Oxycodone HCl Controlled-release Research Articles

Tolerability and efficacy of tapentadol extended release in elderly patients ≥ 75 years of age with chronic osteoarthritis knee or low back pain.

Management of chronic pain in elderly adult patients is often complicated by analgesic medication-related side effects. This post hoc analysis of pooled data evaluated the tolerability and analgesic efficacy of tapentadol extended release (ER) compared with oxycodone controlled release (CR) in elderly adult patients (≥ 75 years of age) with moderate to severe, chronic osteoarthritis knee or low back pain. Data were pooled from three similarly designed, randomized, doubleblind, placebo- and active-controlled, phase 3 studies of tapentadol ER for moderate to severe, chronic osteoarthritis knee (NCT00421928, NCT00486811) or low back (NCT00449176) pain, and data for patients ≥ 75 years of age were evaluated. Each study consisted of a 3-week titration and 12-week maintenance period. Patients received placebo, tapentadol ER (100-250 mg bid), or oxycodone HCl CR (20-50 mg bid). Tolerability was evaluated using adverse event reporting. Efficacy was evaluated using pain intensity ratings (11-point numerical rating scale). For patients ≥ 75 years of age (n = 210), incidences of gastrointestinal treatment-emergent adverse events (TEAEs) overall and TEAEs of vomiting and the composite of nausea and/or vomiting were significantly lower in the tapentadol ER group compared with the oxycodone CR group (all p ≤ 0.0206). Tapentadol ER treatment was associated with significant reductions in pain intensity from baseline to week 15 compared with placebo (p = 0.0075); differences between the oxycodone CR and placebo groups failed to reach statistical significance (p = 0.1195), likely related to a higher treatment discontinuation rate in the oxycodone CR group. No significant differences were observed between the tapentadol ER and oxycodone CR groups in the change in pain intensity from baseline to week 15 (p = 0.2135). In elderly adult patients ≥ 75 years of age with moderate to severe, chronic osteoarthritis knee or low back pain, tapentadol ER (100-250 mg bid) provided significant pain relief compared with placebo and had a better overall gastrointestinal tolerability profile than oxycodone CR.

Abuse of OxyContin® and immediate-release oxycodone in a rural Kentucky county following introduction of reformulated OxyContin: Results from 6-month follow-up interviews

Aims: In August 2010, shipments of original OxyContin (oxycodone HCl controlled-release; OC) stopped and reformulated OxyContin (ORF) started. OxyContin was reformulated to render it more difficult to manipulate for the purposes of intentional abuse. This study describes changes in abuse 1–2 years after ORF introduction among individuals who had abused OC in rural Kentucky. Methods: Structured follow-up interviews assessing opioid use were conducted in 164 individuals who abused OC, 85% of the original sample of individuals interviewed about preand postORF drug use (n=192). Participants reported retrospectively about abuse, including past 30-day use via any route (days/month), in interviews conducted January 2011–April 2012, approximately 6 months after the initial interview. Results: Most participants (76%) selected OC as their preferred drug prior to ORF introduction; (66%) selected immediate release (IR) oxycodone as their preferred drug after ORF introduction. From the initial post-ORF interview to 6-month follow-up, the prevalence and frequency (days/month) of OC abuse declined (60–11% and 11.3–3.3 days/month among those who abused, respectively). During the same time period, prevalence of ORF abuse declined (33–18%); among those who were abusing ORF, frequency remained stable (5.9 vs. 5.7 days/month). At followup, 23% reported attempting to manipulate ORF for purposes of abuse, though only 1 participant selected ORF as the preferred drug. There was a decline in the prevalence of any IR oxycodone abuse (96–85%); the frequency among those abusing IR oxycodone remained relatively constant. Conclusions: OxyContin changed frombeing the preferred drug for themajority of abusers before ORF introduction to the preferred drug for <1% of abusers at follow up, while the prevalence of OC abuse declined due to decreased availability. There was a shift in preference from OC to IR oxycodone as availability of OC declined. Financial support: Supported by Purdue Pharma L.P.

