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Physicians are frequently thought to be a major source of opioids diverted for non-therapeutic purposes, largely because it is so difficult for them to discern which patients might abuse them. In this study we sought to determine whether... more
Physicians are frequently thought to be a major source of opioids diverted for non-therapeutic purposes, largely because it is so difficult for them to discern which patients might abuse them. In this study we sought to determine whether those who were first exposed to an opioid through a physician's prescription, and subsequently developed a substance use disorder, had a history of using psychoactive drugs prior to abusing opioids. Patients entering one of 125 drug treatment programs across the country for opioid abuse were asked to provide detailed histories of psychoactive drug use prior to their initial opioid exposure. Nearly half (47.1%, N=4493) indicated they were first exposed to opioids through a prescription from their physician to treat pain. Of these, 94.6% indicated experience with at least one other psychoactive substance (mean=4.55±0.05) prior to, or coincident with, their first exposure to an opioid from a physician. Alcohol (92.9%), nicotine and/or tobacco (89.5%), and marijuana (87.4%) were used by nearly all patients prior to, or coincident with, their first opioid prescription. If one excludes these drugs, 70.1% (N=2913) still reported some psychoactive drug use of licit or illicit stimulants (77.8%), benzodiazepines (59.8%) or hallucinogens (55.2%). Our results indicate that pain patients who developed a substance use disorder were rarely drug naïve prior to receiving their first opioid prescription. Rather, most have an extensive history of psychoactive drug use. As such, physicians should routinely ascertain complete licit and illicit drug histories in patients for whom they prescribe opioids.
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Rural areas of the United States have been disproportionately impacted by the opioid epidemic, exacerbated by COVID-19-related economic upheavals. While polysubstance use is an important determinant of overdose risk, variability in... more
Rural areas of the United States have been disproportionately impacted by the opioid epidemic, exacerbated by COVID-19-related economic upheavals. While polysubstance use is an important determinant of overdose risk, variability in polysubstance use as a result of numerous factors (e.g., access, preference) has yet to be described, particularly among rural persons with opioid use disorder (PWOUD). Survey data on past-month use of prescription and illicit opioids and 12 non-opioid psychoactive drug classes were analyzed from a national sample of rural (n = 3872) and urban (n = 8153) residents entering treatment for OUD from 2012 to 2019. Trend analyses for opioid and stimulant use were compared between rural and urban PWOUD. Latent class analyses assessed substance use trends through identified typologies of rural/urban PWOUD, which then underwent comparative analyses. By 2019, prescription opioid use remained greater in rural versus urban PWOUD, and methamphetamine use showed greater growth in rural, compared to urban areas. Latent class analyses identified variability in polysubstance use, with five identical subgroups in rural/urban PWOD: high polysubstance, polyprescription, prescription opioid-focused, prescription opioid-focused with polysubstance use, and illicit opioid-focused. Polyprescription was highest in rural areas, with illicit opioid-focused use highest in urban areas. Demographic characteristics, co-morbid conditions and healthcare coverage were all associated with between-group differences. There is significant variability in polysubstance use that may identify specific prevention and treatment needs for subpopulations of OUD patients: interventions focused on reducing opioid prescriptions, early engagement with mental health resources, wider distribution of naloxone, and screening/treatment plans that take into account the use of multiple substances.
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Research Interests: Social Media, Pharmaceutical Chemistry, Medicine, Prescription drug misuse, Population, and 11 moreHumans, Substance Abuse, United States, Female, Male, Oxycodone, Drug Compounding, Delayed-Action Preparations, Surveys and Questionnaires, Psychology and Cognitive Sciences, and Medical and Health Sciences
Objectives Efforts to improve low naloxone uptake to mitigate the current opioid crisis have included coprescribing naloxone with opioid medications and, more recently, expansion through over-the-counter availability, the latter of which... more
Objectives Efforts to improve low naloxone uptake to mitigate the current opioid crisis have included coprescribing naloxone with opioid medications and, more recently, expansion through over-the-counter availability, the latter of which necessitates self-identification of overdose risk by consumers. This study sought to understand perceptions of opioid overdose risk and naloxone among distinct opioid populations at elevated risk for overdose. Methods A cross-sectional, online survey was provided to 2 opioid populations in June 2020. First, chronic pain opioid managed (CPOM; n = 190) individuals currently treated with an opioid prescription (either >50 daily morphine milligram equivalents [73.2%] or benzodiazepine co-use [52.6%]), restricted by confounders. Second, individuals with a history of opioid use disorder (OUD; n = 152) previously participating in a national opioid surveillance study of new entrants to substance use treatment centers. Results Risk perceptions significantly differed, with 60.0% (CPOM) versus 28.9% (OUD) reporting that they were “not at all concerned about overdosing,” and 62.1% (CPOM) versus 19.1% (OUD) perceiving themselves as having “no risk” of overdose. Perceived need for naloxone was lower among CPOM versus OUD patients (48.3% and 71.8%, respectively), whereas 22.6% and 35.0%, respectively, indicated any likelihood of obtaining naloxone in the future. Conclusions Results suggest that a significant proportion of both samples lacked the ability to self-identify their risk of overdose and self-select themselves as needing naloxone, with gaps being more prominent in the CPOM sample. A multi-intervention framework that addresses distinct pathways of behavioral change between unique opioid populations should be considered in conversations surrounding potential transitions to over-the-counter naloxone.
