Trends and uptake of new formulations of controlled-release oxycodone in Canada

Purpose: This study investigated the impact of changing availability of tamper‐deterrent and non‐tamper‐deterrent oxycodone on prescribing patterns of controlled‐release oxycodone across Canada. Methods: We conducted a population‐based, serial cross‐sectional study of controlled‐release oxycodone dispensing from community pharmacies across Canada between October 2007 and April 2016. We calculated rates of dispensing (tablets per 100 population) and reported the relative market share of generic non‐tamper‐deterrent controlled‐release oxycodone. All analyses were reported nationally and stratified by province. Results: After the introduction of a tamper‐deterrent formulation, the national rate of controlled‐release oxycodone dispensing fell by 44.6% (from 26.4 to 14.6 tablets per 100 population from February 2012 to April 2016). Between December 2012 and July 2013, there was moderate uptake of generic non‐tamper‐deterrent controlled‐release oxycodone (968 452 tablets; 16.0% in July 2013), which appeared to have little impact on the overall rate of controlled‐release oxycodone dispensing in Canada. However, the uptake of generic non‐tamper‐deterrent oxycodone varied considerably by province. By April 2016, 55.0% of all controlled‐release oxycodone tablets dispensed in Quebec were for the generic formulation. […

Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats.

Prescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%-10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and addiction need to be developed. The present study evaluated the effects of the highly selective dopamine D3 receptor antagonist VK4-116 ([R]-N-[4-(4-[3-chloro-5-ethyl-2-methoxyphenyl]piperazin-1-yl)-3-hydroxybutyl]-1H-indole-2-carboxamide) on oxycodone addictive-like behaviors. We used a model of extended access to oxycodone self-administration and tested the effects of VK4-116 on the escalation of oxycodone self-administration and withdrawal-induced hyperalgesia and irritability-like behavior in male and female rats. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently decreased the escalation of oxycodone self-administration and reduced withdrawal-induced hyperalgesia and irritability-like behavior in opioid-dependent rats. These findings demonstrate a key role for D3 receptors in both the motivation to take opioids and negative emotional states that are associated with opioid withdrawal and suggest that D3 receptor antagonism may be a viable therapeutic approach for the treatment of OUD

Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA-GABA transmission in highly addicted rats.

Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 μg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder

Analgesic effectiveness and tolerability of oral oxycodone/naloxone and pregabalin in patients with lung cancer and neuropathic pain. An observational analysis

INTRODUCTION: Cancer-related pain has a severe negative impact on quality of life. Combination analgesic therapy with oxycodone and pregabalin is effective for treating neuropathic cancer pain. We investigated the efficacy and tolerability of a dose-escalation combination therapy with prolonged-release oxycodone/naloxone (OXN-PR) and pregabalin in patients with non-small-cell lung cancer and severe neuropathic pain. METHODS: This was a 4-week, open-label, observational study. Patients were treated with OXN-PR and pregabalin. Average pain intensity ([API] measured on a 0-10 numerical rating scale) and neuropathic pain (Douleur Neuropathique 4) were assessed at study entry and at follow-up visits. The primary endpoint was response to treatment, defined as a reduction of API at T28 ≥30% from baseline. Secondary endpoints included other efficacy measures, as well as patient satisfaction and quality of life (Brief Pain Inventory Short Form), Hospital Anxiety and Depression Scale, and Symptom Distress Scale; bowel function was also assessed. RESULTS: A total of 56 patients were enrolled. API at baseline was 8.0±0.9, and decreased after 4 weeks by 48% (4.2±1.9; P<0.0001 vs baseline); 46 (82.1%) patients responded to treatment. Significant improvements were also reported in number/severity of breakthrough cancer pain episodes (P=0.001), Brief Pain Inventory Short Form (P=0.0002), Symptom Distress Scale (P<0.0001), Hospital Anxiety and Depression Scale depression (P=0.0006) and anxiety (P<0.0001) subscales, and bowel function (P=0.0003). At study end, 37 (66.0%) patients were satisfied/very satisfied with the new analgesic treatment. Combination therapy had a good safety profile. CONCLUSION: OXN-PR and pregabalin were safe and highly effective in a real-world setting of severe neuropathic cancer pain, with a high rate of satisfaction, without interference on bowel function

