Systematic Review: Rectal Administration of Medications for Pediatric Procedural Sedation.

BACKGROUND: Per rectum (PR) medication delivery is an alternative to traditional oral (PO), intravenous (IV), or intramuscular (IM) administration of medication for procedural sedation of pediatric emergency department patients. However, many emergency physicians are unfamiliar with its use, and there are no widely adopted guidelines or reviews dedicated to this topic. OBJECTIVE: Our aim was to provide emergency physicians with an overview of PR procedural sedation medications in pediatric patients. METHODS: We performed a PubMed literature search of relevant keywords limited to studies of human subjects published in English between January 1, 1990 and December 31, 2017. We excluded case reports, general review articles, editorial/opinion pieces, correspondence, and abstracts. Two of the authors then conducted a structured review of the selected studies. RESULTS: A total of 315 PubMed citations meeting the search criteria were found. Twenty-eight articles were included for final detailed review. Only 4 of the 28 included studies were conducted in the emergency department setting. A total of 9 different medications have been studied for PR procedural sedation. Sedation effectiveness ranged from 40% to 98%. No life-threatening complications were reported in any of the included clinical trials. Hypoxia was found to occur in up to 10% of those receiving PR sedation. CONCLUSIONS: Pediatric procedural sedation with PR medications appears to be feasible, moderately effective, and safe based on our review of the current literature. However, further studies on its applicability in the emergency department setting are needed.

Evaluation of methohexital as an alternative to propofol in a high volume outpatient pediatric sedation service.

BACKGROUND: Propofol is a preferred agent for many pediatric sedation providers because of its rapid onset and short duration of action. It allows for quick turn around times and enhanced throughput. Occasionally, intravenous (IV) methohexital (MHX), an ultra-short acting barbiturate is utilized instead of propofol. OBJECTIVE: Describe the experience with MHX in a primarily propofol driven outpatient sedation program and to see if it serves as an acceptable alternative when propofol is not the preferred pharmacologic option. METHODS: Retrospective chart review from 2012 to 2015 of patients receiving IV MHX as their primary sedation agent. Data collected included demographics, reason for methohexital use, dosing, type of procedure, success rate, adverse events (AE), duration of the procedure, and time to discharge. RESULTS: Methohexital was used in 240 patient encounters. Median age was 4years (IQR 2-7), 71.8% were male, and 80.4% were ASA-PS I or II. Indications for MHX use: egg+soy/peanut allergy in 93 (38.8%) and mitochondrial disorder 9 (3.8%). Median induction bolus was 2.1mg/kg (IQR, 1.9-2.8), median maintenance infusion was 4.5mg/kg/h (IQR, 3.0-6.0). Hiccups 15 (6.3%), secretions requiring intervention 14 (5.8%), and cough 12 (5.0%) were the most commonly occurring minor AEs. Airway obstruction was seen in 28 (11.6%). Overall success rate was 94%. Median time to discharge after procedure completion was 40.5min (IQR 28-57). CONCLUSION: Methohexital can be used with a high success rate and AEs that are not inconsistent with propofol administration. Methohexital should be considered when propofol is not a preferred option.

Post-electroconvulsive therapy recovery and reorientation time with methohexital and ketamine: a randomized, longitudinal, crossover design trial.