The natural history of adolescent binge drinking: Findings from a 15-year prospective cohort study

Aims: In August 2010, shipments of original OxyContin (oxycodone HCl controlled-release; OC) stopped and reformulated OxyContin (ORF) started. OxyContin was reformulated to render it more difficult to manipulate for the purposes of intentional abuse. This study describes changes in abuse 1–2 years after ORF introduction among individuals who had abused OC in rural Kentucky. Methods: Structured follow-up interviews assessing opioid use were conducted in 164 individuals who abused OC, 85% of the original sample of individuals interviewed about preand postORF drug use (n=192). Participants reported retrospectively about abuse, including past 30-day use via any route (days/month), in interviews conducted January 2011–April 2012, approximately 6 months after the initial interview. Results: Most participants (76%) selected OC as their preferred drug prior to ORF introduction; (66%) selected immediate release (IR) oxycodone as their preferred drug after ORF introduction. From the initial post-ORF interview to 6-month follow-up, the prevalence and frequency (days/month) of OC abuse declined (60–11% and 11.3–3.3 days/month among those who abused, respectively). During the same time period, prevalence of ORF abuse declined (33–18%); among those who were abusing ORF, frequency remained stable (5.9 vs. 5.7 days/month). At followup, 23% reported attempting to manipulate ORF for purposes of abuse, though only 1 participant selected ORF as the preferred drug. There was a decline in the prevalence of any IR oxycodone abuse (96–85%); the frequency among those abusing IR oxycodone remained relatively constant. Conclusions: OxyContin changed frombeing the preferred drug for themajority of abusers before ORF introduction to the preferred drug for <1% of abusers at follow up, while the prevalence of OC abuse declined due to decreased availability. There was a shift in preference from OC to IR oxycodone as availability of OC declined. Financial support: Supported by Purdue Pharma L.P.

Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse‐deterrent controlled‐release tablets in recreational opioid users

The objective of this study was to evaluate abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered, crushed reformulated OxyContin® (oxycodone HCl controlled-release) tablets (ORF), relative to crushed original OxyContin® (OC), oxycodone powder (Oxy API), and OC placebo. This randomized, double-blind, positive- and placebo-controlled crossover study enrolled healthy, adult, nonphysically dependent recreational opioid users with recent history of intranasal drug abuse (N = 27). Active treatments contained oxycodone (30 mg). Pharmacokinetics, pharmacodynamics (e.g., Overall Drug Liking [ODL], Take Drug Again [TDA], and High Visual Analog Scales [VAS]; Subjective Drug Value [SDV]; pupillometry; intranasal irritation), and safety (e.g., adverse events, vital signs, laboratory tests) were assessed to 24 hours postdose. Crushed ORF administration yielded reduced oxycodone Cmax and increased Tmax versus crushed OC and Oxy API. Peak effects for pharmacodynamic measures were delayed with ORF (1–2 hours) versus OC and Oxy API (0.5–1 hour). ODL, TDA, High VAS, and SDV Emax values were significantly lower (P ≤ .05) and some intranasal irritation ratings were greater for ORF versus OC and Oxy API. No significant or unexpected safety findings were observed. Compared with OC and Oxy API, intranasally administered ORF was associated with lower and delayed peak plasma concentrations, decreased drug-liking, and decreased intranasal tolerability. This suggests that ORF has a decreased potential for intranasal oxycodone abuse. There were no significant or unexpected safety findings. As is true for all abuse potential studies, epidemiological or other appropriate post-marketing studies are required to assess the impact of the reduction in intranasal oxycodone abuse potential observed in the present study on real-world patterns of ORF misuse, abuse, and diversion.

Attractiveness of reformulated OxyContin® tablets: assessing comparative preferences and tampering potential

Reformulated OxyContin® (oxycodone HCl controlled-release or ORF) was developed as a tamper and abuse-deterrent product, to reduce the risk of product abuse, misuse and their consequences. This noninterventional single-session study asked participants who were medically-healthy recreational opioid users, aged 18 years and older, to consider how they would use commonly available supplies to tamper with placebo ORF and placebo original OxyContin (OC) tablets, and how they would assess the attractiveness of tampering and abusing ORF tablets, as compared with other opioid formulations. Participants provided information on past opioid use, and they assessed the properties of five nonhypothetical oxycodone products and two hypothetical oxycodone products. Participants provided feedback on tampering preferences, preferred tamper methods for each product, overall tampering potential and product preferences. We had 30 participants (27 males and 3 females; mean age 35 years, range 18-51) complete both the interview and tampering sessions. Participants judged OC as the most attractive, valuable, desirable and most likely to be tampered with, from among all opioid products studied. By contrast, they rated ORF as the least attractive, least valuable, least desirable, and least likely to be tampered with among all the nonhypothetical opioid products studied. These results suggested that recreational drug abusers view ORF tablets as tamper-deterrent products.

