Theodore J. Cicero

Trends in Opioid Analgesic Abuse and Mortality in the United States

BACKGROUND The use of prescription opioid medications has increased greatly in the United States during the past two decades; in 2010, there were 16,651 opioid-related deaths. In response, hundreds of federal, state, and local interventions have been implemented. We describe trends in the diversion and abuse of prescription opioid analgesics using data through 2013. METHODS We used five programs from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System to describe trends between 2002 and 2013 in the diversion and abuse of all products and formulations of six prescription opioid analgesics: oxycodone, hydrocodone, hydromorphone, fentanyl, morphine, and tramadol. The programs gather data from drug-diversion investigators, poison centers, substance-abuse treatment centers, and college students. RESULTS Prescriptions for opioid analgesics increased substantially from 2002 through 2010 in the United States but then decreased slightly from 2011 through 2013. In general, RADARS System programs reported large increases in the rates of opioid diversion and abuse from 2002 to 2010, but then the rates flattened or decreased from 2011 through 2013. The rate of opioid-related deaths rose and fell in a similar pattern. Reported nonmedical use did not change significantly among college students. CONCLUSIONS Postmarketing surveillance indicates that the diversion and abuse of prescription opioid medications increased between 2002 and 2010 and plateaued or decreased between 2011 and 2013. These findings suggest that the United States may be making progress in controlling the abuse of opioid analgesics. (Funded by the Denver Health and Hospital Authority.).

The cellular localization of the two brain specific proteins, S-100 and 14-3-2.

Abstract An attempt has been made to localize, at a cellular level, the two brain specific proteins, S-100 and 14-3-2, by determining their relative concentrations in thalamic nuclei undergoing retrograde cell degeneration after appropriate lesions of the cerebral cortex. As the neuronal degeneration progresses the concentration of the 14-3-2 protein declines so that 6 weeks postoperatively it is only approximately 40% of its control level. On the other hand, there is a slight, but statistically significant, increase in the level of the S-100 protein between the 1st and 4th postoperative weeks which appears to be correlated with the early gliosis in the affected nuclei. On this basis it is suggested that 14-3-2 is primarily a neuronal protein and that the S-100 protein is largely, if not exclusively, confined to glial cells.

A postmarketing surveillance program to monitor Ultram® (tramadol hydrochloride) abuse in the United States

Tramadol HCl, marketed as Ultram in the USA, was introduced as a non-scheduled drug in April 1995 based on the assumption that the risk of abuse was sufficiently low to warrant a non-scheduled status. However, approval was contingent upon the development of an innovative proactive surveillance program, to be overseen by an independent steering committee, which would detect unexpectedly high levels of abuse. The postmarketing surveillance program consisted of systematic collection and scientific evaluation of reports of suspected abuse in high-risk populations surveyed through an extensive key informant network of drug abuse specialists and all spontaneous reports of abuse received through the FDA MedWatch system. Methods to estimate the number of patients prescribed tramadol were also developed. Monthly rates of abuse were calculated as an index of the risk-benefit ratio (i.e., abuse cases per 100,000 patients prescribed the drug). The data for the 3 years since the drug was introduced show that the reported rate of abuse has been low. Although a period of experimentation seemed to occur in the first 18 months after its introduction--which reached a peak rate of approximately two cases per 100,000 patients exposed--during the 2 year period prior to June 1998, the reported rate of abuse has significantly (P = 0.011) declined, reaching levels of less than one case per 100,000 patients in the last 18 months. The overwhelming majority of abuse cases (97%) have been found to occur among individuals with a history of substance abuse and the abuse has been confined to isolated pockets around the country-notably none of which have significant populations of street drug abusers. Thus, the data support the decision not to schedule tramadol and, furthermore, suggest that a proactive post-marketing surveillance program can be successfully developed to effectively monitor abuse of new medications.

Effect of abuse-deterrent formulation of OxyContin.

In 2010, an abuse-deterrent formulation of the widely abused prescription opioid OxyContin replaced the original formulation. After the new formulation was introduced, patients reported that they used OxyContin less often and other drugs (including heroin) more often.

Analgesia and hyperreactivity produced by intracranial microinjections of morphine into the periaqueductal gray matter of the rat

A total of 137 microinjections of morphine sulfate in doses of 1.0–50 μg were made into various midbrain sites of 47 rats implanted with chronic indwelling cannulae. Three to six μg of morphine injected in a 0.5 μl volume produced a marked increase in hot plate reaction time when injected into a circumscribed region of the periaqueductal gray matter ventral to the cerebral aqueduct encompassing the dorsal raphe nucleus and bordering tissue. Microinjections of low doses of morphine in other midbrain loci produced less effective antinociceptive activity or no analgesia at all. Higher doses of morphine (10–50 μg) eliminated the pain response to limb pinching, but in addition caused rats to become “hyperreactive,” i.e., to over respond to a variety of stimuli. Death resulted in seven of these hyperreactive rats. Although mild hyperactivity, i.e., spontaneous motor activation, was frequently observed when 3 μg of morphine was microinjected into more lateral midbrain sites, this dose elicited little or no hyperreactivity. The results of these studies are in agreement with those studies that showed identical sites of action for electrical analgesia in the rat. These results suggest morphine and electrical stimulation have similar mechanisms of action in producing analgesia when these active midbrain sites are involved.

