Assessment of a Naloxone Coprescribing Alert for Patients at Risk of Opioid Overdose: A Quality Improvement Project.

BACKGROUND: Patients taking high doses of opioids, or taking opioids in combination with other central nervous system depressants, are at increased risk of opioid overdose. Coprescribing the opioid-reversal agent naloxone is an essential safety measure, recommended by the surgeon general, but the rate of naloxone coprescribing is low. Therefore, we set out to determine whether a targeted clinical decision support alert could increase the rate of naloxone coprescribing. METHODS: We conducted a before-after study from January 2019 to April 2021 at a large academic health system in the Southeast. We developed a targeted point of care decision support notification in the electronic health record to suggest ordering naloxone for patients who have a high risk of opioid overdose based on a high morphine equivalent daily dose (MEDD) ≥90 mg, concomitant benzodiazepine prescription, or a history of opioid use disorder or opioid overdose. We measured the rate of outpatient naloxone prescribing as our primary measure. A multivariable logistic regression model with robust variance to adjust for prescriptions within the same prescriber was implemented to estimate the association between alerts and naloxone coprescribing. RESULTS: The baseline naloxone coprescribing rate in 2019 was 0.28 (95% confidence interval [CI], 0.24-0.31) naloxone prescriptions per 100 opioid prescriptions. After alert implementation, the naloxone coprescribing rate increased to 4.51 (95% CI, 4.33-4.68) naloxone prescriptions per 100 opioid prescriptions (P < .001). The adjusted odds of naloxone coprescribing after alert implementation were approximately 28 times those during the baseline period (95% CI, 15-52). CONCLUSIONS: A targeted decision support alert for patients at risk for opioid overdose significantly increased the rate of naloxone coprescribing and was relatively easy to build.

Safety, Efficacy, and Cost of 0.4-mg Versus 2-mg Intranasal Naloxone for Treatment of Prehospital Opioid Overdose.

BACKGROUND: Intranasal naloxone is commonly used to treat prehospital opioid overdose. However, the optimal dose is unclear, and currently, no study exists comparing the clinical effect of intranasal naloxone at different doses. OBJECTIVE: The goal of this investigation was to compare the safety, efficacy, and cost of 0.4- versus 2-mg intranasal naloxone for treatment of prehospital opioid overdose. METHODS: A retrospective, cross-sectional study was performed of 218 consecutive adult patients receiving intranasal naloxone in 2 neighboring counties in Southeast Michigan: one that used a 0.4-mg protocol and one that used a 2-mg protocol. Primary outcomes were response to initial dose, requirement of additional dosing, and incidence of adverse effects. Unpooled, 2-tailed, 2-sample t-tests and χ2 tests for homogeneity were performed with statistical significance defined as P <0.05. RESULTS: There was no statistically significant difference between the 2 populations in age, mass, gender, proportion of exposures suspected as heroin, response to initial dose, required redosing, or total number of doses by any route. The overall rate of adverse effects was 2.1% under the lower-dose protocol and 29% under the higher-dose protocol (P < 0.001). The lower-dose protocol was 79% less costly. CONCLUSION AND RELEVANCE: Treatment of prehospital opioid overdose using intranasal naloxone at an initial dose of 0.4 mg was equally effective during the prehospital period as treatment at an initial dose of 2 mg, was associated with a lower rate of adverse effects, and represented a 79% reduction in cost.

Association Between State Laws Facilitating Pharmacy Distribution of Naloxone and Risk of Fatal Overdose.