Efficacy of Tapentadol ER for Managing Moderate to Severe Chronic Pain

Background: Chronic non–cancer-related pain affects a large proportion of the adult population and is often difficult to manage effectively. Although opioid analgesics have been used to relieve chronic pain of different etiologies, opioids are associated with a range of side effects that may reduce patient quality of life and lead to reduced compliance with treatment.Tapentadol is a centrally acting analgesic with 2 mechanisms of action, µ-opioid receptor agonism and norepinephrine reuptake inhibition, that is available in an extended-release formulation for the management of chronic pain. Objective: To review the efficacy of tapentadol extended release (ER) for the management of moderate to severe chronic nociceptive and neuropathic pain. Methods: Efficacy results are summarized for four 15-week phase 3 studies of tapentadol ER in patients with moderate to severe chronic osteoarthritis knee pain (2 studies; ClinicalTrials.gov Identifiers: NCT00421928 and NCT00486811), low back pain (NCT00449176), and pain related to diabetic peripheral neuropathy (DPN; NCT00455520); a one-year phase 3 study of tapentadol ER in patients with moderate to severe chronic osteoarthritis pain or low back pain (NCT00361504); and a pooled analysis of data from the 15-week studies in patients with osteoarthritis knee pain or low back pain. A summary of the comparative tolerability for tapentadol ER and the active comparator used in these studies, oxycodone controlled release (CR), is provided. Results: Results of these studies showed that tapentadol ER (100 - 250 mg bid) was effective for the management of moderate to severe chronic osteoarthritis knee pain, low back pain, and pain related to DPN. Tapentadol ER (100 - 250 mg bid) has been shown to provide comparable pain relief to oxycodone HCl CR (20 - 50 mg bid) for chronic osteoarthritis knee pain and low back pain over up to one year of treatment. Tapentadol ER (100 - 250 mg bid) was associated with an improved tolerability profile, particularly gastrointestinal tolerability profile, and with lower rates of treatment discontinuations and adverse event-related discontinuations compared with oxycodone HCl CR (50 - 250 mg bid) over up to one year of treatment in patients with osteoarthritis knee pain and low back pain. Limitations: Differences in the design and duration of these phase 3 studies may limit comparisons of the efficacy results; nevertheless, this summary of efficacy results demonstrates the broad efficacy of tapentadol ER for different types of nociceptive and neuropathic pain. Conclusions: Tapentadol ER (100 - 250 mg bid) is effective for moderate to severe osteoarthritis pain, low back pain, and pain related to DPN and provides efficacy similar to that of oxycodone HCl CR (20 - 50 mg bid) for patients with osteoarthritis and low back pain. Tapentadol ER treatment has been associated with better gastrointestinal tolerability and compliance with therapy than oxycodone CR, which suggests that tapentadol ER may be a better option for the long-term management of chronic pain. Key words: Chronic pain, tapentadol ER, osteoarthritis pain, low back pain, diabetic peripheral neuropathy, oxycodone CR, opioid, analgesic

92 Difference in Rates of Abuse Following Reformulation of Extended Release Oxycodone Using Data From the RADARS® System Poison Center Program

