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Patterns of growth and development in narcotic-exposed children.

The results of the studies reviewed indicate that intrauterine growth is adversely affected by drug use during pregnancy. Whether the impairment is a direct effect of narcotic exposure or is the result of the interaction of deleterious health, environmental, and socioeconomic factors closely associated with the lifestyle of the woman who abuses drugs cannot be determined at present. Reports on the long-term effects of drug use on growth and intellectual functioning in the offspring of women who abuse drugs are not consistent. While some studies indicate that most of the exposed infants exhibit catchup growth by 6 months of age (Lifschitz et al. 1983, 1985), one methodologically strong study suggests that methadone may have a small direct teratogenic effect reflected in reduced head size at 2 years of age (Hans 1989). Unexplained is the pattern of growth deceleration observed in some narcotic-exposed children (Lifschitz et al. 1983, 1985). The few available reports on long-term outcome concur that narcotic-exposed children have a high incidence of behavioral and learning problems (Strauss et al. 1979; Rosen and Johnson 1985; Wilson 1989), but population studies have been too small to demonstrate that they differ significantly from controls. There is a suggestion that narcotic use during pregnancy promotes a biological vulnerability to adverse environments, manifested in the neurobehavioral and intellectual areas.

Child↗

An in vivo assay for the analysis of the biological potency and structure-activity relationships of narcotics: serum testosterone depletion in the male rat.

An in vivo method for the assessment of the agonistic-antagonistic activities and structure-activity relationships of the narcotics is described. The method, which is based on the depletion of serum testosterone levels by the narcotics in the male, satisfies all of the criteria necessary for a valid narcotic assay: 1) The ability of the narcotics to deplete serum testosterone levels is stereospecific; 2) naloxone competitively inhibits their effects; 3) and the relative potencies of the drugs in depressing serum testosterone levels parallels their activity in inhibiting electrically induced contractions of the guinea-pig ileum, the binding of [3H]opiates to "receptors" in rat brain homogenates and their relative effectiveness as analgesics. Although only rats were used in the current studies, the method can be easily adapted for use in any species, including man.

Analgesics, Opioid↗

Patterns of rates of mortality from narcotics and cocaine overdose in Texas, 1976-87.

Drug overdose mortality data for narcotics and cocaine for Texas for 1976-87 reveal a cyclic pattern of narcotics mortality falling from 0.92 per 100,000 population in 1976 to a low of 0.13 in 1979, and rising to 0.62 in 1986. The data also show a sharp increase in cocaine mortality from 0.07 per 100,000 in 1983 to 0.38 in 1987. The data indicate that men consistently are at higher risk than women for overdose from both categories of drugs. Hispanics in the El Paso and San Antonio areas were found to have much higher risk of mortality from narcotics than expected, while blacks in the Houston and Dallas areas were at higher risk of cocaine mortality. The evidence suggests that narcotics and cocaine mortality is highest among the blue collar categories of the work force. The cyclical pattern of drug overdose mortality suggests the need for more examination of the historical interplay of public policies and social factors against the magnitude of the drug problems. The differences in mortality patterns by sex, ethnicity, and location indicate the need to develop policies and programs that address the unique characteristics of different at-risk populations.

Adult↗

Pharmacology and physiology of narcotics.

Narcotics are explored in this section. Receptor theory is presented. Narcotics are broken into their specific groups (agonist, agonist-antagonist, and pure antagonist) and compared. Narcotic effects, desirable and undesirable, are related to organ systems and common problems found in ICU patients. Pharmacokinetics of classic methods of narcotic delivery are discussed and compared to newer technologies of delivery. Finally, a strategy for decision making in pain control, tying together all the concepts previously discussed, is given.

Humans↗

Efficacy and tolerance of narcotic analgesics at the mu opioid receptor in differentiated human neuroblastoma cells.

Upon differentiation with retinoic acid of the human neuroblastoma cells SH-SY5Y into mature neurons, opioid drugs become highly effective in suppressing prostaglandin E1 (50% inhibition)- and forskolin (70% inhibition)-stimulated adenylate cyclase activity, which was assessed by measuring cyclic AMP accumulation in intact cells. Whereas the SH-SY5Y cells carry both mu and delta receptors in a ratio of mu/delta approximately equal to 5/1, the response is predominantly mediated by the mu receptor. Morphine acts as a strong agonist with an EC50 of 50 to 100 nM which falls into the therapeutic range expected for narcotic analgesic effects mediated by the mu receptor. Narcotic analgesic drugs with only partial agonism fail to evoke full response, which suggests that this cell model could provide a rapid screening assay for narcotic analgesic efficacy. Continued exposure of the cells to morphine resulted in partial tolerance within 12 hr with a 4-fold shift of morphine's EC50 to higher concentrations, whereas longer morphine exposure did not cause any further shift. Thus, the differentiated SH-SY5Y cells provide a suitable system for studying the molecular mechanisms of the narcotic analgesics.

