Opioid treatment for opioid withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems. OBJECTIVES: To assess the effectiveness and safety of using an opioid for treatment of NAS due to withdrawal from opioids in newborn infants. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via Cochrane Register of Studies Web and MEDLINE via Ovid. We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for eligible trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi- and cluster-RCTs which enrolled infants born to mothers with opioid dependence and who were experiencing NAS requiring treatment with an opioid. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 16 trials (1110 infants) with NAS secondary to maternal opioid use in pregnancy. Seven studies at low risk of bias were included in sensitivity analysis. Opioid versus no treatment / usual care: a single trial (80 infants) of morphine and supportive care versus supportive care alone reported no difference in treatment failure (risk ratio (RR) 1.29, 95% confidence interval (CI) 0.41 to 4.07; very low certainty evidence). No infant had a seizure. The trial did not report mortality, neurodevelopmental disability and adverse events. Morphine increased days hospitalisation (mean difference (MD) 15.00, 95% CI 8.86 to 21.14; very low certainty evidence) and treatment (MD 12.50, 95% CI 7.52 to 17.48; very low certainty evidence), but decreased days to regain birthweight (MD -2.80, 95% CI -5.33 to -0.27) and duration (minutes) of supportive care each day (MD -197.20, 95% CI -274.15 to -120.25). Morphine versus methadone: there was no difference in treatment failure (RR 1.59, 95% CI 0.95 to 2.67; 2 studies, 147 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study reported no difference in days hospitalisation (MD 1.40, 95% CI -3.08 to 5.88; 116 infants; low certainty evidence), whereas data from two studies found an increase in days treatment (MD 2.71, 95% CI 0.22 to 5.21; 147 infants; low certainty) for infants treated with morphine. A single study reported no difference in breastfeeding, adverse events, or out of home placement. Morphine versus sublingual buprenorphine: there was no difference in treatment failure (RR 0.79, 95% CI 0.36 to 1.74; 3 studies, 113 infants; very low certainty evidence). Neonatal or infant mortality and neurodevelopmental disability were not reported. There was moderate certainty evidence of an increase in days hospitalisation (MD 11.45, 95% CI 5.89 to 17.01; 3 studies, 113 infants), and days treatment (MD 12.79, 95% CI 7.57 to 18.00; 3 studies, 112 infants) for infants treated with morphine. A single adverse event (seizure) was reported in infants exposed to buprenorphine. Morphine versus diluted tincture of opium (DTO): a single study (33 infants) reported no difference in days hospitalisation, days treatment or weight gain (low certainty evidence). Opioid versus clonidine: a single study (31 infants) reported no infant with treatment failure in either group. This study did not report seizures, neonatal or infant mortality and neurodevelopmental disability. There was low certainty evidence for no difference in days hospitalisation or days treatment. This study did not report adverse events. Opioid versus diazepam: there was a reduction in treatment failure from use of an opioid (RR 0.43, 95% CI 0.23 to 0.80; 2 studies, 86 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study of 34 infants comparing methadone versus diazepam reported no difference in days hospitalisation or days treatment (very low certainty evidence). Adverse events were not reported. Opioid versus phenobarbital: there was a reduction in treatment failure from use of an opioid (RR 0.51, 95% CI 0.35 to 0.74; 6 studies, 458 infants; moderate certainty evidence). Subgroup analysis found a reduction in treatment failure in trials titrating morphine to ≧ 0.5 mg/kg/day (RR 0.21, 95% CI 0.10 to 0.45; 3 studies, 230 infants), whereas a single study using morphine < 0.5 mg/kg/day reported no difference compared to use of phenobarbital (subgroup difference P = 0.05). Neonatal or infant mortality and neurodevelopmental disability were not reported. A single study (111 infants) of paregoric versus phenobarbital reported seven infants with seizures in the phenobarbital group, whereas no seizures were reported in two studies (170 infants) comparing morphine to phenobarbital. There was no difference in days hospitalisation or days treatment. A single study (96 infants) reported no adverse events in either group. Opioid versus chlorpromazine: there was a reduction in treatment failure from use of morphine versus chlorpromazine (RR 0.08, 95% CI 0.01 to 0.62; 1 study, 90 infants; moderate certainty evidence). No seizures were reported in either group. There was low certainty evidence for no difference in days treatment. This trial reported no adverse events in either group. None of the included studies reported time to control of NAS. Data for duration and severity of NAS were limited, and we were unable to use these data in quantitative synthesis. AUTHORS' CONCLUSIONS: Compared to supportive care alone, the addition of an opioid may increase duration of hospitalisation and treatment, but may reduce days to regain birthweight and the duration of supportive care each day. Use of an opioid may reduce treatment failure compared to phenobarbital, diazepam or chlorpromazine. Use of an opioid may have little or no effect on duration of hospitalisation or treatment compared to use of phenobarbital, diazepam or chlorpromazine. The type of opioid used may have little or no effect on the treatment failure rate. Use of buprenorphine probably reduces duration of hospitalisation and treatment compared to morphine, but there are no data for time to control NAS with buprenorphine, and insufficient evidence to determine safety. There is insufficient evidence to determine the effectiveness and safety of clonidine.