Study Objectives: In August 2010, a reformulated version of OxyContin (oxycodone HCl controlled-release) tablets was introduced, which is intended to deter crushing and forms a gel when dissolved, with the goal of deterring abuse through routes that require tampering. This study examines whether there was a decline in rates of abuse and therapeutic errors of OxyContin reported to poison centers participating in the RADARS® System after introduction of reformulated OxyContin (ORF). Poison centers participating in the program covered 90% of the US population in the 3rd quarter of 2011.Methods: Mentions of OxyContin and other prescription products (“exposures”) were obtained on a quarterly basis from participating poison centers. Exposures were coded by reason, including intentional abuse and unintentional therapeutic errors. Therapeutic errors are defined as a deviation from a proper therapeutic regimen that results in the wrong dose, incorrect route of administration, administration to the wrong person, or administration of the wrong substance. Rates were calculated for abuse and for unintentional therapeutic error exposures per 100,000 population and per 1,000 unique recipients of dispensed drug (URDD) for each year/quarter. October 1, 2008 through September 30, 2010 was considered the period before and October 1, 2010 to December 31, 2011 was considered the period after introduction of ORF. These poison center data do not differentiate between exposures to original OxyContin versus ORF in the after period. The mean abuse rates for OxyContin as well as other prescription opioid drugs were compared before and after introduction of ORF using negative binomial regression.Results: There was a 34% (95% CI: 26-42%) decline in the average abuse rate of OxyContin per 100,000 population and 29% (95% CI: 20-36%) decline in the rate per 1,000 URDD after the introduction of ORF. The declines in the abuse rate for OxyContin were greater than changes observed for all other opioids (P<0.0001). There was a 22% (95% CI: 12-32%) decline in the rate of unintentional therapeutic error exposures of OxyContin per 100,000 population and a 16% (95% CI: 10-22%) decline per 1,000 URDD after introduction of ORF. The declines in the therapeutic error rate for OxyContin were greater than changes observed for all other opioids when measured per 100,000 population (p=0.0003), but not when measured per 1,000 URDD (p=0.098). Study Objectives: In August 2010, a reformulated version of OxyContin (oxycodone HCl controlled-release) tablets was introduced, which is intended to deter crushing and forms a gel when dissolved, with the goal of deterring abuse through routes that require tampering. This study examines whether there was a decline in rates of abuse and therapeutic errors of OxyContin reported to poison centers participating in the RADARS® System after introduction of reformulated OxyContin (ORF). Poison centers participating in the program covered 90% of the US population in the 3rd quarter of 2011. Methods: Mentions of OxyContin and other prescription products (“exposures”) were obtained on a quarterly basis from participating poison centers. Exposures were coded by reason, including intentional abuse and unintentional therapeutic errors. Therapeutic errors are defined as a deviation from a proper therapeutic regimen that results in the wrong dose, incorrect route of administration, administration to the wrong person, or administration of the wrong substance. Rates were calculated for abuse and for unintentional therapeutic error exposures per 100,000 population and per 1,000 unique recipients of dispensed drug (URDD) for each year/quarter. October 1, 2008 through September 30, 2010 was considered the period before and October 1, 2010 to December 31, 2011 was considered the period after introduction of ORF. These poison center data do not differentiate between exposures to original OxyContin versus ORF in the after period. The mean abuse rates for OxyContin as well as other prescription opioid drugs were compared before and after introduction of ORF using negative binomial regression. Results: There was a 34% (95% CI: 26-42%) decline in the average abuse rate of OxyContin per 100,000 population and 29% (95% CI: 20-36%) decline in the rate per 1,000 URDD after the introduction of ORF. The declines in the abuse rate for OxyContin were greater than changes observed for all other opioids (P<0.0001). There was a 22% (95% CI: 12-32%) decline in the rate of unintentional therapeutic error exposures of OxyContin per 100,000 population and a 16% (95% CI: 10-22%) decline per 1,000 URDD after introduction of ORF. The declines in the therapeutic error rate for OxyContin were greater than changes observed for all other opioids when measured per 100,000 population (p=0.0003), but not when measured per 1,000 URDD (p=0.098).

Efficacy and Safety of Tapentadol Extended Release Compared with Oxycodone Controlled Release for the Management of Moderate to Severe Chronic Pain Related to Osteoarthritis of the Knee

