Fentanyl Formulations Research Articles

Efficacy of reconstituted intravenous fentanyl to sublingual solution versus oral morphine syrup for breakthrough pain among patients with chronic gynecologic cancer pain: A randomized, double-blind, placebo-controlled trial.

To evaluate the efficacy of reconstituted intravenous fentanyl to sublingual solution (IFS) in relieving breakthrough pain as compared with OM. In this randomized, double-blind, double-dummy, placebo-controlled trial, patients with gynecologic cancer aged ≥18 years experiencing chronic cancer pain with breakthrough pain were enrolled. Patients were randomly allocated (1:1) to receive either 50 μg IFS or 5 mg OM. Pain intensity level was assessed at 5, 15, 30, 45, 60, and 120 min after treatment. The primary outcome was the reduction in pain intensity at 15 min in the intention-to-treat population (ClinicalTrials.gov, NCT05037539). Between June 15, 2021 and December 30, 2021, 40 participants were equally and randomly assigned to receive IFS or OM. The primary outcome was significantly higher in the IFS group (4.25 vs. 1.05, p < 0.0001). The secondary outcomes also showed higher reduction in pain intensity at 5 min in the IFS group. Subsequent breakthrough pain did not differ between the two groups. However, the reduction in pain was lower in the IFS group at 45, 60, and 120 min, where pain was classified as mild. No severe adverse effects were observed in both groups. Burning sensation without noticeable lesion was found in 20% of the IFS group. IFS can reduce early breakthrough pain. IFS may be considered for breakthrough pain when rapid-acting fentanyl formulations are unavailable.

Pronounced declines in dispensed licit fentanyl, but not fentanyl derivatives

Fentanyl and its derivatives are highly utilized opioid-based analgesics provided to patients in various formulations, but this agent has also been implicated in many overdoses when misused. The evolving opioid crisis has increased pressure on the healthcare industry to monitor opioid prescriptions. Different policies and procedures implemented to contain the crisis have impacted the utilization of some opioids. A prior report identified three-fold differences between states in fentanyl use. This study explored fentanyl distribution patterns from 2010 to 2019. The amount of fentanyl base distributed from 2010 to 2019 was obtained from the Drug Enforcement Administration. Sufentanil, alfentanil, and remifentanil were also analyzed from 2010 to 2017, the most recent year reported. Prescriptions, units, and reimbursement for 2010 and 2019 were obtained from Medicaid and fentanyl prescriber specialty from Medicare Part D. There was a 65.5% decrease in the overall milligrams of fentanyl per person distributed corrected for population. Ohio had the greatest decrease (-79.3%), while Mississippi saw the smallest (-44.5%). There was a 6.8-fold regional difference in the quantity of fentanyl distributed per person in 2010 from hospitals (South Dakota=775.2, Alabama=113.2 μg/person). The regional difference was also sizeable for pharmacies (6.2-fold, Mississippi=1,025.3, Washington DC=165.6). Medicaid reimbursement in 2019 was $165 million for over eight hundred-thousand prescriptions with the majority for generic (99.7%) and injectable (77.6%) formulations. Interventional pain management and anesthesia were over-represented, and hematology/oncology significantly under-represented for fentanyl prescriptions in Medicare. The distribution of fentanyl-based substances decreased, although not uniformly, in the US over the last decade. Additionally, the most prescribed formulations of fentanyl have transitioned away from transdermal, potentially in an effort to regulate its availability. The considerable state-level disparities observed for fentanyl distribution from pharmacies and hospitals warrant further attention as there may be regional practices which are incongruent with evidence-based medicine.

Rapid-Onset Opioids for Management of Breakthrough Cancer Pain: Considerations for Daily Practice.

