Theodore Cicero - Academia.edu (original) (raw)
Papers by Theodore Cicero
Alcohol and Drug Problems in Women, 1980
There is relatively little information on the effects of psychoactive drugs on neuroendocrine fun... more There is relatively little information on the effects of psychoactive drugs on neuroendocrine function in humans or animals of either sex. In this brief narrative, those data that are available are reviewed. As is evident, in some areas there are few or no data on the effects of psychoactive drugs on neuroendocrine function in the female, providing little basis for a review of male—female differences in neuroendocrine responses to psychoactive drugs. Nevertheless, it is hoped a state-of-the-art analysis of the male will provide a firm basis for badly needed future studies of the female.
Research communications in substance abuse, 1987
Research Communications in Substance Abuse, 1987
Addictive Behaviors, Feb 1, 2017
Physicians are frequently thought to be a major source of opioids diverted for non-therapeutic pu... 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.
Preventive Medicine, Nov 1, 2021
Rural areas of the United States have been disproportionately impacted by the opioid epidemic, ex... 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.
Drug and Alcohol Dependence, Nov 1, 2016
Background: The development of abuse deterrent formulations is one strategy for reducing prescrip... more Background: The development of abuse deterrent formulations is one strategy for reducing prescription opioid misuse and abuse. A putative abuse deterrent formulation of oxycodone extended release (OxyContin ®) was introduced in 2010. Early reports demonstrated reduced abuse and diversion, however, an analysis of social media found 32 feasible methods to circumvent the abuse deterrent mechanism. We measured trends of diversion, abuse and street price of OxyContin to assess the durability of the initial reduction in abuse. Methods: Data from the Poison Center Program, Drug Diversion Program, Opioid Treatment Program, Survey of Key Informant Patients Program and StreetRx program of the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS ®) System were used. The average quarterly rates of abuse and diversion for OxyContin were compared from before reformulation to the rate in second quarter 2015. Rates were adjusted for population using US Census data and drug availability. Results: OxyContin abuse and diversion declined significantly each quarter after reformulation and persisted for 5 years. The rate of abuse of other opioid analgesics increased initially and then decreased, but to lesser extent than OxyContin. Abuse through both oral and non-oral routes of self-administration declined following the reformulation. The geometric mean difference in the street price of reformulated OxyContin was 36% lower than the reformulated product in the year after reformulation. Discussion: Despite methods to circumvent the abuse deterrent mechanism, abuse and diversion of Oxy-Contin decreased promptly following the introduction of a crush-and solubility-resistant formulation and continued to decrease over the subsequent 5 years.
Journal of Addiction Medicine, Sep 22, 2022
Objectives Efforts to improve low naloxone uptake to mitigate the current opioid crisis have incl... 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.
The Journal of Pain, Apr 1, 2013
Journal of opioid management, Nov 1, 2007
Buprenorphine was approved in late 2004 for the treatment of opioid abuse and dependence in speci... 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 paper thumbnail of Autoradiography of [3H]U-69593 binding sites in rat brain: evidence for κ opioid receptor subtypes](https://attachments.academia-assets.com/107431717/thumbnails/1.jpg)
](European Journal of Pharmacology, Sep 1, 1988
In vitro quantitative autora&ography was used to determine the dlstnbutxon of [~H]U-69593 binding... more In vitro quantitative autora&ography was used to determine the dlstnbutxon of [~H]U-69593 binding sites m rat brain The highest density of binding was found in areas of the tel-and dlencephalon while certain areas of the mesand metencephalon were moderately labeled The distribution of [3H]U-69593 binding sites corresponds closely (but not preosely) to the dismbunon of sites labeled by [*H]EKC and [3H]bremazocme at room temperature but differs substantially from the distnbutlon of sites labeled by [~H]EKC at 4°C (as described by others) These anatomical findings support previous biochemical ewdence in&citing that [3H]U-69593 selectively labels a ~ oplold receptor subtype with characteristics that differ from the ~ receptors labeled by [3H]EKC at 4°C
Drug and Alcohol Dependence, Apr 1, 2003
In 1994, the Drug Abuse Advisory Committee (DAAC) of the Food and Drug Administration (FDA) concl... more In 1994, the Drug Abuse Advisory Committee (DAAC) of the Food and Drug Administration (FDA) concluded that Ultram † (tramadol hydrochloride) could be marketed as an analgesic drug without scheduling under the Controlled Substances Act based upon extensive pre-clinical, clinical and European epidemiological data. However, to guard against unexpectedly high levels of abuse in the United States, the DAAC recommended that an independent steering committee (ISC) be appointed to proactively monitor abuse/dependence. In the event that high rates of abuse were found, this ISC was given the authority to immediately recommend to the FDA that Ultram † be scheduled. In the course of the surveillance project, the ISC received reports of withdrawal following abrupt discontinuation of Ultram † and in some instances, following dose reductions. In most cases, the withdrawal symptoms consisted of classical opioid withdrawal, but in some cases were accompanied by withdrawal symptoms not normally observed in opiate withdrawal, such as hallucinations, paranoia, extreme anxiety, panic attacks, confusion and unusual sensory experiences such as numbness and tingling in one or more extremities. Withdrawal symptoms of either type were one of the more prevalent adverse events associated with chronic Ultram † use, comprising nearly 40% of all adverse events reported with Ultram †. Most of these consisted of typical opiate withdrawal symptoms, but 1 in 8 cases presented as atypical. These results indicate that physicians and other healthcare professionals need to be aware of the potential of Ultram † to induce withdrawal of the classical opioid type, and that atypical withdrawal may also occur.