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Research Interests: Business, Pain, Medicine, Substance Use, Social and Behavioral Sciences, and 11 moreOxycodone, Socioeconomic Status, Arts and Humanities, Prescription Opioids, Hydrocodone, Oxymorphone, Hydromorphone, Tapentadol, Psychology and Cognitive Sciences, Medical and Health Sciences, and Medical prescription
Buprenorphine was approved in late 2004 for the treatment of opioid abuse and dependence in specially trained and certified physicians' offices. At... more
Buprenorphine was approved in late 2004 for the treatment of opioid abuse and dependence in specially trained and certified physicians' offices. At the time of the approval, there was a regulatory concern that given the anticipated wide exposure there would be unexpectedly high levels of abuse in the high-risk population for which it was intended. To assess its abuse potential, the authors recruited more than 1000 individuals seeking treatment for prescription opioid abuse from 100 stand-alone (i.e., self-pay or insurance) drug abuse treatment programs around the country to determine whether they misused buprenorphine in the past 30 days to get high. The results indicate that there was a time-related increase in the number of subjects who used buprenorphine to get high, reaching 30-35 percent of individuals completing a questionnaire in the second quarter of 2006. At this time, it was equivalent to the misuse of methadone, both of which, however, were considerably lower than hydrocodone and oxycodone. Thereafter, the number of individuals using buprenorphine to get high dropped in a near linear fashion to less than 20 percent of those completing a questionnaire in the second quarter of 2007, significantly lower than that for methadone, oxycodone, and hydrocodone. The most likely interpretation of these data is that the poly-substance-abusing population, for whom buprenorphine is intended, experimented with this medication for its mood-altering effects for a period of time, but presumably because of its lack of euphorogenic properties, its use has now dissipated. Additionally, support for this conclusion is the very rare endorsement of buprenorphine as a primary drug (<3 percent of the total sample). Thus, the results indicate that it is unlikely that buprenorphine abuse will ever reach the epidemic that was feared by some regulatory groups and that its use in opioid detoxification and maintenance should continue.
Research Interests: Risk assessment, Medicine, Affect, Population, Humans, and 15 moreSubstance Abuse, United States, Female, Male, Buprenorphine, Oxycodone, Clinical Sciences, Questionnaires, Methadone, Adult, Public health systems and services research, Time Factors, Risk Assessment, Hydrocodone, and Drug prescriptions
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Research Interests: Psychiatry, Treatment, Medicine, Anxiety, Humans, and 15 moreToxicity, United States, Exploration, Drug Withdrawal, Tramadol, Risk factors, Drug abuse, Adverse Event, Kindling, Risk Factors, ANXIETY, Food and Drug Administration, Psychology and Cognitive Sciences, Medical and Health Sciences, and Substance Withdrawal Syndrome
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Morphine and naloxone exert age-dependent effects on secretion of luteinizing hormone (LH) in the male rat. Morphine suppresses LH secretion at very early stages of development, well before puberty, whereas naloxone does not increase LH... more
Morphine and naloxone exert age-dependent effects on secretion of luteinizing hormone (LH) in the male rat. Morphine suppresses LH secretion at very early stages of development, well before puberty, whereas naloxone does not increase LH until after puberty. The mechanisms underlying these age-dependent effects of opiates on the hypothalamic-pituitary-gonadal axis in pre- and postpubertal rats are poorly understood at the present time. The purpose of the present studies was to examine one plausible explanation of these effects: that morphine and naloxone act through different receptors in the pubescent male rat than they do in adults to influence LH secretion. Specifically, we examined whether naloxone blocks the effects of morphine on LH in prepubescent and adult rats which would be anticipated if both drugs were exerting their effects on LH via the same opiate receptor. Surprisingly, we found that naloxone did not reverse the effects of morphine on serum LH levels in the prepubescent animal, although it fully reversed this effect in adults. This non-naloxone-reversible effect of morphine appeared to be specific to LH, since naloxone antagonized morphine's effects on several other hormones (e.g., prolactin and corticosterone) and completely attenuated morphine's antinociceptive activity in prepubescent rats. Additionally, naloxone precipitated a withdrawal syndrome in the prepubescent morphine-dependent animal that was quantitatively and qualitatively the same as in adults.(ABSTRACT TRUNCATED AT 250 WORDS)
Research Interests: Endocrinology, Aging, Drug interactions, Medicine, Prolactin, and 15 moreInternal Medicine, Pubmed, Animals, Corticosterone, Male, Morphine, Rats, Amino Acid Sequence, Sensitivity and Specificity, Naloxone, Luteinizing Hormone, Opiate, Nociceptors, Molecular Sequence Data, and Pharmacology and pharmaceutical sciences
Abuse-Deterrent Formulations of Prescription Opioids To the Editor Cicero and Ellis1 reported that 25% to 30% of individuals entering a group of substance abuse treatment centers endorse the reformulated OxyContin as a drug they had... more
Abuse-Deterrent Formulations of Prescription Opioids To the Editor Cicero and Ellis1 reported that 25% to 30% of individuals entering a group of substance abuse treatment centers endorse the reformulated OxyContin as a drug they had abused in the previous 30 days. Although Cicero and Ellis1 reported that the rate of endorsement of OxyContin fell from 46% to 25%, the popular press has portrayed the report as evidence that abuse-deterrent formulations are ineffective. The Survey of Key Informants’ Patients (SKIP) program on which Cicero and Ellis1 reported is one part of the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) system, a national multicomponent surveillance system focusing specifically on the abuse and diversion of prescription drugs.2 The analysis omitted that the number of OxyContin endorsements by individuals in the SKIP program has fallen from an average of 0.273 abuse endorsements per 100 000 population 1 year prior the reformulation to 0.157 per 100 000 population in the second quarter of 2014, indicating a 42% decline. Another RADARS program, the Opioid Treatment Program (OTP), shares with SKIP identical questions regarding drugs the respondent has abused in the previous 30 days. The OTP represents a slightly different population—individuals entering substance abuse programs that use medical substitution therapy such as methadone or buprenorphine. In the OTP, the number of OxyContin endorsements has fallen from an average of 0.593 abuse endorsements per 100 000 population 1 year prior to the reformulation to 0.172 per 100 000 population, marking a 71% decline. We conclude that the abuse-deterrent formulations are indeed effective at reducing diversion and abuse. This conclusion is also supported by evidence from other research.3,4 Finally, the RADARS system also includes surveillance programs including drug diversion and poison centers.2 In these programs, diversion and intentional abuse of OxyContin have decreased 53% and 38%, respectively, in the first 2 years after reformulation and have subsequently decreased further.5 Abuse-deterrent formulations of prescription opioids are one effective measure to reduce prescription drug abuse. They are not a panacea, but they offer the promise of discouraging individuals who decide to crush their medication for the purpose of abuse.