OBJECTIVES: Methohexital, a barbiturate anesthetic commonly used for electroconvulsive therapy (ECT), possesses dose-dependent anticonvulsant properties, and its use can interfere with effective seizure therapy in patients with high seizure thresholds. Ketamine, an N-methyl-d-aspartate antagonist with epileptogenic properties not broadly used for ECT inductions, is a commonly used induction agent for general anesthesia. Recent studies suggest that the use of ketamine is effective in allowing successful ECT treatment in patients with high seizure thresholds without an increase in adverse effects. In this preliminary study, we directly compared the recovery and reorientation times of subjects receiving ketamine and methohexital for ECTs. METHODS: Twenty patients were randomized in a crossover design to receive methohexital and ketamine for ECT inductions in alternating fashion in 6 trials. Primary outcome measures were recovery time (voluntary movement, respiratory effort, blood pressure, consciousness, and O2 saturation) and reorientation time. Secondary outcome measures were individual recovery variables, adverse effect occurrence, and seizure duration. RESULTS: Overall recovery time was not significantly different between the 2 treatment arms (F(1, 17) = 0.72; P = 0.41). Reorientation time was faster in the methohexital arm (F(1, 17) = 9.23; P = 0.007). CONCLUSION: Ketamine inductions resulted in higher number of adverse effects, higher subject dropout rates, and a longer reorientation time with respect to methohexital inductions. No significant difference in postanesthesia recovery time was found between the ketamine and methohexital arms. Intolerability to ketamine affected a significant proportion of subjects and suggests that ketamine should remain as an alternative or adjunctive agent for patients with high seizure thresholds.

Different regimens of intravenous sedatives or hypnotics for electroconvulsive therapy (ECT) in adult patients with depression.

BACKGROUND: Depression is a common mental disorder. It affects millions of people worldwide and is considered by the World Health Organization (WHO) to be one of the leading causes of disability. Electroconvulsive therapy (ECT) is a well-established treatment for severe depression. Intravenous anaesthetic medication is used to minimize subjective unpleasantness and adverse side effects of the induced tonic-clonic seizure. The influence of different anaesthetic medications on the successful reduction of depressive symptoms and adverse effects is unclear. OBJECTIVES: This review evaluated the effects of different regimens of intravenous sedatives and hypnotics on anti-depression efficacy, recovery and seizure duration in depressed adults undergoing ECT. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12); MEDLINE via Ovid SP (from 1966 to 31 December 2012); and EMBASE via Ovid SP (from 1966 to 31 December 2012). We handsearched related journals and applied no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and cross-over trials evaluating the effects of different intravenous sedatives and hypnotics for ECT. We excluded studies and trials using placebo or inhalational anaesthetics and studies that used no anaesthetic. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. When possible, data were pooled and risk ratios (RRs) and mean differences (MDs), each with 95% confidence intervals (CIs), were computed using the Cochrane Review Manager statistical package (RevMan). MAIN RESULTS: We included in the review 18 RCTs (599 participants; published between 1994 and 2012). Most of the included trials were at high risk of bias.We analysed the results of studies comparing six different intravenous anaesthetics.Only a few studies comparing propofol with methohexital (four studies) and with thiopental (three studies) could be pooled.No difference was noted in the reduction of depression scores observed in participants treated with propofol compared with methohexital (low-quality evidence). These four studies were not designed to detect differences in depression scores.The duration of electroencephalograph (EEG) and of motor seizures was shorter in the propofol group compared with the methohexital group (low-quality evidence). No difference was seen in EEG seizure duration when propofol was compared with thiopental (low-quality evidence).Time to recovery (following commands) was longer among participants after anaesthesia with thiopental compared with propofol (low-quality evidence).For the remaining comparisons of anaesthetics, only single studies or insufficient data were available. Adverse events were inadequately reported in eligible trials, and none of the included trials reported anaesthesia-related mortality. AUTHORS' CONCLUSIONS: Most of the included studies were at high risk of bias, and the quality of evidence was generally low. The studies were not designed to detect clinically relevant differences in depression scores. Anaesthetic agents should be chosen on the basis of adverse effect profile, emergence and how these medications affect seizure duration. If it is difficult to elicit an adequately long seizure, methohexital may be superior to propofol (low-quality evidence). If a patient is slow to recover from anaesthesia, propofol may allow a faster time to follow commands than thiopental (low-quality evidence). A factor of clinical concern that was not addressed by any study was adrenal suppression from etomidate. Optimal dosages of intravenous sedatives or hypnotics have not yet been determined.Larger well-designed randomized studies are needed to determine which intravenous anaesthetic medication leads to the greatest improvement in depression scores with minimal adverse effects.

