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PubMed1997

Population growth kinetics of Tetrahymena pyriformis exposed to selected nonpolar narcotics.

This study describes effects of selected nonpolar narcotics of varying hydrophobicity (quantified by the 1-octanol-water partition coefficient, log Kow) and molecular structure on the population growth kinetics of the freshwater ciliate Tetrahymena pyriformis. The response of Tetrahymena exposed to different nonpolar narcotics varied from a change in generation time to a change in lag phase with similar generation time compared to control. Two narcotics with high (>3.00), intermediate (>0.00 and <3.00), and low log Kow (<0. 00) values were tested. Growth of Tetrahymena inhibited up to 85% by the high log Kow toxicants (2-decanone and butylbenzene) grew with similar rates as the control, but exhibited increased lag time, suggesting that the protozoan became acclimated to toxicant stress. Results from growth of Tetrahymena in the low log Kow toxicants (ethanol and acetone) indicate an increased generation time with increasing concentration. Cells inhibited by the intermediate log Kow chemicals, 1-pentanol and anisole, exhibited a response that was a combination of the previously mentioned two contrary responses. Cells inhibited <35% with 1-pentanol and <50% with anisole grew with similar generation times as control flasks, whereas in cells inhibited >35% or >50%, respectively, the doubling times were longer than control growth.

Animals↗
PubMed1988

Impact of non-narcotic oral analgesics on pain management.

Of the four categories of oral analgesics, three have been available since the 19th century. Although adequate doses of the more potent oral opioids such as morphine and methadone are effective even in severe pain, the commonly used "weak" narcotics such as codeine and propoxyphene are no more effective than usual doses of aspirin or acetaminophen. Furthermore, the opioids produce gastrointestinal and central nervous system adverse effects, and, during long-term administration, tolerance may develop and there is a risk of drug dependence. Aspirin and acetaminophen are the traditional agents of choice for oral analgesic therapy; until 10 years ago, there were no single-entity, oral analgesics--with the exception of large doses of oral narcotics--that were more effective than usual doses of aspirin or acetaminophen. However, there is a ceiling on the analgesic effect attainable with safe doses of these drugs, which may in part be overcome through the use of the third category of oral analgesics, combinations of aspirin or acetaminophen with oral opioids. The fourth category of oral analgesics constitutes the most important recent development in pain management with analgesic drugs: the newer peripherally acting, nonsteroidal anti-inflammatory analgesics, some of which are clearly more efficacious than aspirin or acetaminophen and compare favorably not only with full doses of narcotic combination products but even, in some cases, with strong injectable opioids. On repeated dosing, some nonsteroidal anti-inflammatory drugs are better tolerated than aspirin and some have a much longer duration of analgesic effect than aspirin or acetaminophen. Further study is needed to compare nonsteroidal anti-inflammatory drugs among themselves and to determine their value in chronic pain and in combination therapy.

Acetaminophen↗
PubMed1975

Congenital malformations of the central nervous system produced by narcotic analgesics in the hamster.

Maternal dose--fetal teratogenic response data were obtained for a variety of narcotic and related compounds by single subcutaneous injections of the drugs into pregnant hamsters during the critical periods of central nervous system organogenesis. The number of abnormal fetuses from females injected with diacetylmorphine (heroin), thebaine, phenazocine, pentazocine, propoxyphene, and methadone increased as the maternal dose of the compounds was increased. By contrast, morphine, hydromorphone, and meperidine produced an increase in the number (per cent) of fetal anomalies only up to a certain maternal dose level. Further increases in maternal dose levels did not produce additional fetal anomalies. Comparative studies of single and multiple maternal doses indicated that diacetylmorphine (heroin) and methadone produced a four- to sixfold increase in fetal anomalies with repetitive doses whereas the percentage of malformed fetuses remained the same with hydromorphone (Dilaudid). The narcotic antagonists nalorphine, naloxone, levallophan, and cyclazocine blocked the teratogenic effects of both single and multiple doses of the narcotics.

Abnormalities, Drug-Induced↗
PubMed1985

Narcotic antagonist-induced hypotension in the spontaneously hypertensive rat.

Intravenous naloxone or naltrexone produced transient, dose-related reductions in the mean arterial pressure (MAP) and heart rate (HR) of urethane-anesthetized spontaneously hypertensive rats (SHRs). Yet these same doses of narcotic antagonists reduced HR but not MAP of normotensive Wistar-Kyoto rats (WKYs). Such effects were not observed upon administration to SHRs of increasing doses of methylnaltrexone, which possesses no central activity. (+)-Naloxone, which does not block opiate receptors, reduced HR but not MAP of both SHRs and WKYs. These findings indicate that SHRs and WKYs differ in their MAP and HR responses to narcotic antagonists. The high doses required for effect plus the brevity of the responses suggest that these drug effects are perhaps not mu-opiate receptor-mediated; however, the methylnaltrexone and (+)-naloxone findings clearly implicate a central specificity of action. We conclude that narcotic antagonist-induced changes in MAP and HR in SHRs are possibly specific and central in origin yet not mediated by mu-opiate receptors.