Anxiolytic effect of homeopathic preparation of Pulsatilla nigricans in Swiss albino mice.

BACKGROUND: The homeopathic preparation of Pulsatilla nigricans is used in the treatment of anxiety related disorders. Though in clinical use for many years, the anxiolytic activity of Pulsatilla nigricans (Puls) has not been evaluated experimentally. Hence the present study was conducted in Swiss albino mice to evaluate the anxiolytic activity of Puls and compare its activity with the standard anxiolytic drug, diazepam. METHODS: Twenty four mice were divided into 4 groups of 6 animals each, control, standard and two test groups. The control group was treated Ethyl alcohol 10 ml/kg. The standard group received Diazepam, 1 mg/kg. Puls 3x and 6x solutions were given at the dose of 10 ml/kg to the test groups. All animals were given the test and control treatments orally for 15 days. The anxiolytic effect was tested on days 1, 8 and 15 using the Elevated Plus Maze (EPM) and Open Field Test (OFT). RESULTS: Both diazepam and Puls showed significant anxiolytic activity in EPM and OFT test compared to control. The total number of entries and time spent in open arm in EPM was increased by both diazepam and Puls, the effect of 3x dilution of Puls was greater than diazepam. In the OFT the number of squares crossed, rearing and assisted rearings decreased with both diazepam and Puls compared to control and the anxiolytic effect of diazepam was greater than Puls. The anxiolytic effect is greater for the 3x dilution than 6x dilution of Puls. CONCLUSION: The study showed an anxiolytic effect of homeopathic preparation of Pulsatilla nigricans comparable to that found with a standard drug.

Evaluation of diazepam as a drug treatment for water hemlock (Cicuta species) poisoning in Spanish goats.

Water hemlocks (Cicuta spp.) are toxic members of the Apiaceae plant family. The best drug treatment for the convulsions associated with acute water hemlock poisoning in livestock and humans has not been determined experimentally. This work compared the therapeutic actions of benzodiazepines (diazepam) and barbiturates (phenobarbital) on water hemlock poisoning in a goat model. C. maculata tubers were orally dosed to goats. Experimental groups consisted of; control saline; 20 mg/kg phenobarbital; 1.0 mg/kg diazepam; 10 mg/kg diazepam; and 1.0 mg/kg diazepam administered as needed to moderate convulsions by intravenous (i.v.) infusion. Diazepam provided nearly instant control of convulsions. Clinical signs of poisoning were completely controlled for the duration of the experiment in the goats that received the 10 mg/kg diazepam dose. These results suggest that diazepam is effective at managing the clinical signs of water hemlock poisoning in goats. We speculate that diazepam can be used as a potential treatment for water hemlock poisoning in other livestock species and humans.

