Nelson Sessler - Academia.edu (original) (raw)

Papers by Nelson Sessler

Research paper thumbnail of PSY48 Butrans® Rems Health Care Provider Training Guide Recall Testing

Value in Health, Jun 1, 2012

Research paper thumbnail of ORIGINAL REPORT Reductions in reported deaths following the introduction of extended- release oxycodone (OxyContin) with an abuse-deterrent formulation†

Purpose Abuse of opioid analgesics for their psychoactive effects is associated with a large numb... more Purpose Abuse of opioid analgesics for their psychoactive effects is associated with a large number of fatalities. The effect of making opi-oid tablets harder to crush/dissolve on opioid-related fatalities has not been assessed. The objective of this study was to assess the impact of introducing extended-release oxycodone (ERO [OxyContin®]) tablets containing physicochemical barriers to crushing/dissolving (reformulated ERO) on deaths reported to the manufacturer. Methods All spontaneous adverse event reports of death in the US reported to the manufacturer between 3Q2009 and 3Q2013 involving ERO were used. The mean numbers of deaths/quarter in the 3 years after reformulated ERO introduction were compared with the year before. Changes in the slope of trends in deaths were assessed using spline regression. Comparison groups consisted of non-fatal reports involving ERO and fatality reports involving ER morphine. Results Reports of death decreased 82 % (95 % CI: 89, 73) from the year be...

Research paper thumbnail of Changes in nonmedical use of OxyContin after reformulation with abuse deterrent properties

Drug and Alcohol Dependence, 2017

incident 12-to-23-year-old drinkers who have a prior history of cannabis use. Three questions are... more incident 12-to-23-year-old drinkers who have a prior history of cannabis use. Three questions are framed: (1) Is this proportion lower among 'law-abiding' newly incident drinkers who delay their first drink to age 21 years? (2) Before age 21, will the proportion show an age-related monotonic increase? (3) Will a male excess in this proportion emerge in mid-adolescence, before age 21? Methods: The 2002-2013 US National Surveys on Drug Use and Health identified 32,878 newly incident drinkers via confidential standardized computer-assisted self-interviews, and assessed alcohol and cannabis onset timing. Newly incident drinkers are those with first drink in the 12 months before assessment. Analysisweighted proportions and delta method variances are derived, with meta-analysis summaries. Results: Looking across age strata of newly incident drinkers, we found monotonically rising age-specific cannabis history proportions across adolescence, with a peak estimate seen at age 17 years (Males: 26%; 95%CI = 24%, 29%; Females: 17%; 95%CI = 15%, 19%). A male excess in antecedent cannabis use emerges at age 14 and persists until the legal drinking age at 21. Thereafter, males and females have similar proportions. Evaluated using an epidemiological mutoscope view, individual cohorts show a generally congruent pattern, with starting age held constant. Conclusions: The observed proportion shows monotonic increase to age 17, running congruent with age-specific cannabis incidence rates generally, then drops, suggesting that any increase in the proportion after age 18 must be driven largely by greater persistence of cannabis use among established cannabis users. Therefore, we expect to find different latent classes of newly incident drinkers before and after age 17. The observed male-female differences suggest age-related variation in underlying mechanisms. Financial support: NIDA T32 DA021129 & K05DA015799; Michigan State University.

Research paper thumbnail of Comparison of abuse, suspected suicidal intent, and fatalities related to the 7-day buprenorphine transdermal patch versus other opioid analgesics in the National Poison Data System

Postgraduate medicine, 2017

Prescription opioid related abuse, suicide and death are significant public health problems. This... more Prescription opioid related abuse, suicide and death are significant public health problems. This study compares rates of poison center calls categorized as intentional abuse, suspected suicidal intent or fatality for the 7-day buprenorphine transdermal system/patch (BTDS) with other extended-release and long-acting (ER/LA) opioids indicated for chronic pain. Retrospective 24-month cohort study using National Poison Data System data from July 2012 through June 2014. BTDS was introduced in the United States in January 2011. Numbers and rates of calls of intentional abuse, suspected suicidal intent and fatalities were evaluated for BTDS, ER morphine, ER oxycodone, fentanyl patch, ER oxymorphone and methadone tablets/capsules, using prescription adjustment to account for community availability. Rate ratios (RR) and 95% confidence intervals (CI) were calculated. Absolute numbers and prescription-adjusted rates of intentional abuse and suspected suicidal intent with BTDS were significant...

Research paper thumbnail of Non-oral abuse of immediate-release hydrocodone

Drug and Alcohol Dependence, 2015

83% to 100%, and none of the participants missed more than one counseling session. There was a si... more 83% to 100%, and none of the participants missed more than one counseling session. There was a significant decrease in opioid (heroin) use, 68% of the participants reported using heroin at 1 month, 13% at 2 months and none after 3 months of treatment. Fifty-one (35.2%)wereHIV-positive,with fournotpreviously known to be positive. All 51 HIV-positive participants received HIV treatment. Eighty-nine (68.0%)were HCV-positive, 42 (46.7%)were newlydiagnosed.Only2participants (2.4%)had receivedHCVtreatment. Conclusions: At 6-month, the findings showed the added value of an integrated treatment programondrug use, HIV detection, and access to HIV care. Long-term follow-up is needed to confirm the impact of this program. Financial support: NIDA R01-DA033671-01.