Methohexital and succinylcholine dosing for electroconvulsive therapy (ECT): actual versus ideal.

This report compares the actual doses of methohexital and succinylcholine used for optimal anesthesia and muscle relaxation in electroconvulsive therapy with written guidelines for dosing. The initial doses of methohexital and succinylcholine in milligrams per kilogram were reviewed and compared with subsequent doses of each agent after adjustments were made for individual patient responses during treatment. The dose of methohexital required to induce general anesthesia for most patients is 1.0 mg/kg. The dose of succinylcholine required to provide adequate muscle relaxation during electroconvulsive therapy is 0.9 mg/kg, although there is considerable variability in patient response to this drug.

[Methohexital for treatment of intracranial hypertension]. / Methohexital zur Therapie des erhöhten intrakraniellen Drucks.

BACKGROUND: Barbiturate coma therapy is a useful method to control increased intracranial pressure (ICP) in patients with severe brain damage if standard measures have failed to lower ICP. Pentobarbital (not available in Germany) and thiopental (in Germany only approved for induction of anesthesia) have frequently been used in patients with intracranial hypertension and the effects and side-effects are well-described. However, little is known about the effect of methohexital (the only barbiturate in Germany approved for maintaining anesthesia) in lowering increased ICP. Therefore, the effect of methohexital on ICP was studied in patients where standard measures had failed to control intracranial hypertension. METHOD: A retrospective observational study was carried out with the inclusion criteria of patient age ≥18 years and methohexital therapy for 12 h or more with ICP monitoring in place. Methohexital was administered following a standardized algorithm to patients for whom standard measures, such as deep anesthesia, normoventilation, cerebral perfusion pressure (CPP) >65 mmHg, osmotherapy, neurosurgical evacuation of mass lesions, had failed to lower ICP. Methohexital was used if the ICP had risen above 20-25 mmHg for more the 20-30 min and otherwise manageable causes for the ICP increase had been ruled out. Methohexital was given continuously in addition to standard analgesia and sedation in doses of 2-4-6 mg/kg body weight (BW), depending on the ICP lowering effect. The records of the patient data management system from the years 2008/2009 were used to compare the ICP and CPP before and during methohexital administration. For statistical analyses Student's t-test was applied for measured values and the χ(2)-test was applied for percentage values whereby p<0.05 was defined as being statistically significant. RESULTS: During the study period 36 patients required methohexital therapy and 30 fulfilled the inclusion criteria. In 26 out of 30 patients the data were complete and these 26 patients were included in the data analyses. Of the patients 6 (23%) died due to elevated intracranial hypertension and 20 patients (77%) survived. In all patients methohexital lowered the ICP from 25.2 mmHg (standard deviation, SD ±4.3 mmHg) to 19.8 mmHg (SD ±12.5 mmHg) within the first 24 h, this result closely failed to reach a level of significance. In the 20 survivors methohexital lowered the ICP from 25.88 mmHg (SD ±4.8 mmHg) to 14.25 mmHg (SD ±6.9 mmHg) within the first 24 h, which is statistically highly significant. In non-survivors the ICP had risen from 24 mmHg (SD ±2.6 mmHg) to 32 mmHg (SD ±16.3 mmHg) within the first 24 h despite all efforts. Due to the CPP driven volume and vasopressor therapy no significant changes in the CPP during methohexital administration were observed. No significant changes in brain temperature (as possible cause for the decrease of the ICP) were observed. Non-survivors received significantly more methohexital due to increased ICP and required significantly more vasopressor therapy to maintain a sufficient CPP. CONCLUSIONS: Methohexital showed a clear trend for decreasing ICP in patients with intracranial hypertension refractory to standard therapeutic measures. In survivors the effect was highly significant. Patients not responding to methohexital therapy seemed to have an unfavorable outcome.

Cardiac effects of induction agents in the septic rat heart.