Tapentadol is a novel, centrally acting analgesic with mu-opioid receptor agonist and norepinephrine reuptake inhibitor activity. to evaluate the efficacy and safety of Tapentadol extended release (ER) compared with oxycodone controlled release (CR) for management of moderate to severe chronic osteoarthritis-related knee pain. this was a randomized, double-blind, active- and placebo-controlled, parallel-arm, multicentre, phase III study during which patients received Tapentadol ER, oxycodone CR or placebo for a 3-week titration period followed by a 12-week maintenance period. The study was carried out at sites in Australia, Canada, New Zealand and the US. A total of 1030 patients with chronic osteoarthritis-related knee pain were randomized to receive Tapentadol ER 100-250 mg twice daily, oxycodone HCl CR 20-50 mg twice daily or placebo. Primary endpoints (as determined prior to initiation of the study) were the changes from baseline in average daily pain intensity (rated by patients on an 11-point numerical rating scale) over the last week of maintenance and over the entire 12-week maintenance period; last observation carried forward was used to impute missing values after early treatment discontinuation. efficacy and safety were evaluated for 1023 patients. Tapentadol ER significantly reduced average pain intensity from baseline to week 12 of the maintenance period versus placebo (least squares mean [LSM] difference [95% CI], -0.7 [-1.04, -0.33]), and throughout the maintenance period (-0.7 [-1.00, -0.33]). Oxycodone CR significantly reduced average pain intensity from baseline throughout the maintenance period versus placebo (LSM difference [95% CI], -0.3 [-0.67, -0.00]) but not at week 12 (-0.3 [-0.68, 0.02]). A significantly higher percentage of patients achieved > or =50% improvement in pain intensity in the Tapentadol ER group (32.0% [110/344]) compared with the placebo group (24.3% [82/337]; p = 0.027), indicating a clinically significant improvement in pain intensity, while a significantly lower percentage of patients achieved > or =50% improvement in pain intensity in the oxycodone CR group (17.3% [59/342]; p = 0.023 vs placebo). In the placebo, Tapentadol ER and oxycodone CR groups, respectively, 61.1% (206/337), 75.9% (261/344) and 87.4% (299/342) of patients reported at least one treatment-emergent adverse event (TEAE); incidences of gastrointestinal-related TEAEs were 26.1% (88/337), 43.0% (148/344) and 67.3% (230/342). treatment with Tapentadol ER 100-250 mg twice daily or oxycodone HCl CR 20-50 mg twice daily was effective for the management of moderate to severe chronic osteoarthritis-related knee pain, with substantially lower incidences of gastrointestinal-related TEAEs associated with treatment with Tapentadol ER than with oxycodone CR.

Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study

Objective: To evaluate the efficacy and safety of tapentadol extended release (ER) for the management of moderate to severe chronic low back pain.Research design: Patients (N = 981) were randomized 1:1:1 to receive tapentadol ER 100 – 250 mg b.i.d., oxycodone HCl controlled release (CR) 20 – 50 mg b.i.d., or placebo over 15 weeks (3-week titration period, 12-week maintenance period).Main outcome measures: Efficacy was assessed as change from baseline in average pain intensity (11-point NRS) at week 12 of the maintenance period and throughout the maintenance period; last observation carried forward was used to impute missing pain scores. Adverse events (AEs) were monitored throughout the study.Results: Tapentadol ER significantly reduced average pain intensity versus placebo at week 12 (least squares mean difference vs placebo [95% confidence interval], −0.8 [−1.22, −0.47]; p < 0.001) and throughout the maintenance period (−0.7 [−1.06,−0.35]; p < 0.001). Oxycodone CR significantly reduced average pain intensity versus placebo at week 12 (−0.9 [−1.24,−0.49]; p < 0.001) and throughout the maintenance period (−0.8 [−1.16,−0.46]; p < 0.001). Tapentadol ER was associated with a lower incidence of treatment-emergent AEs (TEAEs) than oxycodone CR. Gastrointestinal TEAEs, including constipation, nausea, and vomiting, were among the most commonly reported TEAEs (placebo, 26.3%; tapentadol ER, 43.7%; oxycodone CR, 61.9%). The odds of experiencing constipation or the composite of nausea and/or vomiting were significantly lower with tapentadol ER than with oxycodone CR (both p < 0.001).Conclusions: Tapentadol ER (100 – 250 mg b.i.d.) effectively relieved moderate to severe chronic low back pain over 15 weeks and had better gastrointestinal tolerability than oxycodone HCl CR (20 – 50 mg b.i.d.).

Safety and tolerability of tapentadol extended release (ER) versus oxycodone controlled release (CR) in elderly patients with chronic low back or osteoarthritis pain