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The effects of a single morphine pellet (75 mg) implanted in developing male rats at 27 days of age on reproductive endocrine parameters were compared to those found in adult (65-day-old) animals after the same treatment. The pellets were... more
The effects of a single morphine pellet (75 mg) implanted in developing male rats at 27 days of age on reproductive endocrine parameters were compared to those found in adult (65-day-old) animals after the same treatment. The pellets were left in place to provide the release of morphine during critical phases of puberty and sexual maturation and to prevent an abrupt withdrawal syndrome upon pellet removal which would confound our results. Developing rats were sacrificed at representative intervals after pellet insertion to assess the development of key indices of reproductive endocrinology; adult rats were sacrificed at the same time intervals to permit an evaluation of age-related differences in the sensitivity to opiate-induced endocrine disturbances. Our results showed that morphine markedly influenced a number of endocrine parameters associated with the maturation of the hypothalamic-pituitary-gonadal axis in developing rats for prolonged periods of time, whereas the effects of the opiate in the adult rat were relatively modest and transient. In the developing rat, serum luteinizing hormone (LH), testosterone, the wet tissue weights of the seminal vesicles and testes and hypothalamic LH-releasing hormone (LHRH) levels were substantially depressed immediately after pellet implantation and these effects persisted for up to 4 weeks when compared to placebo-implanted, age-matched controls. In contrast to these results, adult rats showed only transient effects (less than 1 week) of morphine on certain reproductive endocrine parameters (e.g., serum LH, testosterone and the weights of the seminal vesicles) and no effects on others (e.g., testes weights and hypothalamic LHRH).(ABSTRACT TRUNCATED AT 250 WORDS)
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The opiate agonist morphine caused a dose- and time-dependent suppression of lordosis responding in ovariectomized guinea pigs treated with estradiol-17 beta and progesterone. The suppression of lordosis by morphine appears to be mediated... more
The opiate agonist morphine caused a dose- and time-dependent suppression of lordosis responding in ovariectomized guinea pigs treated with estradiol-17 beta and progesterone. The suppression of lordosis by morphine appears to be mediated by opiate receptors since the opiate antagonist naloxone blocked its effects both in terms of the percentage of animals showing lordosis and the duration of individual responses. Naloxone, when given alone, did not affect lordosis responding in estradiol-17 beta + progesterone-primed animals and did not induce lordosis in animals primed with estradiol-17 beta alone. Thus, endogenous opioids might not tonically inhibit lordosis under the physiological conditions examined. The alpha-noradrenergic agonist clonidine did not reverse the effects of morphine on lordosis. Thus, the inhibitory effects of morphine on this behavior might be independent of its presynaptic effects on norepinephrine release in brain.
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The effects of alcohol on testicular interstitial fluid (TIF) volume and the secretion of testosterone and beta-endorphin (beta E) into this important testicular compartment were assessed in the rat. Alcohol time- and dose-response curves... more
The effects of alcohol on testicular interstitial fluid (TIF) volume and the secretion of testosterone and beta-endorphin (beta E) into this important testicular compartment were assessed in the rat. Alcohol time- and dose-response curves were constructed for changes in TIF volume and the bioactive concentrations of testosterone and immunoreactive beta E (i-beta E). Alcohol (3 g/kg) decreased TIF volumes and increased TIF i-beta E secretion 0.5 to 6 hr after injection and decreased TIF testosterone 1 to 6 hr after injection. These effects were dose-related at 2 hr postinjection. The possible role of alcohol-induced reductions in serum luteinizing hormone and testosterone levels in mediating the effects of alcohol on TIF volume was also examined. We found that pretreating rats with human chorionic gonadotropin, which reversed alcohol-induced suppression in levels of serum gonadotropins and testosterone, failed to reverse the effects of alcohol on TIF volume and the secretion of testosterone and i-beta E. These results indicate that alcohol decreases TIF volume, inhibits TIF testosterone secretion and stimulates TIF i-beta E secretion and, furthermore, suggest that these effects are not indirectly mediated by decreased levels of gonadotropins or testosterone, but by direct effects of alcohol on gonadal function. The strong inverse correlation between TIF i-beta E and testosterone secretion after alcohol administration and previous evidence that testicular opioids inhibit the biosynthesis of testosterone suggest that alcohol may act through testicular beta E to suppress the synthesis and release of testosterone in the testes.