Research paper thumbnail of Buprenorphine Transdermal Delivery System in Adults with Persistent Noncancer-Related Pain Syndromes Who Require Opioid Therapy: A Multicenter, 5-Week Run-in and Randomized, Double-Blind Maintenance-of-Analgesia Study

Clinical Therapeutics, 2007

Objective: This study compared the efficacy and safety profile of buprenorphine transdermal deliv... more Objective: This study compared the efficacy and safety profile of buprenorphine transdermal delivery system (BTDS) and placebo in subjects with persistent noncancer-related pain who required opioid analgesics. Methods: This was a multicenter, double-blind, parallel-group study in adult subjects (age ≥18 years) with at least a 2-month history of noncancer-related pain for which they received oral opioid combination agents. The study employed a maintenance-of-analgesia, or randomized-withdrawal, design. During a 7-to 21-day open-label run-in phase, all subjects received BTDS, titrated as needed. Subjects who achieved stable pain control and were able to tolerate BTDS in the run-in phase were randomly assigned to continue BTDS at the dose achieved during the run-in phase or to receive placebo for up to 14 days. Acetaminophen 500-mg tablets were provided as escape (rescue) medication. Subjects completed the study on day 14 or when they met predefined criteria for ineffective treatment: requiring >1 g of acetaminophen as escape medication on any day of the double-blind evaluation phase, requiring a change in study drug dose, having difficulty keeping the patch affixed, or discontinuing because of ineffective treatment without meeting any of the first 3 criteria. The primary efficacy variable was the proportion of subjects with ineffective treatment. Secondary efficacy variables were the time to ineffective treatment; the proportion of subjects who reached ineffective treatment or discontinued for any reason other than ineffective treatment; and the amount of escape medication used. Assessment of the safety profile was based on adverse events and changes in vital signs and physical and laboratory findings. Results: Five hundred eighty-eight subjects entered the open-label run-in phase, and 267 (129 BTDS, 138 placebo) were subsequently randomized to doubleblind treatment. Demographic characteristics were similar between the double-blind BTDS and placebo groups (61.2% and 63.8% female, respectively; 99.2% and 98.6% white; mean [SD] age, 56.2 [13.3] and 59.2 [11.5] years). In the primary efficacy analysis, the proportion of subjects with ineffective treatment was lower with BTDS than with placebo (51.2% vs 65.0%; 95% CI, 1.09-2.95); the odds of ineffective treatment were 1.79 times greater for placebo relative to BTDS (P = 0.022). In the secondary efficacy analyses, the median time from the first dose of double-blind study drug to ineffective treatment was significantly longer with BTDS than with placebo (median, 10 vs 3 days; P = 0.011). The proportion of subjects who reached ineffective treatment or discontinued for reasons other than ineffective treatment was lower in the BTDS group compared with the placebo group (55.0% vs 67.9%); the odds of ineffective treatment or discontinuation for a reason other than ineffective treatment was 1.76 times greater with placebo compared with BTDS (P = 0.028). The mean amount of escape medication used was significantly lower in the BTDS group than in the placebo group (1.7 vs 2.2 acetaminophen tablets per

Research paper thumbnail of Poster 154

Archives of Physical Medicine and Rehabilitation, 2005

Research paper thumbnail of Comparison of overdose rates among patients prescribed buprenorphine patch, fentanyl, patch and morphine in the UK

The Journal of Pain, 2013

Research paper thumbnail of Improving study conduct and data quality in clinical trials of chronic pain treatments: IMMPACT recommendations

The Journal of Pain, 2019

This is a repository copy of Improving study conduct and data quality in clinical trials of chron... more This is a repository copy of Improving study conduct and data quality in clinical trials of chronic pain treatments: IMMPACT recommendations.

Research paper thumbnail of Disproportionality analysis of buprenorphine transdermal system and cardiac arrhythmia using FDA and WHO postmarketing reporting system data

Postgraduate medicine, 2017

Positive-controlled clinical studies have shown a dose dependent effect of buprenorphine transder... more Positive-controlled clinical studies have shown a dose dependent effect of buprenorphine transdermal system on QTc interval prolongation. This study provides assessment of the buprenorphine transdermal system and cardiac arrhythmia using US FDA and WHO postmarketing reporting databases. Disproportionality analysis of spontaneously reported adverse events to assess whether the reporting rate of cardiac arrhythmia events was disproportionately elevated relative to expected rates of reporting in both FDA and WHO databases. Cardiac arrhythmia events were identified using the standardized Medical Dictionary for Regulatory Activities query for torsade de pointes and/or QT prolongation (TdP/QTP). The threshold for a signal of disproportionate adverse event reporting was defined as the lower 90% confidence limit ≥ 2 of the Empiric Bayes geometric mean in FDA database and as the lower 95% confidence limit of the Informational Component >0 in WHO database. There were 124 (<1%) and 77 (2...

Research paper thumbnail of A randomized, placebo-controlled, double-blinded, parallel-group, 5-week study of buprenorphine transdermal system in adults with osteoarthritis

Journal of Opioid Management, 2010

This multicenter, parallel-group, 35-day study in adults with osteoarthritis (OA) pain evaluated ... more This multicenter, parallel-group, 35-day study in adults with osteoarthritis (OA) pain evaluated the analgesic efficacy and safety of buprenorphine transdermal system (BTDS) designed for 7-day wear. Patients with OA pain inadequately controlled with nonsteroidal antiinflammatory drugs or patients who had taken opioids for OA pain within the past year entered a 7-day run-in period during which they took ibuprofen only. Patients with pain &amp;amp;amp;amp;amp;amp;gt; or = on a 0-10 scale had their ibuprofen discontinued and were randomized into a 28-day double-blinded period to receive either BTDS at 1 of 3 dose levels (5, 10, or 20 microg/b) or placebo. Doses were titrated to effectiveness over a period of 21 days and maintained for 7 days. No rescue medication was allowed during the study. The primary efficacy measure was the proportion of patients who achieved treatment success, defined as a patient satisfaction score of good, very good, or excellent (on day 28 or at early discontinuation) for those who did not discontinue due to ineffective treatment. More BTDS-treated patients experienced treatment success than placebo TDS-treated patients (44 percent and 32 percent; odds ratio = 1.66, p = 0.036). Fewer patients taking BTDS titrated to the highest dose compared with placebo (p &amp;amp;amp;amp;amp;amp;lt; 0.05). There were two serious adverse events (both in the placebo group) and no deaths. The most common (&amp;amp;amp;amp;amp;amp;gt; or =5 percent) adverse events reported in BTDS-treated patients were nausea, headache, dizziness, somnolence, application site pruritus, and vomiting. Compared with placebo, BTDS treatment was effective in treating patients with moderate to severe pain due to OA of the knee or hip. BTDS was well-tolerated.