Anticonvulsants for poisoning by the organophosphorus compound soman: pharmacological mechanisms.

Exposure to high doses of organophosphorus nerve agents such as soman, even with carbamate pretreatment, produces a variety of toxic cholinergic signs, including secretions, convulsions and death. Evidence suggests that soman-induced convulsions may be associated with postexposure brain neuropathology. The purpose of this study was to investigate the pharmacologic mechanism of action of soman-induced convulsions and of anticonvulsant drugs. Various classes of compounds were evaluated for their efficacy in preventing soman-induced convulsions in rats pretreated with the oxime HI-6 to increase survival time, along with various doses of the test compounds (IM) either in the absence or presence of atropine sulfate (16 mg/kg, IM) 30 minutes prior to a soman challenge dose (180 micrograms/kg, SC; equivalent to 1.6 x LD50) that produced 100% convulsions. Without atropine sulfate, only tertiary anticholinergics (scopolamine, trihexyphenidyl, biperiden, benactyzine, benztropine, azaprophen and aprophen), caramiphen, carbetapentane and MK-801 were effective anticonvulsants. In the presence of atropine sulfate, the benzodiazepines (diazepam, midazolam, clonazepam, loprazolam and alprazolam), mecamylamine, flunarizine, diphenylhydantoin, clonidine, CGS 19755 and Organon 6370 studied were effective. We have examined the possibility that diazepam may exert some of its anticonvulsant effects through cholinergic mechanisms and found that a reduced release of ACh into synapses after diazepam and atropine treatment may account for diazepam's anticonvulsant activity against soman. We also found that at anticonvulsant doses biperiden and trihexyphenidyl each significantly reversed the effects of soman on striatal levels of DOPAC and HVA, the metabolites of dopamine, and have concluded that in addition to actions on muscarinic receptors, the anticonvulsant effects of these anticholinergics in soman poisoning may be partially related to their actions on the striatal dopaminergic system. These findings allow us to postulate that central muscarinic cholinergic mechanisms are primarily involved in eliciting the convulsions following exposure to soman and that subsequent recruitment of other excitatory neurotransmitter systems and loss of inhibitory control may be responsible for sustaining the convulsions and for producing the subsequent brain damage. Future studies to confirm these neuropharmacological mechanisms are proposed.

Variability in heparin effect on serum drug binding.

Heparinized saline was given to seven men and one woman, aged 21 to 42 yr, after a 14-hr fasting period and 2 hr after breakfast; blood was collected in nonoheparinized tubes. Diazepam (D alpha) and warfarin (W alpha) free fractions were determined in serum by equilibrium dialysis to which radiolabeled drug was added. After 50 U heparin (Harris LO14) intravenously, the maximum effect on D alpha, W alpha, and free fatty acids (FFA) developed in 5 min and lasted 20 to 30 min. D alpha rose and W alpha fell (p < 0.01) at 5 min. Cumulative doses of heparin increased FFAs (F4,16 = 18.29, p < 0.0005). D alpha rises (r = 0.73, p < 0.001) and W alpha falls (r = -0.74, p < 0.001) correlated with changes in FFAs. D alpha rises and W alpha falls were greater postprandially than in the fasted state (p < 0.01). Five subjects were randomly assigned up to 400 U intravenously of each of two different heparin lots (Harris LO14, and Organon LA39.) The FFA rises (reflecting heparin lipolytic activity, F1,32 = 179.62, p < 0.0005), D alpha rises (F1,32 = 34.22, p < 0.0005), and the W alpha falls (F1,32 = 33.20, p < 0.0005) by heparin Harris LO14 were greater than those by heparin Organon LA39. Although small doses of heparin, such as those in heparin locks, can affect drug binding, the extent and variability of the effect depends on the biologic activity of the heparin, and varies with manufacturer and lot, exact time of sampling, and eating.

Nonfatty acid-modulated variations in drug binding due to heparin.