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The effects of acute alcohol administration on myo-inositol and myo-inositol 1-phosphate levels in the male rat cerebral cortex were examined. At a dose of 3 g/kg, alcohol reduced myo-inositol 1-phosphate levels in the cortex by 60%... more
The effects of acute alcohol administration on myo-inositol and myo-inositol 1-phosphate levels in the male rat cerebral cortex were examined. At a dose of 3 g/kg, alcohol reduced myo-inositol 1-phosphate levels in the cortex by 60% within 30 min after its injection. A significant depression in myo-inositol 1-phosphate was found 5 min after the injection of alcohol, and maximal levels of depression occurred at 30 min. Levels of myo-inositol 1-phosphate remained significantly depressed for 6 hr and then gradually recovered, reaching normal values of 24 hr after the initial injection. There was an excellent inverse correlation (rxy = 0.96) between myo-inositol 1-phosphate levels and blood alcohol levels at all time intervals examined. Dose-response analyses indicated that the half-maximal (ED50) decrease in myo-inositol 1-phosphate levels occurred at a dose of 1.6 g/kg of alcohol. In contrast to these effects, myo-inositol levels were not significantly altered by any dose of alcohol at any time interval examined. Because of the rapidity of changes in myo-inositol 1-phosphate after acute alcohol administration and the excellent negative correlation between blood alcohol levels and changes in myo-inositol 1-phosphate, alcohol-induced alterations in myo-inositol 1-phosphate appear to be the direct effect of alcohol per se and may participate in the acute pharmacological effects of the drug.
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We reported previously that in the presence of appropriate blocking agents [3H]ethylketocyclazocine selectively labels a non-mu, non-delta, non-kappa binding site with opioid receptor characteristics. We now report that chronic treatment... more
We reported previously that in the presence of appropriate blocking agents [3H]ethylketocyclazocine selectively labels a non-mu, non-delta, non-kappa binding site with opioid receptor characteristics. We now report that chronic treatment with the opiate antagonist naltrexone dramatically increases the number of these binding sites in rat brain, as well as the number of mu, delta and kappa receptors. This finding further supports the concept that the [3H]ethylketocyclazocine site is an opioid receptor and previously reported evidence indicating that it might be the beta-endorphin-specific epsilon receptor that has been hypothesized to exist for some time. The affinity of naltrexone for the putative epsilon site in vivo appears to be similar to its affinity for mu and delta receptors, since a single 30-mg naltrexone pellet was sufficient to induce a maximal rate of up-regulation for all three types of sites. In contrast, a maximal rate of kappa receptor up-regulation requires at least four naltrexone pellets and, therefore, the affinity of naltrexone for this site in vivo appears to be considerably lower than for the other sites. Unexpectedly, we found that the naltrexone-induced increase in binding to all four types of receptors continued to increase through 60 days of naltrexone exposure, the longest treatment period examined, and that the increases in receptor binding were linear with exposure time. This finding is contradictory to the generally held view that antagonist-induced opioid receptor up-regulation in brain increases asymptotically, leveling off after a relatively brief treatment period.
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Generic drugs account for half of all prescription drug purchases in the United States. Although they are bioequivalent to their branded counterparts, they are typically sold at substantial discounts from the branded price. Given this,... more
Generic drugs account for half of all prescription drug purchases in the United States. Although they are bioequivalent to their branded counterparts, they are typically sold at substantial discounts from the branded price. Given this, the purpose of this analysis is to examine the impact of the introduction of generic forms of selected opioids on their diversion to the illicit marketplace. The analgesics in this analysis include oxycodone ER (extended release), and the fentanyl transdermal patch. The data were collected through a post-marketing surveillance initiative supported by the Researched Abuse Diversion and Addiction-Related Surveillance (RADARS) System risk management program, gathered on a quarterly basis from a national sample of police and regulatory agencies. The results indicate that with oxycodone ER and the fentanyl transdermal patch, the diversion of their generic formulations occurs less often than that of the branded products, and that the introduction of the generic formulations did not significantly increase the overall levels of diversion during the period covered by this analysis. Although diversion did not increase in the short-term, the need for longer term monitoring appears warranted.
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1. Res Commun Chem Pathol Pharmacol. 1974 Jan;7(1):17-24. Effects of morphine on the secondary sex organs and plasma testosterone levels of rats. Cicero TJ, Meyer ER, Bell RD, Wiest WG. PMID: 4811448 [PubMed - indexed for MEDLINE]. MeSH... more
1. Res Commun Chem Pathol Pharmacol. 1974 Jan;7(1):17-24. Effects of morphine on the secondary sex organs and plasma testosterone levels of rats. Cicero TJ, Meyer ER, Bell RD, Wiest WG. PMID: 4811448 [PubMed - indexed for MEDLINE]. MeSH Terms: ...
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We have shown previously that chronic morphine administration to adolescent male rats produced a number of gender specific deficits in their offspring. The purpose of the present studies was to extend our earlier observations by examining... more
We have shown previously that chronic morphine administration to adolescent male rats produced a number of gender specific deficits in their offspring. The purpose of the present studies was to extend our earlier observations by examining the acute, direct effects of morphine exposure to male rats on their fertility and the development of viable offspring. Sexually mature male rats were injected with a single dose of morphine (25 mg/kg) and 24 hr later were bred with drug-naive females. Fertility rates (vaginal plugs and pregnancies) were monitored throughout the breeding period as was the development of the offspring. Our results showed that a large, acute dose of morphine given to drug-naive male rats 24 hr before the initiation of breeding had no effect on fertility rates, but produced several adverse effects on fetal outcome. Litter sizes in morphine-derived offspring were considerably smaller than in controls and mortality rates were more than 6 times higher. Moreover, morphine-derived male, but not female, offspring had a significantly enhanced sensitivity to the antinociceptive effects of morphine. Collectively, these data suggest that acute paternal morphine exposure just before breeding with drug-naive females had no effect on fertility, but exerted negative effects on the viability and development of their offspring. These results represent the most compelling evidence to date that paternal opiate exposure can adversely affect fetal outcome and are particularly striking in that they were produced by a single injection of morphine. We are aware of no animal studies, clinical cases or anecdotal reports in humans in which such a phenomenon has been described.