Research paper thumbnail of Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro

American Journal of Physiology Renal Physiology, Mar 1, 1992

Metabolic acidosis induces net calcium flux (JCa) from cultured neonatal mouse calvariae through ... more Metabolic acidosis induces net calcium flux (JCa) from cultured neonatal mouse calvariae through physicochemical and cell-mediated mechanisms. To determine the role of osteoblasts in acid-induced JCa, collagen synthesis and alkaline phosphatase activity were assessed in calvariae incubated in reduced pH and bicarbonate medium, a model of metabolic acidosis (Met), and compared with controls (Ctl). Collagen synthesis fell from 30.5 +/- 1.1 in Ctl to 25.1 +/- 0.4% with Met, and alkaline phosphatase decreased from 403 +/- 25 in Ctl to 298 +/- 21 nmol Pi.min-1.mg protein-1 with Met. During acidosis JCa was correlated inversely with percent collagen synthesis (r = -0.743, n = 11, P = 0.009) and with alkaline phosphatase activity (r = -0.453, n = 22, P = 0.034). To determine the role of osteoclasts in acid-induced JCa, osteoclastic beta-glucuronidase activity was determined in Ctl and Met in the absence or presence of the osteoclastic inhibitor calcitonin (CT, 3 x 10(-9) M). Met increased beta-glucuronidase (5.9 +/- 0.2) compared with Ctl (4.6 +/- 0.3 micrograms phenolphthalein released.bone-1.h-1), whereas CT inhibited beta-glucuronidase in both Ctl and Met (3.1 +/- 0.2 and 3.5 +/- 0.3, respectively). During acidosis JCa was correlated directly with beta-glucuronidase activity (r = 0.683, n = 42, P less than 0.001). Thus the cell-mediated component of JCa during acidosis in vitro appears to result from a combination of inhibited osteoblastic and stimulated osteoclastic activity.

Research paper thumbnail of Critical role of bicarbonate in calcium release from bone

American Journal of Physiology Renal Fluid and Electrolyte Physiology, Sep 1, 1992

Calcium release from cultured bone is pH dependent; net calcium flux (JCa) from bone increases wi... more Calcium release from cultured bone is pH dependent; net calcium flux (JCa) from bone increases with decreasing pH. At a similar decrement in pH there is greater JCa when acidosis is produced by a low medium bicarbonate concentration ([HCO3-]), a model of metabolic acidosis (Met), compared with an increased medium PCO2, a model of respiratory acidosis (Resp). To separate the role of [HCO3-] from that of pH in inducing JCa we cultured calvariae for 3 h under three different neutral (pH approximately 7.4) isohydric environments [control (Ctl), fully compensated Met (C-Met), or fully compensated Resp (C-Resp)] and two different acid (pH approximately 7.1) isohydric environments (Met or Resp). During neutral pH (Ctl, C-Met, and C-Resp) there was JCa from bone during C-Met (decreased [HCO3-]), no net flux during Ctl (normal [HCO3-]), and JCa into bone during C-Resp (increased [HCO3-]); and JCa was correlated inversely with [HCO3-] (r = -0.824, n = 36, P less than 0.001). During acid pH there was greater JCa from bone during Met (decreased [HCO3-]) than during Resp (normal [HCO3-]); and JCa was again correlated inversely with [HCO3-] (r = -0.848, n = 22, P less than 0.001). JCa from bone during Met and Resp was greater than C-Met and C-Resp, respectively. The addition of the osteoclastic inhibitor salmon calcitonin did not alter the relative JCa results. Thus at a constant pH the magnitude of JCa from cultured neonatal mouse calvariae appears dependent on the [HCO3-]; the lower the [HCO3-], the greater the calcium efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Greater unidirectional calcium efflux from bone during metabolic, compared with respiratory, acidosis

American Journal of Physiology Renal Physiology, Mar 1, 1992

There is a smaller net calcium efflux from bone in vitro during respiratory (increased PCO2) than... more There is a smaller net calcium efflux from bone in vitro during respiratory (increased PCO2) than metabolic (decreased [HCO3-] acidosis. This could be due to the elevated PCO2, which would lessen the driving force for mineral dissolution and increase the driving force for mineralization with respect to carbonated apatite in the bone mineral. To test this hypothesis, we injected neonatal mice with 45Ca and dissected the radiolabeled calvariae 24 h later. The live calvariae were then cultured for 24 h under conditions simulating respiratory acidosis (Resp, pH = 7.225 +/- 0.003, PCO2 = 87.5 +/- 0.1 mmHg), severe respiratory acidosis (SResp, pH = 7.072 +/- 0.004, PCO2 = 103.0 +/- 0.5 mmHg), metabolic acidosis (Met, pH = 7.212 +/- 0.003, HCO3- = 15.5 +/- 0.1 meq/l), or normal acid-base status (Ctl, pH = 7.452 +/- 0.003, PCO2 = 40.0 +/- 0.2 mmHg, HCO3- = 27.8 +/- 0.2 meq/l) and bidirectional net calcium flux (JCa) and unidirectional 45Ca release were determined. There was greater JCa from bone during Met than Resp, and JCa was not different from Met during SResp despite the latter having a significantly lower pH. There was greater unidirectional 45Ca release from bone during Met than Resp, SResp, or Ctl. There was a similar direct correlation between JCa and 45Ca efflux in the respiratory and metabolic groups. However, when calvarial osteoclast activity was inhibited with calcitonin,although there was again greater JCa and 45Ca release with a metabolic compared with respiratory acidosis, there was a greater proportion of 45Ca release than JCa from bone.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Changes in age-specific rates of doctor-shopping for opioids following introduction of reformulated Oxycontin® tablets

Drug and Alcohol Dependence, 2015

Research paper thumbnail of Non-oral abuse of immediate-release hydrocodone

Drug and Alcohol Dependence, 2015

Research paper thumbnail of Reductions in reported deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent formulation

