A Single Dose of Intrathecal Morphine Without Local Anesthetic Provides Long-Lasting Postoperative Analgesia After Radical Prostatectomy and Nephrectomy.

PURPOSE: Pain after open urological procedures is often intense. The aim of the study was to compare the efficacy of intrathecal morphine with systemic analgesia approaches. DESIGN: Prospective, randomized, single-blind controlled study. METHODS: Patients undergoing open prostatectomy or nephrectomy were randomly divided into the intervention group or the control group. Patients in the intervention group received morphine 250 mcg in 2.5 mL saline intrathecally. Anesthesia was identical in both groups. All patients were admitted to the intensive care unit (ICU) postoperative and received paracetamol 1 g intravenously every 6 hours and diclofenac 75 mg intramuscularly every 12 hours. If postoperative pain exceeded four on the numeric rating scale, morphine 10 mg was administered subcutaneously. Pain intensity, time to first dose of morphine, morphine doses, and side effects were recorded. FINDINGS: In total, 41 patients were assigned to the intervention group and 57 to the control group. The time to administration of the first dose of morphine was significantly (P < .001) longer in the intervention group when compared to controls. This observation was also noted individually for patients undergoing nephrectomy (36.86 hours vs 4.06 hours) and prostatectomy (33.13 hours vs 4.5 hours). Many patients did not need opioids after surgery in the intervention group (nephrectomy 72% vs 3%, prostatectomy 75% vs 4.5%, P < .001). There was no significant difference in the incidence of side effects. CONCLUSIONS: The results of our study confirmed that preoperative intrathecal morphine provides long-lasting analgesia and reduces the need for postoperative systemic administration of opioids. Adverse effects are minor and comparable between groups.

Endogenous ligands of benzodiazepine binding site have inverse agonistic properties.

Benzodiazepines have been widely used in clinical praxis for many decades. They act as GABAA receptor agonists and possess muscle-relaxant, hypnotic-sedative, anticonvulsant, and anxiolytic properties. Flumazenil acts as a benzodiazepine receptor antagonist (subunits α1, α2, α3, and α5) or partial agonist (subunits α4 and α6). It competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepines. In our experiments, administration of flumazenil in rabbits was surprisingly associated with anxiolytic effects similar to those of midazolam. Additionally, flumazenil significantly and dose-dependently decreased the total number of vocalizations in rats, i.e. it was anxiolytic. These observations seem to be in contrast to the effect of flumazenil in humans, where it is believed to produce mainly anxiogenic effects. It seems that in individuals, who exhibit anxiogenic behavior or in individuals with anticipation anxiety, flumazenil acts as an anxiolytic agent, while in individuals without any signs of anxiety, flumazenil can also act as anxiogenic agent. Thus, we hypothesize that flumazenil is associated with decreased intensity of anticipatory anxiety due to occupancy of benzodiazepine binding sites by an endogenous ligand with inverse agonistic properties.

Determination of midazolam in rabbit plasma by GC and LC following nasal and ocular administration.

GC with nitrogen phosphorus detection and HPLC with UV detection were used to determine midazolam (MDZ) levels in rabbit plasma following ocular and nasal administration. For GC with nitrogen phosphorus detection, the analyte was extracted from the plasma using a three-step liquid-liquid extraction including extraction with an isopropanol/butyl chloride mixture in an alkaline solution, followed by extractions with 1 M HCl, and finally with an alkaline solution of butyl chloride. The recovery of MDZ was dependent on the sample alkalization time prior to the final extraction. The procedure increased the recovery of MDZ up to 99.6%. Improved sample preparation led to a significant increase in the sensitivity of the determination by GC with nitrogen phosphorus detection. The achieved detection limit was 0.34 ng/mL, which is ten times lower than that obtained using HPLC with UV detection. The small plasma volume was another advantage of the GC with nitrogen phosphorus detection method (200 µL per assay). Both administration routes of the anesthetic (nasal and ocular) resulted in comparable plasma MDZ levels. Kinetic simulation of the MDZ plasma was performed for both administration routes.

The influence of clonidine on oral ketamine-midazolam premedication in intellectually disabled patients indicated for dental procedures: double-blind comparison of two sedation regimes.