Pain, Jul 1, 2009
We used a large medical insurance claims database to identify three groups: chronic opioid (>180 ... more We used a large medical insurance claims database to identify three groups: chronic opioid (>180 therapeutic days, N=3726); acute opioid use (<10 therapeutic days, N=37,108); and a non-opioid group (N=337,366) who filled at least one insurance claim but none for opioids. Our results showed that, although chronic opioid users represented only 0.65% of the total population, they filed 4.56% of all insurance claims, used 45% of all opioid analgesics and had much more physical and psychiatric co-morbidity than the acute opioid or non-opioid samples. Women were substantially overrepresented (>63%) in the chronic pain group and used a much greater share of all medical services than males especially as they grew older. Although our data suggest that chronic pain is optimally managed in a multidisciplinary patient-and gender-specific treatment plan, this was rarely the case with internists being the primary, and often only, physician seen. Moreover, our data suggest that opioids were often used for conditions in which they are generally not indicated (e.g. arthritis and headaches) or contraindicated by co-existing physical ailments (COPD). Finally, we conclude that adherence to the WHO analgesic ladder and other pain treatment guidelines was relatively infrequent: first, opioid extended release preparations which are ideally suited for chronic pain were used only in 1 in 4 patients; and, second, the selection of a weak (propoxyphene, codeine, tramadol) or strong opioid (e.g. morphine, oxycodone, etc.) seemed to be driven by numerous factors not necessarily related to the intensity or duration of pain.
Analytical Biochemistry, Jul 1, 1973
Alcohol and Alcoholism, Sep 1, 2014
Drug and Alcohol Dependence, Jul 1, 1980
PubMed, 1993
Morphine and naloxone exert age-dependent effects on secretion of luteinizing hormone (LH) in the... 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)
JAMA Psychiatry, Aug 1, 2015
Abuse-Deterrent Formulations of Prescription Opioids To the Editor Cicero and Ellis1 reported tha... 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.
Pharmacoepidemiology and Drug Safety, Nov 9, 2018
Purpose: Oral use is the primary route of administration among non-medical prescription opioid us... more Purpose: Oral use is the primary route of administration among non-medical prescription opioid users. While progression to non-oral routes and shifts to stronger opioids have been previously studied as ways to cope with tolerance, the prevalence and patterns of those who cope by increasing the number of pills/tablets ingested at one time (ie, multi-pill use) has not been assessed. Methods: A subset (N = 231) of treatment-seeking opioid users from a national opioid surveillance system, participating in the Researchers and Participants Interacting Directly (RAPID) Program, completed an online survey centered on multi-pill use. Results: Over two-thirds of non-medical prescription opioid users had a history of multi-pill use (67.7%), defined as ingesting four or more of the same pill, intact and at the same time. Among these (n = 154), the median maximum number of pills taken at one time was eight, with over 20% ingesting 11 or more pills in a single instance. Nearly half engaged in multi-pill ingestion more than once a day in the past month (43.8%), with accessibility to lower dose pills being the primary motivator (85.4%). Hydrocodone immediate-release (IR) compounds were by far the most frequently endorsed (90.3%), followed by oxycodone IR tablets with acetaminophen (76.0%) and oxycodone IR tablets containing no acetaminophen/ibuprofen (56.5%). Conclusions: These results indicate that the ingestion of multiple opioid pills/tablets is extremely common among treatment-seeking opioid users. This, and other forms of non-medical oral use of prescription opioids, should be taken under consideration when developing prevention and intervention efforts targeting the opioid epidemic.