Pharmacoepidemiology and drug safety, 2014

Abuse of opioid analgesics for their psychoactive effects is associated with a large number of fa... more Abuse of opioid analgesics for their psychoactive effects is associated with a large number of fatalities. The effect of making opioid tablets harder to crush/dissolve on opioid-related fatalities has not been assessed. The objective of this study was to assess the impact of introducing extended-release oxycodone (ERO [OxyContin(®) ]) tablets containing physicochemical barriers to crushing/dissolving (reformulated ERO) on deaths reported to the manufacturer. All spontaneous adverse event reports of death in the US reported to the manufacturer between 3Q2009 and 3Q2013 involving ERO were used. The mean numbers of deaths/quarter in the 3 years after reformulated ERO introduction were compared with the year before. Changes in the slope of trends in deaths were assessed using spline regression. Comparison groups consisted of non-fatal reports involving ERO and fatality reports involving ER morphine. Reports of death decreased 82% (95% CI: -89, -73) from the year before to the third year...

Research paper thumbnail of Decreased bone carbonate content in response to metabolic, but not respiratory, acidosis

The American journal of physiology, 1993

In vitro cultured neonatal mouse calvariae release calcium and buffer the medium proton concentra... more In vitro cultured neonatal mouse calvariae release calcium and buffer the medium proton concentration in response to a decrease in the medium pH caused by a reduction in bicarbonate concentration ([HCO3-]), a model of metabolic acidosis, but not to an equivalent decrease in pH caused by an increase in the partial pressure of carbon dioxide (PCO2), a model of respiratory acidosis. We have postulated that the medium is in equilibrium with the carbonated apatite in bone. To determine whether bone carbonate is depleted during models of acidosis, we cultured calvariae in control medium (pH approximately 7.4, PCO2 approximately 43, [HCO3-] approximately 26) or in medium in which the pH was equivalently reduced by either a decrease in [HCO3-] (metabolic acidosis, pH approximately 7.1, [HCO3-] approximately 13) or an increase in PCO2 (respiratory acidosis, pH approximately 7.1, PCO2 approximately 86) and determined net calcium flux (JCa) and bone carbonate content. We found that compared wi...

Research paper thumbnail of Response of genetic hypercalciuric rats to a low calcium diet

Kidney International, 1993

Response of genetic hypercalciuric rats to a low calcium diet. A fundamental mechanism for hyperc... more Response of genetic hypercalciuric rats to a low calcium diet. A fundamental mechanism for hypercalciuria in genetic hypercalciuric rats appears due to a primary increase in intestinal calcium absorption. However previous studies could not exclude additional mechanisms to account for the hypercalciuria. To determine if enhanced bone mineral dissolution either as a primary abnormality or secondary to a defect in renal tubule calcium reabsorption is responsible for a component of the augmented calcium excretion we studied rats continually inbred for hypercalciuria. Nineteenth generation adult female idiopathic hypercalciuric (IH) and non-inbred control (Ctl) rats were fed 13 glday of a normal calcium diet (0.6% calcium, NCD) for 10 days. Urine calcium excretion over the last seven days was greater in IH (34 2 mgI7 day) than in CtI (2.9 0.3, P < 0.01) rats. Some rats in each group were continued on the same diet while others were fed a low calcium diet (0.02% calcium, LCD) for an additional 10 days; balance measurements were made over the final seven days. With LCD, urine calcium excretion was -8-fold higher in IH compared to Ctl (13 2 mg/7 day vs. 1.6 0.1, IH vs. Ct!, respectively, P < 0.01). In IH rats percent calcium absorption was greater (59 3% vs. 45 3, IH vs. Ct!, P < 0.01), however calcium retention was negative (-1.9 2.0 mg/7 day vs. 6.5 0.5, IH vs. Ctl, P < 0.01) compared to Ctl rats. The fall in urine calcium excretion when IH rats are fed LCD indicates that enhanced intestinal calcium absorption is a primary mechanism of the hypercalciuria. However, the continued hyperca!ciuria and negative calcium retention during LCD indicates that an additional mechanism of hypercalciuria leads to a loss of bone mineral. Whether this additional mechanism is a primary bone resorptive process or due to an inability to conserve urinary calcium remains to be determined.

Research paper thumbnail of Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats

Kidney International, 1994

Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats. We have e... more Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats. We have established a colony of genetic hypercalciuric (IH) rats as a model of idiopathic hypercalciuria in humans. To test the hypothesis that hypercalciuria can cause crystallization in kidneys through increased supersaturation, in the absence of confounding effects of diet and whatever complex inhibitor disorders underlay stone disease, we fed males and females of the 21st generation of IH rats 13 g per day of a low calcium (LCD, 0.02% Ca), followed by a normal calcium (NCD, 0.6% Ca) and then a high calcium (HCD, 1.2% Ca) diet, each for seven days. During the last 24 hours of each period complete urine collections were obtained and analyzed for all substances known to affect urinary calcium oxalate (CaOx) and brushite (CaHPO4) supersaturation. Relative supersaturation with respect to the solid phases of CaOx and CaHPO4 were then calculated. Compared to same gender controls (Ctl) urine calcium excretion was higher in the female IH rats on all diets and in the male IH rats on NCD and HCD. The female and male IH rats on NCD and HCD were supersaturated with respect to CaOx; however, the male and female Ctl were supersaturated with respect CaOx only on HCD. The female IH rats on NCD and HCD and the male IH rats on NCD were supersaturated with respect to CaHPO4; however, neither the male nor female Ctl rats were supersaturated with respect to CaHPO4 on any diet. On NCD and HCD urine supersaturation with respect to CaHPO4 by females exceeded that of males. Kidney calcium content was greater in the female IH rat (120 13 g/g kidney) than in any other group (male III, 68 6; female Ctl, 74 4 and male Ctl 62 4; all P < 0.01 vs. female IH) and calcium content was correlated with CaHPO4 but not CaOx. Thus, female IH rats have greater urinary CaHPO4 supersaturation than Ctl rats or male IH rats, and these female IH rats have a greater kidney calcium content.

