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. […

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

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

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

Pharmacogenetics of analgesic drugs

• Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. • Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. • While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). • Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. • This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain

Innovative Drug Delivery and Formulation Designs To Deter Drug Abuse/Misuse Related To Suicide

Patients with a history of abuse/misuse of pain and psychotic medications are at high risk for suicide. Novel drug delivery and formulation approaches have been explored to reduce the potential of drug abuse/misuse and to improve patient compliance. This chapter reviews the design and mechanism of five successful products in the opioid and anti-psychotic categories. Embeda™ is an extended release capsule containing morphine pellets with a sequestered core of naltrexone; naltrexone acts as an aversive agent and is released only when the product is crushed. Remoxy® is an extended release oxycodone capsule with a highly viscous liquid fill content which is resistant to most common methods of tampering. Suboxone® is a sublingual tablet or film strip of buprenorphine with naloxone as an aversive agent; naloxone has poor sublingual/oral bioavailability and does not exert its activity unless the product is abused by the injectable route. Risperidal® Consta®, is a biweekly intramuscular injection of risperidone based on a biodegradable polymer microsphere technology. Invega® Sustenna® is a once-monthly intramuscular injection of paliperidone based on the water insoluble prodrug approach. The review of these five new drug products showcases the novel formulation tools and technologies available to deter drug abuse/misuse in patients who are at high risk of suicide

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

The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users

Aims: Activation of PPARγ by pioglitazone (PIO) has shown some efficacy in attenuating addictive-like responses in laboratory animals. The ability of PIO to alter the effects of opioids in humans has not been characterized in a controlled laboratory setting. The proposed investigation sought to examine the effects of PIO on the subjective, analgesic, physiological and cognitive effects of oxycodone (OXY). Methods: During this investigation, nondependent prescription opioid abusers (N = 17 completers) were maintained for 2-3 weeks on ascending daily doses of PIO (0 mg, 15 mg, 45 mg) prior to completing a laboratory session assessing the aforementioned effects of OXY [using a within-session cumulative dosing procedure (0, 10, and 20 mg, cumulative dose = 30 mg)]. Results: OXY produced typical mu opioid agonist effects: miosis, decreased pain perception, and decreased respiratory rate. OXY also produced dose-dependent increases in positive subjective responses. Yet, ratings such as: drug "liking," "high," and "good drug effect," were not significantly altered as a function of PIO maintenance dose. Discussion: These data suggest that PIO may not be useful for reducing the abuse liability of OXY. These data were obtained with a sample of nondependent opioid users and therefore may not be applicable to dependent populations or to other opioids. Although PIO failed to alter the abuse liability of OXY, the interaction between glia and opioid receptors is not well understood so the possibility remains that medications that interact with glia in other ways may show more promise