Alcohol and Drug Problems in Women, 1980
There is relatively little information on the effects of psychoactive drugs on neuroendocrine fun... more There is relatively little information on the effects of psychoactive drugs on neuroendocrine function in humans or animals of either sex. In this brief narrative, those data that are available are reviewed. As is evident, in some areas there are few or no data on the effects of psychoactive drugs on neuroendocrine function in the female, providing little basis for a review of male—female differences in neuroendocrine responses to psychoactive drugs. Nevertheless, it is hoped a state-of-the-art analysis of the male will provide a firm basis for badly needed future studies of the female.
Research communications in substance abuse, 1987
Research Communications in Substance Abuse, 1987
Addictive Behaviors, Feb 1, 2017
Physicians are frequently thought to be a major source of opioids diverted for non-therapeutic pu... 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&amp;amp;amp;#39;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.
Preventive Medicine, Nov 1, 2021
Rural areas of the United States have been disproportionately impacted by the opioid epidemic, ex... 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.
Drug and Alcohol Dependence, Nov 1, 2016
Background: The development of abuse deterrent formulations is one strategy for reducing prescrip... more Background: The development of abuse deterrent formulations is one strategy for reducing prescription opioid misuse and abuse. A putative abuse deterrent formulation of oxycodone extended release (OxyContin ®) was introduced in 2010. Early reports demonstrated reduced abuse and diversion, however, an analysis of social media found 32 feasible methods to circumvent the abuse deterrent mechanism. We measured trends of diversion, abuse and street price of OxyContin to assess the durability of the initial reduction in abuse. Methods: Data from the Poison Center Program, Drug Diversion Program, Opioid Treatment Program, Survey of Key Informant Patients Program and StreetRx program of the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS ®) System were used. The average quarterly rates of abuse and diversion for OxyContin were compared from before reformulation to the rate in second quarter 2015. Rates were adjusted for population using US Census data and drug availability. Results: OxyContin abuse and diversion declined significantly each quarter after reformulation and persisted for 5 years. The rate of abuse of other opioid analgesics increased initially and then decreased, but to lesser extent than OxyContin. Abuse through both oral and non-oral routes of self-administration declined following the reformulation. The geometric mean difference in the street price of reformulated OxyContin was 36% lower than the reformulated product in the year after reformulation. Discussion: Despite methods to circumvent the abuse deterrent mechanism, abuse and diversion of Oxy-Contin decreased promptly following the introduction of a crush-and solubility-resistant formulation and continued to decrease over the subsequent 5 years.
Journal of Addiction Medicine, Sep 22, 2022
Objectives Efforts to improve low naloxone uptake to mitigate the current opioid crisis have incl... 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.
The Journal of Pain, Apr 1, 2013
Journal of opioid management, Nov 1, 2007
Buprenorphine was approved in late 2004 for the treatment of opioid abuse and dependence in speci... more Buprenorphine was approved in late 2004 for the treatment of opioid abuse and dependence in specially trained and certified physicians&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; 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 (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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.
European Journal of Pharmacology, Sep 1, 1988
In vitro quantitative autora&ography was used to determine the dlstnbutxon of [~H]U-69593 binding... more In vitro quantitative autora&ography was used to determine the dlstnbutxon of [~H]U-69593 binding sites m rat brain The highest density of binding was found in areas of the tel-and dlencephalon while certain areas of the mesand metencephalon were moderately labeled The distribution of [3H]U-69593 binding sites corresponds closely (but not preosely) to the dismbunon of sites labeled by [*H]EKC and [3H]bremazocme at room temperature but differs substantially from the distnbutlon of sites labeled by [~H]EKC at 4°C (as described by others) These anatomical findings support previous biochemical ewdence in&citing that [3H]U-69593 selectively labels a ~ oplold receptor subtype with characteristics that differ from the ~ receptors labeled by [3H]EKC at 4°C
Drug and Alcohol Dependence, Apr 1, 2003
In 1994, the Drug Abuse Advisory Committee (DAAC) of the Food and Drug Administration (FDA) concl... more In 1994, the Drug Abuse Advisory Committee (DAAC) of the Food and Drug Administration (FDA) concluded that Ultram † (tramadol hydrochloride) could be marketed as an analgesic drug without scheduling under the Controlled Substances Act based upon extensive pre-clinical, clinical and European epidemiological data. However, to guard against unexpectedly high levels of abuse in the United States, the DAAC recommended that an independent steering committee (ISC) be appointed to proactively monitor abuse/dependence. In the event that high rates of abuse were found, this ISC was given the authority to immediately recommend to the FDA that Ultram † be scheduled. In the course of the surveillance project, the ISC received reports of withdrawal following abrupt discontinuation of Ultram † and in some instances, following dose reductions. In most cases, the withdrawal symptoms consisted of classical opioid withdrawal, but in some cases were accompanied by withdrawal symptoms not normally observed in opiate withdrawal, such as hallucinations, paranoia, extreme anxiety, panic attacks, confusion and unusual sensory experiences such as numbness and tingling in one or more extremities. Withdrawal symptoms of either type were one of the more prevalent adverse events associated with chronic Ultram † use, comprising nearly 40% of all adverse events reported with Ultram †. Most of these consisted of typical opiate withdrawal symptoms, but 1 in 8 cases presented as atypical. These results indicate that physicians and other healthcare professionals need to be aware of the potential of Ultram † to induce withdrawal of the classical opioid type, and that atypical withdrawal may also occur.