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Although it appears that corticosterone may play an important role in determining vulnerability to drugs of abuse, few studies have examined drug effects on factors that affect corticosterone efficacy. Thus, studies were carried out to... more
Although it appears that corticosterone may play an important role in determining vulnerability to drugs of abuse, few studies have examined drug effects on factors that affect corticosterone efficacy. Thus, studies were carried out to assess the effects of morphine on corticosteroid-binding globulin (CBG), the major glucocorticoid binder in blood. Since CBG-bound hormone is thought to be physiologically inactive, changes in CBG levels could affect corticosterone action independently of hormone levels per se. We found that morphine caused a marked naltrexone-preventable increase (approximately 160%) in CBG in adult male rats. Elevated levels were seen by three days and were maximal at seven days after morphine pellet (75 mg) implantation. CBG levels remained elevated while morphine was detectable in blood and returned toward normal as the drug cleared from the system. A single morphine pellet was sufficient to induce a marked increase in the concentration of CBG and two or more pellets caused maximal upregulation. Baseline and stress levels of total corticosterone (bound and unbound) were normal after chronic exposure to morphine. However, due to the elevated level of CBG, the amount of free, physiologically active hormone was dramatically reduced. These results suggest that morphine may exert potent effects on corticosterone action that are not revealed by measurement of corticosterone alone. Furthermore, the increase in CBG resulting from chronic exposure to morphine might contribute to the perpetuation of drug use and to adverse effects of drug exposure by impairing normal functions of corticosterone.
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It has been shown in developing male rats that morphine maximally depresses serum luteinizing hormone (LH) levels as early as postnatal day 15. In contrast, naloxone fails to increase serum LH in the prepubescent male rat but, coincident... more
It has been shown in developing male rats that morphine maximally depresses serum luteinizing hormone (LH) levels as early as postnatal day 15. In contrast, naloxone fails to increase serum LH in the prepubescent male rat but, coincident with the onset of puberty (30-35 days of age), the antagonist becomes increasingly more effective until adult appropriate responses are achieved at sexual maturation. The purpose of the present studies was to examine and characterize further the dichotomous response to naloxone and morphine in the prepubescent male rat. We found that the inability of naloxone to affect a release in LH-releasing hormone (LHRH) was not related to pharmacokinetic factors as the dose and time-response characteristics were identical in young and adult animals. In addition, our results indicated that the release of LHRH and its actions on the pituitary to promote LH release were equivalent in prepubescent and adult rats, indicating that if naloxone was capable of releasing LHRH then robust increases in LH should have occurred. Our results indicate further that the ineffectiveness of naloxone in prepubescent animals was not unique to this compound inasmuch as kappa antagonists also were devoid of activity in young animals but were highly effective in adults; delta opiate antagonists failed to increase LH either in young or adult animals. In contrast to these data, we observed that mu and kappa agonists were equipotent in depressing serum LH levels in both young and adult animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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An acute injection of an intoxicating dose of alcohol to male rats 24 hours prior to breeding with drug-naive females produced no discernible effect on copulatory activity, as reflected in vaginal plugs, but resulted in markedly (>... more
An acute injection of an intoxicating dose of alcohol to male rats 24 hours prior to breeding with drug-naive females produced no discernible effect on copulatory activity, as reflected in vaginal plugs, but resulted in markedly (> 50%) reduced pregnancy rates. Fetal outcome was also markedly affected in offspring sired by alcohol-treated males: litter sizes were appreciably smaller (30%) and fetal mortality was more than 2 times higher than in controls. These results suggest that paternal alcohol use, like maternal alcohol abuse, may adversely affect fertility and fetal outcome.
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We previously reported that chronic exposure of male rats to morphine markedly increases the concentration of corticosteroid-binding globulin (CBG) in blood. This in turn appears to greatly reduce the amount of corticosterone available to... more
We previously reported that chronic exposure of male rats to morphine markedly increases the concentration of corticosteroid-binding globulin (CBG) in blood. This in turn appears to greatly reduce the amount of corticosterone available to intracellular receptors. In the study reported here, we found that in contrast to the effect in males, morphine has no apparent effect on CBG in females. This pronounced sex difference does not appear to be attributable to differences in morphine pharmacokinetics, short-term actions of gonadal hormones in adulthood or sex differences in CBG or corticosterone levels. In any case, it is evident that morphine does not decrease the level of physiologically active corticosterone through CBG in females as it appears to do in males. On the other hand, we also found a distinct sex difference with regard to the effects of morphine on corticosterone. Chronic exposure to morphine had no apparent effect on corticosterone levels in males but resulted in markedly lower levels in females. Thus, morphine appears to cause a deficit in physiologically active corticosterone in both sexes but by different mechanisms.
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Earlier studies of cocaine's effects on the hypothalamic-pituitary-adrenal (HPA) axis used nonresponse-contingent designs in which the investigator determined dose, timing, and route of administration. It is important to evaluate whether... more
Earlier studies of cocaine's effects on the hypothalamic-pituitary-adrenal (HPA) axis used nonresponse-contingent designs in which the investigator determined dose, timing, and route of administration. It is important to evaluate whether "control" over cocaine delivery is a significant determinant of cocaine's HPA axis effect. This study measured cocaine's effects on plasma adrenocorticotropic hormone and cortisol, using nonresponse-contingent injections followed later by response-contingent cocaine delivery. In addition, the effects of cocaine history on the HPA response to a noncontingent injection of 1 mg/kg of cocaine were measured. HPA effects of corticotropin-releasing hormone (CRF) were also measured. Male and female rhesus monkeys, with surgically placed venous catheters, were tested in their home cages. Up to 13 injections of saline and cocaine (0.01-, 0.03-, 0.1-, and 0.3-mg/kg/injection) were administered at 10-min intervals (nonresponse-contingent condition) and on a fixed ratio 30, time out 10-min schedule of reinforcement. Overall, cocaine delivered response contingently produced larger, more dose-dependent HPA responses than did noncontingent delivery. The HPA response to a 1 mg/kg cocaine infusion in cocaine-naive monkeys was not predictive of the HPA effect of this dose subsequent to acquisition of cocaine self-administration. Overall, male monkeys had larger HPA responses to cocaine than did female monkeys. Finally, the HPA effects of CRF were significantly correlated with those of large cocaine doses delivered nonresponse contingently, but not with response-contingent administration.