Animals↗
PubMed1990

Antibodies to morphine in workers exposed to opiates at a narcotics manufacturing facility and evidence for similar antibodies in heroin abusers.

According to the International Narcotics Control Board, over 45,000 kg of morphine and 54,000 kg of codeine were ethically manufactured in 1986 at three facilities in the United States. Little information exists about possible adverse health effects associated with workplace exposure to opiate compounds in this industry. Because there are no specific federal standards for workplace exposure to narcotic dusts, exposure-control defaults to the nuisance dust standard (10 mg/m3, as an 8 hr time-weighted average). Narcotics manufacturing workers were evaluated for anti-morphine IgG before and 10 mo. after the implementation of an improved respiratory protection program (RPP). Significantly elevated IgG levels were measured before the improved RPP (P less than 0.005). After the improved RPP, a significant reduction was observed (P less than 0.001), suggesting that specific antibody levels could be used as biomarkers of exposure. Inhibition studies showed that the antibodies were specifically directed against morphine with some cross reactivity with morphine derivatives. Preliminary results are also shown which indicate that similar anti-morphine antibodies are present in the sera of intravenous heroin abusers. Elevated levels (P less than 0.05) of anti-morphine antibodies were detected in sera from heroin abusers, providing evidence that similar antibodies may be produced from non-occupational exposure to opiates. These finding have potentially far-reaching implications for addiction research and drug testing.

Air Pollution↗
PubMed1994

Vancomycin hypersensitivity: synergism with narcotics and "desensitization" by a rapid continuous intravenous protocol.

BACKGROUND: We examined the clinical spectrum of patients with persistent adverse reactions to vancomycin, assessed contributing factors, and evaluated the efficacy and safety of a rapid continuous intravenous "desensitization" protocol in these patients. METHODS: Seven patients with serious staphylococcal infections resistant to beta-lactam antibiotics whose adverse reactions to vancomycin persisted despite slowing of the vancomycin infusion and pretreatment with H1-antihistamine were studied. All seven patients underwent a rapid continuous intravenous desensitization protocol with multiple small increases in vancomycin concentration tightly regulated with a syringe pump. RESULTS: Most of the seven patients safely achieved, during the first day, a vancomycin infusion rate (VIR) sufficient, or close to sufficient, to provide the desired vancomycin dose. In three patients there appeared to be a threshold VIR beyond which adverse reactions were repeatedly elicited; these reactions abated when the VIR was slightly lowered. Narcotic administration was found to adversely affect treatment with vancomycin. After concurrent narcotic administration was discontinued in three patients, they and the other four patients successfully completed the full course of treatment with vancomycin. CONCLUSION: Patients whose adverse reactions to vancomycin did not respond to slowing of the infusion rate and additional H1-antihistamines can be safely treated with a rapid continuous intravenous desensitization protocol and discontinuance of narcotic administration.

Adolescent↗
PubMed1984

Clonidine treatment of neonatal narcotic abstinence syndrome.

Clonidine hydrochloride, an alpha 2-adrenergic agonists, was used to treat seven infants who were passively addicted to narcotics because of maternal methadone maintenance. In six of seven infants, the major symptoms of narcotic withdrawal were ameliorated after a total daily oral dose of 3-4 micrograms/kg/day was achieved. One infant failed to respond. No toxic side effects of clonidine were observed at the dosage level used. The results of this pilot study suggest that clonidine may be a safe therapeutic agent for the treatment of neonatal narcotic abstinence syndrome (NNAS). Clonidine treatment of NNAS remains strictly investigational at this time. The relative efficacy and safety of clonidine versus other currently used drug regimens for NNAS also remains to be determined.

Administration, Oral↗
PubMed1981

Comparison of the antinociceptive activity of intraventricularly administered acetylcholine to narcotic antinociception.

