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The pharmacokinetics of a fixed dose of midazolam (0.3 mg kg-1 i.v.) were studied in detail in 115 healthy patients or volunteers and nine were found with a prolonged elimination half-life. A further 102 patients had an abbreviated pharmacokinetic study, of whom five showed a similar abnormality. Defective hepatic metabolism of midazolam may be a factor in the aetiology of what appears to be a true phenomenon, occurring in 6% of over 200 fit subjects given a standard dose of the drug. [ABSTRACT FROM AUTHOR]

1 The effect of intravenous cimetidine 200 mg or 400 mg on the absorption of lorazepam 2.5 mg tablet and diazepam 10 mg tablet and capsule was studied. 2 Considerable individual variation in plasma concentrations was found with all preparations. 3 Cimetidine increased the absorption of diazepam and lorazepam. 4 Capsule preparations of diazepam generally produced higher drug plasma concentrations than the tablets. [ABSTRACT FROM AUTHOR]

1 Mild analgesics pose particular problems in evaluation because of difficulty in getting suitable patients, the frequent use of oral administration and their long-term use. 2 Despite their limitations it is possible to quantify both pain severity and pain relief using either 'pain scores' or 'visual analogues'. 3 A trained observer can add information in addition to the patient's interpretation of pain. 4 There are particular problems using crossover studies with analgesics and the sequential method of evaluating results is not as useful with mild analgesics as with more potent drugs. 5 Opinions differ as to the importance of dummy medication in the study of analgesic drugs; difficulties may arise from ethical as well as practical reasons. 6 In the overall evaluation of mild analgesics it is important to consider their long term side effects. 7 Access to a large number of patients with a constant pain of 6-8 h duration and a smaller number with long- term pain is the most important prerequisite in the evaluation of mild analgesic drugs. [ABSTRACT FROM AUTHOR]

1 The ability of cyclizine (50 mg) and perphenazine (2.5 and 5.0 mg) to counteract the emetic effects of pethidine (100 mg) and morphine (10 and 15 mg) was compared in women undergoing a standard minor operation with a standard anaesthetic. 2 Perphenazine (5.0 mg) was as effective an anti-emetic as cyclizine (50 mg) and both were more effective than perphenazine (2.5 mg). 3 The reduction in vomiting and nausea by cyclizine (50 mg) and perphenazine (5 mg) was approximately the same following pethidine (100 mg) and morphine (10 mg) but much less against the larger dose of morphine. 4 Both anti-emetics had a rapid onset of action but their anti-emetic activity did not last as long as the emetic effect of morphine. 5 Perphenazine (5 mg) was accompanied by an unacceptably high incidence of restlessness. 6 In clinical practice cyclizine (50 mg) is preferred to perphenazine (5 mg) as an anti-emetic. [ABSTRACT FROM AUTHOR]

In a randomised crossover study in volunteers plasma midazolam levels were estimated for 24 h following 15 mg by mouth, either preceded by no medication or following 24 h therapy with ranitidine. Administration of the H2-receptor blocker significantly increased bioavailability of the benzodiazepine and resulted in higher plasma levels for the first 6 h after taking midazolam. This was accompanied by a greater soporific effect. [ABSTRACT FROM AUTHOR]

The incidence of postoperative illness was monitored for 6 hours in 74 women premedicated with nalbuphine, 10 mg, and undergoing short gynecologic operations of similar duration under methohexitalnitrous oxide-oxygen anesthesia. Each patient received P6 acupuncture for 5 minutes at the time of administration of premedication. In random order the site of the acupuncture had been previously infiltrated with normal saline solution in half of the patients and 1% lidocaine in the remaining patients. Postoperative emetic sequelae occurred significantly more often in those who received lidocaine compared with the group that received saline solution. This demonstrates the ability of a local anesthetic administered at the point of stimulation to block the antiemetic action of P6 acupuncture in a manner similar to that shown by others for analgesia.

The beneficial effects of transcutaneous electrical stimulation of the P6 antiemetic point (Neiguan) as an adjuvant to standard antiemetics was studied in over 100 patients in whom chemotherapy-induced sickness was not adequately controlled by antiemetics alone. Although the results were not quite as good as with invasive acupuncture, more than 75% patients achieved considerable benefit from what was a non-toxic procedure. The use of large diffuse low impedence electrodes simplifies the technique. The 2 hourly application of Sea Bands prolongs the antiemetic action. Best results were obtained from the 2 hourly self-administration of 5 min of transcutaneous electrical stimulation of P6 using a simple battery-operated TENS machine (15 Hz) to activate a large, easy-to-place surface electrode and increasing current until Qi is elicited.

Previous work from our department has shown that P6 acupuncture is an effective adjuvant to conventional antiemetic therapy for patients having cytotoxic drugs. However, its efficacy is limited to about 8 h. The current studies show that the application of an elasticized wrist band with a stud placed over the acupuncture point, and pressed regularly every 2 h, will prolong the antiemetic action for 24 h. This proved more effective in hospitalized patients (20/20) than in outpatients (15/20), presumably due to the encouragement given to regularly press the stud. Nausea and vomiting remain problems with cancer chemotherapy despite the use of antiemetics. Following encouraging results with P6 acupuncture (ACP) in postoperative sickness this has been shown to be effective in cancer chemotherapy in 105 patients who, despite the use of conventional antiemetics had been sick following the previous treatment. Electrical stimulation (10 Hz DC) of P6 point for 5 min before administration of the cytotoxic drugs was effective in preventing sickness in 66% and only 6% got no benefit. The ACP was given with the antiemetics which the patients had been receiving. Although there were no side effects with the ACP, the benefit only lasted 6-8 h. This was not important in hospitalized patients where the treatment could be repeated, but was a problem with outpatients. It has been shown that pressure on the P6 point (acupressure) has an antiemetic action. A commercially available elasticized band with a plastic stud (Sea Band) is an effective method of applying pressure to P6 point.(ABSTRACT TRUNCATED AT 250 WORDS)