BACKGROUND: Dental procedures on intellectually disabled patients represent a clinical challenge. The oral administration of sedating drugs can remediate the problems with cooperation and enable the medical procedures to take place. Standard guidelines are lacking for oral sedation of the intellectually disabled. OBJECTIVE: To compare two oral combinations of sedating drugs in terms of time to the onset and achievement of full sedation, vital signs, behavioral measures and safety. METHODS: In a group of 29 intellectually disabled patients we compared two oral combinations for analgosedation: ketamine (5 mg/kg) - clonidine 2 µg/kg - midazolam 0.3 mg/kg (N=17) or ketamine 5 mg/kg - midazolam 0.3 mg/kg (N= 12 patients). Drugs were dissolved in a sweet drink. RESULTS: Full sedation was achieved within 25 min. in 27 patients and serious side effects were not detected. Clonidine in combination with ketamine and midazolam did not exert any significant effect by means of the onset of sedation, time to the achievement of full sedation, vital signs and behavioral measures of sedation (Vancouver Interaction and Calmness Scale) and agitation (Pittsburgh Agitation Scale). CONCLUSIONS: Our study is the first to document that oral administration of ketamine and midazolam in low doses represents a safe and effective method of premedication in intellectually disabled patients indicated for dental procedures. Clonidine co-administration did not exert any substantial benefit and should be left out in this clinical setting.

Short term pharmacological immobilization in macaque monkeys.

OBJECTIVE: To develop a safe and effective immobilization protocol in rhesus monkeys, which is not based on dissociative anaesthetic agent. STUDY DESIGN: Prospective, randomised, experimental trial. ANIMALS: Twenty rhesus monkeys, weighing 2.6-8.0 kg, 1-3 years of age, of both sexes. METHODS: The monkeys received 50 µg kg(-1) medetomidine, 0.25 mg kg(-1) midazolam and 5 µg kg(-1) fentanyl with 150 IU hyaluronidase intramuscularly (IM). The animals were closely observed for behavioural changes and reaction to sound stimulus. Pulse rate and oxygen saturation of haemoglobin (SpO(2) ) were monitored every 5 minutes, for 20 minutes. After this period, 250 µg kg(-1) atipamezole or a placebo was administered IM and behavioural changes were closely observed. RESULTS: Full immobilization was observed after mean 269 ± SD 116 seconds. Ten minutes after injection mean arterial oxygen saturation of haemoglobin was 94 ± 4%, but did not fall significantly further. The median pulse rate was 116 beats minute(-1) 5 minutes after the administration of the drug. This level further decreased to a median level of 108 beats minute(-1) 20 minutes after the drug's administration. The median time to recover from immobilization was significantly shorter after atipamezole administration when compared to placebo (2.7 versus 55 minutes). All animals awoke smoothly and no side effects such as vomiting or agitation were observed. CONCLUSIONS: Short term and reversible pharmacological immobilization was achieved using combination of midazolam, medetomidine, and fentanyl. CLINICAL RELEVANCE: The present study demonstrates that 20-minute pharmacological immobilization with a combination of midazolam, medetomidine, and fentanyl is feasible in rhesus monkeys with minimal effect on heart rate.

The effect of the novel partial alpha2-adrenoceptor agonist naphthylmedetomidine on the basic cardiorespiratory parameters and behavior in rhesus monkeys.

BACKGROUND: The aim of this study was to compare cardiorespiratory and behavioral profile of a new alpha 2-adrenoceptor ligand naphthylmedetomidine with medetomidine in rhesus monkeys. METHODS: Naphthylmedetomidine or medetomidine (50 microg/kg) together with ketamine (3 mg/kg) and hyaluronidase (150 IU/kg) i.m was administered to 35 rhesus monkeys. Behavioral changes were then observed together with blood pressure, heart rate and oxygen saturation of hemoglobin. RESULTS: The onset of sedation, ataxia, and reduction of aggression was similar in both treatment groups. Immobilization was observed only in medetomidine treated animals, while in naphthylmedetomidine treated animals loss of aggressiveness was observed but the animals never completely lost mobility. Naphthylmedetomidine showed less prominent effects on cardiorespiratory functions compared with medetomidine. CONCLUSIONS: Our results suggest that naphthylmedetomidine can be used to induce sedation in primates and other small animals while avoiding the serious side effects observed after administration of the currently used full alpha(2)-AR agonists.

The effect of the novel alpha-2-adrenoceptor agonist naphthylmedetomidine on pulse rate, arterial blood pressure and sedation in rabbits.