INTRODUCTION: The current debate about the side effects of induction agents, e.g. possible adrenal suppression through etomidate, emphasizes the relevance of choosing the correct induction agent in septic patients. However, cardiovascular depression is still the most prominent adverse effect of these agents, and might be especially hazardous in septic patients presenting with a biventricular cardiac dysfunction--or so-called septic cardiomyopathy. Therefore, we tested the dose-response direct cardiac effects of clinically available induction agents in an isolated septic rat heart model. METHODS: A polymicrobial sepsis was induced via cecal ligation and single puncture. Hearts (n = 50) were isolated and randomly assigned to five groups, each receiving etomidate, s(+)-ketamine, midazolam, propofol, or methohexitone at concentrations of 1 x 10-8 to 1 x 10-4 M. Left ventricular pressure, contractility and lusitropy, and coronary flow were measured. Cardiac work, myocardial oxygen delivery, oxygen consumption, and percentage of oxygen extraction were calculated. RESULTS: All of the induction agents tested showed a dose-dependent depression of cardiac work. Maximal cardiac work dysfunction occurred in the rank order of s(+)-ketamine (-6%)

Comparison of methohexital and pentobarbital as sedative agents for pediatric emergency department patients for computed tomography.

OBJECTIVES: To determine if there are differences in the duration of sedation between pediatric emergency department (PED) patients receiving methohexital and PED patients receiving pentobarbital for the purpose of obtaining a head computed tomographic (CT) scan. METHODS: Retrospective cohort study of PED patients receiving either methohexital or pentobarbital for a sedated head CT. Data were collected on patient demographics and medical condition, indications for head CT, duration of sedation, medication dosage, and medication adverse events. Primary analyses investigated whether there were differences between the 2 groups. Secondary analysis determined whether the need for additional sedative doses contributed to observed differences between groups. RESULTS: The patients receiving methohexital completed their head CT more quickly and needed less total sedation monitoring than those receiving pentobarbital. The need for additional doses of medication does not appear to be responsible for the observed difference. Adverse medication events were minor and comparable between groups. CONCLUSIONS: Methohexital may be superior to pentobarbital for the purpose of sedating PED patients for head CT.

Pediatric Electroconvulsive Therapy: An Anesthesiologist's Perspective.

Proper planning and communication between psychiatry and anesthesiology teams is vital to conferring the greatest therapeutic benefit to children presenting for electroconvulsive therapy while minimizing risk. Anesthesia for the child undergoing electroconvulsive therapy should ideally provide deep hypnosis, ensure muscle relaxation to reduce injury, have minimal effect on seizure dynamics, and allow for rapid recovery to baseline neurologic and cardiopulmonary status. Unique factors for pediatric electroconvulsive therapy include the potential need for preoperative anxiolytic and inhalational induction of anesthesia, which must be weighed against the detrimental effects of anesthetic agents on the evoked seizure quality required for a successful treatment.

Seizures during intracarotid methohexital and amobarbital testing.

BACKGROUND: Methohexital and amobarbital have been used as agents for Wada testing in the presurgical evaluation of patients with epilepsy. Previous experience with methohexital as an anesthetic indicates that methohexital may decrease seizure threshold and may trigger seizures. METHODS: A retrospective chart review of 760 intracarotid amobarbital and methohexital tests was performed to determine the frequency of seizures associated with preoperative intracarotid barbiturate testing for language and memory lateralization. RESULTS: Sixteen patients (2.1%) who had seizures were found. In 3 patients, seizures occurred prior to barbiturate injection, and in 13, following barbiturate injection. After injection of amobarbital, 4 of 538 patients (0.7%) had a seizure. Nine of 222 patients had a seizure after methohexital injection (4.1%) (P=0.001). CONCLUSION: Patients with a previous history of epilepsy may be at higher risk for seizures after methohexital injection as compared with amobarbital injection.

Use of Methohexital and Dexmedetomidine for Maintenance of Anesthesia in a Patient With Mitochondrial Myopathy: A Case Report.