Background and ObjectiveRapid-onset opioids (ROOs) are effective treatments for breakthrough cancer pain (BTcP) given their rapid onset of action and relatively short duration of analgesia. The aim of this article is to describe specific considerations for the use of ROOs in daily practice, focusing on dose titration and treatment of specific populations.Type of ReviewWe conducted a narrative review on the use of ROOs for BTcP. We selected papers according to the following search terms: “breakthrough cancer pain” and “rapid onset opioids”.ResultsROOs may be considered as the most suitable drugs to treat BTcP and can be used “on-demand”. Several fentanyl formulations are available and have been associated with control of BTcP and with improvement in quality of life. Various titration schemes have been used to optimize ROO dosing; however, a dose-proportional scheme could be considered safe and effective in most patients. Specific formulations may be more suitable for specific patient subgroups; for example, patients with oral mucositis may prefer intranasal to oral formulations. Moreover, elderly patients or those without caregivers should be clearly educated on the use of these formulations. A key element in achieving successful treatment of BTcP is awareness of the barriers to pain management, including poor overall assessment, patient reluctance to take opioids or report pain, and physician reluctance to prescribe opioids.ConclusionA personalized approach is fundamental when prescribing a medication for BTcP, and careful attention should be given to drug choice and route of administration, and to the need for alternative therapeutic options.

Impact of Three Safety Interventions Targeting Off-Label Use of Immediate-Release Fentanyl on Prescription Trends: Interrupted Time Series Analysis.

Background: The Spanish health authorities are concerned by the off-label use of immediate-release formulations of fentanyl (IRF) in noncancer pain and cancer pain in patients with no chronic pain therapy. Aim: To evaluate the impact of different interventions to improve appropriateness of IRF prescription on off-label prescription. Patients and methods: We used interrupted time series (ITS) to estimate immediate and trend changes of IRF prescription for noncancer pain (NCP) and breakthrough cancer pain (BCP) in patients with and without chronic cancer pain therapy associated with two medication reviews (I1 and I2) and the issue of a safety warning letter (I3) with data from a Spanish region with 5 million inhabitants, from 2015 to 2018. Results: The use of IRF for NCP in the region Valencia was reduced from about 1,800 prescriptions per week to around 1,400. The first medication review was followed by an immediate level change of −192.66 prescriptions per week (p < 0.001) and a downward trend change of −6.75 prescriptions/week (p < 0.001), resulting in a post-intervention trend of −1.99 (p < 0.001). I2 was associated with a trend change of -23.07 (p < 0.001) prescriptions/week. After I3, the trend changed markedly to 27.23 additional prescriptions/week, for a final post-intervention trend of 2.17 (p < 0.001). Controlled-ITS provided comparable results. For potentially inappropriate BCP use, the second medication review was followed by a downward, immediate level change of −10.10 prescriptions/week (p = 0.011) and a trend change of 2.31 additional prescriptions/week (p < 0.001) and the issue of the safety warning (I3) was followed by a downward trend change of −2.09 prescriptions/week (p = 0.007). Conclusion: Despite IRF prescription for NCP decreased, the interventions showed modest and temporary effect on off-label prescription. Our results call for a review of the design and implementation of safety interventions addressing inappropriate opioid use.

Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers.

Background For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug's high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h ∗ pg/ml, CV% = 32.86), followed by intravenous (672 h ∗ pg/ml, CV% = 32.18) and intranasal administration (515 h ∗ pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted absolute bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

Observational study of efficacy, safety, and tolerability of fentanyl in Korean cancer patients (OASIS)

Abstract Background: Sublingual fentanyl (Abstral) has been developed to provide rapid-onset analgesia in breakthrough cancer pain (BTcP). While the efficacy and safety of the fentanyl tablet have been already confirmed in clinical trials, there is no real-world evidence regarding the effectiveness and safety of this agent in the control of BTcP. Aims: To observe the effectiveness, safety and tolerability of Abstral for the alleviation of BTcP in Korean patients. Methods: The study is a non-interventional, observational study conducted in 13 hospitals in the Republic of Korea. Cancer patients (targeted number: 309), prescribed with Abstral due to the inability to control BTcP with other fentanyl products, are to be followed up for 12 weeks to collect the information about dose titration, pain status, quality of life, and adverse events. Conclusions: The list of inclusion and exclusion criteria is relatively short, which will likely make the study group more representative for the entire population of cancer patients with BTcP. All treatment-related decisions are left solely on the investigator's discretion, which will enable to analyze the treatment outcomes in various clinical scenarios, unlikely to be tested in a traditional clinical trial. These two features seem to be essential for the successful management of BTcP, a highly heterogeneous condition requiring an individualized approach. Further, the study includes patients who did not respond to other fentanyl formulations, and hence, it might explain whether switching from one immediate-release fentanyl to another is associated with a clinical benefit and/or specific risk. Trial registration: ClinicalTrials.gov with the identifier NCT03895762.