Pain, Jul 1, 2009
We used a large medical insurance claims database to identify three groups: chronic opioid (>180 ... more We used a large medical insurance claims database to identify three groups: chronic opioid (>180 therapeutic days, N=3726); acute opioid use (<10 therapeutic days, N=37,108); and a non-opioid group (N=337,366) who filled at least one insurance claim but none for opioids. Our results showed that, although chronic opioid users represented only 0.65% of the total population, they filed 4.56% of all insurance claims, used 45% of all opioid analgesics and had much more physical and psychiatric co-morbidity than the acute opioid or non-opioid samples. Women were substantially overrepresented (>63%) in the chronic pain group and used a much greater share of all medical services than males especially as they grew older. Although our data suggest that chronic pain is optimally managed in a multidisciplinary patient-and gender-specific treatment plan, this was rarely the case with internists being the primary, and often only, physician seen. Moreover, our data suggest that opioids were often used for conditions in which they are generally not indicated (e.g. arthritis and headaches) or contraindicated by co-existing physical ailments (COPD). Finally, we conclude that adherence to the WHO analgesic ladder and other pain treatment guidelines was relatively infrequent: first, opioid extended release preparations which are ideally suited for chronic pain were used only in 1 in 4 patients; and, second, the selection of a weak (propoxyphene, codeine, tramadol) or strong opioid (e.g. morphine, oxycodone, etc.) seemed to be driven by numerous factors not necessarily related to the intensity or duration of pain.
Analytical Biochemistry, Jul 1, 1973
Alcohol and Alcoholism, Sep 1, 2014
Drug and Alcohol Dependence, Jul 1, 1980
PubMed, 1993
Morphine and naloxone exert age-dependent effects on secretion of luteinizing hormone (LH) in the... 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)
JAMA Psychiatry, Aug 1, 2015
Abuse-Deterrent Formulations of Prescription Opioids To the Editor Cicero and Ellis1 reported tha... 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.
Pharmacoepidemiology and Drug Safety, Nov 9, 2018
Purpose: Oral use is the primary route of administration among non-medical prescription opioid us... more Purpose: Oral use is the primary route of administration among non-medical prescription opioid users. While progression to non-oral routes and shifts to stronger opioids have been previously studied as ways to cope with tolerance, the prevalence and patterns of those who cope by increasing the number of pills/tablets ingested at one time (ie, multi-pill use) has not been assessed. Methods: A subset (N = 231) of treatment-seeking opioid users from a national opioid surveillance system, participating in the Researchers and Participants Interacting Directly (RAPID) Program, completed an online survey centered on multi-pill use. Results: Over two-thirds of non-medical prescription opioid users had a history of multi-pill use (67.7%), defined as ingesting four or more of the same pill, intact and at the same time. Among these (n = 154), the median maximum number of pills taken at one time was eight, with over 20% ingesting 11 or more pills in a single instance. Nearly half engaged in multi-pill ingestion more than once a day in the past month (43.8%), with accessibility to lower dose pills being the primary motivator (85.4%). Hydrocodone immediate-release (IR) compounds were by far the most frequently endorsed (90.3%), followed by oxycodone IR tablets with acetaminophen (76.0%) and oxycodone IR tablets containing no acetaminophen/ibuprofen (56.5%). Conclusions: These results indicate that the ingestion of multiple opioid pills/tablets is extremely common among treatment-seeking opioid users. This, and other forms of non-medical oral use of prescription opioids, should be taken under consideration when developing prevention and intervention efforts targeting the opioid epidemic.