Intraventricularly administered acetylcholine inhibits mouse tail-flick latency in a dose-dependent manner with an ED50 of about 20 microgram. This antinociceptive activity is not mimicked by biogenic amine neurotransmitters (i.e. norepinephrine, epinephrine, dopamine, serotonin or histamine) and is not markedly affected by selective depletors of brain catecholamines or serotonin. However, pretreatment with reserpine or tetrabenazine dramatically reduces acetylcholine-induced antinociception. Tolerance develops rapidly to the antinociceptive effects of acetylcholine. Cross-tolerance to morphine in acetylcholine-tolerance mice is minimal, but the antinociceptive activity of acetylcholine is markedly reduced in mice chronically pretreated with morphine. Acetylcholine-induced antinociception differs from narcotic antinociception in the reversed stereoselectivity of several narcotic antagonists and in the in vivo pA2 values for inhibition by naloxone. Therefore, the antinociceptive activity of intraventricularly administered acetylcholine cannot be described as a specific narcotic action.

Acetylcholine↗
PubMed1991

Evaluation of a spring-loaded syringe driver for the subcutaneous administration of narcotics.

A simple spring-loaded syringe driver was tested for the subcutaneous administration of narcotic analgesics and antiemetics. With concentrations of 2 to 10 mg/mL of hydromorphone and 10 to 50 mg/mL of morphine, the infusion rate during preclinical testing was 1.01 +/- 0.1 mL/hr (range 0.70-1.2 mL/hr). The rate of infusion was not modified by the concentration of narcotic in solution. Clinical trials were performed with morphine in 17 patients, and with hydromorphone in 11 patients. The duration of the infusion was 21 +/- 11 days. The most frequent reason for discontinuation was death (22 cases). The average duration of the site of infusion was 6.3 +/- 4 days. When used subcutaneously, the rate of infusion of the device was 1 +/- 0.15 mL/hr (range 0.70-1.30 mL/hr). Patients and nurses were satisfied with the simplicity and safety of the device. Cost analysis shows that this device is significantly less expensive than currently available portable infusion devices. We conclude that the Medifuse Pump is an inexpensive, safe and effective device for the subcutaneous infusion of narcotics and antiemetics.

Adult↗
PubMed1991

A cost-minimization study of cancer patients requiring a narcotic infusion in hospital and at home.

We conducted a retrospective, non-randomized, cost-minimization study, from the perspective of the Ministry of Health, to compare the cost of managing cancer patients who required narcotic infusions, in hospital and at home. Our medical costs averaged $369.72 per inpatient day and $150.24 per outpatient day (saving $219.48 per diem, 1988 Canadian dollars), while narcotic costs were the same for any given patient in both settings. Sensitivity analysis showed that no reasonable changes in the quantity and cost of services reduced our savings by more than 50%. During incremental analysis, savings increased as more outpatient days were managed by our centre, from $0.00 for 318 days, to more than $500,000 for over 2000 days per annum. As this program has been extremely cost effective and preferred by our patients, other hospitals and central funding agencies might consider establishing a regional outpatient narcotic infusion program to reduce their costs.

Canada↗
PubMed2004

Narcotic administration and stenosing lesions of the upper airway--a potentially lethal combination.

Two cases are reported where significant narrowing of the upper airway in association with narcotic administration resulted in respiratory compromise and death. Case 1: A 29-year-old woman with upper airway narrowing due to tonsillar enlargement from an Epstein-Barr infection was admitted to hospital, administered morphine and left in a room on her own with the door closed. She was found dead several hours later. At autopsy there was significant narrowing of the upper airway due to tonsillomegaly with a blood morphine level of 0.16 mg/L. Case 2: A 48-year-old woman with severe narrowing of her glottic inlet from recurrent squamous cell carcinoma and an intravenous drug taking history was found dead at her home. At autopsy there was evidence of recent and remote intravenous drug administration with marked narrowing of the glottis due to a recurrent tumor with a blood morphine level of 0.48 mg/L. In both cases, death was due to the effects of severe upper airway narrowing in combination with the respiratory depressant actions of morphine. Additional exacerbating factors may have included muscle weakness, drowsiness and reduced clearance of airway secretions from the effects of morphine. Narcotic administration in individuals with compromised upper airways should be undertaken extremely circumspectly and hospital protocols should ensure constant surveillance if this has been undertaken. Individuals who self administer narcotics should also be made aware of the dangers if there is coincidental upper airway narrowing. Toxicological evaluation in fatal cases of upper airway narrowing/stenosis may be extremely useful in revealing compounding factors such as opiate administration.

Adult↗
PubMed2004

Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy.