Breakthrough cancer pain in 2020.

An overview on breakthrough cancer pain (BTCP), including inherent limitations of the terminology, assessment, clinical presentation, and treatment options. The estimated prevalence of BTCP is dependent on the defined cutoffs for controlled background pain and the magnitude of the pain flare. In addition, pain flares outside the definition of BTCP are prevalent. In the 11th Revision of the International Classification of Diseases, the temporal characteristics of cancer pain are described as continuous background pain and intermittent episodic pain. BTCP should be assessed by validated methods, and the patient perspective should be included. The pain may be related to neoplastic destruction of bone, viscera, or nerve tissue and is characterized by rapid onset, high intensity, and short duration. Treatment directed towards painful metastases must be considered. Due to pharmacological properties mirroring the pain characteristics, transmucosal fentanyl formulations are important for the treatment of BTCP. Oral immediate release opioids can be used for slow-onset or predictable BTCP. For more difficult pain conditions, parenteral, or even intrathecal pain medication, may be indicated. All clinically relevant episodic pains must be adequately treated in accordance with the patient's preferences. Transmucosal fentanyl formulations are effective for BTCP.

Recent Use of Synthetic Cannabinoids, Synthetic Opioids, and Other Psychoactive Drug Groups among High-risk Drug Users

ABSTRACT The use of synthetic cannabinoids receptor agonists (SCRA) and synthetic opioids is associated with significant morbidity and mortality. This study examined the patterns-of-use of prescription oral opioids or transdermal fentanyl formulations, and SCRA, among 342 patients enrolled in treatment for drug-dependence in Israel. 16.1% of participants reported recent (past-12 months) SCRA use, while 24.9% reported recent use of prescription oral opioids, transdermal fentanyl patches, or both. Odds of reporting recent use of SCRA were positively and significantly associated with reporting recent use of cannabis (Adjusted Odds Ratio [AOR] 9.86, 95% Confidence Interval [CI] 4.44–21.90) and synthetic cathinones (AOR 5.47, CI 2.50–11.96). Recent use of prescription oral opioids or transdermal fentanyl formulations use was positively and significantly associated with recent use of gabapentinoids (AOR 14.33, CI 7.10, 28.90), stimulants (AOR 7.12, CI 3.82,13.28), heroin (AOR 5.81, CI 3.39,9.97), benzodiazepines (AOR 4.63, CI 2.74,7.84), synthetic cathinones (AOR 4.12, CI 1.95, 8.70), and hallucinogens (AOR 2.48, CI 1.24, 2.96). Clinicians should be informed about the extent of prescription oral opioids or transdermal fentanyl formulations and SCRA use among high-risk drug users, and the associated higher odds of concomitantly using other psychoactive substance, for they represent actual risk to patients and complicate treatment.

