not pimozide, attenuated the hypoxic effects of etorphine; 3 min after injection, metoclopramide increased the PaO(2) by 7.5+/-6.3 mmHg and buspirone by 6+/-6.6 mmHg (F=3.9, P=0.02). These effects were similar to those of doxapram (8+/-7 mmHg, F=3.9; P>0.05). Neither metoclopramide nor buspirone significantly increased ventilation, but they increased PaO(2) by significantly improving the alveolar-arterial oxygen partial pressure gradient (A-a gradient, F=1.4, P<0.05), indicating improved oxygen diffusion. Metoclopramide and buspirone transiently improved blood oxygenation of opioid-immobilized impala, probably by improving ventilation-perfusion ratios, without reversing catatonic immobilization.

Acid-base balance and ventilation during sternal and lateral recumbency in field immobilized black rhinoceros (Diceros bicornis) receiving oxygen insufflation: a preliminary report.

Posture, ventilation, and acid-base balance using auricular venous blood values (pH, lactate, base excess [BE], HCO(3)(-), PO(2), SO(2), and PCO(2)), oxygen saturation of hemoglobin (SpO(2)), and end-tidal carbon dioxide (P(ET)CO(2)) were compared between sternal (STE) and lateral (LAT) recumbency in free-ranging black rhinoceros (Diceros bicornis bicornis) receiving oxygen insufflation. Data are reported as median, minimum, and maximum (median [minimum, maximum]). Thirty-six desert-adapted black rhinoceros (20 male, 16 female; age 8 [1.5, 33] yr) were immobilized in Namibia in March and April of 2008, from a helicopter, by remote intramuscular injection with etorphine HCl, azaperone, and hyaluronidase. Time from darting to recumbency was 6.0 (3, 15.5) min. Data were organized into two sampling periods: sample period 1 (P1, collected within 0-20 min postdarting; 13 [6.5, 19] min) and sample period 2 (P2, collected between 20-40 min postdarting; 32 [22.3, 39] min). All animals were acidemic (pH 7.24 [7.07, 7.32]) and hypoxemic (PO(2) 51 [38, 95.2]; SO(2) 78 [64, 96] mmHg) after capture. Lactate at P1 was 7.2 (3.2, 16.8) mmol/l and decreased (P=0.01) to 4.6 (1.2, 10.9) mmol/l at P2. At P2, lactate was less (P=0.06) in LAT 3.5 (1.2, 8.6) mmol/l than in STE posture 7.4 (3.1, 10.9) mmol/l. In P2, PO(2), SO(2), and SpO(2) were higher (P=0.02, 0.10, and 0.01, respectively) in STE than in LAT. End-tidal carbon dioxide in LAT was 38 (26, 47) mmHg and increased (P<0.001) rapidly to 48 (37, 55) mmHg when animals were moved into STE; no corresponding change in PCO(2) was observed. These preliminary findings suggest that STE posture in recumbent black rhinoceros reduces dead-space ventilation and improves oxygenation. Lateral posture was associated with lower blood lactate, quicker lactate recovery, or both. It is possible that the posture of recumbent rhinoceros after capture affects lactate accumulation and clearance, or both, and procedures should consider positioning in order to enhance perfusion.

Overdose during chemical restraint in a black rhinoceros (Diceros bicornis).

A juvenile female black rhinoceros (Diceros bicornis) was successfully treated after overdose of drugs used for chemical restraint. Subsequent general anaesthesia for surgical reduction of a recurrent rectal prolapse was uneventful. Over a 25-minute period before transportation to the veterinary hospital, the animal received a total dose of 1.225 mg etorphine, 30 mg acepromazine and 30 mg detomidine. Based on an estimated mass of 200 kg, these corresponded to doses of 6.1 microg kg(-1) etorphine, 150 microg kg(-1) acepromazine, and 150 microg kg(-1) detomidine which constitutes considerable overdose for each drug given separately, notwithstanding the synergy that probably resulted when the three drugs were present concurrently. The estimated body mass may have substantially overestimated the actual body mass and exacerbated overdosage. The animal was recumbent and apnoeic on arrival at the hospital. Heart sounds were auscultated and a weak peripheral pulse was palpated; no pulse deficits were detected, although the heart rate was low. The trachea was intubated, inspired breath was enriched with oxygen and the lungs ventilated manually. Diprenorphine (1.5 mg) was given intravenously and spontaneous breathing resumed 11 minutes later. After induction of general anaesthesia using isoflurane, emergency surgery for correction of rectal prolapse was performed, from which the animal recovered uneventfully. The case highlights some of the practical problems that may be encountered in dealing with dangerous and unfamiliar species.

Severe hypoxaemia in field-anaesthetised white rhinoceros (Ceratotherium simum) and effects of using tracheal insufflation of oxygen.