Provision of anesthesia for patients with mitochondrial disorders is associated with a unique set of challenges. These disorders are rare, which complicates efforts to develop high quality, evidence-based guidelines to inform the perioperative management of those who suffer from them. Accordingly, case reports remain an important source of information regarding their care. Here we present the case of a 27-year-old female patient with mitochondrial myopathy and a history suggestive of malignant hyperthermia susceptibility who received general anesthesia for 2 consecutive surgeries. The induction agents included fentanyl, ketamine, and methohexital. The maintenance agents were methohexital, sufentanil, and dexmedetomidine.

Hyperlipidemia sink for anesthetic agents.

We present a case that involves anesthetic resistance during anesthesia for electroconvulsive therapy. Despite adequate dosing of both intravenous and inhalation anesthetics, our patient was resistant to induction of the state of general anesthesia. Subsequently, we noticed extreme hyperlipidemia. We hypothesized that the patient's extreme hyperlipidemia served as an anesthetic "sink" and prevented the full dose of intravenous agents from quickly reaching their intended site of action.

Self-administration of methohexital, midazolam and ethanol: effects on the pituitary-adrenal axis in rhesus monkeys.

RATIONALE: There is disagreement in the literature with respect to how drugs of abuse affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, and whether these changes in endocrine function may be related to the rewarding effects of these drugs. OBJECTIVES: To determine whether reinforcing drugs with different mechanisms of action affect HPA axis function at doses at which they serve as reinforcers. METHODS: Seven monkeys (6 male) were randomly assigned to self-administer methohexital-a barbiturate (n=4), midazolam-a benzodiazepine (n=3), or ethanol (n=5). Each monkey had a surgically implanted indwelling venous catheter, and was trained to respond on a fixed ratio of 30 lever presses to receive an injection of drug or saline. Blood samples were obtained before, during, and after the self-administration sessions for the measurement of ACTH and cortisol by radioimmunoassay. RESULTS: Although methohexital, midazolam, and ethanol all maintained self-administration behavior across a range of doses, they differed in their effects on ACTH and cortisol. Ethanol inhibited ACTH and cortisol secretion. Methohexital and midazolam both tended to decrease ACTH and cortisol at large doses, and increase these hormones at small doses, but the HPA effects of neither drug differed significantly from when saline was available. CONCLUSIONS: The neutral overall effect of methohexital and midazolam on HPA activity is consistent with other monkey and human studies, whereas the inhibitory effect of self-administered ethanol in the monkey contrasts with both the rat and human literature. The data in this study suggest that a change in HPA axis activity is not a requirement for drug-reinforced behavior in monkeys.

Bispectral analysis during pediatric procedural sedation.

OBJECTIVE: Bispectral analysis (BIS) is a technology using EEG information from a forehead electrode to calculate an index (0-100; 0 = coma, 90-100 = awake). Our objective was to determine the degree of agreement between sedation scales and BIS values in pediatric patients undergoing sedation. METHODS: Patients ages 2 to 17 years, undergoing procedural sedation, were enrolled. Sedation was performed in the customary manner with the addition of BIS monitoring and assessment of a clinical sedation scale: the Observer's Assessment of Alertness/Sedation (OAA/S), every 5 minutes during the sedation procedure. Clinical scales were performed by an investigator blinded to the BIS index. The association between a clinical scale and BIS scores was analyzed using longitudinal regression analysis. RESULTS: We enrolled 47 subjects; 55% were sedated with ketamine and midazolam and the remaining 45% received methohexital, propofol or midazolam and a narcotic. The results of the regression analysis demonstrated a highly significant association between the OAA/S score and BIS value (beta = 5.0, 95% CI 4.3 to 5.7, P < 0.0001). Patients were divided into 2 groups, those sedated with ketamine and those sedated with nonketamine medications. The association between OAA/S score and BIS value was not statistically significant for the ketamine population (beta = 0.809, 95% CI -0.1 to 1.7, P = 0.09), but remained significant for the nonketamine subjects (beta = 8.6, 95% CI 7.7 to 9.4, P < 0.0001). CONCLUSIONS: The OAA/S sedation scale predicts the BIS value for pediatric patients undergoing procedural sedation when sedated with certain medications, excluding ketamine.

Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen.

BACKGROUND AND PURPOSE: A combined therapeutic approach has been advocated repeatedly for treatment of focal cerebral ischemia. A clinical example of combined therapy is administration of nimodipine, mannitol, dexamethasone, and barbiturates during temporary occlusion of a cerebral artery in neurovascular surgery. We have recently demonstrated outstanding neuroprotective properties of a combination therapy with magnesium (calcium antagonist and glutamate antagonist), tirilazad (antioxidant), and mild hypothermia (MTH). In this study we compared this treatment strategy with the customary treatment options in a rat model of transient focal cerebral ischemia. METHODS: Sprague-Dawley rats (n=120) were subjected to 90 minutes of middle cerebral artery occlusion by an intraluminal filament (n=10 per group). In experiment 1, the customary treatment options (nimodipine, mannitol, dexamethasone, methohexital) were evaluated as monotherapy and in combination. In experiment 2, the customary and the new combination therapy (MTH) were compared. Mild hypothermia (33 degrees C) was maintained for 2 hours. Neurological examinations were performed daily. Infarct size was assessed histologically after 7 days. RESULTS: In experiment 1, infarct volume was attenuated by 34% at maximum, with mannitol and methohexital being the most effective drugs given as monotherapy. In experiment 2, combined administration of the customary treatment options had no additive effect (infarct volume -36%). Combination therapy with MTH reduced total infarction by 73% and almost completely abolished cortical infarction (-91%). None of the animals of this group had any residual neurological deficit at the end of the observation period (P<0.05 versus all other groups). CONCLUSIONS: The efficacy of drugs (monotherapy or in combination) most commonly used for neuroprotection during neurovascular surgery is limited. The newly proposed combination therapy (magnesium, tirilazad, and mild hypothermia), which is based on pathophysiological considerations, seems to be a promising alternative for neuroprotection in cerebrovascular surgery.

Drug modification of ECT: methohexital and diazepam. II.

A systematic comparison of methohexital and diazepam as anesthetics in the drug modification of ECT was done by holding atropinizaton, succinylcholine-depolarizing neuromuscular blockade, and resuscitation constant while monitoring four ECT in each of 24 patients. Each patient served as his own control, and two dosages of each drug (0.25 and 0.35 mg/kg diazepam, 0.9 and 1.1 mg/kg methohexital) were given each patient in all possible orderings (4! = 24) in a scheduled experimental design in which methohexital was given by very rapid (5 sec) and diazepam was given by the recommended slower (60 sec) infusion. The data revealed significant differences and methohexital was superior. Eight of 48 (17%) EKGs were abnormal post-ECT with methohexital, 18 of 48 (38%, phi = 5.3, p < 0.025) with diazepam. Five of 24 (21%) patients had an abnormal post-ECT EKG with methohexital, 15 of 24 (60%, phi 8.6, p < 0.005) with diazepam. Significantly more ventricular premature contractions (VPCs) occurred after diazepam. Diazepam records contained both more numerous and more extensive EKG abnormalities. Methohexital induction was clinically superior as well; there was little of the induction restlessness seen in seven treatments with diazepam (phi2 7.6, p < 0.01). The differences were less marked than in a previous study in which diazepam was given as rapidly as methohexital. Methohexital has been demonstrated to be the anexthesia of safety and choice for ECT when compared to diazepam.

Factors affecting amnesia, seizure duration, and efficacy in ECT.

Twenty-nine patients given unilateral ECT were tested for memory with each treatment. Forgetting of nonverbal material correlated positively with seizure duration and with anesthetic dose. Seizure duration did not correlate with forgetting of verbal material or with changes in Hamilton depression ratings. Seizure duration was inversely related to succinylcholine and methohexital doses. These findings suggest that muscle relaxant and anesthetic doses can be adjusted to lessen the amnestic effects of ECT. There are, however, insufficient data on the relationship between seizure length and ECT efficacy to specify a minimum duration for seizures, individually or cumulatively.