Le mésusage du fentanyl en France : 2010 à 2015

The aim of this study was to evaluate the French use, misuse and abuse/dependence of non-injectable forms of fentanyl (transdermal and transmucosal fentanyl formulations). Problematic use of transdermal and transmucosal fentanyl formulations was evaluated using an approach combining multiple sources of information: (1) spontaneous notifications recorded during 6years (2010-2015) for transdermal fentanyl form and 3years for transmucosal fentanyl forms and (2) data from annual epidemiological systematic surveys conducted by the French Addictovigilance Network during 6years (2010-2015). In all, 147cases were notified for transdermal fentanyl formulation and 109cases for transmucosal fentanyl formulations. According to the galenic formulation, analysis of these cases emphasizes different profiles: for transdermal fentanyl formulation, two consumption profiles: 1/mainly for analgesic effects (74%): women (61%), 47years, with addictive and/or psychiatric history (46%), treated for chronic non-cancer related pain (93%), 2/seeking positive psychic effects other than analgesia (26%): men (82%), 32years, with addictive and/or psychiatric history (87%) and having obtained the fentanyl patch illegally (60%) for non-medical use. For transmucosal fentanyl formulations, only one consumption profile was observed: women (52%), 48years, with addictive (24%) and/or psychiatric history (28%), off label indication (72%) (indications for non-cancer pain and/or no or insufficient opioid background treatment). The misuse of transmucosal fentanyl formulations implies a high risk of adverse effects: those already known of opioid-based drugs, sometimes lethal (withdrawal syndrome, respiratory and central nervous system depression…) but also serious reactions at the application site (buccal or nasal). For the transdermal fentanyl formulation, 27cases (18%) of involuntary intoxication were observed, of which 25were serious. Nineteen deaths involving both forms of fentanyl have been reported (2for the transmucosal formulations and 17for the transdermal formulation). Our results report significant and worrying misuse of transmucosal fentanyl formulations with wide off-label use and also primary dependence on fentanyl, regardless of galenic formulation, in patients treated for chronic non cancer pain. Given the significant risks of fentanyl, it is necessary to continue the monitoring of misuse, in particular, thanks to the activities of the French Addictovigilance network allowing a multisource approach and who provides information concerning cases of abuse, misuse and dependence.

Working towards a consensus on the oncological approach of breakthrough pain: a Delphi survey of Spanish experts.

PurposeThere is a lack of standards for the diagnosis, assessment and management of breakthrough cancer pain (BTcP). La Fundación ECO (the Foundation for Excellence and Quality in Oncology) commissioned a study to establish a consensus and lay the foundations for the appropriate management of BTcP in oncology patients.Patients and methodsA modified Delphi survey comprising two rounds was used to gather and analyze data, which was conducted over the Internet. Each statement that reached a consensus with the respondents was defined as a median consensus score (MED) of ≥7, and agreement among panelists as an interquartile range (IQR) of ≤3.ResultsIn total, 69 medical oncologists responded, with a broad consensus that BTcP implied exacerbations of high-intensity pain, as opposed to moderate pain. Furthermore, they concurred that appropriate diagnostic equipment is needed, and that rapid-onset fentanyl formulations should be the preferred treatment for BTcP management. The panelists agreed that a lack of appropriate information and training to attend to patients, as well as limited patient visitation rights, were barriers to effective BTcP management. Regarding gaps in detected knowledge, the panelists were unsure of the measures necessary to assess the burden of the disease on the patient’s quality of life and associated medication costs. Alongside this, there was a lack of awareness of the technical specifics of the different formulations of rapid-onset fentanyl.ConclusionThese results represent the current status of BTcP management. They may inform recommendations and provide a framework for future research.

Study Finds REMS Program for Fentanyl Formulation Inadequate

Most prescriptions for transmucosal immediate-release fentanyl medications are written off label, a situation the FDA seeks to address by requiring more documentation and a patient registry.

Individual variations in fentanyl pharmacokinetics and pharmacodynamics in preterm infants

Fentanyl pharmacokinetics and pharmacodynamics are lacking in preterm infants. Our aim was to study these and their relation with a new formulation of fentanyl 5μg/mL for procedural pain. Preterm infants were given 0.5 (n=20, median gestational age 26.5; range 23.3-34.1weeks) and 2μg/kg (n=8, 27.4; 25.3-30.7weeks) fentanyl, respectively, before skin-breaking procedures or tracheal intubation. Blood samples were collected after ten minutes, two, four, eight and 24hours. Physiologic parameters were monitored and pain scores assessed. The median fentanyl concentrations were 0.18, 0.15, 0.15 and 0.57, 0.37, 0.35ng/mL at 15-31minutes, two and four hours and the half-lives were 1.6 to 20.5 or 4.1 to 32.6hours for the low- and high-dose groups, respectively. A significant correlation was seen between weight at study inclusion and half-life (Spearman's r=-0.9, p<0.001), volume of distribution (r=-0.8, p<0.01) and clearance (r=-0.9, p<0.01) in the low-dose group (n=9). Pain assessment results were not correlated to pharmacokinetic variables. Fentanyl was well tolerated. The inter-individual variation of fentanyl pharmacokinetics is large in preterm infants, and the dose of 0.5μg/kg seems not effective for skin-breaking procedures.