In a phase 3, randomized, open-label, 1-year safety study in adults with moderate-to-severe chronic low back or osteoarthritis pain, tapentadol ER (100-250mg bid) provided similar pain relief to oxycodone HCl CR (20-50mg bid), with improved gastrointestinal tolerability (ClinicalTrials.gov Identifier:NCT00361504). This post-hoc analysis evaluated incidences of and study discontinuations due to overall and gastrointestinal treatment-emergent adverse events (TEAEs) among patients ≥65 years of age. Times to onset of and discontinuations due to constipation, nausea, or vomiting were estimated using Kaplan-Meier plots (treatment differences compared using the log-rank test); the percentage of treatment days with these TEAEs was calculated (treatment differences compared using the Wilcoxon test). Of 1,117 patients analyzed for safety, 312 were ≥65 years (tapentadol ER, n=245; oxycodone CR, n=67). Among patients ≥65 years in the tapentadol ER and oxycodone CR groups, respectively, 87.8% and 94.0% of patients reported ≥1 TEAE and 57.6% and 76.1% of patients reported gastrointestinal TEAEs (most were mild or moderate). Patients ≥65 years who received tapentadol ER versus oxycodone CR experienced significantly lower percentages of treatment days with nausea (5.39% vs 14.0%), vomiting (2.4% vs 7.2%), or constipation (14.9% vs 31.6%); all nominal P≤0.0021. Times to first onset of these TEAEs were significantly longer with tapentadol ER versus oxycodone CR (all nominal P≤0.0002 [log-rank test]). In the tapentadol ER and oxycodone CR groups, respectively, any TEAE led to study discontinuation in 33.1% and 49.3% and gastrointestinal TEAEs led to study discontinuation in 14.3% and 31.3% of patients ≥65 years. Times to withdrawal due to nausea, vomiting, or constipation were significantly longer with tapentadol ER versus oxycodone CR (all nominal P≤0.0099). Tapentadol ER was associated with better gastrointestinal tolerability and a lower rate of study discontinuations due to TEAEs than oxycodone CR in patients ≥65 with moderate-to-severe chronic pain. (OMJSA and Grünenthal GmbH supported this study.)

Tapentadol extended release (ER) versus oxycodone controlled release (CR) for management of chronic low back or osteoarthritis pain: influence of prior opioid experience on study discontinuations due to constipation, nausea, or vomiting

In a phase 3, randomized, open-label, 1-year safety study in patients with moderate-to-severe chronic low back or osteoarthritis pain, tapentadol ER (100-250mg bid; n=894) demonstrated similar pain relief to oxycodone HCl CR (20-50mg bid; n=223), with lower incidences of gastrointestinal treatment-emergent adverse events (TEAEs; ClinicalTrials.gov:NCT00361504). This post-hoc data analysis evaluated study discontinuations due to any TEAE and due to constipation, nausea, or vomiting for patients stratified by prior opioid experience (defined as use of opioid medications ≤3 months before screening).

The effect of FDA approval of a generic competitor to OxyContin ® (oxycodone HCl controlled-release) tablets on the abuse of oxycodone

Controversy exists concerning whether abuse of oxycodone will increase after the introduction of generic controlled-release (CR) oxycodone. We evaluated the effect of FDA approval of generic CR oxycodone on the misuse/abuse of oxycodone, hydrocodone, methadone and morphine utilizing data from eight poison control centers (PCC). PCC intentional exposure (IE) reason codes were used as measures of abuse. Opioid-specific quarterly IE rates (per 100,000 population and per 10,000 patients) were calculated for 1 year before and after approval (March 24, 2004). Changes in regression slopes (1 year before to 1 year after) and in IE rates (1 quarter before to 1 quarter after) were analyzed using Poisson regression. The regression slopes for oxycodone, methadone and morphine did not change after approval but decreased significantly for hydrocodone. None of the prescription opioids’ IE rates significantly increased after approval. When changes in oxycodone's IE rates were compared to the other opioids, no statistically significant differences were found, indicating a lack of time–opioid interaction. These results did not vary when population rates or patient rates were used. PCC data indicate that approval of generic CR oxycodone was not followed by an immediate unfavorable effect on the misuse/abuse of oxycodone.

Oxycodone Involvement in Drug Abuse Deaths. II. Evidence for Toxic Multiple Drug-Drug Interactions