Changes in free fatty acids (FFAs) do not always correlate with variations in drug binding. To dissociate heparin effects on FFAs and drug binding, six healthy fasting subjects received 50 units (USP) IV heparin (Harris L932) with and without protamine (3.2 mg IV). Protamine completely suppressed heparin-induced rises in FFAs and warfarin free fraction (W alpha), but diazepam free fraction (D alpha) increased (P less than 0.005). In vitro, increasing concentrations of heparin added to serum increased D alpha (P less than 0.0005) and W alpha (P less than 0.005) without changing FFAs. In eight subjects given 50 units IV heparin (Harris L014), FFAs (P less than 0.001) and propranolol free fraction (P alpha) rose (P less than 0.01), but variations in FFAs and P alpha did not correlate (r = 0.18). When two different heparin lots (Harris L014 and Organon LA39) were tested in vivo. Harris L014 heparin increased FFAs (P less than 0.005) and P alpha (P less than 0.0005), but variations in FFAs and P alpha correlated poorly (r = 0.43, P less than 0.05). In contrast, the Organon LA39 heparin did not change FFAs, but did increase P alpha (P less than 0.0005); variations in FFAs and P alpha did not correlate (r = 0.22). These results indicate that heparin-induced variations in drug binding are not exclusively related to changes in FFAs.

Side effects in the neonate from psychotropic agents excreted through breast-feeding.

Neuroleptics, antidepressants, lithium, anxiolytics, and hypnotics may be excreted in breast milk. Because of the danger to the neonate, drugs such as diazepam, lithium, bromides, reserpine, and opium alkaloids should not be given to lactating women, and barbiturates, haloperidol, and penfluridol should be administered with caution. The side effects produced as a result of breast-feeding of the infant by mothers consuming psychotropic drugs are reviewed and possible preventive measures are discussed.

Paediatric anaesthesia: pharmacological considerations.

The young infant differs from the adult in his quantitative responses to many anaesthetic drugs and adjuncts. In the neonate, the larger extracellular fluid volume and blood volume, the smaller muscle mass and fat stores, and presumable greater blood flow to the central organs, not only influence the distribution of drugs to their active site but also secondary redistribution. The neonatal hepatic anzyme systems responsible for the metabolism of drugs are incompletely developed or absent. Glomerular filtration, important for drug excretion, is inefficient by adult standards. The neonate has increased toxicity and sensitivity to a variety of sedative-hypnotics, narcotics, and local anaesthetics. On the other hand, the infant requires more suxamethonium (succinylcholine) and ketamine on a weight basis that does the adult. The response of some infants to non-depolarising muscle relaxants resembles that of the myasthenic patients. The rate of uptake of alveolar levels of inhalation anesthetics is more rapid in infants and children than in adults. In addition, the neonate requires more anaesthetic than the adult for a given surgical stimulus. Biotransformation of inhalation anaesthetics is limited in neonates. Awareness of these pharmacological differences and their probable explanations allows one to provide rational, safer anaesthesia to infants.

Aggressive intensive care treatment of very elderly patients with tetanus is justified.

Tetanus is now rare in industrialized countries, occurring mainly in elderly patients. To assess whether aggressive therapy of these patients in the intensive care unit is justified, we retrospectively studied all patients with tetanus hospitalized in our institution between 1968 and 1989. Patients over the age of 70 years fared as well as those under 70 years and recovered without sequelae. These results favor aggressive treatment of elderly patients with tetanus in the intensive care unit.

Suppression of shivering decreases oxygen consumption and improves hemodynamic stability during postoperative rewarming.