Current management of breakthrough cancer pain according to physicians from pain units in Spain.

Current evidence suggests the need to improve the management of breakthrough cancer pain (BTcP). For this reason, we aimed to assess the opinion of a panel of experts composed exclusively of physicians from pain units, who play a major role in BTcP diagnosis and treatment, regarding the key aspects of BTcP management. An ad hoc questionnaire was developed to collect real-world data on the management of BTcP. The questionnaire had 5 parts: (a) organizational aspects of pain units (n = 12), (b) definition and diagnosis (n = 3), (c) screening (n = 3), (d) treatment (n = 8), and (e) follow-up (n = 7). A total of 89 pain-unit physicians from 13 different Spanish regions were polled. Most of them agreed on the traditional definition of BTcP (78.9%) and the key features of BTcP (92.1%). However, only 30.3% of participants used the Davies' algorithm for BTcP diagnosis. Respondents preferred to prescribe rapid-onset opioids [mean 77.0% (SD 26.7%)], and most recommended transmucosal fentanyl formulations as the first option for BTcP. There was also considerable agreement (77.5%) on the need for early follow-up (48-72h) after treatment initiation. Finally, 65.2% of participants believed that more than 10% of their patients underused rapid-onset opioids. There was broad agreement among pain experts on many important areas of BTcP management, except for the diagnostic method. Pain-unit physicians suggest that rapid-onset opioids may be underused by BTcP patients in Spain, an important issue that need to be evaluated in future studies.

The role of rapid onset fentanyl products in the management of breakthrough pain in cancer patients.

Breakthrough pain is defined as transient aggravation of pain that arises, despite well controlled or stable baseline pain. It may be preceded by known factors or occur spontaneously. Its prevalence is high and it considerably affects patients' quality of life. Therefore, proper clinical evaluation and treatment is required. Fentanyl transmucosal formulations have become the treatment of choice for spontaneous (idiopathic) episodes because of their rapid onset of action, brief period of analgesia, and easy administration via transmucosal routes. All rapid onset fentanyl formulations show better efficacy than placebo or immediate-release opioids administered via the oral route, with an onset of analgesia within 15 min. Furthermore, most patients show considerable tolerance of these fentanyl formulations, and severe side effects that can potentially be induced by opioids are rarely observed. However, the treatment of breakthrough pain should be adjusted to suit specific patient requirements. Nevertheless, particularly in predictable bursts of pain and also in spontaneous episodes of breakthrough pain with slowly intensifying pain, immediate-release formulations of opioids may play an important role.

Real World Experience with Sublingual Fentanyl for the Treatment of Sickle Cell Vaso-Occlusive Episodes in Adults in a Tertiary Canadian Emergency Department