Research paper thumbnail of PSY48 Butrans® Rems Health Care Provider Training Guide Recall Testing

Value in Health, Jun 1, 2012

Research paper thumbnail of ORIGINAL REPORT Reductions in reported deaths following the introduction of extended- release oxycodone (OxyContin) with an abuse-deterrent formulation†

Purpose Abuse of opioid analgesics for their psychoactive effects is associated with a large numb... more Purpose Abuse of opioid analgesics for their psychoactive effects is associated with a large number of fatalities. The effect of making opi-oid tablets harder to crush/dissolve on opioid-related fatalities has not been assessed. The objective of this study was to assess the impact of introducing extended-release oxycodone (ERO [OxyContin®]) tablets containing physicochemical barriers to crushing/dissolving (reformulated ERO) on deaths reported to the manufacturer. Methods All spontaneous adverse event reports of death in the US reported to the manufacturer between 3Q2009 and 3Q2013 involving ERO were used. The mean numbers of deaths/quarter in the 3 years after reformulated ERO introduction were compared with the year before. Changes in the slope of trends in deaths were assessed using spline regression. Comparison groups consisted of non-fatal reports involving ERO and fatality reports involving ER morphine. Results Reports of death decreased 82 % (95 % CI: 89, 73) from the year be...

Research paper thumbnail of Changes in nonmedical use of OxyContin after reformulation with abuse deterrent properties

Drug and Alcohol Dependence, 2017

incident 12-to-23-year-old drinkers who have a prior history of cannabis use. Three questions are... more incident 12-to-23-year-old drinkers who have a prior history of cannabis use. Three questions are framed: (1) Is this proportion lower among 'law-abiding' newly incident drinkers who delay their first drink to age 21 years? (2) Before age 21, will the proportion show an age-related monotonic increase? (3) Will a male excess in this proportion emerge in mid-adolescence, before age 21? Methods: The 2002-2013 US National Surveys on Drug Use and Health identified 32,878 newly incident drinkers via confidential standardized computer-assisted self-interviews, and assessed alcohol and cannabis onset timing. Newly incident drinkers are those with first drink in the 12 months before assessment. Analysisweighted proportions and delta method variances are derived, with meta-analysis summaries. Results: Looking across age strata of newly incident drinkers, we found monotonically rising age-specific cannabis history proportions across adolescence, with a peak estimate seen at age 17 years (Males: 26%; 95%CI = 24%, 29%; Females: 17%; 95%CI = 15%, 19%). A male excess in antecedent cannabis use emerges at age 14 and persists until the legal drinking age at 21. Thereafter, males and females have similar proportions. Evaluated using an epidemiological mutoscope view, individual cohorts show a generally congruent pattern, with starting age held constant. Conclusions: The observed proportion shows monotonic increase to age 17, running congruent with age-specific cannabis incidence rates generally, then drops, suggesting that any increase in the proportion after age 18 must be driven largely by greater persistence of cannabis use among established cannabis users. Therefore, we expect to find different latent classes of newly incident drinkers before and after age 17. The observed male-female differences suggest age-related variation in underlying mechanisms. Financial support: NIDA T32 DA021129 & K05DA015799; Michigan State University.

Research paper thumbnail of Comparison of abuse, suspected suicidal intent, and fatalities related to the 7-day buprenorphine transdermal patch versus other opioid analgesics in the National Poison Data System

Postgraduate medicine, 2017

Prescription opioid related abuse, suicide and death are significant public health problems. This... more Prescription opioid related abuse, suicide and death are significant public health problems. This study compares rates of poison center calls categorized as intentional abuse, suspected suicidal intent or fatality for the 7-day buprenorphine transdermal system/patch (BTDS) with other extended-release and long-acting (ER/LA) opioids indicated for chronic pain. Retrospective 24-month cohort study using National Poison Data System data from July 2012 through June 2014. BTDS was introduced in the United States in January 2011. Numbers and rates of calls of intentional abuse, suspected suicidal intent and fatalities were evaluated for BTDS, ER morphine, ER oxycodone, fentanyl patch, ER oxymorphone and methadone tablets/capsules, using prescription adjustment to account for community availability. Rate ratios (RR) and 95% confidence intervals (CI) were calculated. Absolute numbers and prescription-adjusted rates of intentional abuse and suspected suicidal intent with BTDS were significant...

Research paper thumbnail of Non-oral abuse of immediate-release hydrocodone

Drug and Alcohol Dependence, 2015

83% to 100%, and none of the participants missed more than one counseling session. There was a si... more 83% to 100%, and none of the participants missed more than one counseling session. There was a significant decrease in opioid (heroin) use, 68% of the participants reported using heroin at 1 month, 13% at 2 months and none after 3 months of treatment. Fifty-one (35.2%)wereHIV-positive,with fournotpreviously known to be positive. All 51 HIV-positive participants received HIV treatment. Eighty-nine (68.0%)were HCV-positive, 42 (46.7%)were newlydiagnosed.Only2participants (2.4%)had receivedHCVtreatment. Conclusions: At 6-month, the findings showed the added value of an integrated treatment programondrug use, HIV detection, and access to HIV care. Long-term follow-up is needed to confirm the impact of this program. Financial support: NIDA R01-DA033671-01.