Importance: Given high rates of opioid-related fatal overdoses, improving naloxone access has become a priority. States have implemented different types of naloxone access laws (NALs) and there is controversy over which of these policies, if any, can curb overdose deaths. We hypothesize that NALs granting direct authority to pharmacists to provide naloxone will have the greatest potential for reducing fatal overdoses. Objectives: To identify which types of NALs, if any, are associated with reductions in fatal overdoses involving opioids and examine possible implications for nonfatal overdoses. Design, Setting, and Participants: State-level changes in both fatal and nonfatal overdoses from 2005 to 2016 were examined across the 50 states and the District of Columbia after adoption of NALs using a difference-in-differences approach while estimating the magnitude of the association for each year relative to time of adoption. Policy environments across full state populations were represented in the primary data set. The association for 3 types of NALs was associated: NALs providing direct authority to pharmacists to prescribe, NALs providing indirect authority to prescribe, and other NALs. The study was conducted from January 2017 to January 2019. Exposures: Fatal and nonfatal overdoses in states that adopted NAL laws were compared with those in states that did not adopt NAL laws. Further consideration was given to the type of NAL passed in terms of its association with these outcomes. We hypothesize that NALs granting direct authority to pharmacists to provide naloxone will have the greatest potential for reducing fatal overdoses. Main Outcomes and Measures: Fatal overdoses involving opioids were the primary outcome. Secondary outcomes were nonfatal overdoses resulting in emergency department visits and Medicaid naloxone prescriptions. Results: In this evaluation of the dispensing of naloxone across the United States, NALs granting direct authority to pharmacists were associated with significant reductions in fatal overdoses, but they may also increase nonfatal overdoses seen in emergency department visits. The effect sizes for fatal overdoses grew over time relative to adoption of the NALs. These policies were estimated to reduce opioid-rated fatal overdoses by 0.387 (95% CI, 0.119-0.656; P = .007) per 100 000 people in 3 or more years after adoption. There was little evidence of an association for indirect authority to dispense (increase by 0.121; 95% CI, -0.014 to 0.257; P = .09) and other NALs (increase by 0.094; 95% CI, -0.040 to 0.227; P = .17). Conclusions and Relevance: Although many states have passed some type of law affecting naloxone availability, only laws allowing direct dispensing by pharmacists appear to be useful. Communities in which access to naloxone is improved should prepare for increases in nonfatal overdoses and link these individuals to effective treatment.

Implementation and assessment of a naloxone-training program for first-year student pharmacists.

BACKGROUND AND PURPOSE: Develop a naloxone training activity and assess the activity's impact on increasing student pharmacist knowledge and confidence to counsel about management of opioid overdose and naloxone administration. EDUCATIONAL ACTIVITY AND SETTING: First-year student pharmacists participated in a naloxone training activity in an abilities laboratory course. The students completed pre-lab questions, received a brief lecture about responding to an opioid overdose, and then practiced counseling and administering intranasal and intramuscular naloxone using training kits. An Objective Structured Clinical Examination (OSCE) was conducted to assess students' ability to counsel on intranasal naloxone use in response to opioid overdose. Students completed self-assessments about their confidence in counseling patients about management of opioid overdose and naloxone administration following the OSCE and at course end. FINDINGS: 158 students participated and the average OSCE score was 82%. In the post-encounter self-assessment, 93% of students agreed or completely agreed that the OSCE improved their confidence in counseling about management of an opioid overdose and intranasal naloxone administration. Fifty-nine students completed the end-of-course survey and >90% of respondents reported they were somewhat or very confident in their ability to administer intranasal or intramuscular naloxone, recognize the opioid overdose symptoms, and counsel about intranasal naloxone use. Confidence in counseling about use of intramuscular naloxone was slightly lower. SUMMARY: Further study of training programs to increase future healthcare professionals' ability to respond to opioid overdoses is warranted. Incorporation of a short training activity can increase student pharmacists' knowledge and confidence in counseling patients about opioid overdose and naloxone administration.

Assessing the Risk of Prehospital Administration of Naloxone with Subsequent Refusal of Care.

BACKGROUND: EMS providers frequently encounter opioid-toxic patients who receive naloxone and then refuse further medical care. Older studies revealed this practice to be safe. In light of the evolving patterns of opioid abuse, this study attempted to determine the safety of this practice. METHODS: This is a retrospective review of all patient encounters by the Los Angeles Fire Department (LAFD) between July 1, 2011-December 31, 2013. All LAFD patient encounters are stored electronically. These electronic records were reviewed for subjects who received naloxone had a documented respiratory rate (RR) less than 12, and subsequently refused transport. Data abstracted included name, social security number (SSN), date of birth (DOB), date of EMS encounter, age, and treatment rendered. The names, SSN, and DOB, as available, were supplied to the coroner's office. The Coroner's records were reviewed to determine if a patient with the same or similar name (e.g., Jon vs. Jonathan) had died within 24 hours, 30 days, or 6 months of the initial EMS encounter. The abstractor was blinded to the study hypothesis. RESULTS: 205 subjects were identified; the median (IQR) age was 41 (29-53) years. 27 (13%) were female. One subject (0.49%) died within 24 hours of the initial EMS encounter. The cause of death (COD) was coronary artery disease and heroin use. Two additional subjects (1. %) died within 30 days. One of these subjects died 6 days later; the COD is unknown. The other subject died 20 days after the EMS encounter; the COD was cardiovascular disease and liver cirrhosis. No additional subjects were identified at the 6 month follow up. A third subject died of a heroin overdose 16 months after the initial EMS encounter, but was beyond the pre-defined follow up period. CONCLUSIONS: The practice of receiving pre-hospital naloxone by paramedics and subsequently refusing care is associated with an extremely low short- and intermediate-term mortality. Despite an evolving pattern of opioid abuse, the results of this study are consistent with previously reported studies.