OBJECTIVE: The aim of this study was to investigate the effect of a novel alpha-2-adrenoceptor (alpha(2)-AR) agonist, naphthylmedetomidine, on cardiorespiratory function and sedation in rabbits in comparison with medetomidine. STUDY DESIGN: Prospective, randomized, experimental trial. ANIMALS: Forty-two chinchilla rabbits of both sexes, weighing 2.5-4.5 kg. METHODS: The rabbits received 350 microg kg(-1) naphthylmedetomidine (n = 21) or medetomidine (n = 21) intramuscularly according to a randomization scheme. Arterial blood pressure (AP), oxygen saturation of haemoglobin (SpO(2)), pulse rate (PR) and righting reflex were monitored for 20 minutes after injection. RESULTS: Both drugs significantly decreased PR. The effect of medetomidine was significantly greater than that of naphthylmedetomidine and was evident within 1 minute. The decrease in PR after naphthylmedetomidine administration first appeared after 4 minutes. Medetomidine decreased the SpO(2) after 3 minutes but there was no effect after naphthylmedetomidine. Medetomidine decreased the mean, systolic and diastolic AP within 5 minutes of administration but naphthylmedetomidine had no effect. The mean time to loss of righting reflex was 185 and 714 seconds after the administration of medetomidine and naphthylmedetomidine respectively. CONCLUSIONS AND CLINICAL RELEVANCE: These results provide the first description of the effects of naphthylmedetomidine on cardiovascular and psychomotor functions in rabbits. Further work is required to reveal the anaesthetic sparing, analgesic or sedative effect of partial naphthylmedetomidine.

Selective antiaggressive effect of an alpha-2 adrenoceptor agonist naphthylmedetomidine in mice.

Alpha-2 adrenoceptors (alpha(2)-ARs) are critically involved in regulating neurotransmitter release from sympathetic nerves and neurons and play an important role in the regulation of awareness, arousal and vigilance. In our recent study, dexmedetomidine, a full alpha(2)-AR agonist, produced antiaggressive effects in the social conflict test in mice at doses that were twice smaller than those producing sedation. The aim of this study was to ascertain antiaggressive effect of a novel drug naphthylmedetomidine, with a more selective alpha(2)-AR activity. Behavioral effects of naphthylmedetomidine (150-1200 microg/kg i.p.) were studied in the activity cage and in the social conflict tests in mice. Naphthylmedetomidine dose dependently decreased aggressive behavior during social conflict in aggressive mice with significant reduction already at the lowest doses tested (150 microg/kg), whereas locomotion and social investigation were significantly decreased only after four times bigger dose of naphthylmedetomidine (600 microg/kg) in aggressive mice. Naphthylmedetomidine had no effect on aggression in nonaggressive mice. Naphthylmedetomidine reduced locomotion in the activity cage significantly only at the highest doses tested (600 and 1200 microg/kg), and this effect was only partially reversed by administration of high doses of an alpha-2 antagonist atipamezole (3 and 10 mg/kg). In nonaggressive mice, the difference between the dose reducing dominant social behavior (social investigation) and locomotion (150 and 300 microg/kg, respectively) was smaller than in aggressive mice. In conclusion, naphthylmedetomidine showed a very strong and selective antiaggressive effect in aggressive mice, which was devoid of locomotion-inhibiting/sedative effect. This study suggests that naphthylmedetomidine may have clinical potential as antiaggressive drug.

Dexmedetomidine selectively suppresses dominant behaviour in aggressive and sociable mice.

Dexmedetomidine is a highly specific alpha2-adrenoreceptor agonist, which is now clinically used to induce sedation in patients in the intensive care units. Behavioural effects of dexmedetomidine have been little studied so far. The drug was reported to reduce behaviour such as locomotion or measures of anxiety or aggression in animals. The aim of the present study was to ascertain whether dexmedetomidine inhibits behaviour uniformly or with respect to particular stimuli or situations. Therefore, behavioural effects of dexmedetomidine were studied in the social conflict test in male mice (after three weeks of individual housing), which provides a wide spectrum of behavioural activities in two types of animals (aggressive and sociable mice) as well as in the activity cage. Dexmedetomidine (5-40 microg/kg i.p.) decreased locomotion in the activity cage and this effect was fully antagonized by atipamezole, a selective alpha2-adrenereceptor antagonist. However, dexmedetomidine did not reduce locomotion during social conflict. The only significant effects during social conflict were a selective and dose-dependent antiaggressive effect in aggressive mice and a selective reduction of social investigation ('sociability') in sociable mice. Thus, dexmedetomidine appears to inhibit predominantly dominant behaviour evoked by biologically important stimuli. The ability of dexmedetomidine to reduce aggression might be utilized for treatment of aggressive states. Sedation caused by dexmedetomidine can be easily disrupted and thus the drug may have an advantage over benzodiazepines or neuroleptics, which are used in this indication.