Foundations of Opioid Risk Management

Increased abuse and diversion of prescription opioids has been a consequence of the increased availability of opioids to address the widespread problem of undertreated pain. Opioid risk management refers to the effort to minimize harms associated with opioid therapy while maintaining appropriate access to therapy. Management of these linked public health issues requires a coordinated and balanced effort among a disparate group of stakeholders at the federal, state, industry, practitioner, and patient levels. This paper reviews the principles of opioid risk management by examining the epidemiology of prescription opioid abuse in the United States; identifying key stakeholders involved in opioid risk management and their responsibilities for managing or monitoring opioid abuse and diversion; and summarizing the mechanisms currently used to monitor and address prescription opioid abuse. Limitations of current approaches, and emerging directions in opioid risk management, are also presented.

WALLERIAN DEGENERATION IN RABBIT OPTIC NERVE: CELLULAR LOCALIZATION IN THE CENTRAL NERVOUS SYSTEM OF THE S-100 AND 14-3-2 PROTEINS

Abstract— The S‐100 and 14‐3‐2 proteins, which are found only in nervous tissues, were measured in degenerating rabbit optic nerve at 0, 5 10, 20, 40, 60, 80, 100, 150 and 200 days after unilateral enucleation in order to obtain indications of the cellular localization of these proteins in the central nervous system. S‐100 increased and 14‐3‐2 decreased (both approximately 70 per cent) in cut nerves by 200 days of degeneration. Changes in amounts of the proteins were related to cellular alterations which characterize the degenerative process, as demonstrated by electron microscopy. In uncut nerves (intact eye) from these experimental animals, S‐100 increased and 14‐3‐2 decreased slightly at 5 days, after which time the levels of each returned to those approximating the content in corresponding nerves from unoperated control animals. No appreciable change in total soluble proteins was measured in degenerating or intact nerves. Since S‐100 increased and 14‐3‐2 decreased in the degenerating optic nerve as it became relatively enriched in glial constituents but impoverished in axonal content, it is suggested that S‐100 is primarily a glial protein and 14‐3‐2 predominantly a neuronal protein in the central nervous system.

Nitric oxide control of steroidogenesis: Endocrine effects of NG-nitro-L-arginine and comparisons to alcohol

Recent studies suggest that nitric oxide (NO) may regulate hormone biosynthesis and secretion. This was tested by treating male rats with NG-nitro-L-arginine methyl ester (NAME), a NO synthase inhibitor, and measuring serum and testicular interstitial fluid testosterone and serum corticosterone, luteinizing hormone (LH), and prolactin (PRL). The effect of NG-nitro-L-arginine (NA), a less-soluble form of the same NO synthase inhibitor, on the reproductive suppressant actions of alcohol was also examined. NAME increased testosterone and corticosterone secretion dose-dependently without affecting LH and PRL secretion. The alcohol-induced suppression of testosterone or LH secretion was not altered by treatment with NA. Although effects of NAME and NA on other systems may be involved, these results indicate that testicular and adrenal steroidogenesis are negatively regulated by endogenous NO and that NO does not regulate LH and PRL secretion or inhibit the testicular steroidogenic pathway in the same way as alcohol.

REGIONAL CHANGES IN CNS LEVELS OF THE S‐100 AND 14‐3‐2 PROTEINS DURING DEVELOPMENT AND AGING OF THE MOUSE

The levels of the S‐100 and 14‐3‐2 proteins were determined in a number of regions of mouse brain at intervals from 1 day to 30 months of age. Both S‐100 and 14‐3‐2 were found in measurable amounts as early as the first day of postnatal age but did not begin to accumulate rapidly in the forebrain, brain stem and cerebellum of the mouse brain until some time between the 7th and 14th days. From days 14 to 28 the levels of S‐100 and 14‐3‐2 in each region continued to increase rapidly with the exception of the forebrain where the rate of accumulation of S‐100 appeared to lag considerably behind that in the other regions. The proteins continued to accumulate at a rapid rate until approximately 6 months of age.

Changes in the concentrations of the two brain specific proteins, s-100 and 14-3-2, during the development of the avian optic tectum.

Summary The concentrations of the two brain specific proteins, 14-3-2 which is predominantly neuronal, and S-100 which is glial, have been determined in the optic tectum of a series of chick embryos between the 3rd day of incubation and the 9th week post-hatching. Both proteins first appear during the 4th day of incubation at about the time the first differentiated cells can be recognized morphologically. The level of the two proteins shows little increase during the ensuing 8 days at which time cell proliferation ceases, but between about the 17th day of incubation and the 2nd week after hatching the concentration of both proteins increases more-or-less exponentially. Thereafter the rate of increase declines rapidly, but there is a slow continuing increase for some weeks until adult levels are reached. Although the changes in concentration of the two proteins show a close parallelism, the concentration of 14-3-2 is approximately 100 times greater than that of the S-100 protein at each stage in development.