Metabolism of Oxycodone in Human Hepatocytes from Different Age Groups and Prediction of Hepatic Plasma Clearance

Oxycodone is commonly used to treat severe pain in adults and children. It is extensively metabolized in the liver in adults, but the maturation of metabolism is not well understood. Our aim was to study the metabolism of oxycodone in cryopreserved human hepatocytes from different age groups (3 days, 2 and 5 months, 4 years, adult pool) and predict hepatic plasma clearance of oxycodone using these data. Oxycodone (0.1, 1, and 10 μM) was incubated with hepatocytes for 4 h, and 1 μM oxycodone also with CYP3A inhibitor ketoconazole (1 μM). Oxycodone and noroxycodone concentrations were determined at several time points with liquid chromatography–mass spectrometry. In vitro clearance of oxycodone was used to predict hepatic plasma clearance, using the well-stirred model and published physiological parameters. Noroxycodone was the major metabolite in all batches and ketoconazole inhibited the metabolism markedly in most cases. A clear correlation between in vitro oxycodone clearance and CYP3A4 activity was observed. The predicted hepatic plasma clearances were typically much lower than the published median total plasma clearance from pharmacokinetic studies. The data suggests that there are no children-specific metabolites of oxycodone. Moreover, CYP3A activity seems to be the major determinant in metabolic clearance of oxycodone regardless of age group or individual variability in hepatocyte batches

Effects of Sex and Estrous Cycle on Intravenous Oxycodone Self-Administration and the Reinstatement of Oxycodone-Seeking Behavior in Rats

The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures. In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a fixed-ratio 1 schedule of reinforcement in daily 2-hr sessions, and a dose-response function was subsequently determined (0.003-0.03 mg/kg/inf). In experiment 2, a separate group of adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone for 8 sessions, followed by 0.01 mg/kg/inf oxycodone for 10 sessions. Responding was then extinguished, followed by sequential footshock-induced and cue-induced reinstatement tests. In the dose-response experiment, oxycodone produced a typical inverted U-shape function with 0.01 mg/kg/inf representing the maximally effective dose in both sexes. No sex differences were detected in the reinforcing efficacy of oxycodone. In the second experiment, the reinforcing effects of 0.01-0.03 mg//kg/inf oxycodone were significantly attenuated in females during proestrus/estrus as compared to metestrus/diestrus phases of the estrous cycle. Neither males nor females displayed significant footshock-induced reinstatement of oxycodone seeking, but both sexes exhibited significant cue-induced reinstatement of oxycodone seeking at magnitudes that did not differ either by sex or by estrous cycle phase. These results confirm and extend previous work suggesting that sex does not robustly influence the primary reinforcing effects of oxycodone nor the reinstatement of oxycodone-seeking behavior. However, our findings reveal for the first time that the reinforcing efficacy of IV oxycodone varies across the estrous cycle in female rats

Trends in long-term prescribing of dependence forming medicines

Using patient-level primary care data to estimate the extent to which antidepressant medicines are prescribed to people continuously for long periods of time. Aim This descriptive research used patient-level primary care data to estimate the extent to which antidepressant medicines are prescribed to people continuously for long periods of time. The study also drew on survey data and data on the number of prescriptions dispensed. Findings - The number of antidepressant prescriptions dispensed each year in England doubled between 2008 and 2018 - Survey data show that the proportion of adults reporting use of antidepressants in the past year increased in the 1990s, and again between 2007 and 2014 - The average length of time that antidepressants are continuously prescribed to people for has increased over time. - Some types of antidepressants (for example, tricyclics and other antidepressants) tend to be prescribed for longer periods than other types (such as SSRIs). - In 2014, one in twelve prescribing periods for tricyclics and other antidepressants lasted for three years or more Methods The analyses in this report are descriptive and show the overall prevalence of long-term prescribing in each year. We used a sample of around 50,000 patients prescribed at least one antidepressant medicine between 2000 and 2017. This was drawn from the Clinical Practice Research Datalink (CPRD). The CPRD contains data about prescriptions issued by GPs (including the length and size of prescription) and characteristics of the patients prescribed to (such as their age, sex, and area where they live). Medicines were grouped for analysis into: tricyclics, selective serotonin reuptake inhibitors (SSRIs), and other ADMs. The length of individual prescriptions and continuous prescribing periods were derived using information on consultation dates, the quantity of tablets prescribed, and the numeric daily dose

Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone

Purpose: The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone. Methods: The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2mg/kg). Results: Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo. Conclusions: Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodon

Effects of tapentadol on pain, motor symptoms and cognitive functions in Parkinson\u2019s disease

Background: Pain is a common and undertreated non-motor symptom in patients with Parkinson\u2019s disease (PD). Opioids have been seldom used in PD because they could worsen cognitive and motor functions. Objective: We aimed to assess efficacy and tolerability of tapentadol in PD patients. Methods: We retrospectively reviewed 21 PD patients treated with tapentadol extended release (ER) for chronic pain. Patients were evaluated before treatment and at 3 and 6 months during treatment for pain intensity (current, 24-hour average, and minimum and worst) with a 0-10 Numerical Rating Scale and the painDETECT questionnaire; for motor symptom severity with the Unified Parkinson\u2019s Disease Rating Scale part III and the Hoehn and Yahr scale; for cognitive functions with MiniMental Status Examination, Corsi\u2019s Block Tapping test, Digit Span, Digit-Symbol Substitution test, FAS test, Rey\u2019s Auditory Verbal Learning test, Trail Making-A and -B, and the 9 Hole-Peg Test; for anxiety and depression with the Hospital Anxiety and Depression Scale; and for the quality of life with the Short Form-12 for Quality of Life. Data were analyzed by one-way ANOVA and paired t-test, and by Friedman\u2019s and Wilcoxon\u2019s test. Statistical significance was taken in all cases as P < 0,05. Results: Pain intensity decreased over the course of treatment. No differences were found in PD symptom severity and dopaminergic drug dosages between pretreatment and treatment evaluations . No decrement in cognitive neuropsychological performances was found and an improvement was observed in Digit Span, Digit-Symbol Substitution test and FAS test. The levels of anxiety, depression and of quality of life improved. Overall tapentadol ER was well tolerated and most patients reported no or mild and short-lived gastroenterological and neurological side effects. Conclusions: These results indicate the potential efficacy and tolerability of medium-high dose of tapentadol ER for the treatment of pain in PD

The Role of Cytochrome P450 3A Inducers and Inhibitors in the Metabolism and the Effects of Oxycodone

Oxycodone is an opioid used in the treatment of moderate or severe pain. It is principally metabolized in the liver by cytochrome P450 3A (CYP3A) enzymes whereas approximately 10% is metabolized by CYP2D6. Little is known about the interactions between oxycodone and other drugs, herbals and nutritional substances. In this work the effects of CYP3A inducers rifampicin and St. John’s wort and CYP3A inhibitors voriconazole, grapefruit juice, ritonavir and lopinavir/ritonavir were investigated on the pharmacokinetics and pharmacodynamics of oxycodone. All studies were randomized, balanced, placebo-controlled crossover clinical studies in healthy volunteers. The plasma concentrations of oxycodone and its metabolites were determined for 48 hours and pharmacodynamic parameters were recorded for 12 hours in each study. Pharmacokinetic parameters were calculated by noncompartmental methods. Rifampicin decreased the plasma concentrations, analgesic effects, and oral bioavailability of oral oxycodone. St. John’s wort reduced the concentrations of oxycodone and diminished the self-reported drug effect. Voriconazole increased the exposure to oral oxycodone by 3.6-fold whereas grapefruit juice, which inhibits predominantly the intestinal CYP3A, elevated the mean concentrations of oxycodone by 1.7-fold. Ritonavir and lopinavir/ritonavir increased the mean AUC of oxycodone by 3.0- and 2.6-fold, respectively, and prolonged its elimination half-life. In spite of increased oxycodone plasma concentrations during concomitant administration of CYP3A inhibitors, the analgesic effects were not increased. These studies show that the induction or inhibition of CYP3A alters the pharmacokinetics and pharmacologic effects of oxycodone. The exposure to oxycodone decreased after induction and increased after inhibition of CYP3A. As a conclusion, the clinicians should avoid concomitant administration of CYP3A inducers or inhibitors and oral oxycodone. If this is not possible, they should be prepared to interactions leading to impaired analgesia after CYP3A inducers or increased adverse effects after CYP3A inhibitors and oral oxycodone.Siirretty Doriast