We decided to test the hypothesis that possibly by combining a narcotic antagonist and amino-acid therapy consisting of an enkephalinase inhibitor (D-phenylalanine) and neurotransmitter precursors (L-amino- acids) to promote neuronal dopamine release might enhance compliance in methadone patients rapidly detoxified with the narcotic antagonist Trexan (Dupont, Delaware). In this regard, Thanos et al. [J. Neurochem. 78 (2001) 1094] and associates found increases in the dopamine D2 receptors (DRD2) via adenoviral vector delivery of the DRD2 gene into the nucleus accumbens, significantly reduced both ethanol preference (43%) and alcohol intake (64%) of ethanol preferring rats, which recovered as the DRD2, returned to baseline levels. This DRD2 overexpression similarly produced significant reductions in ethanol non-preferring rats, in both alcohol preference (16%) and alcohol intake (75%). This work further suggests that high levels of DRD2 may be protective against alcohol abuse [JAMA 263 (1990) 2055; Arch, Gen. Psychiatr. 48 (1991) 648]. The DRD2 A1 allele has also been shown to associate with heroin addicts in a number of studies. In addition, other dopaminergic receptor gene polymorphisms have also associated with opioid dependence. For example, Kotler et al. [Mol. Phychiatr. 3 (1997) 251] showed that the 7 repeat allele of the DRD4 receptor is significantly overpresented in the opioid-dependent cohort and confers a relative risk of 2.46. This has been confirmed by Li et al. [Mol. Psychiatry 2 (1997) 413] for both the 5 and 7 repeat alleles in Han Chinese case control sample of heroin addicts. Similarly Duaux et al. [Mol. Psychiatry 3 (1998) 333] in French Heroin addicts, found a significant association with homozygotes alleles of the DRD3-Bal 1. A study from NIAAA, provided evidence which strongly suggests that DRD2 is a susceptibility gene for substance abusers across multiple populations (2003). Moreover, there are a number of studies utilizing amino-acid and enkephalinase inhibition therapy showing reduction of alcohol, opiate, cocaine and sugar craving behavior in human trials (see Table 1). Over the last decade, a new rapid method to detoxify either methadone or heroin addicts utilizing Trexan sparked interest in many treatment centers throughout the United States, Canada, as well as many countries on a worldwide basis. In using the combination of Trexan and amino-acids, results were dramatic in terms of significantly enhancing compliance to continue taking Trexan. The average number of days of compliance calculated on 1000 patients, without amino-acid therapy, using this rapid detoxification method is only 37 days. In contrast, the 12 subjects tested, receiving both the Trexan and amino-acid therapy was relapse-free or reported taking the combination for an average of 262 days (p < 0.0001F). Thus coupling amino-acid therapy and enkephalinase inhibition while blocking the delta-receptors with a pure narcotic antagonist may be quite promising as a novel method to induce rapid detox in chronic methadone patients. This may also have important ramifications in the treatment of both opiate and alcohol-dependent individuals, especially as a relapse prevention tool. It may also be interesting too further test this hypothesis with the sublingual combination of the partial opiate mu receptor agonist buprenorphrine.

Adult↗
PubMed1998

Sigmoidal compression rate-dependence of inert gas narcotic potency in rats: implication for lipid vs. protein theories of inert gas action in the central nervous system.

Inert gases at raised pressure exert anaesthetic effects. It is assumed that anaesthesia by the inert gases is fundamentally similar to anaesthesia produced by general anaesthetics. However, do general anaesthetics bind directly to proteins or influence activity by indirectly perturbing membrane lipids still remains a major question. Although the pressure required to achieve anaesthesia with inert gases has been suggested to exert potentially some pressure antagonism per se, this has not been studied yet to our knowledge. We investigated this possibility using nitrogen, argon, and nitrous oxide. Whatever the narcotic agent used, our results showed that the pressure of narcotic required to induce anaesthetic effects increased, as compression rate increased, in a sigmoid fashion rather than in a linear fashion. Evidence for sigmoïdal responses vs. linear responses depended of the narcotic potency of the anaesthetic agent used (nitrogen: r2=0.973 vs. r2=0.941; argon: r2=0. 971 vs. r2=0.866; nitrous oxide: r2=0.995 vs. r2=0.879). Since a linear antagonism is predicted by lipid theories, we think it likely that these findings indicate that inert gases bind to a modulatory site of a protein receptor and act as allosteric modulators. Since other workers provided evidence for binding processes using volatile anaesthetics, the present findings could indicate that all classes of general anaesthetics, including inert gases, could act by binding directly to proteins rather than by dissolving in some lipids of the cellular membrane.

Anesthetics, Inhalation↗
PubMed1992

Alcohol and narcotics. Epidemiology and pregnancy risks.