Thirty-three patients undergoing elective myocardial revascularization were prospectively randomized into two study groups (Group S and Group P) to permit evaluation of the effects of shivering on oxygen consumption per minute (VO2), carbon dioxide production per minute (VCO2), and hemodynamic performance. Group S was allowed to shiver during the postoperative rewarming period, and Group P received hourly injections of pancuronium bromide and Metubine (metocurine) sulfate with sedation to block the shivering response. Group S demonstrated significantly higher increases in VO2 and VCO2, lower systolic blood pressure and mixed venous oxygen saturation, and a greater use of inotropic support than the patients in Group P. Suppression of the shivering response minimized increases in VO2 and VCO2, improved hemodynamic stability, and resulted in a decreased need for inotropic support.

Lack of cardiovascular stimulation during endotracheal intubation in cardiac surgical patients anesthetized with diazepam-ketamine-pancuronium.

Anesthesia was induced with diazepam-ketamine-pancuronium in 12 adult patients scheduled for cardiac surgery. Intubation caused no significant changes in arterial blood pressure, heart rate, or plasma levels of norepinephrine and epinephrine. Circulatory stability was an advantage in critically ill patients.

Sedation for fibreoptic bronchoscopy: comparison of alfentanil with papaveretum and diazepam.

Sedation for fibreoptic bronchoscopy should produce optimal conditions for the operator, patient comfort and rapid recovery allowing early discharge home. We have compared a regimen producing 'light' sedation with a more traditional regimen producing 'deep' sedation. Seventy-six patients undergoing fibreoptic bronchoscopy under topical anaesthesia were randomized to receive either light sedation with the short acting opiate, alfentanil (median dose 1.1 mg, range 0.5-2.6 mg) or deep sedation with a combination of papaveretum (median dose 10 mg, range 5-15 mg) and diazepam (median dose 8 mg, range 0-20 mg). Both techniques gave equally good operating conditions, although patients given alfentanil coughed less than those given papaveretum and diazepam (U = 2.814 P less than 0.01). Patients recorded their degree of apprehension on a visual analogue scale prior to sedation and the actual degree of comfort experienced after recovery. There was no significant difference between apprehension or comfort between the groups. This was despite a higher degree of amnesia for an irrelevant object shown during the bronchoscopy in the deeply sedated group (chi 2 = 21.084 P less than 0.001). Patients given alfentanil performed significantly better in a modified Romberg test (chi 2 = 4.357 P less than 0.05) and a visualisation test (t = 3.035 P less than 0.01) two hours after the bronchoscopy. Alfentanil produced good operating conditions, patient comfort, less cough and a more rapid recovery, compared to the deep sedation regimen, and is an ideal sedative for fibreoptic bronchoscopy.

Diazepam abuse in pregnant women on methadone maintenance. Implications for the neonate.

The authors found that the course and treatment of narcotic withdrawal in two neonates was complicated by prenatal exposure to high doses of diazepam, or Valium (Roche Laboratories, Nutley, NJ). Both of the mothers were on methadone maintenance for narcotic dependency prior to the diagnosis of pregnancy. The authors documented maternal intake of diazepam in the range of 40-60 mg/day for a duration of 4-27 weeks prior to delivery. Both infants initially responded well to medical therapy for narcotic withdrawal, but at 7-14 days of age, withdrawal symptoms intensified, requiring an increase in the dosages of Paregoric (UDL Laboratories, Rockford, IL) and opium tincture in both infants and the addition of phenobarbital therapy in one infant. Both infants continued on medical therapy until they reached 1 month of age. Diazepam use by pregnant women can be associated with a later presentation of withdrawal symptoms in the neonate than that induced by the use of other drugs. Close follow-up during the first month of life is warranted for infants exposed to diazepam prenatally.

Anesthetic management of a morbidly obese woman with a massive ovarian cyst.

Morbid obesity affects 3% to 5% of the U.S. population and poses challenging problems to the anesthesiologist during the perioperative period. We present a unique case of the management of a morbidly obese woman complicated by a massive ovarian cyst. The major cardiopulmonary, metabolic, and technical features special to this patient population are discussed.

A simple, cheap, effective and safe procedure for general anesthesia.