Research Interests: Psychology, Medicine, Corticotropin Releasing Hormone, Female, Pubmed, and 13 moreAnimals, Cocaine, Male, Self-administration, Time Factors, Saline, Operant Conditioning, Adrenocorticotropic Hormone, Macaca Mulatta, Area Under Curve, Blood Specimen Collection, hydrocortisone, and Pharmacology and pharmaceutical sciences
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Morphine levels in rat brain were measured by the multiple ion detection method (mass fragmentography), using a computer-controlled gas chromatograph-mass spectrometer, and were correlated with the analgesic activity of the narcotic at... more
Morphine levels in rat brain were measured by the multiple ion detection method (mass fragmentography), using a computer-controlled gas chromatograph-mass spectrometer, and were correlated with the analgesic activity of the narcotic at intervals up to 6 hours after the injection. Morphine levels in brain reached a peak of 346 ng/g of tissue wet weight 30 minutes after the subcutaneous injection of 10 mg/kg of morphine sulfate and then declined rapidly over the next 3 hours. Between 3 and 6 hours after the injection of morphine, the brain concentration decreased slightly but was still readily detectable at 6 hours after injection. An excellent correlation (r = 0.923) was found between the concentration of morphine in brain and analgesic activity, as measured by the hot plate method. The multiple ion detection method for the measurement of morphine appears to meet all of the criteria necessary for any drug assay: sensitivity, specificity and ease of analysis.
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The ontogeny of the effects of alcohol on serum testosterone levels was examined in male rats throughout sexual maturation (25-70 days). Alcohol decreased serum testosterone levels in rats 45 days or older as expected. In contrast to... more
The ontogeny of the effects of alcohol on serum testosterone levels was examined in male rats throughout sexual maturation (25-70 days). Alcohol decreased serum testosterone levels in rats 45 days or older as expected. In contrast to these results, we found precisely the opposite effects in prepubescent male rats (25-30 days old): namely, a marked stimulation of serum testosterone. Alcohol produced dose-dependent increases in serum testosterone levels in the prepubescent animal with increases of over 300% observed. In contrast to the biphasic effects of alcohol on serum testosterone levels in the developing animal, we found either no changes or modest decreases in serum luteinizing hormone levels at all ages tested. These data indicate that the increase in testosterone occurred independently of changes in luteinizing hormone in the prepubescent animal. Thus, it appears that the primary site of action of alcohol on the hypothalamic-pituitary-gonadal axis in prepubescent male rats is the testes and that alcohol acts to directly stimulate testosterone's biosynthesis. In contrast, alcohol appears to act at both central and testicular sites in rats 45 days or older to depress the synthesis and release of testosterone. The mechanisms underlying these age-dependent, biphasic effects of alcohol on serum testosterone levels are unknown at the present time, but it seems unlikely that differences in the biodisposition of alcohol were involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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The effects of castration on liver alcohol dehydrogenase (ADH) activity and the in vivo metabolism of ethanol were examined in the male Sprague-Dawley-derived rat. It was found that castration led to immediate (24 hr) increases in the... more
The effects of castration on liver alcohol dehydrogenase (ADH) activity and the in vivo metabolism of ethanol were examined in the male Sprague-Dawley-derived rat. It was found that castration led to immediate (24 hr) increases in the ADH-dependent metabolism of ethanol which persisted for at least 6 weeks postcastration. Testosterone completely reversed the effects of castration. Moreover, when increases in liver ADH activity and the metabolism of ethanol were allowed to develop to maximal levels (2 weeks), a single s.c. injection of testosterone promptly reversed the effects of castration, such that by 24 hr castrated animals were indistinguishable from controls. Thus, it appears that in the male Sprague-Dawley-derived rat liver ADH activity and the in vivo metabolism of ethanol are under the control of testosterone. Because narcotics have also been shown to depress serum testosterone levels, and there is good evidence of significant pharmacological and biochemical interactions between the narcotics and ethanol, we examined whether chronic administration of morphine led to testosterone-reversible increases in the ADH-dependent metabolic disposition of ethanol. We found that chronic morphine administration, at doses sufficient to markedly depress serum testosterone levels (> 85%), produced large increases in liver ADH activity and the clearance of ethanol. Concurrent administration of testosterone completely abolished this effect. These data may, therefore, provide the first evidence of a biochemical mechanism involved in the interactions between morphine and ethanol. Furthermore, our results suggest that drug-induced reductions in serum testosterone may serve as an important mechanism involved in the cross-tolerance observed between ethanol and many abused, sedative-hypnotic drugs which share the common ability to decrease serum testosterone.