Assessment of the appropriateness of naloxone administration to patients receiving long-term opioid therapy.

BACKGROUND: The most dangerous adverse effect of opioids is respiratory depression. Naloxone is used to reverse this, although in patients receiving long-term opioid therapy it can cause acute opioid withdrawal and opioid-refractory pain. OBJECTIVE: To determine if naloxone is appropriately administered to patients receiving long-term opioid therapy. METHODS: This retrospective case series based on chart reviews systematically identified patients over one year in a district general hospital. All patients aged 18 years or older receiving long-term opioid therapy admitted to medicine, surgery or the high dependency unit who were administered naloxone during their admission were included. RESULTS: A total of 1206 patient drug administration records were reviewed. Sixteen patients receiving long-term opioid therapy were administered naloxone. Twelve of these did not have opioid-induced respiratory depression and four did not have respiratory rate and oxygen saturations documented in the medical notes. All naloxone doses administered were higher than those recommended by national guidelines for this patient group. CONCLUSIONS: No patient receiving long-term opioid therapy who was administered naloxone had evidence of respiratory depression. More thorough assessment and documentation are needed. Verbal and physical stimulation as well as oxygenation should be considered prior to naloxone administration; this should be followed by close observation, hydration, renal function tests and opioid dose review.

Clinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures?

CONTEXT: Take-home naloxone is increasingly provided to prevent heroin overdose deaths. Naloxone 0.4-2.0 mg is licensed for use by injection. Some clinicians supply improvised nasal naloxone kits (outside licensed approval). Is this acceptable? AIMS: (1) To consider provision of improvised nasal naloxone in clinical practice and (2) to search for evidence for pharmacokinetics and effectiveness (versus injection). METHODS: (1) To document existing nasal naloxone schemes and published evidence of pharmacokinetics (systematic search of the CINAHL, Cochrane, EMBASE and MEDLINE databases and 18 records included in narrative synthesis). (2) To analyse ongoing studies investigating nasal naloxone (WHO International Clinical Trials Registry Platform and US NIH RePORT databases). FINDINGS: (1) Multiple studies report overdose reversals following administration of improvised intranasal naloxone. (2) Overdose reversal after nasal naloxone is frequent but may not always occur. (3) Until late 2015, the only commercially available naloxone concentrations were 0.4 mg/ml and 2 mg/2 ml. Nasal medications are typically 0.05-0.25 ml of fluid per nostril. The only published study of pharmacokinetics and bioavailability finds that nasal naloxone has poor bioavailability. QUESTIONS FOR DEBATE: (1) Why are pharmacokinetics and bioavailability data for nasal naloxone not available before incorporation into standard clinical practice? (2) Does nasal naloxone have the potential to become a reliable clinical formulation? (3) What pre-clinical and clinical studies should precede utilization of novel naloxone formulations as standard emergency medications? CONCLUSIONS: The addictions treatment field has rushed prematurely into the use of improvised nasal naloxone kits. Evidence of adequate bioavailability and acceptable pharmacokinetic curves are vital preliminary steps, especially when effective approved formulations exist.

[Clinical and economical evaluation of new analgesics for the management of chronic pain]. / Valutazione clinica ed economica di nuovi analgesici per la gestione del dolore cronico.