Adenylyl Cyclases↗

The pharmacology of 20681-S and 20682-S, 6-oxo-N-cyclopropylmethylmorphinans, as narcotic antagonist analgesics.

It has been demonstrated that L-3hydroxy-6-oxo-N-cyclopropylmethylmorphinan methansulfonate (20681-S) and L-3,14-dihydroxy-6-oxo-N-cyclopropylmethylmorphinan methansulfonate (20682-S), have antinociceptive and narcotic antagonistic properties. In the rodent antinociceptive test, the action of 20681-S was more potent and of longer duration than that of morphine and of cyclazocine after subcutaneous or oral administration. The antinociceptive effect of 20682-S ranked between that of morphine and that of pentazocine in the mouse acetic acid-writhing test. Both compounds possessed potent narcotic antagonistic activities, 20682-S being more active than naloxone and oxilorphan and 20681-S being equipotent with cyclazocine. The latent side effects (respiratory depression and fall in blood pressure) and the acute toxicity of 20681-S and 20682-S, were less than those of reference narcotic antagonists or of narcotic antagonist analgesics.

Analgesics↗

A rapid, quantitative in vivo assay for narcotic antagonists.

Tail skin temperature (TST) response of morphine-dependent rats was evaluated as a potential in vivo assay for the activity of narcotic antagonists. Dependency was produced in rats by repeated subcutaneous implantation of morphine-containing pellets and TST was evaluated by thermistor probes attached to the dorsal surface of the tail. TST was determined prior to and following administration of either naloxone (NAL: 0, 0.01, 0.1, 0.5 or 1.0 mg/kg body weight); naltrexone (NALT: 0.001, 0.005, 0.01, 0.02 or 0.1 mg/kg body weight); or 6-Desoxy-6-methylenenaltrexone (DM-NALT: 0.001, 0.005, 0.01, 0.02 or 0.1 mg/kg body weight). Each of the narcotic antagonists caused a dose-dependent increase in tail skin temperature in morphine dependent rats. The initial TST increase was observed by 5 minutes and the maximal TST response occurred 15 to 25 minutes after drug administration. For each drug evaluated, a linear relationship was observed between the dose and maximal change in TST and between the dose and the area under the TST response curve. Determination of ED50 for the TST response revealed the expected relative potency for the narcotic antagonists evaluated: DM-NALT greater than NALT greater than NAL. Thus, the TST-response test is a rapid and quantitative bioassay for the evaluation of compounds for narcotic antagonistic activity.

Animals↗

Cholangiographic demonstration of relief of narcotic-induced spasm of the sphincter of Oddi.

Narcotics are known to cause spasm of the sphincter of Oddi. This spasm may be difficult to distinguish from obstruction of the distal common bile duct on operative cholangiograms in cases where narcotics are used perioperatively. A case is presented in which narcotic-induced spasm of the sphincter of Oddi, clearly demonstrated in an operative cholangiogram, is reversed by a narcotic antagonist, thereby avoiding an unnecessary common duct exploration.

Adult↗

Dose- and time-dependent effects of narcotic analgesics on intracranial self-stimulation in the rat.

Rats were trained to bar-press in order to obtain electrical stimulation of the medial forebrain bundle through chronically implanted electrodes. Dose-response and time-effect curves were determined for morphine (1.0-30 mg/kg), levorphanol (0.1 to 3.0 mg/kg), methadone (0.1-3.0 mg/kg), meperidine (1.0-30 mg/kg), oxymorphone (0.03-1.0 mg/kg), and d-amphetamine (0.1-3.0 mg/kg). Dose-response and time-effect curves were also determined for morphine (1.0-30 mg/kg) in rats that had received multiple injections of morphine over a period of 3 days. All of the narcotic analgesics produced dose-related decreases in responding; the durations of these decreases were also dose-related. The relative potencies of the five narcotic analgesics with respect to the rate-decreasing effects for selt-stimulation responding were: oxymorphone greater than levorphanol greater than methadone greater than morphine greater than meperidine. In morphine-tolerant rats the rate-decreasing effects of morphine on responding for selt-stimulation were attenuated. These findings suggest that narcotic analgesics from diverse chemical families have a similar, predominantly depressant, effect on self-stimulation behavior and that the relative potencies of a series of narcotics for this effect are similar to those demonstrated for other properties of these drugs.