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This study was designed to examine the effects of self-administered cocaine on hypothalamic-pituitary-adrenal (HPA) axis activity in rhesus monkeys. Initially, basal release of cortisol and adrenocorticotropic hormone (ACTH) was measured... more
This study was designed to examine the effects of self-administered cocaine on hypothalamic-pituitary-adrenal (HPA) axis activity in rhesus monkeys. Initially, basal release of cortisol and adrenocorticotropic hormone (ACTH) was measured in singly housed male and female monkeys (n = 9) over a 24-h period using plasma samples obtained from indwelling venous catheters. Basal cortisol and ACTH levels in both male and female rhesus monkeys demonstrated a circadian pattern of release, with peak levels for cortisol (19.60 +/- 2.16 microgram/dl) and ACTH (19.63 +/- 2.56 pg/ml) measured at 6:00 AM. The nadir for ACTH (6.27 +/- 0.62 pg/ml) occurred at 6:00 PM, preceding the cortisol nadir (5.55 +/- 1.21 microgram/dl) at 9:00 PM. The reinforcing effects of saline, 0.01, 0.03, 0.1, and 0.3 mg/kg/injection cocaine were then evaluated using a fixed-ratio 30, time-out 10-min schedule of reinforcement in seven male monkeys. Blood was sampled before, during, and after self-administration sessions. Self-administration of cocaine produced dose-dependent increases in cortisol and ACTH. One dose of cocaine (0.03 mg/kg/injection), although reliably self-administered, did not produce a significant increase in HPA axis activity. These results indicate that although cocaine dose-dependently increases HPA axis activity, the HPA effect is more likely a consequence of overall cocaine intake than it is an indicator of cocaine doses that are sufficient to maintain self-administration behavior.
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The effects of chronic morphine administration on a variety of rat organs were examined. Only the prostates and seminal vesicles were affected by a 3-day period of morphine pellet implantation. In these organs, particularly the seminal... more
The effects of chronic morphine administration on a variety of rat organs were examined. Only the prostates and seminal vesicles were affected by a 3-day period of morphine pellet implantation. In these organs, particularly the seminal vesicles, morphine produced a marked decrease in both the wet and dry tissue weight and a reduction in their secretory activity. This apparent morphine-induced atrophy of these important accessory sex organs was not due to a change in the nutritional status of the animals but rather appeared to be associated with a pronounced (87 percent) reduction in the serum testosterone levels of morphine-treated rats when compared to control levels. The effect of morphine on the secondary sex organs was reversed by withdrawing the animals from morphine administration for a period of 7 days. These data suggest that the role of physiological and endocrinological factors in the narcotic addict's sexual difficulties be examined.
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The effects of narcotics on several aspects of the hypothalamic-pituitary-gonadal axis were examined in the male rat. Our results indicate that a large number of narcotics acutely depress serum luteinizing hormone levels and that these... more
The effects of narcotics on several aspects of the hypothalamic-pituitary-gonadal axis were examined in the male rat. Our results indicate that a large number of narcotics acutely depress serum luteinizing hormone levels and that these reduced gonadotropin levels lead to a subsequent fall (1-2 hours later) in serum testosterone levels. The luteinizing hormone-depleting effect of the narcotics appears to represent a specific narcotic action since the (-)-isomers of the narcotics were much more effective than the ()-isomers, naloxone antagonized their effects and tolerance rapidly developed. Further, our studies indicate that the impairment of the functional and structural integrity of the secondary sex organs produced by chronic narcotic administration is not due to a direct effect of these drugs since they have no effect on the uptake of subcellular distribution of testosterone in the secondary sex organs or on the androgen-dependent accumulation of myo-inositol. Consequently, it appears that the testosterone depletion produced by the narcotics is solely responsible for their adverse effect on the secondary sex organs. The results of these studies suggest that the effects of the narcotics on the hypothalamic-pituitary-gonadal axis are confined to either the hypthalamus or the pituitary gland.
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The effects of a single injection of morphine (20 mg/kg) on serum testosterone levels were examined in the male rat. Within 2 hours after the morphine injection, testosterone levels were significantly lower than control levels. The... more
The effects of a single injection of morphine (20 mg/kg) on serum testosterone levels were examined in the male rat. Within 2 hours after the morphine injection, testosterone levels were significantly lower than control levels. The decline in testosterone levels reached a maximum 4 hours after the administration of morphine, at which time testosterone levels were reduced by more than 85% with respect to controls. The ability of a large number of narcotics to depress serum testosterone levels, 4 hours after their administration, was also examined. All narcotics depressed testosterone levels significantly and their potency relative to morphine was comparable to that observed in several other preparations, such as the guinea-pig ileum and mouse vas deferens. The testosterone-depleting effects of the narcotics appear to represent specific narcotic effects since the (-)-isomers of the narcotics were considerably more potent than the (+)-isomers, naloxone competitively inhibited the effects of morphine on testosterone levels and tolerance developed to the testosterone-depleting effects of these drugs. Acute treatment with morphine also lowered serum luteinizing hormone levels, and this reduction preceded the fall in testosterone levels by 1 to 2 hours.
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Prescription drug diversion involves the unlawful channeling of regulated pharmaceuticals from legal sources to the illicit marketplace, and can occur along all points in the drug delivery process -- from the original manufacturing site,... more
Prescription drug diversion involves the unlawful channeling of regulated pharmaceuticals from legal sources to the illicit marketplace, and can occur along all points in the drug delivery process -- from the original manufacturing site, to the wholesale distributor, the physician's office, the retail pharmacy, or the patient. Although a number of recent scientific papers have discussed the problems associated with diversion, empirical data on the scope and magnitude of diversion are limited in the literature. This paper presents findings from a national diversion survey being conducted as part of risk management initiatives supported by Denver Health and Hospital Authority, designed to monitor the abuse and diversion of a variety of prescription opioid analgesics. On a quarterly basis, diversion investigators in 300 jurisdictions distributed throughout the 50 states, the District of Columbia, and Puerto Rico are sent short questionnaires designed to elicit data on the extent of drug diversion in their areas. During the 20-quarter survey period reported in this paper, a total of 64,655 cases of prescription drug diversion were reported from all of the participating sites. The most widely diverted opioid was hydrocodone, in that it was mentioned in 38.2% of the cases, followed by oxycodone, mentioned in 24.3% of the cases. By contrast, the proportions of cases in which other opioids were mentioned were significantly smaller. The diversion of opioids appears in all 50 states, the District of Columbia, and Puerto Rico, with especially high concentrations in rural areas. How all of these prescription opioids are being diverted to the street, however, is not altogether clear, and in many ways, diversion is a "black box" requiring concentrated systematic study.