Research paper thumbnail of Buprenorphine Transdermal Delivery System in Adults with Persistent Noncancer-Related Pain Syndromes Who Require Opioid Therapy: A Multicenter, 5-Week Run-in and Randomized, Double-Blind Maintenance-of-Analgesia Study

Clinical Therapeutics, 2007

Objective: This study compared the efficacy and safety profile of buprenorphine transdermal deliv... more Objective: This study compared the efficacy and safety profile of buprenorphine transdermal delivery system (BTDS) and placebo in subjects with persistent noncancer-related pain who required opioid analgesics. Methods: This was a multicenter, double-blind, parallel-group study in adult subjects (age ≥18 years) with at least a 2-month history of noncancer-related pain for which they received oral opioid combination agents. The study employed a maintenance-of-analgesia, or randomized-withdrawal, design. During a 7-to 21-day open-label run-in phase, all subjects received BTDS, titrated as needed. Subjects who achieved stable pain control and were able to tolerate BTDS in the run-in phase were randomly assigned to continue BTDS at the dose achieved during the run-in phase or to receive placebo for up to 14 days. Acetaminophen 500-mg tablets were provided as escape (rescue) medication. Subjects completed the study on day 14 or when they met predefined criteria for ineffective treatment: requiring >1 g of acetaminophen as escape medication on any day of the double-blind evaluation phase, requiring a change in study drug dose, having difficulty keeping the patch affixed, or discontinuing because of ineffective treatment without meeting any of the first 3 criteria. The primary efficacy variable was the proportion of subjects with ineffective treatment. Secondary efficacy variables were the time to ineffective treatment; the proportion of subjects who reached ineffective treatment or discontinued for any reason other than ineffective treatment; and the amount of escape medication used. Assessment of the safety profile was based on adverse events and changes in vital signs and physical and laboratory findings. Results: Five hundred eighty-eight subjects entered the open-label run-in phase, and 267 (129 BTDS, 138 placebo) were subsequently randomized to doubleblind treatment. Demographic characteristics were similar between the double-blind BTDS and placebo groups (61.2% and 63.8% female, respectively; 99.2% and 98.6% white; mean [SD] age, 56.2 [13.3] and 59.2 [11.5] years). In the primary efficacy analysis, the proportion of subjects with ineffective treatment was lower with BTDS than with placebo (51.2% vs 65.0%; 95% CI, 1.09-2.95); the odds of ineffective treatment were 1.79 times greater for placebo relative to BTDS (P = 0.022). In the secondary efficacy analyses, the median time from the first dose of double-blind study drug to ineffective treatment was significantly longer with BTDS than with placebo (median, 10 vs 3 days; P = 0.011). The proportion of subjects who reached ineffective treatment or discontinued for reasons other than ineffective treatment was lower in the BTDS group compared with the placebo group (55.0% vs 67.9%); the odds of ineffective treatment or discontinuation for a reason other than ineffective treatment was 1.76 times greater with placebo compared with BTDS (P = 0.028). The mean amount of escape medication used was significantly lower in the BTDS group than in the placebo group (1.7 vs 2.2 acetaminophen tablets per

Research paper thumbnail of Poster 154

Archives of Physical Medicine and Rehabilitation, 2005

Research paper thumbnail of Comparison of overdose rates among patients prescribed buprenorphine patch, fentanyl, patch and morphine in the UK

The Journal of Pain, 2013

Research paper thumbnail of Improving study conduct and data quality in clinical trials of chronic pain treatments: IMMPACT recommendations

The Journal of Pain, 2019

This is a repository copy of Improving study conduct and data quality in clinical trials of chron... more This is a repository copy of Improving study conduct and data quality in clinical trials of chronic pain treatments: IMMPACT recommendations.

Research paper thumbnail of Disproportionality analysis of buprenorphine transdermal system and cardiac arrhythmia using FDA and WHO postmarketing reporting system data

Postgraduate medicine, 2017

Positive-controlled clinical studies have shown a dose dependent effect of buprenorphine transder... more Positive-controlled clinical studies have shown a dose dependent effect of buprenorphine transdermal system on QTc interval prolongation. This study provides assessment of the buprenorphine transdermal system and cardiac arrhythmia using US FDA and WHO postmarketing reporting databases. Disproportionality analysis of spontaneously reported adverse events to assess whether the reporting rate of cardiac arrhythmia events was disproportionately elevated relative to expected rates of reporting in both FDA and WHO databases. Cardiac arrhythmia events were identified using the standardized Medical Dictionary for Regulatory Activities query for torsade de pointes and/or QT prolongation (TdP/QTP). The threshold for a signal of disproportionate adverse event reporting was defined as the lower 90% confidence limit ≥ 2 of the Empiric Bayes geometric mean in FDA database and as the lower 95% confidence limit of the Informational Component >0 in WHO database. There were 124 (<1%) and 77 (2...

Research paper thumbnail of A randomized, placebo-controlled, double-blinded, parallel-group, 5-week study of buprenorphine transdermal system in adults with osteoarthritis

Journal of Opioid Management, 2010

This multicenter, parallel-group, 35-day study in adults with osteoarthritis (OA) pain evaluated ... more This multicenter, parallel-group, 35-day study in adults with osteoarthritis (OA) pain evaluated the analgesic efficacy and safety of buprenorphine transdermal system (BTDS) designed for 7-day wear. Patients with OA pain inadequately controlled with nonsteroidal antiinflammatory drugs or patients who had taken opioids for OA pain within the past year entered a 7-day run-in period during which they took ibuprofen only. Patients with pain &amp;amp;amp;amp;amp;amp;gt; or = on a 0-10 scale had their ibuprofen discontinued and were randomized into a 28-day double-blinded period to receive either BTDS at 1 of 3 dose levels (5, 10, or 20 microg/b) or placebo. Doses were titrated to effectiveness over a period of 21 days and maintained for 7 days. No rescue medication was allowed during the study. The primary efficacy measure was the proportion of patients who achieved treatment success, defined as a patient satisfaction score of good, very good, or excellent (on day 28 or at early discontinuation) for those who did not discontinue due to ineffective treatment. More BTDS-treated patients experienced treatment success than placebo TDS-treated patients (44 percent and 32 percent; odds ratio = 1.66, p = 0.036). Fewer patients taking BTDS titrated to the highest dose compared with placebo (p &amp;amp;amp;amp;amp;amp;lt; 0.05). There were two serious adverse events (both in the placebo group) and no deaths. The most common (&amp;amp;amp;amp;amp;amp;gt; or =5 percent) adverse events reported in BTDS-treated patients were nausea, headache, dizziness, somnolence, application site pruritus, and vomiting. Compared with placebo, BTDS treatment was effective in treating patients with moderate to severe pain due to OA of the knee or hip. BTDS was well-tolerated.