Background: Vaso-occlusive episodes (VOEs) are the most common complication of Sickle Cell Disease (SCD) and associated with acute chest syndrome (ACS), multi-organ failure (MOF), sudden death, and early mortality. International guidelines recommend administration of parenteral opioid analgesia within 30-60 minutes of presentation to an emergency department (ED) to improve VOE outcomes. Rapidity of action and non-invasive administration make trans-mucosal formulations of fentanyl (TFF) appealing for treatment. A study comparing multi-modal analgesia with TFF in adult SCD patients found a significant reduction in pain scores in the TFF group. Toronto General Hospital (TGH) ED treats over 900 SCD patients. TFF was administered to non-opiate naïve patients presenting with VOE at the TGH ED between September 2015 and November 2016.Objective: To evaluate the difference in 24-hour oral morphine equivalent (MEQ) usage in adult SCD patients who received TFF for one episode of VOE treated at TGH ED between September 2015 and November 2016, in comparison to the preceding ED visit during which no TFF was administered to the same patients.Methods: SCD patients with a diagnosis of “sickle cell disease with crisis” who received TFF were identified through the TGH ED pharmacy database. Electronic medical records for their relevant visits were reviewed. For both visits, we recorded: MEQ administered in the preceding 24-hours to presentation, number of doses of TFF (each dose was 100 mcg and assumed to be 60 mg MEQ), and additional MEQs 24 hours subsequently. We further documented time in the ED, days to discharge, change in 11-point pain scores (0-10) over 24 hours, as well as baseline characteristics including age, gender, use of disease-modifying therapy, and number of VOEs in the prior 12 months. Hemoglobin, sickle hemoglobin percentage (Hb S%), absolute reticulocyte count, lactate dehydrogenase (LDH), total bilirubin, presence of acute/chronic kidney or liver disease, maximal oxygen requirements, ACS, MOF, readmission within 72 hours, or death were also recorded.Results: 201 patients were identified with a diagnosis of SCD. TGH pharmacy database identified TFF distribution at 19 separate patient visits. 3 were excluded as patients had sickle cell trait (SCT) rather than SCD, or no evidence of either; 1 because the patient refused TFF, and 1 where TFF receipt was unconfirmed. A further 5 were excluded as they had a previous visit during which TFF use was analyzed, and 2 because there was no prior comparison visit.Amongst the remaining 7 paired patient visits, there were no differences in MEQ in the 24 hours preceding ED presentation and all patients had homozygous sickle hemoglobin. Mean age was 29.14 (+/-7.69), median 27 and range 18 to 41 years. 57% were receiving disease-modifying therapy. Mean VOEs in the preceding 12-months was 5.13 (+/-2.76), median 4 and range of 2-11. One patient had pre-existing CKD and one had cirrhosis.Wilcoxon Rank Sums were used to compare outcomes between the 7 paired patient-visits (Table 1), and there was a significant difference in MEQ 24-hours after presentation (556 mg for the TFF visit vs. 197 mg for the non-TFF visit) with moderately strong evidence (p = 0.03125), but no differences in change in pain scores, time spent in ED, admission duration or oxygen requirements. Laboratory values were variably collected, but average hemoglobin (94 vs. 98 g/L), Hb S% (68 vs. 69%), and total bilirubin (74 vs. 73 micromoles/L) were consistent between visits. Average LDH levels were higher during the TFF visit (762 vs. 528 units/L), while absolute reticulocyte counts were lower (207 vs. 250 x 109/L). There was 1 ACS, and 1 return to ED within 72 hours, and both events were associated with TFF use. There were no MOF or deaths.Conclusion: TFF administration in adult SCD patients presenting with VOE appears to be safe, but was unexpectedly associated with significantly higher 24-hour MEQ use, which may reflect more severe VOE episodes at the TFF visits, as patients had higher LDH values, and increased complications (ACS and return to ED). However, there were no significant differences in other outcomes including change in pain scores, time spent in ED, admission duration or oxygen requirements. Overall, utilization of TFF in the TGH ED for SCD VOEs was low. DisclosuresNo relevant conflicts of interest to declare.

Trends and Outcomes Associated With Using Long-Acting Opioids During Delivery Hospitalizations.

To assess trends in use of long-acting opioids during delivery hospitalizations. The Perspective database, an administrative inpatient database that includes medication receipt, was analyzed to evaluate patterns of long-acting opioid use during delivery hospitalizations from January 2006 through March 2015. Medications evaluated included methadone, formulations including buprenorphine and extended-release formulations of oxycodone, morphine, fentanyl, and other opioids. Temporal trends in use of these medications were determined. Unadjusted and adjusted models evaluating the role of demographic and hospital factors were created evaluating both use of these medications and risk for severe morbidity. Risk for severe morbidity was determined based on Centers for Disease Control and Prevention criteria. Our analysis included 2,994,630 delivery hospitalizations meeting study criteria. Over the entire study period, use of long-acting opioids increased significantly from 457 to 844 per 100,000 deliveries. Although buprenorphine and methadone use increased, use of other long-acting opioids decreased. In 2006, methadone and buprenorphine accounted for less than one third of all long-acting opioids used during delivery hospitalizations. By 2015, buprenorphine and methadone represented 73.5% of long-acting opioids used. In adjusted and unadjusted models, risk for severe morbidity was significantly lower with buprenorphine or methadone compared with other long-acting opioids. Restricting the cohort to only women with drug abuse or dependence, risk for severe morbidity was lower with methadone and buprenorphine than without any long-acting opioids. Increased use of methadone and buprenorphine in this study supports the feasibility of use of these medications during pregnancy and uptake of clinical recommendations for women with opioid use disorder. Use of methadone and buprenorphine is associated with decreased maternal morbidity, although causation cannot be presumed from this study model.