In a strictly controlled clinical situation, (postoperative sickness) where variables were reduced to a minimum, it was possible to demonstrate an effective prophylactic antiemetic action of P6 (Neiguan) acupuncture. Manual and electrical invasive (needling) stimulation of this point were equally effective. Non-invasive stimulation (transcutaneous electrical or pressure) was effective in the early postoperative period, but the effect did not last as long as for invasive acupuncture--although it was as good as standard antiemetics. Stimulation of a "dummy" acupuncture point was ineffective as was administration of the acupuncture after the emetic stimulus (opioid). This effect can be blocked by local anaesthesia at the P6 point. Acupressure (P6) is moderately effective in reducing morning sickness, but here there is more of a psychological element as pressure on a "dummy" point gives some alleviation of symptoms. Given in conjunction with standard antiemetics, P6 acupuncture is a useful adjuvant in reducing sickness after cancer chemotherapy. This effect can be prolonged for 24 hours by acupressure.

Having seen pregnant women pressing the P6 point as a preventative for morning sickness, stimulation of this point for 5-10 minutes by invasive (manual or electrical acupuncture) or non-invasive (transcutaneous electrical stimulation or acupressure) means was studied as an antiemetic. In well controlled studies it was shown that acupuncture administered before the opioid premedication significantly reduced postoperative sickness for 6-8 hours. Non-invasive methods were effective for a shorter period of time, with nausea and/or vomiting often occurring after 2 hours. To be effective the treatment has to be given before the opioid. Its effect can be abolished by local anesthesia. Stimulation of a dummy point near the elbow is ineffective. While acupressure reduces morning sickness, the pressure has to be applied for 5 minutes every 2 hours. There is probably a large psychological element in this. The most rewarding results are obtained when P6 stimulation is used in conjunction with standard antiemetics before cancer chemotherapy. Here again the invasive approach is more effective than non-invasive. Recent studies have involved self-stimulation using a portable battery-operated square wave stimulator fixed at 10 Hz, and a large EKG surface electrode on the P6 point. Stimulation is applied for 5 minutes every two hours. While modern antiemetics can control vomiting, they are relatively ineffective against nausea, but this can be controlled by regular use of the stimulator. The results are most promising.

Details are reported of 41 incidents where women reported fantasies during sedation with IV midazolam or diazepam: 27 of them had some sexual element and 20 were unpleasant experiences. The events occurred in a logical sequence and all were certain of their authenticity. Some led to litigation against the sedationist. Out of 25 verified reports made by patients of incidents occurring during sedation, 17 did not happen and in 9/13 clear descriptions there was some relation between the fantasy and something that really happened under sedation. All occurred with what are now considered large doses of the drugs. During or following sedation lady patients should not be treated or examined without the presence of a responsible third person. The use of the injectable benzodiazepines, diazepam and more recently midazolam, with their sedative, amnesic and relaxing properties have made unpleasant operative procedures, particularly those usually carried out under local analgesia, more acceptable to many patients. These include oral endoscopy and dental procedures and operations under spinal or epidural analgesia. These drugs also provide good sedation during ventilatory support and in the intensive care unit. Over a long period of time these benzodiazepines have proven to be, in appropriate doses, among the safest in medicine for short term use. There have however been a few cases of what can be described as "fantasies" occurring during sedation: events occurring in a logical sequence which are very real to the patient and yet, on the evidence of two or more independent witnesses, did not occur. Many of these have had an element of sexual trespass.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect on heart rate of different rates of injection (10 seconds, 1, 3 and 5 minutes) of a fixed dose (neostigmine 2.5 mg and atropine 1.2 mg) and a weight-related dose (neostigmine 50 micrograms/kg and atropine 25 micrograms/kg) of neostigmine-atropine mixture given for the reversal of residual competitive neuromuscular block was studied in 196 healthy adult patients. In both series slow injection lessened and delayed the initial rise in heart rate. The subsequent fall in heart rate was less when the drugs were injected over 3 min compared with the 10 seconds and 1 minute injection groups but when given over 5 minutes there was a steady fall in heart rate, more so with the weight-related dose. It is recommended that a neostigmine and atropine mixture should be administered over 3 min.

Midazolam, a new water-soluble benzodiazepine, was investigated as an intravenous anaesthetic agent in 260 adult patients in doses ranging from 0.15 to 0.5 mg/kg using a variety of premedications. Its onset of action was generally slow, taking up to 3 minutes to exert its maximum effect. A wide variability in response was found in that some unpremedicated patients were satisfactorily anaesthetised with 0.15 mg/kg while other were only moderately sedated following doses of 0.5 mg/kg. Less variability was found in the elderly who also required smaller doses. Narcotic premedication potentiated the sedative effect of midazolam. Few respiratory or cardiovascular effects were noted apart from hiccough following the larger doses. The incidence of venous sequelae was much lower than that found following diazepam.

The relative merits of a potent narcotic and a spinal analgesic to affect the stress response to a standard operation have been assessed. Forty-five fit patients scheduled for abdominal hysterectomy were allocated at random to three groups, referred to as standard (i.v. anaesthesia alone), spinal (spinal plus i.v. anaesthesia) and fentanyl (fentanyl plus i.v. anaesthesia) groups. In the doses used, fentanyl produced the most effective attenuation of the cardiovascular, hormonal and metabolic responses to stress, but had the disadvantage of prolonged respiratory depression. Spinal anaesthesia gave only a modified blockade of the response to stress and did not obtund the response to intubation.