Analgesics, Opioid↗

Peptidase inhibitors reduce opiate narcotic withdrawal signs, including seizure activity, in the rat.

Narcotic withdrawal was precipitated by administration of naloxone in a low dose at 2 h after the final dose of morphine in a 9-day dependency-inducing schedule. Withdrawal was characterized by leaps, increased nocifensor activity and by cerebral cortical epileptiform activity, the latter not generally reported to be prominent in narcotic withdrawal. Single large doses of morphine did not provoke epileptiform activity at 2 h postinjection but did induce an acute opioid dependency wherein a moderately high dose of naloxone, ineffective in non-dependent rats, provoked upward leaping and electrocortical epileptiform activity. Pretreatment of the 9-day dependent rats with peptidase inhibitors, administered intracerebroventricularly, significantly reduced withdrawal severity including the epileptiform activity. We propose that peptidase inhibitors protect certain species of endogenous opioids and/or other neuropeptides that tend to suppress expression of the narcotic withdrawal syndrome. Furthermore, our findings suggest that epileptiform activity is a nascent form of cerebral activity hitherto largely unnoticed in narcotic withdrawal and that neuropeptides may be involved in certain epileptic states.

Animals↗

Nociception in mice after chronic stress and chronic narcotic antagonists during maturation.

The effects of chronic, mild stress and chronic narcotic antagonism during maturation of mice on the sensitivity to pain and to the analgesic effect of morphine were examined. Analgesia was measured using the tail-flick assay. Chronic stress, produced simply by the subcutaneous injection of mice twice daily with saline starting day 5 postpartum, produced an increased in the sensitivity of these mice, when mature, to the analgesic effect of morphine. A similar schedule of saline injections for 4 weeks in adult mice did not alter the sensitivity of those mice to the analgesic effects of morphine. Chronic injections of narcotic antagonists during maturation did not produce an effect on morphine analgesia different from that after chronic injections of saline. However chronic exposure to narcotic antagonists since conception, compared to chronic injections since day 5 postpartum in the offspring, did produce differential effects on the control tail-flick latencies such that naloxone during gestation decreased, while naloxone during gestation and postpartum increased tail-flick latencies. These data suggest that exposure to chronic stress during early development is responsible for an altered sensitivity to narcotic analgesics while exposure to naloxone during maturation affects pain perception.

Aging↗

Antecedents of narcotic use and addiction. A study of 898 Vietnam veterans.

Previous studies of predictors of narcotic abuse have been retrospective and based on samples of long-term addicts obtained from legal or medical channels. There are several methodological problems in this approach. The present study is an attempt to test certain alleged predictors of narcotic use in a cohort of 898 Vietnam veterans. The design overcomes several of the methodological weaknesses of previous studies. Eight variables which have been reported as predictors of drug use or addiction in the drug literature were inquired about during a personal interview which included the premilitary life of each subject. The antecedent variables were socioeconomic background, inner city residence, psychiatric illness, broken home, race, employment history, education and antisocial history. Using information obtained from interviews and military records, we then tested the predictive value of each of these antecedents by comparing narcotic used and addiction in Vietman and use after Vietnam in men differing with respect to each antecedent. Results indicate that some of the variables were very poor, and others very good predictors of the various levels of narcotic involvement. The predictive value and overall importance of each of the variables we tested are discussed.

Adult↗

Femoral nerve block as an alternative to parenteral narcotics for pain control after anterior cruciate ligament reconstruction.

Anterior cruciate ligament (ACL) reconstruction is associated with significant postoperative pain, usually requiring parenteral narcotics. A prospective study of arthroscopically assisted autograft patellar tendon ACLR was initiated using Winnie's "three-in-one" femoral nerve block (FNB) as the primary means of postoperative pain control. Patient satisfaction and absence of parenteral narcotic use indicated clinical success. Of 24 patients studied, 92% had no parenteral narcotics administered following FNB. Ninety-five percent of patients believed FNB was beneficial and would request another. The average duration of pain control was 29 hours and the majority of patients (79%) believed discharge was possible within 23 hours. There were two patients who failed to respond to FNBs (8%) and no major complications. FNB is a safe, reliable, and effective form of analgesia following ACLR, eliminating the need for parenteral narcotics.