365 The Effect of an Electronic Decision Support Tool on Emergency Department Prescribing of Naloxone

The prescription of naloxone or “take-home naloxone” has been advised for patients who are at risk for opioid overdose. The provision of naloxone from the ED for these patients is a relatively new operational implementation. The purpose of this study was to evaluate the effect of an electronic health record (EHR) best practice alert (BPA) on the prescription of naloxone from the ED. This was a cross-sectional study performed at a tertiary care health system’s 2 EDs (1 urban and 1 suburban). Included were patients 18 years of age and older who were considered high-risk for opioid overdose based on: 1) the listing of methadone or fentanyl formulations in the EHR medication list, and 2) a documented diagnosis of “substance abuse” or the ICD10 equivalent diagnosis in the EHR and 3) prescription of an opioid at ED discharge. Methadone and fentanyl derivatives were chosen because they are considered high-risk opioids as identified by the Joint Commission Sentinel Event Alert on opioids. A BPA fired in the EHR for those patients who met these high-risk criteria. The BPA informed the ED provider of the patient’s high-risk status for opioid overdose and asked the ED provider if a discharge prescription for naloxone should be issued. The provider could choose to prescribe naloxone via the BPA or disregard the prompt. Data on naloxone prescribing rates at ED discharge were collected from 5/1/2016 after the BPA was implemented through 10/31/2017. There were no prescriptions given at discharge for naloxone from the ED during the 18 months prior to the implementation of the BPA. During the 18 months after the BPA was implemented, there were 596 ED discharges for which the BPA was triggered. Among these, 22 (3.7%) received a prescription at discharge for naloxone. An additional 73 patients received a prescription without receiving a BPA. The majority of patients were male (55.3%) and were between 35-64 years of age (69.2%). Visits with a naloxone discharge prescription were more likely to have a higher acuity ESI score of 1 or 2 compared to those without a prescription (15.4% versus 5.8%, p<0.001). Visits where a naloxone prescription were more likely to be given compared to visits where it was not given were those with an ESI score of 1 or 2 (15.4% versus 5.8%, p<0.001). Among visits with and without a naloxone prescription, there were no differences among sex, age group or patients with multiple visits (p’s>0.05). Implementation of a BPA in the EHR used to identify patients considered high-risk of opioid overdose resulted in a small increase in the rate of naloxone prescriptions issued for this population and a higher increase in prescribing among those not considered high-risk for overdose. Reasons for higher rates of naloxone prescribing among those patients for whom the BPA did not activate in the EHR may be attributed to general increased provider awareness of the availability of the antidote. Overall, more focus is needed to facilitate prescribing of naloxone from the ED among high-risk patients.

Fentanyl and its derivatives as a group of new psychoactive substances (designer drugs)

Fentanyl has been known for many years. It has been widely used in emergency medicine and anaesthesiology. Due to its strong action, it gained a reputation of a popular addictive drug. Over the past years, fentanyl derivatives, produced as new psychoactive substances (designer drugs), have become a growing problem in clinical and forensic toxicology due to their non-therapeutic use. Both the variability in the construction of fentanyls and, consequently, the change in toxokinetic properties, as well as their high toxicity, often lead people to take this group of compounds to fatal intoxication. The purpose of this paper is to present various formulations of fentanyl and to discuss the properties of fentanyl and its derivatives, with particular emphasis on the toxicity of this group of compounds. Reviewing the available literature, the authors also focused on presenting the therapeutic concentrations of fentanyl and its most popular analogues, comparing them with the concentrations observed in lethal opioid poisonings.