Recent surveys suggest that the abuse of drugs, often in combination, is pervasive throughout society. Adverse consequences of drug abuse tend to be attributed to the single drug "most likely" to be responsible. This is frequently seen in fatality cases, particularly those involving opioids. However, it is difficult to determine the specific cause of death when multiple drugs are involved. Although enhanced toxicity of alcohol and other centrally acting drugs with opioids has been well established in animal studies, there is a paucity of data in well-controlled human studies. We evaluated 1014 fatality cases involving oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug-drug interactions. We previously reported on these cases, and we classified them by a standardized method into groups that distinguished cases unrelated to drug abuse from those related to drug abuse, cases that involved only OXC from cases involving multiple drugs, drug-induced fatalities from drug-related fatalities, and cases in which the specific drug product OxyContin (oxycodone HCl controlled-release) Tablets were identified from cases where OxyContin was not identified. Our working hypothesis was that OXC in combination with other centrally acting drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood concentrations of OXC in multiple-drug-induced deaths compared to single (OXC only)-drug-induced deaths. Assessment of blood levels determined by specific assay methodology (primarily gas chromatography-mass spectrometry) in these cases provided the following mean postmortem concentrations of OXC: multiple-drug-induced deaths, OxyContin identified, 0.93 microg/mL (N = 167); multiple-drug-induced deaths, OxyContin not identified, 0.73 microg/mL (N = 579); single (OXC)-drug-induced deaths, OxyContin identified, 1.55 microg/mL (N = 12); and single (OXC)-drug-induced deaths, OxyContin not identified, 1.70 microg/mL (N = 15). Overall, mean OXC concentration trends were as follows: single (OXC)-drug-induced, drug-abuse deaths > multiple-drug-induced drug-abuse deaths > drug-related drug-abuse deaths approximately deaths unrelated to drug abuse; and deaths in which OxyContin was identified approximately deaths in which OxyContin was not identified, whether the deaths involved oxycodone alone or multiple drugs. Drug abuse patterns in the multiple-drug-induced cases were complex. Over 135 drugs that were considered to be plausibly contributory to enhanced toxicity were identified in body fluids and tissues. Evaluation of mean OXC blood concentrations in cases that contained one, two, three, four, five, and six or more contributory drugs in combination demonstrated consistently lower mean OXC concentrations than those cases in which OXC was the only drug identified. A smaller number of cases were evaluated in the multiple-drug-induced groups in which OXC was paired with a single other contributory drug. The overall mean OXC concentration for these cases was 0.71 microg/mL (N = 90) as compared to 1.64 microg/mL (N = 27) for the cases in the single drug-induced groups. The consistent finding of lower mean OXC blood levels associated with multiple-drug-induced fatalities supports the stated hypothesis that OXC in combination with other centrally active drugs is more toxic than when OXC was the only drug involved. It was concluded that in cases of multiple-drug fatalities, cause of death (COD) should not be attributed to any single drug. Rather, the unique combination of drugs, the pattern of drug use/abuse, and individual factors, such as tolerance to the respiratory depressant effects of opioids, must be taken into account in arriving at a valid COD statement.

Commentary on: Borrows DL, Hagardorn AN, Harlan GC, Wallen EDB, Ferslew KE. A fatal drug interaction between oxycodone and clonazepam. J Forensic Sci 2003;48(3):683-86.

Abstract Sir: This letter is in response to information published within a case report written by David L. Burrows et al. in the May 2003 issue of J Forensic Sci (1). We credit the authors for bringing to light the potentially fatal consequence of the concomitant abuse of two central nervous system (CNS) depressant drugs, such as oxycodone and clonazepam, as there may be an under-appreciation of such a risk. The risk of fatal overdose is indeed substantially increased when opioids are abused in combination with other CNS active drugs (2). However, in the article, titled “A fatal drug interaction between oxycodone and clonazepam,” the authors provide a table with OxyContin® (oxycodone HCl controlled-release) pharmacokinetic and dosage information (Table 1) that is inaccurate and potentially misleading.

Opioids: clinical pharmacology: Population pharmacokinetic (PPK) modeling of oxycodone (OC) and its active metabolite, oxymorphone (OM) following administration of CR-oxycodone (OxyContin®)