Administration, Oral↗

Neonatal narcotic abstinence: Effects of pharmacotherapeutic agents and maternal drug usage on nutritive sucking behavior.

An uncoordinated and ineffectual sucking reflex is a major manifestation of neonatal narcotic abstinence and may have important consequences for the infant's subsequent well being. Measures of nutritive sucking were used to monitor the severity of neonatal narcotic abstinence in a series of infants born to narcotic-dependent mothers who were either attending the methadone clinic or else were "street addicts." In all these infants, sucking measures were significantly reduced relative to normal control subjects. Furthermore, the sucking behavior of infants born to mothers attending the methadone clinic was significantly more depressed than that of infants born to street addicts. In regard to the salutary effects of pharmacotherapy for neonatal narcotic abstinence, infants treated with paregoric approached normal control levels and showed significantly better sucking than those treated with phenobarbital or diazepam. The latter drug practically eliminated all spontaneous nutritive sucking behavior.

Diazepam↗

The effect of maternal narcotic addiction on the newborn infant.

This paper presents a review of the literature on the effects of maternal narcotic addictions upon the foetus and newborn infant. Six children born to 'registered' narcotic addicts were studied, and particular attention was paid to any signs of narcotic withdrawal that might occur after birth. Although all the mothers took heroin or methadone regularly up to the time of delivery, minor physical signs which might have been considered part of the withdrawal syndrome occurred in only one baby. The absence of major withdrawal signs found in this study contrasts with previous findings. The reasons for these differences are discussed, and the implications of these observations for the management of the pregnant narcotic addict and her newborn infant are considered.

Abnormalities, Drug-Induced↗

Predictive value of intrathecal narcotic trials for long-term therapy with implantable drug administration systems in chronic non-cancer pain patients.

This study retrospectively investigated the predictive value of intrathecal narcotic trials for long-term drug utilization via implantable pumps in chronic non-cancer patients. Data were derived from 86 patients who were categorized according to the intrathecal narcotic dose that resulted in the optimal trial response. The response during the trial period and the pattern of long-term utilization of morphine was studied, as was the impact of age, gender and diagnosis. The analysis revealed that low dose responders had lower daily dose requirements at 18 months than standard dose and high dose responders. It also showed that women had lower total daily dose requirements at 18 and 24 months and that individuals over 65 years of age had lower total daily dose requirements at 18 months. A trend toward a disproportionately higher use of adjuvant drugs and narcotic substitutions was found among high dose responders, while a trend toward a disproportionately higher total daily dose was found among cervicalgia patients. The findings indicate that the responsiveness to an intrathecal narcotic during a trial, along with the diagnosis at the time of implantation, and the patient's age and gender can shed light on the long-term utilization of intrathecal analgesics in chronic non-cancer patients. This information may be used to better select patients and design trials that more closely reflect long-term drug utilization.

Journal Article↗

Brief courses of palliative radiotherapy for metastatic bone pain: a pilot cost-minimization comparison with narcotic analgesics.

The use of radiotherapy to treat metastatic bone pain is being challenged by claims of high cost and by more readily available, noninvasive treatment approaches. The authors assessed the effectiveness of brief courses of radiotherapy in reducing pain and estimated cost data for a pilot comparison between radiotherapy and narcotic analgesics in patients with cancer. A representative group of outpatients undergoing brief courses of radiotherapy with Karnofsky scores above 70 and without serious comorbidities were recruited from 1995 through 1996. Patients indicated their pain at rest and with movement on a scale of from 1 to 10 both before and up to 12 months after radiotherapy. Radiotherapy costs were estimated from Medicare-allowable charges. Narcotic analgesia costs were estimated from published values. In 66 patients with 131 individually treated sites, median at rest pain score decreased by about 4 points after treatment (5.58 [-/+3.28] before treatment vs. 1.55 [-/+1.8] after treatment; p < 0.05). Median with movement pain score was about 5 points lower after treatment (7.32 [-/+2.72] before treatment vs. 1.94 [-/+2.07] after treatment; p < 0.05). No differences were found when stratifying by type of pain, tumor histologic type, or skeletal site. The estimated cost per patient ranged from $1,200 to $2,500 for radiotherapy. This compares with an estimated cost of $9,000 to $36,000 for 9 months of narcotics. In this pilot study, a brief course of radiotherapy significantly reduced pain and appeared to be cost effective when compared with narcotic analgesia. A full economic evaluation is warranted.

Aged↗