Changes in consumption of opioid analgesics in Israel 2009 to 2016: An update focusing on oxycodone and fentanyl formulations.

The purpose of the study is to assess opioid (morphine, methadone, oxycodone, pethidine, and fentanyl) consumption in Israel during 2009 to 2016 and identify recent trends. Data for all treatment settings, private and public, for the years 2009 to 2016, were extracted from the Israel Ministry of Health's Pharmaceutical Administration database. The data were used to calculate defined daily doses (DDD) per 1000 inhabitants per day, of the various drugs. Consumption of the 5 opioids increased by 68%, from 3.40 DDD/1000 inhabitants/day in 2009 to 5.72 DDD/1000 inhabitants/day in 2016. This trend resulted mostly from increases in oxycodone consumption from 0.50 DDD/1000 inhabitants/day to 2.03 DDD/1000 inhabitants/day (namely, 4-fold) and in fentanyl consumption, from 1.09 DDD/1000 inhabitants/day to 2.33 DDD/1000 inhabitants/day (about 2-fold). The use of the 3 remaining opioids decreased substantially as follows: pethidine from 0.03 DDD/1000/day in 2009 to 0.007 DDD/1000 inhabitants/day in 2016 (-67%), methadone from 1.61 DDD/1000 inhabitants/day to 1.20 DDD/1000 inhabitants/day (-25%), and morphine from 0.17 DDD/1000 inhabitants/day to 0.15 DDD/1000 inhabitants/day (-12%). An increasing trend was also observed in the use of oxycodone/naloxone (Targin) and oxycodone/acetaminophen (Percocet) combinations, while a decrease was observed in the use of pure oxycodone formulations. The increase in opioid consumption persisted throughout the years 2009 to 2016. This has been associated with substantial changes in the patterns of prescribing opioids, characterized by increases in oxycodone and fentanyl prescriptions and decreases in morphine, methadone, and pethidine prescriptions. A national program aiming to ensure safe use of opioids in the treatment of chronic pain is warranted.

Changes in the dispensing of opioid medications in Canada following the introduction of a tamper-deterrent formulation of long-acting oxycodone: a time series analysis.

In February 2012, a reformulated tamper-deterrent form of long-acting oxycodone, OxyNeo, was introduced in Canada. We investigated the impact of the introduction of OxyNeo on patterns of opioid prescribing. We conducted population-based, cross-sectional analyses of opioid dispensing in Canada between 2008 and 2016. We estimated monthly community pharmacy dispensing of oral formulations of codeine, morphine, hydromorphone and oxycodone, and a transdermal formulation of fentanyl, and converted quantities to milligrams of morphine equivalents (MMEs) per 1000 population. We used time series analysis to evaluate the effect of the introduction of OxyNeo on these trends. National dispensing of long-acting opioids fell by 14.9% between February 2012 and April 2016, from 36 098 MMEs to 30 716 MMEs per 1000 population (p < 0.01). This effect varied across Canada and was largest in Ontario (reduction of 22.8%) (p = 0.01) and British Columbia (reduction of 30.0%) (p = 0.01). The national rate of oxycodone dispensing fell by 46.4% after the introduction of OxyNeo (p < 0.001); this was partially offset by an increase of 47.8% in hydromorphone dispensing (p < 0.001). Although dispensing of immediate-release opioids was a substantial contributor to overall population opioid exposure across Canada, it was unaffected by the introduction of OxyNeo (p > 0.05 in all provinces). The findings suggest that the introduction of a tamper-deterrent formulation of long-acting oxycodone in Canada, against a background of changing public drug benefits, was associated with sustained changes in selection of long-acting opioids but only small changes in the quantity of long-acting opioids dispensed. This illustrates the limited effect a tamper-deterrent formulation and associated coverage policy can have when other, non-tamper-deterrent alternatives are readily available.