Research paper thumbnail of Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro

American Journal of Physiology Renal Physiology, Mar 1, 1992

Metabolic acidosis induces net calcium flux (JCa) from cultured neonatal mouse calvariae through ... more Metabolic acidosis induces net calcium flux (JCa) from cultured neonatal mouse calvariae through physicochemical and cell-mediated mechanisms. To determine the role of osteoblasts in acid-induced JCa, collagen synthesis and alkaline phosphatase activity were assessed in calvariae incubated in reduced pH and bicarbonate medium, a model of metabolic acidosis (Met), and compared with controls (Ctl). Collagen synthesis fell from 30.5 +/- 1.1 in Ctl to 25.1 +/- 0.4% with Met, and alkaline phosphatase decreased from 403 +/- 25 in Ctl to 298 +/- 21 nmol Pi.min-1.mg protein-1 with Met. During acidosis JCa was correlated inversely with percent collagen synthesis (r = -0.743, n = 11, P = 0.009) and with alkaline phosphatase activity (r = -0.453, n = 22, P = 0.034). To determine the role of osteoclasts in acid-induced JCa, osteoclastic beta-glucuronidase activity was determined in Ctl and Met in the absence or presence of the osteoclastic inhibitor calcitonin (CT, 3 x 10(-9) M). Met increased beta-glucuronidase (5.9 +/- 0.2) compared with Ctl (4.6 +/- 0.3 micrograms phenolphthalein released.bone-1.h-1), whereas CT inhibited beta-glucuronidase in both Ctl and Met (3.1 +/- 0.2 and 3.5 +/- 0.3, respectively). During acidosis JCa was correlated directly with beta-glucuronidase activity (r = 0.683, n = 42, P less than 0.001). Thus the cell-mediated component of JCa during acidosis in vitro appears to result from a combination of inhibited osteoblastic and stimulated osteoclastic activity.

Research paper thumbnail of Critical role of bicarbonate in calcium release from bone

American Journal of Physiology Renal Fluid and Electrolyte Physiology, Sep 1, 1992

Calcium release from cultured bone is pH dependent; net calcium flux (JCa) from bone increases wi... more Calcium release from cultured bone is pH dependent; net calcium flux (JCa) from bone increases with decreasing pH. At a similar decrement in pH there is greater JCa when acidosis is produced by a low medium bicarbonate concentration ([HCO3-]), a model of metabolic acidosis (Met), compared with an increased medium PCO2, a model of respiratory acidosis (Resp). To separate the role of [HCO3-] from that of pH in inducing JCa we cultured calvariae for 3 h under three different neutral (pH approximately 7.4) isohydric environments [control (Ctl), fully compensated Met (C-Met), or fully compensated Resp (C-Resp)] and two different acid (pH approximately 7.1) isohydric environments (Met or Resp). During neutral pH (Ctl, C-Met, and C-Resp) there was JCa from bone during C-Met (decreased [HCO3-]), no net flux during Ctl (normal [HCO3-]), and JCa into bone during C-Resp (increased [HCO3-]); and JCa was correlated inversely with [HCO3-] (r = -0.824, n = 36, P less than 0.001). During acid pH there was greater JCa from bone during Met (decreased [HCO3-]) than during Resp (normal [HCO3-]); and JCa was again correlated inversely with [HCO3-] (r = -0.848, n = 22, P less than 0.001). JCa from bone during Met and Resp was greater than C-Met and C-Resp, respectively. The addition of the osteoclastic inhibitor salmon calcitonin did not alter the relative JCa results. Thus at a constant pH the magnitude of JCa from cultured neonatal mouse calvariae appears dependent on the [HCO3-]; the lower the [HCO3-], the greater the calcium efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Greater unidirectional calcium efflux from bone during metabolic, compared with respiratory, acidosis

American Journal of Physiology Renal Physiology, Mar 1, 1992

There is a smaller net calcium efflux from bone in vitro during respiratory (increased PCO2) than... more There is a smaller net calcium efflux from bone in vitro during respiratory (increased PCO2) than metabolic (decreased [HCO3-] acidosis. This could be due to the elevated PCO2, which would lessen the driving force for mineral dissolution and increase the driving force for mineralization with respect to carbonated apatite in the bone mineral. To test this hypothesis, we injected neonatal mice with 45Ca and dissected the radiolabeled calvariae 24 h later. The live calvariae were then cultured for 24 h under conditions simulating respiratory acidosis (Resp, pH = 7.225 +/- 0.003, PCO2 = 87.5 +/- 0.1 mmHg), severe respiratory acidosis (SResp, pH = 7.072 +/- 0.004, PCO2 = 103.0 +/- 0.5 mmHg), metabolic acidosis (Met, pH = 7.212 +/- 0.003, HCO3- = 15.5 +/- 0.1 meq/l), or normal acid-base status (Ctl, pH = 7.452 +/- 0.003, PCO2 = 40.0 +/- 0.2 mmHg, HCO3- = 27.8 +/- 0.2 meq/l) and bidirectional net calcium flux (JCa) and unidirectional 45Ca release were determined. There was greater JCa from bone during Met than Resp, and JCa was not different from Met during SResp despite the latter having a significantly lower pH. There was greater unidirectional 45Ca release from bone during Met than Resp, SResp, or Ctl. There was a similar direct correlation between JCa and 45Ca efflux in the respiratory and metabolic groups. However, when calvarial osteoclast activity was inhibited with calcitonin,although there was again greater JCa and 45Ca release with a metabolic compared with respiratory acidosis, there was a greater proportion of 45Ca release than JCa from bone.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Changes in age-specific rates of doctor-shopping for opioids following introduction of reformulated Oxycontin® tablets

Drug and Alcohol Dependence, 2015

Research paper thumbnail of Non-oral abuse of immediate-release hydrocodone

Drug and Alcohol Dependence, 2015

Research paper thumbnail of Reductions in reported deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent formulation