A simplified, safe and flexible technique of anesthesia, based on a limited number of relatively cheap drugs, and allowing ventilation with air, was applied to 60 patients undergoing operations of at least 60 minutes' duration. The required depth of hypnosis was produced by intravenous diazepam or gamma-OH, whilst droperidol and fentanyl provided a satisfactory degree of sedation and analgesia. Pancuronium bromide was used for muscle relaxation. Spontaneous respiration was resumed immediately after postoperative use of nalorphine and neostigmine. The anesthetic course was smooth and predictable, with cardiovascular stability and an uneventful postoperative recovery. Emphasis is laid on the suitability of this procedure on the Battle Field or in Developing Countries, and on its safety (no toxic volatile liquids). (Acta anaesth. belg., 1976, 27, 25-34).

[Anesthetic induction with Althesin or diazepam in patients undergoing an aortocoronary bypass]. / Induction anesthésique avec Alfatésine ou diazépam chez des patients opérés pour pontage aorto-coronarien.

The haemodynamic effects of induction of anaesthesia with diazepam (group D) and Althesin (group A) were studied in 25 coronary patients under betablockers with good myocardial function. Haemodynamic variables monitored were vascular pressures, cardiac output and systolic time intervals. The effects of both drugs were observed when used alone (time I) and in combination with fentanyl, pancuronium and nitrous oxide (time II). The results seemed to show that Althesin (12.51% fall in SI and 10.79% increase in PEP/LVET) depressed myocardial function more than diazepam (no significant difference), but the introduction of fentanyl, pancuronium and nitrous oxide removed the differences between the drugs as to their effect on myocardial performance. These drugs added a depressant effect to diazepam (13.83% fall in SI and 15.77% increase in PEP/LVET) without increasing Althesin's negative inotropic effect. However, in group A at time II, the pulmonary arterial pressure, the wedge pressure and the pulmonary vascular resistance were significantly reduced, while they remained stable in the diazepam group.

Anaesthetic management for atlanto axial subluxation.

A number of disease processes including congenital anomalies, malunited odontoid fractures, rheumatoid arthritis and tuberculosis can result in atlanto axial subluxation. The patient population presenting for surgery is therefore varied in age and general condition, ranging from fit young men to steroid dependent frail arthritic patients. The degree of instability and the spinal cord compression are also variable. Gauging these parameters has an important bearing on the anaesthetic management. We present management of six patients with atlanto axial subluxation in our institution.

Anesthetic management of conray toxicity.

Conray (meglumine iothalamate), the contrast media frequently used in shuntograms for diagnosing malfunctioning ventriculo-peritoneal shunts, will occasionally cause severe muscular spasms and seizures. In this article, the authors describe anesthetic and critical care management of a case with this complication.

[Spectrum of psychotropic effects and mechanism of action of ultra low doses of the antibodies to S-100 protein (proproten)]. / Spektr psikhotropnykh effectov i mekhanizm deistviia sverkhmalykh doz antitel k belku S-100 (proproten).

Proproten contains ultra-low doses of affinity purified antibodies to S-100 protein dynamized according to the rules of homeopathy. S-100 is regulator of brain integrative activity and takes part in synaptic processes. In experiment on outbred rats proproten demonstrates significant anxiolytic, antidepressant and antiamnestic effects after single and repeated administration. Proproten is similar to the well-known reference preparations diazepam, amitriptyline and piracetam in activity. Proporten's advantage over these drugs is no sedative, myorelaxation and amnestic effects. Psychotropic effects of proproten are likely to result from modulation of synaptic transmission in limbic structures of brain.

[Anesthesia for cesarean section: drug transfer to fetus during anesthesia].

One case of prenatally diagnosed congenital diaphragmatic hernia was reviewed in terms of the anesthetic managements. Concentrations of diazepam, pancuronium and fentanyl were measured in maternal, fetal and umbilical serum. As expectedly, the transition of diazepam through the placenta was large and the concentration of diazepam in the fetal serum was equal to that of maternal serum, but only a small amount of pancuronium was transferred.