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ABSTRACT
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Page 1. TIlE .JOtRNAL OF PhARMACOLOGY AN!) EXPERIMENTAL THERAPEUTICS Vol. 189, No. 1 Copyright © i974 by The Willianis & Wilkins Co. Printed in USA ALPHA ADRENERGIC BLOCKING AGENTS: ANTI-NOCICEPTIVE ACTIVITY... more
Page 1. TIlE .JOtRNAL OF PhARMACOLOGY AN!) EXPERIMENTAL THERAPEUTICS Vol. 189, No. 1 Copyright © i974 by The Willianis & Wilkins Co. Printed in USA ALPHA ADRENERGIC BLOCKING AGENTS: ANTI-NOCICEPTIVE ACTIVITY AND ENhANCEMENT ...
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The effects of ethanol and acetaldehyde on testicular steroidogenesis were examined. We found that ethanol markedly inhibited the gonadotropin-stimulated production of testosterone in enzymatically dispersed cell preparations of the... more
The effects of ethanol and acetaldehyde on testicular steroidogenesis were examined. We found that ethanol markedly inhibited the gonadotropin-stimulated production of testosterone in enzymatically dispersed cell preparations of the testes of adult rats. The effects of ethanol on testicular steroidogenesis appeared to be noncompetitive since testosterone production could not be restored to nondrug-treated levels even by extremely high concentrations of gonadotropin. Acetaldehyde also inhibited testicular steroidogenesis in vitro but was between 1000 and 4000 times more effective than ethanol. As little as 50 microM acetaldehyde was effective in suppressing testicular steroidogenesis, whereas much higher (200 mM) concentrations of ethanol were required. Our results further demonstrated that cell viability was unaffected by incubation with very high concentrations of ethanol and acetaldehyde, indicating that the two drugs did not simply irreversibly impair the ability of the dispersed cells to appropriately respond to stimulation by gonadotropins. These results suggest that ethanol directly inhibits testicular steroidogenesis, but that acetaldehyde is much more potent.
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The effects of adolescent morphine exposure on the sexual maturation of male rats, their reproductive capacity and the development of their progeny were examined. Groups of prepubescent male rates (25-27 days of age) were implanted with... more
The effects of adolescent morphine exposure on the sexual maturation of male rats, their reproductive capacity and the development of their progeny were examined. Groups of prepubescent male rates (25-27 days of age) were implanted with morphine- or placebo-pellets (one on Day 1, then two pellets on Days 4, 7 and 10); the pellets were not removed to assure the sustained release of morphine for 3 to 4 weeks and to avoid the confounding effects of a precipitated withdrawal syndrome. Groups of animals were sacrificed at weekly intervals through adulthood for an assessment of reproductive endocrine function. A large group, however, was also bred with drug-naive primiparous females at 85 days of age (8 weeks after morphine or placebo pellet implantation), when the acute and chronic effects of morphine on reproductive endocrine parameters had dissipated; their fertility and the development of the male and female progeny was characterized. Our results indicated that morphine exposure during adolescence led to a pronounced inhibition of a number of indices of sexual maturation (e.g., serum testosterone and luteinizing hormone levels and reduced weights of the testes and seminal vesicles). Breeding morphine- and placebo-implanted male rats with drug-naive females resulted in smaller liters derived from morphine-treated fathers when compared to controls, but in all other respects the development of the offspring in the two groups were equivalent. However, upon reaching adulthood, a number of selective endocrine differences were detected in morphine-derived offspring when compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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The effects of chronic alcohol administration on reproductive endocrinology in the developing male rat were examined. Prepubescent male rats (25 days of age) were maintained on an alcohol liquid diet or were pair-fed a control diet until... more
The effects of chronic alcohol administration on reproductive endocrinology in the developing male rat were examined. Prepubescent male rats (25 days of age) were maintained on an alcohol liquid diet or were pair-fed a control diet until early adulthood and selected indices of sexual maturation were examined at weekly intervals. To determine whether sexually immature animals were more sensitive to the effects of alcohol than adults, fully mature male animals were exposed to an identical period of alcohol exposure and comparisons were made between the two groups. The results demonstrated that alcohol significantly affected many of the primary indices of puberty and sexual maturation. The normal pubertal increases in serum testosterone levels, the weights of the testes and secondary sex organs and beta-endorphin levels in the hypothalamus were substantially reduced in alcohol-exposed animals compared with controls. In contrast to these results, the effects of alcohol on reproductive endocrinology in the fully mature animal were transitory and of considerably less magnitude. After a 2-week alcohol-free period, male rats exposed to alcohol during development were bred with drug-naive primiparous females. Although the same number of pregnancies resulted from matings between alcohol-exposed males and drug-naive females compared with controls, litter sizes were significantly smaller in alcohol-derived offspring than in controls. In all other respects, such as body weights, sex ratios, mortality rates and gross developmental features (eye opening, incisor eruption and testes descent), alcohol-derived offspring were identical with controls. Upon closer examination, however, significant disturbances were detected in alcohol-derived male offspring.(ABSTRACT TRUNCATED AT 250 WORDS)