White rhinoceros anaesthetised with etorphine and azaperone combination develop adverse physiological changes including hypoxia, hypercapnia, acidosis, tachycardia and hypertension. These changes are more marked in field-anaesthetised rhinoceros. This study was designed to develop a technique to improve safety for field-anaesthetised white rhinoceros by tracheal intubation and oxygen insufflation. Twenty-five free-ranging white rhinoceros were anaesthetised with an etorphine and azaperone combination for translocation or placing microchips in their horns. Once anaesthetised the rhinoceros were monitored prior to crating for transportation or during microchip placement. Physiological measurements included heart and respiratory rate, blood pressure and arterial blood gas samples. Eighteen rhinoceros were intubated using an equine nasogastric tube passed nasally into the trachea and monitored before and after tracheal insufflation with oxygen. Seven rhinoceros were not intubated or insufflated with oxygen and served as controls. All anaesthetised rhinoceros were initially hypoxaemic (percentage arterial haemoglobin oxygen saturation (%O2Sa) = 49% +/- 16 (mean +/- SD) and PaO2 = 4.666 +/- 1.200 kPa (35 +/- 9 mm Hg)), hypercapnic (PaCO2 = 8.265 +/- 1.600 kPa (62 +/- 12 mm Hg)) and acidaemic (pHa = 7.171 +/- 0.073 ). Base excess was -6.7 +/- 3.9 mmol/l, indicating a mild to moderate metabolic acidosis. The rhinoceros were also hypertensive (systolic blood pressure = 21.861 +/- 5.465 kPa (164 +/- 41 mm Hg)) and tachycardic (HR = 107 +/- 31/min). Following nasal tracheal intubation and insufflation, the %O2Sa and PaO2 increased while blood pHa and PaCO2 remained unchanged. Tracheal intubation via the nose is not difficult, and when oxygen is insufflated, the PaO2 and the %O2Sa increases, markedly improving the safety of anaesthesia, but this technique does not correct the hypercapnoea or acidosis. After regaining their feet following reversal of the anaesthesia, the animals' blood gas values return towards normality.

Dihydroetorphine: physical dependence and stereotypy after continuous infusion in the rat.

In a previous study in this laboratory, exposure of rhesus monkeys to intermittent, high doses of dihydroetorphine for 42 days did not evoke behavioral signs of physical dependence on this opioid either after it was abruptly withdrawn or after challenge with a high dose of naloxone. To investigate further the physical dependence capacity of this opioid, it was given by infusion to rats thereby exposing receptors chronically and continuously to this opioid. Abstinence expressed as body weight loss, irritability, and wet-dog shakes was observed after abrupt withdrawal of the low-dose regimen (5,10, 40 and 40 microg/kg per day for 4 days, respectively). The high-dose regimen (10, 20 and 80 microg/kg per day for 3 days, respectively) produced stereotypy and physical dependence. Although many reported molecular events and dependence studies suggest otherwise, dihydroetorphine's propensity to produce physical dependence, an important determinant of opioid abuse, is real.

[Clinical assessment of physical dependence potential of dihydroetorphine hydrochloride (DHE)].

This paper reports the DHE substitution clinical trial in 38 heroin addicts. The CINA (Clinical Institute Narcotic Assessment) scale was used to assess physical dependence potential. The CINA scale contains 10 opioid withdrawal signs (nausea, vomiting, gooseflesh, sweating, restlessness, tremor, larcrimation, nasal congestion, yawning, changes in heart rate and systolic blood pressure) and 3 opiate withdrawal symptoms (abdominal pain, muscle pain and feeling hot or cold). For each subject admitted to the Drug Detoxification and Treatment Center his (her) status on each of the 13 items of CINA were immediately rated. Then, naloxone 0.4 mg was injected iv to precipitate withdrawal symptoms and at 5, 10, 15 min after the naloxone injection, the CINA score of each patient was rated again. The differences among the scores of pre- and post-naloxone injection is a measurement of the degree of withdrawal symptoms. Then, a single dose of DHE was administered sublingually to each patient, all withdrawal symptoms disappeared. These results show that DHE can compete with naloxone for opioid receptors. A good dose-response relationship was found between the 100% suppressive withdrawal sign doses of DHE and the degree of withdrawal sign in heroin addicts. The physical dependence potential of DHE given to heroin addicts sublingually was probably more than that of methadone given to heroin addicts orally by making reference to the report of Dr. Peachy.

The use of etorphine/methotrimeprazine and midazolam as an anaesthetic technique in laboratory rats and mice.

The results of a preliminary evaluation of etorphine/methotrimeprazine ('Small Animal Immobilon') and midazolam in rats and mice are reported, and this regimen is compared to fentanyl/fluanisone/midazolam in mice. In rats, a surgical plane of anaesthesia with good muscle relaxation was produced, but blood gas analysis showed the presence of severe hypoxia, hypercapnia and acidosis. In mice etorphine/methotrimeprazine/midazolam and fentanyl/fluanisone/midazolam produced adequate anaesthesia, but blood gas analysis showed severe respiratory depression with both regimens. Since etorphine/methotrimeprazine/midazolam produced severe respiratory depression in rats and mice it is suggested that this regimen is used with caution. Administration of supplemental oxygen would seem advisable when using either etorphine/methotrimeprazine/midazolam or fentanyl/fluanisone/midazolam in rats and mice.