The management of chronic pain still represent a challenge for physicians. Opioids are the main stem in the treatment of chronic severe pain, not only for their potency, but as they act as central drugs. The main limit to their utilization in clinical practice is the prevalence of side effects, in particular in the gastrointestinal tract, whose constipation represents the most common. Two new formulations are nowadays available on the market: tapentadol PR (TAP PR) and oxycodone/naloxone (OXN). A recent meta-analysis showed that both drugs have a better tolerability profile than a tradizional opioid, such as oxycodone CR (OXY CR), but TAP PR reduces by 47% (RR=0.53) the percentage of patients discontinuing treatment because of side effects, compared to 24% (RR=0.76) of OXN. A similar advantage has been reported in the reduction of the risk of developing nausea and/or vomiting: TAP PR reduces the risk by 47% (RR=0.53), while OXN reduces the risk by only by 10% (RR=0.90). Both drugs reduced by about 40% the risk of constipation (RR=0.61 for TAP PR and for OXN). These results have been recently confirmed by a direct comparison of the two formulations (TAP PR vs OXN) in patients with chronic low back pain with neuropathic component. Both drugs were reported to be effective in reducing pain intensity and neuropathic symptoms, however TAP PR resulted superior to OXN in terms of analgesic efficacy, quality of life, and tolerability, in particular regarding constipation and adherence to treatment. A pharmacoeconomic analysis can be useful to understand the costs of these clinical advantages, and can be done by using a probabilistic analisys and by populating a Markov model that simulates the transition in time of 100 patients through 4 different possible health states: 1) still on treatment; 2) presence of adverse events; 3) discontinuation; 4) death. Both treatments (TAP PR and OXN) have been shown to have an excellent cost-effectiveness profile. In the case of OXN, in one year, 0.29 QALYs were gained compared to the use of OXY CR at an additional cost of € 138 resulting in a cost per QALY gained of € 475 (€ 138/0.29). In the case of TAP PR, instead, 0.31 QALYs were gained with additional savings due to the reduction of drug side effects, hospitalizations and emergency department access. Therefore, the use of TAP PR implies an average saving of € 31.6 per patient. These data are the results of a pharmacoeconomic model and require a further validation in clinical practice.

Clinical and economic evaluation of tapentadol extended release and oxycodone/naloxone extended release in comparison with controlled release oxycodone in musculoskeletal pain.

OBJECTIVE: Chronic pain is a leading cause of disability and represents a relevant societal burden. Opioids are widely used for managing chronic non-cancer pain; however, the high incidence of side effects is often the main reason for discontinuation. Two formulations have recently been studied to improve the tolerability of opioids (tapentadol extended release [ER] and oxycodone/naloxone ER), but a direct comparison between these drugs is not available in the literature. The comparative cost effectiveness of these two drugs has not previously been assessed. The objective of this meta-analysis is a clinical and economic evaluation of tapentadol ER and oxycodone/naloxone ER for the treatment of musculoskeletal pain, by indirect comparison with controlled release (CR) oxycodone. METHODS: A structured literature review was conducted to identify published data for the health-economic model. The authors performed a meta-analysis on three selected randomized controlled trials (RCTs) for each treatment (tapentadol ER and oxycodone/naloxone ER). As measure of treatment effect, risk ratio was calculated, compared to the control active treatment (CR oxycodone), for the following outcomes: discontinuation rate due to adverse events, due to gastrointestinal (GE) side effects and central nervous system (CNS) side effects. A Markov model was developed to compare the cost effectiveness of tapentadol ER and oxycodone/naloxone ER. Four health states were defined: (1) patients still on treatment; (2) occurrence of adverse events (gastroenterology, central nervous system); (3) treatment discontinuation as consequence of ineffectiveness of treatment; and (4) treatment discontinuation as consequence of adverse events. RESULTS: Both drugs showed a significant clinical advantage over the active control, CR oxycodone; however, tapentadol ER resulted in a better risk ratio reduction for the primary outcome of discontinuation rate due to adverse events and for the secondary outcome nausea and vomiting. The two drugs gave equivalent results in the capacity of reduction of constipation risk. In the economic evaluation both interventions were cost effective compared with CR oxycodone. However, tapentadol ER showed the most favorable results as in 65% of cases it was less costly and produced a considerable quality adjusted life years (QALY) gain. The higher impact of tapentadol ER on the cost effectiveness results was probably due to the price and the lower incidence of adverse events and related discontinuation rate, resulting in a further economic advantage. CONCLUSION: Both tapentadol ER and oxycodone/naloxone ER are cost effective interventions compared with CR oxycodone; however, tapentadol ER was shown to provide better clinical outcomes at lower costs.

The history of the development of buprenorphine as an addiction therapeutic.

This paper traces the early 21st century success of the agonist-antagonist buprenorphine and the combination drug buprenorphine with naloxone within the broader quest to develop addiction therapeutics that began in the 1920s as the search for a nonaddictive analgesic. Drawing on archival research, document analysis, and interviews with contemporary actors, this paper situates the social organization of laboratory-based and clinical research within the domestic and international confluence of several issues, including research ethics, drug regulation, public attitudes, tensions around definitions of drug addiction, and the evolving roles of the pharmaceutical industry. The fervor that drove the champions of buprenorphine must be understood in relation to (1) the material work of research and pharmaceutical manufacturing; (2) the symbolic role of buprenorphine as a solution to numerous problems with addiction treatment evident by the mid-1970s; the destigmatization and individualization of addicts as patients; and (3) the complex configurations of public and private partnerships.