Among alcohol and narcotics, alcohol is most comprehensively documented as a teratogen. However, for all other narcotics, data are continuously accumulating, convincingly displaying the teratogenic effects. The proportions between "somatic" teratogenicity and "behavioral" teratogenicity vary between the different agents. Preventive work in prenatal clinics and among social workers, as well as objective mass media attention to the problem, seems to have lowered the incidence of severe fetal alcohol syndrome where the above-mentioned activities have been practiced. The female alcohol consumption in Sweden decreased from 1976 to 1985; thereafter, a slow continuous increase is underway again. In Sweden the number of recruits to narcotic abuse peaked in the 1970s and early 1980s. Thereafter, the number of recruits among females decreased, but abuse has continued among the members of the older age groups.

Alcohol Drinking↗
PubMed2003

Patients discharged with a prescription for acetaminophen-containing narcotic analgesics do not receive appropriate written instructions.

To determine whether patients given prescriptions for acetaminophen-containing narcotic analgesics receive appropriate discharge instructions to reduce their intake of or stop taking other acetaminophen-containing products, we evaluated discharge instructions given by an urban, tertiary-care emergency department from September 1 to September 18, 2001 to find patients discharged while taking narcotic-analgesic compounds containing acetaminophen. We evaluated these discharge instructions to determine whether they included instructions to reduce or discontinue the use of acetaminophen compounds. Among the 1,505 discharge instructions evaluated, we found that 108 patients were discharged with a narcotic-analgesic combination product containing acetaminophen. Of these 108 patients, none of those given a prescription for such an acetaminophen-containing product was instructed to reduce or discontinue the use of other acetaminophen products. Emergency physicians, during the specified study period, did not explain to their patients the need to reduce the use of other acetaminophen-containing products when prescribing acetaminophen-containing medications. Further inquiry into this potentially dangerous activity is warranted.

Acetaminophen↗
PubMed1982

Dural permeability to narcotics: in vitro determination and application to extradural administration.

The permeability of cranial and lumbar dura to various substances including a number of narcotic analgesics was measured in vitro. Preliminary data On human postmortem material is reported. Permeability had a linear relation to the inverse of the square root of molecular weight. This is the expected relationship for a diffusion process dependent upon molecular weight. The differential mass selectivity coefficients for lumbar and cranial dura were calculated; they were similar at 0.8 and 0.9. This was greater than for diffusion in simple liquids, but much less than that for biological lipid membranes. This suggests that the low rates of diffusion are a property of the thickness of the dura rather than any inherent impermeability. A simple model for the dural transfer of drugs is described, and applied to narcotics. Its purposes were to suggest: the factors involved in the dural transfer of drugs; the physicochemical properties of drugs relevant to their dural transfer; worthwhile measurements in future studies. The model indicates that drug molecular weight and rate of absorption are important determinants of the efficiency of dural transfer. Low molecular weight and slow absorption produce high dural transfers. When applied to narcotics, these factors could produce a difference of up to an order of magnitude in the amount transferred directly across the dura.

Absorption↗
PubMed1986

Narcotics do not alter the heat response of unmyelinated primary afferents in monkeys.

Recent reports of opiate receptors in the peripheral nervous system have led to the hypothesis that the analgesic action of opiates might, in part, result from a reduction in response of peripheral nerve fibers thought to be concerned with signaling pain (nociceptive afferents). The authors examined the effects of the narcotics, fentanyl (up to 30 micrograms/kg, iv) and morphine (1 mg/kg, iv), on the response of single unmyelinated afferents (C-fiber nociceptors and warm fibers), recorded in monkeys, to heat stimuli applied to their receptive fields. Neither narcotic affected the response of the afferents. In addition, naloxone did not affect their response. Thus, an alteration of cutaneous nociceptor response is unlikely to contribute to the analgesic action of narcotics.

Action Potentials↗
PubMed1978

Bacterial endocarditis in narcotic addicts: analysis of arterial blood gases.

We studied the arterial blood gas determinations done on the first hospital day in 14 narcotic addicts with bacterial endocarditis (group 1) and six addicts with other medical complications of narcotic addiction (group 2). The arterial oxygen tension (PaO2) was 67.3 +/- 3.3 mm Hg (SEM) in group 1, and 75.0 +/- 6.4 mm Hg in group 2, with no statistically significant difference (P less than .20) between the groups. The arterial CO2 tension (PaCO2), 27.8 +/- 1.7 mm Hg, in group 1 was significantly lower (P less than .005) than that of group 2, 40.1 +/- 3.7 mm Hg. The arterial blood pH, 7.47 +/- 0.01 units, in group 1 was significantly higher (P less than .025) than that of group 2, 7.36 +/- 0.06 pH units. Abnormal blood gas values were found in each of the patients in group 1 with a normal admission chest roentgenogram. Arterial blood gas determinations may be useful in the initial examination of ill narcotic addicts.

Carbon Dioxide↗