Pharmacoepidemiology and drug safety, 2014

Abuse of opioid analgesics for their psychoactive effects is associated with a large number of fa... more Abuse of opioid analgesics for their psychoactive effects is associated with a large number of fatalities. The effect of making opioid tablets harder to crush/dissolve on opioid-related fatalities has not been assessed. The objective of this study was to assess the impact of introducing extended-release oxycodone (ERO [OxyContin(®) ]) tablets containing physicochemical barriers to crushing/dissolving (reformulated ERO) on deaths reported to the manufacturer. All spontaneous adverse event reports of death in the US reported to the manufacturer between 3Q2009 and 3Q2013 involving ERO were used. The mean numbers of deaths/quarter in the 3 years after reformulated ERO introduction were compared with the year before. Changes in the slope of trends in deaths were assessed using spline regression. Comparison groups consisted of non-fatal reports involving ERO and fatality reports involving ER morphine. Reports of death decreased 82% (95% CI: -89, -73) from the year before to the third year...

Research paper thumbnail of Decreased bone carbonate content in response to metabolic, but not respiratory, acidosis

The American journal of physiology, 1993

In vitro cultured neonatal mouse calvariae release calcium and buffer the medium proton concentra... more In vitro cultured neonatal mouse calvariae release calcium and buffer the medium proton concentration in response to a decrease in the medium pH caused by a reduction in bicarbonate concentration ([HCO3-]), a model of metabolic acidosis, but not to an equivalent decrease in pH caused by an increase in the partial pressure of carbon dioxide (PCO2), a model of respiratory acidosis. We have postulated that the medium is in equilibrium with the carbonated apatite in bone. To determine whether bone carbonate is depleted during models of acidosis, we cultured calvariae in control medium (pH approximately 7.4, PCO2 approximately 43, [HCO3-] approximately 26) or in medium in which the pH was equivalently reduced by either a decrease in [HCO3-] (metabolic acidosis, pH approximately 7.1, [HCO3-] approximately 13) or an increase in PCO2 (respiratory acidosis, pH approximately 7.1, PCO2 approximately 86) and determined net calcium flux (JCa) and bone carbonate content. We found that compared wi...

Research paper thumbnail of Response of genetic hypercalciuric rats to a low calcium diet

Kidney International, 1993

Response of genetic hypercalciuric rats to a low calcium diet. A fundamental mechanism for hyperc... more Response of genetic hypercalciuric rats to a low calcium diet. A fundamental mechanism for hypercalciuria in genetic hypercalciuric rats appears due to a primary increase in intestinal calcium absorption. However previous studies could not exclude additional mechanisms to account for the hypercalciuria. To determine if enhanced bone mineral dissolution either as a primary abnormality or secondary to a defect in renal tubule calcium reabsorption is responsible for a component of the augmented calcium excretion we studied rats continually inbred for hypercalciuria. Nineteenth generation adult female idiopathic hypercalciuric (IH) and non-inbred control (Ctl) rats were fed 13 glday of a normal calcium diet (0.6% calcium, NCD) for 10 days. Urine calcium excretion over the last seven days was greater in IH (34 2 mgI7 day) than in CtI (2.9 0.3, P < 0.01) rats. Some rats in each group were continued on the same diet while others were fed a low calcium diet (0.02% calcium, LCD) for an additional 10 days; balance measurements were made over the final seven days. With LCD, urine calcium excretion was -8-fold higher in IH compared to Ctl (13 2 mg/7 day vs. 1.6 0.1, IH vs. Ct!, respectively, P < 0.01). In IH rats percent calcium absorption was greater (59 3% vs. 45 3, IH vs. Ct!, P < 0.01), however calcium retention was negative (-1.9 2.0 mg/7 day vs. 6.5 0.5, IH vs. Ctl, P < 0.01) compared to Ctl rats. The fall in urine calcium excretion when IH rats are fed LCD indicates that enhanced intestinal calcium absorption is a primary mechanism of the hypercalciuria. However, the continued hyperca!ciuria and negative calcium retention during LCD indicates that an additional mechanism of hypercalciuria leads to a loss of bone mineral. Whether this additional mechanism is a primary bone resorptive process or due to an inability to conserve urinary calcium remains to be determined.

Research paper thumbnail of Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats

Kidney International, 1994

Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats. We have e... more Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats. We have established a colony of genetic hypercalciuric (IH) rats as a model of idiopathic hypercalciuria in humans. To test the hypothesis that hypercalciuria can cause crystallization in kidneys through increased supersaturation, in the absence of confounding effects of diet and whatever complex inhibitor disorders underlay stone disease, we fed males and females of the 21st generation of IH rats 13 g per day of a low calcium (LCD, 0.02% Ca), followed by a normal calcium (NCD, 0.6% Ca) and then a high calcium (HCD, 1.2% Ca) diet, each for seven days. During the last 24 hours of each period complete urine collections were obtained and analyzed for all substances known to affect urinary calcium oxalate (CaOx) and brushite (CaHPO4) supersaturation. Relative supersaturation with respect to the solid phases of CaOx and CaHPO4 were then calculated. Compared to same gender controls (Ctl) urine calcium excretion was higher in the female IH rats on all diets and in the male IH rats on NCD and HCD. The female and male IH rats on NCD and HCD were supersaturated with respect to CaOx; however, the male and female Ctl were supersaturated with respect CaOx only on HCD. The female IH rats on NCD and HCD and the male IH rats on NCD were supersaturated with respect to CaHPO4; however, neither the male nor female Ctl rats were supersaturated with respect to CaHPO4 on any diet. On NCD and HCD urine supersaturation with respect to CaHPO4 by females exceeded that of males. Kidney calcium content was greater in the female IH rat (120 13 g/g kidney) than in any other group (male III, 68 6; female Ctl, 74 4 and male Ctl 62 4; all P < 0.01 vs. female IH) and calcium content was correlated with CaHPO4 but not CaOx. Thus, female IH rats have greater urinary CaHPO4 supersaturation than Ctl rats or male IH rats, and these female IH rats have a greater kidney calcium content.