Buprenorphine and buprenorphine/naloxone diversion, misuse, and illicit use: an international review.

The diversion, misuse, and non-medically supervised use of buprenorphine and buprenorphine/naloxone by opioid users are reviewed. Buprenorphine and buprenorphine/naloxone are used globally as opioid analgesics and in the treatment of opioid dependency. Diversion of buprenorphine and buprenorphine/naloxone represents a complex medical and social issue, and has been widely documented in various geographical regions throughout the world. We first discuss the clinical properties of buprenorphine and its abuse potential. Second, we discuss its diversion and illicit use on an international level, as well as motivations for those activities. Third, we examine the medical risks and benefits of buprenorphine's non-medically supervised use and misuse. These risks and benefits include the effect of buprenorphine's use on HIV risk and the risk of its concomitant use with other medications and drugs of abuse. Finally, we discuss the implications of diversion, misuse, and non-medically supervised use (including potential measures to address issues of diversion); and potential areas for further research.

Clinical experience with fortnightly buprenorphine/naloxone versus buprenorphine in Italy: preliminary observational data in an office-based setting.

Buprenorphine/naloxone is a new option for the management of opioid dependence. It has a reduced potential for abuse or misuse compared with methadone and buprenorphine alone, and has a long half-life allowing less frequent dosing. Buprenorphine/naloxone appears to be well suited for the management of opioid dependence in an office-based setting. The aim of this study was to evaluate the efficacy and safety of a buprenorphine/naloxone combination treatment in an office-based setting. Therefore, we evaluated the effect on misuse/diversion, quality of care, quality of life and service delivery. Seventy-eight patients were switched to buprenorphine/naloxone from either methadone or buprenorphine alone; the median duration of previous buprenorphine or methadone treatment was 10 years. Patients received buprenorphine/naloxone and were evaluated throughout a 1-year follow-up period. Treatment was self-administered by the patients every 2 weeks and the mean buprenorphine dosage at 1 year was 8 mg/day. Comparisons were made before and after the switch for patients who switched from buprenorphine alone to buprenorphine/naloxone. Switching to buprenorphine/naloxone was not associated with clinically relevant problems in 50% of patients studied. Buprenorphine/naloxone provided satisfactory coverage of withdrawal symptoms in 78.1% of patients, and 50% of patients were satisfied with buprenorphine/naloxone therapy. Seventy-eight per cent of patients reported improved psychosocial functioning. The majority of patients (approximately 85%) were negative for opioids during toxicological testing. A significantly higher proportion of treatment recipients were highly satisfied during buprenorphine/naloxone administration (p < 0.001 compared with buprenorphine given before the switch). Other outcomes were similar during buprenorphine and buprenorphine/naloxone administration. Fortnightly self-administration of buprenorphine/naloxone appeared to be cost saving for the clinic. Buprenorphine/naloxone is an effective and safe treatment option for the outpatient management of opioid dependence.

Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers.

BACKGROUND: Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). METHODS: Intravenous heroin users (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. RESULTS: Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of 'drug liking' and 'desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. CONCLUSIONS: These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment.

Safety and health policy considerations related to the use of buprenorphine/naloxone as an office-based treatment for opiate dependence.

Opiate dependence remains a fundamental challenge confronting health delivery systems and is often characterized as a social and moral issue. The impact of this disorder on healthcare policy is changing with the increased incidence of HIV, hepatitis C, and tuberculosis infections in opiate-dependent patients. These medical illnesses have substantial effect on escalating healthcare costs, and, therefore, also affect healthcare policy priorities, which are responsive to these costs. Pharmacological treatments for opiate dependence have had limited success; often the consequence of limited access to care. Hence, there is a need to develop new pharmacotherapies for opiate dependence that extend the range of clinical options, including new first-line treatment approaches. This paper will focus on the safety and health policy considerations related to the use of buprenorphine and buprenorphine/naloxone based on data derived from clinical trials and post-marketing surveillance that provide evidence for the use of the medications as first-line treatments in an office-based environment. The evaluation of this evidence formed the basis by the National Institute on Drug Abuse to support and pursue the evaluation and registration of buprenorphine/naloxone and buprenorphine in a public/private sector cooperative effort to become an office-based, first-line treatment for opiate dependence.