Anosognosia during intracarotid barbiturate anesthesia: unawareness or amnesia for weakness.

Previous studies have demonstrated asymmetric hemispheric contributions to deficit awareness during hemisphere inactivation with intracarotid barbiturate infusion (Wada studies). These observations provide insight into the neuropsychological basis of anosognosia for hemiparesis (AHP), arguing against earlier explanations based upon psychological denial, global cognitive disturbance, or emotional indifference. Although prior Wada studies equated AHP after the procedure with AHP during the period of deficit, a selective memory failure could also account for these findings. We, therefore, assessed the occurrence of AHP during and after right-hemisphere inactivation in a group of epilepsy patients undergoing preoperative Wada testing. Because aphasia obscures assessment of deficit awareness during left carotid studies, we compared the frequency of AHP between right- and left-hemisphere inactivation only after recovery. As noted in earlier reports, AHP was present significantly more often after right- than left-hemisphere inactivation. The proportions of subjects with AHP during right-hemisphere anesthesia compared with the proportion of subjects with AHP after the procedure were statistically equivalent, suggesting that the AHP observed after right-hemisphere anesthesia results from true failure of deficit awareness rather than inability to recall the deficit.

Pharmacokinetics of rectal drug administration, Part I. General considerations and clinical applications of centrally acting drugs.

Generally, oral administration is the route of choice in the daily practice of pharmacotherapy. However, in some circumstances this is impractical or even impossible (during nausea and vomiting or convulsions, in uncooperative patients and before surgery). In these cases, the rectal route may represent a practical alternative and rectal administration is now well accepted for delivering, for example, anticonvulsants, non-narcotic and narcotic analgesics, theophylline, antiemetics and antibacterial agents, and for inducing anaesthesia in children. It may also represent an interesting alternative to intravenous or other injection routes of drug administration. The rate and extent of rectal drug absorption are often lower than with oral absorption, possibly an inherent factor owing to the relatively small surface area available for drug uptake. In addition, the composition of the rectal formulation (solid vs liquid, nature of the suppository base) appears to be an important factor in the absorption process by determining the pattern of drug release. This relation between formulation and drug uptake has been clearly demonstrated for drugs like diazepam, paracetamol (acetaminophen), indomethacin, methadone and diflunisal. Coadministration of absorption-promoting agents (surfactants, sodium salicylate, enamines) represents another approach towards manipulating rectal drug absorption, although this concept requires further research concerning both efficacy and safety. For a number of drugs the extent of rectal absorption has been reported to exceed oral values, which may reflect partial avoidance of hepatic first-pass metabolism after rectal delivery. This phenomenon has been reported for morphine, metoclopramide, ergotamine, lidocaine (lignocaine) and propranolol. Rectal drug delivery in a site- and rate-controlled manner using osmotic pumps or hydrogel formulations may provide opportunities for manipulating systemic drug concentrations and drug effects. The extent of first-pass metabolism may be influenced (lidocaine), depending on the site of drug administration in the rectum. The rate of delivery may determine systemic drug action and side effects (nifedipine), and it may affect the local action of concurrently administered absorption promoters on drug uptake (cefoxitin). Local irritation is increasingly being acknowledged as a possible complication of rectal drug therapy. Long term medication with rectal ergotamine and acetylsalicylic acid, for example, may result in rectal ulceration, and irritation after a single administration of several drugs and formulations has been described. The assessment of tolerability and safety is imperative in the design of rectal formulations. Recent studies corroborate the clinical relevance of rectal drug therapy, and the value of the rectal route as an alternative to parenteral administration has been assessed for several drugs, e.g. diazepam, midazolam, morphine and diclofenac.(ABSTRACT TRUNCATED AT 400 WORDS)