The purpose was to develop a PPK model that simultaneously predicts the plasma concentrations of OC and OM following OxyContin® (oxycodone HCL controlled-release) Tablets administration. Data were pooled from two Phase I studies in order to build the parent-metabolite model in NONMEM. In the first dose escalating study, OM was administered to healthy volunteers either as intravenous injection or oral solution. The second study provided OC and OM plasma levels after oral administration of OxyContin®. Oxymorphone undergoes significant first pass effects resulting in bioavailability of 5%, whereas oxycodone is less prone to first pass effects and its bioavailability is >50%. Significant intersubject variability was observed following OM administration. An 8-compartment model with 18 pharmacokinetic (PK) parameters was established where the rate of OM formation from oxycodone was estimated as mean (interindividual variability; %CV): 8.27(40%). The estimates of clearances for OM and OC were: 43.3(58) L/h and 94.7(44) L/h, respectively and estimates of volume of distribution for OM and OC were: 77.4(36) L and 541.0(37) L, respectively, were also estimated. External validation of the PPK model was performed by comparing the model-predicted values to the observed OC and OM plasma levels after oxycodone dosing. The model provides good estimates of the PPK parameters and their associated variabilities for both OC and OM. The model is useful in predicting both the parent and metabolite exposures following all dosing regimens of OxyContin®. The model quantified the very low bioavailability and the high inter-subject variability that was observed following oral oxymorphone administration.

Avinza® – 24-h sustained-release oral morphine therapy

Avinza® is a once-daily, extended-release oral morphine preparation. It has a pharmacokinetic profile that exhibits less peak-to-trough fluctuations in plasma concentration whilst providing analgesia statistically identical to that produced by MS Contin® (controlled-release morphine sulfate), Oxycontin® (oxycodone HCl controlled-release) and six doses of oral morphine sulfate administered every 4 h. Avinza improves quality of sleep by several measures but interestingly gives the best sleep improvement when given in the morning rather than at night. It causes the same side effects of other opioids: constipation, nausea, vomiting, somnolence and mood swings. Doses of 30 – 60 mg/day have been shown to be well tolerated by patients with osteoarthritis (even in the elderly), who have failed other medications.

Avinza� ? 24-h sustained-release oral morphine therapy

Avinza® is a once-daily, extended-release oral morphine preparation. It has a pharmacokinetic profile that exhibits less peak-to-trough fluctuations in plasma concentration whilst providing analgesia statistically identical to that produced by MS Contin® (controlled-release morphine sulfate), Oxycontin® (oxycodone HCl controlled-release) and six doses of oral morphine sulfate administered every 4 h. Avinza improves quality of sleep by several measures but interestingly gives the best sleep improvement when given in the morning rather than at night. It causes the same side effects of other opioids: constipation, nausea, vomiting, somnolence and mood swings. Doses of 30 – 60 mg/day have been shown to be well tolerated by patients with osteoarthritis (even in the elderly), who have failed other medications.

(218) Outcomes Associated with Fentanyl Transdermal System and Oxycodone Controlled-Release in a California Medicaid Population

Introduction: In addition to chronic pain interfering with physical and mental functioning, certain medications used to treat chronic pain may have undesirable effects. A health insurance claims database study was conducted to identify the incidence of two side effects that may be associated with chronic opioid use-constipation and drowsiness-and to compare the risk of developing these conditions. Methods: The California Medicaid (Medi-Cal) database was used to identify the number of chronic pain patients who received a prescription for Duragesic® (fentanyl transdermal system), OxyContin® (oxycodone HCL controlled-release), or codeine between July 1, 1994 and November 30, 1999. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were used to define constipation (564.0) and drowsiness (780.09). Amphetamine use (defined using NDC codes) was also examined as a marker of drowsiness, since these drugs are likely to be used as a stimulant in drowsy patients. Results: A total of 1,422,427 patients met these criteria, the majority of whom were codeine patients (codeine only = 1,411,251; transdermal fentanyl only = 8,198; oxycodone controlled-release only = 2,978). Oxycodone controlled-release patients had a 58% greater risk of developing constipation compared with transdermal fentanyl (RR = 1.58, p < 0.001); codeine patients had a 26% greater risk of this outcome compared with transdermal fentanyl (RR = 1.26, p = 0.001). Oxycodone controlled-release patients were 34% more likely to be drowsy than transdermal fentanyl patients (RR = 1.34, p = 0.040). Amphetamine use was significantly higher in oxycodone controlled-release patients compared with transdermal fentanyl patients (RR = 2.79, p < 0.001). Amphetamine use in the codeine group was not significantly different from the transdermal fentanyl group. Conclusions: These preliminary findings suggest that patients prescribed Duragesic® (fentanyl transdermal system) have a significantly lower risk of developing constipation or drowsiness compared with OxyContin® (oxycodone HCL controlled-release). Future research will consider the impact of confounding factors-such as age, drug strength, and short-acting opioid usage-on these outcomes.