Rationale
Cannabidiol (CBD) products lacking regulatory approval are being used to self-treat a myriad of conditions and for their unsubstantiated health benefits. The scientific evidence supporting ...these claims largely arises not from controlled clinical trials, but from the recognition that CBD has numerous biological targets. Yet, CBD is commonly consumed and often in over-the-counter products that are unapproved and of unknown composition. Epidiolex® is the only product that has undergone rigorous pharmacokinetic assessment and testing in clinical trials; it was approved as a non-scheduled drug by the U.S. Food and Drug Administration for the treatment of intractable childhood-onset seizures. However, studies investigating CBD for other medical conditions are limited in number and often lack the scientific rigor, controls, or sample sizes required to draw clinically meaningful conclusions. Although Epidiolex® is safe for human consumption, recent changes in regulation of commercially available CBD products have resulted in limited quality control and products marketed with unknown CBD bioavailability. Even scientifically rigorous studies have used different sources of CBD and different suspension vehicles for administration, making it difficult to compare results among studies and resolve mixed outcomes.
Objectives
This paper reviews the molecular targets, pharmacokinetics, and safety and abuse liability of CBD; additionally, the extant evidence on its potential therapeutic effects for neurological disorders, pain, inflammation, conditions related to immune function, psychiatric disorders, and substance use are described.
•COVID-19 pandemic disrupted treatment service delivery and harm reduction.•Individuals with opioid use disorder may be at heightened risk of opioid overdose.•Emergency medical services (EMS) data is ...a timely source for overdose surveillance.•Kentucky EMS opioid overdose runs increased significantly during COVID-19 period.•In contrast, average EMS daily runs for other conditions leveled or declined.
Individuals with opioid use disorder may be at heightened risk of opioid overdose during the COVID-19 period of social isolation, economic distress, and disrupted treatment services delivery. This study evaluated changes in daily number of Kentucky emergency medical services (EMS) runs for opioid overdose between January 14, 2020 and April 26, 2020.
We evaluated the statistical significance of the changes in the average daily EMS opioid overdose runs in the 52 days before and after the COVID-19 state of emergency declaration, March 6, 2020.
Kentucky EMS opioid overdose daily runs increased after the COVID-19 state emergency declaration. In contrast, EMS daily runs for other conditions leveled or declined. There was a 17% increase in the number of EMS opioid overdose runs with transportation to an emergency department (ED), a 71% increase in runs with refused transportation, and a 50% increase in runs for suspected opioid overdoses with deaths at the scene. The average daily EMS opioid overdose runs with refused transportation increased significantly, doubled to an average of 8 opioid overdose patients refusing transportation every day during the COVID-19-related study period.
This Kentucky-specific study provides empirical evidence for concerns that opioid overdoses are rising during the COVID-19 pandemic and calls for sharing of observations and analyses from different regions and surveillance systems with timely data collection (e.g., EMS data, syndromic surveillance data for ED visits) to improve our understanding of the situation, inform proactive response, and prevent another big wave of opioid overdoses in our communities.
Background and Aims
Since its market release, gabapentin has been presumed to have no abuse potential and subsequently has been prescribed widely off‐label, despite increasing reports of gabapentin ...misuse. This review estimates and describes the prevalence and effects of, motivations behind and risk factors for gabapentin misuse, abuse and diversion.
Methods
Databases were searched for peer‐reviewed papers demonstrating gabapentin misuse, characterized by taking a larger dosage than prescribed or taking gabapentin without a prescription, and diversion. All types of studies were considered; grey literature was excluded. Thirty‐three papers met inclusion criteria, consisting of 23 case studies and 11 epidemiological reports. Published reports came from the United States, the United Kingdom, Germany, Finland, India, South Africa and France, and two analyzed websites not specific to a particular country.
Results
Prevalence of gabapentin misuse in the general population was reported to be 1%, 40–65% among individuals with prescriptions and between 15 and 22% within populations of people who abuse opioids. An array of subjective experiences reminiscent of opioids, benzodiazepines and psychedelics were reported over a range of doses, including those within clinical recommendations. Gabapentin was misused primarily for recreational purposes, self‐medication or intentional self‐harm and was misused alone or in combination with other substances, especially opioids, benzodiazepines and/or alcohol. Individuals with histories of drug abuse were most often involved in its misuse.
Conclusions
Epidemiological and case report evidence suggests that the anti‐epileptic and analgesic medication gabapentin is being misused internationally, with substance abuse populations at special risk for misuse/abuse.
Background
The USA has recently entered the third decade of the opioid epidemic. Opioid overdose deaths reached a new record of over 74,000 in a 12-month period ending April 2021. Naloxone is the ...primary opioid overdose reversal agent, but concern has been raised that naloxone is not efficacious against the pervasive illicit high potency opioids (i.e., fentanyl and fentanyl analogs).
Methods
This narrative review provides a brief overview of naloxone, including its history and pharmacology, and the evidence regarding naloxone efficacy against fentanyl and fentanyl analogs. We also highlight current advances in overdose treatments and technologies that have been tested in humans.
Results and conclusions
The argument that naloxone is not efficacious against fentanyl and fentanyl analogs rests on case studies, retrospective analyses of community outbreaks, pharmacokinetics, and pharmacodynamics. No well-controlled studies have been conducted to test this argument, and the current literature provides limited evidence to suggest that naloxone is ineffective against fentanyl or fentanyl analog overdose. Rather a central concern for treating fentanyl/fentanyl analog overdose is the rapidity of overdose onset and the narrow window for treatment. It is also difficult to determine if other non-opioid substances are contributing to a drug overdose, for which naloxone is not an effective treatment. Alternative pharmacological approaches that are currently being studied in humans include other opioid receptor antagonists (e.g., nalmefene), respiratory stimulants, and buprenorphine. None of these approaches target polysubstance overdose and only one novel approach (a wearable naloxone delivery device) would address the narrow treatment window.
The endogenous opioid and cannabinoid receptor systems are widely distributed and co-localized throughout central and peripheral nervous system regions. A large body of preclinical evidence suggests ...that there are functional interactions between these two systems that may be leveraged to address various health conditions. Numerous animal studies have shown that cannabinoid agonists (e.g., delta-9-tetrahydrocannabinol Δ9-THC) enhance the analgesic effects of µ-opioid analgesics as evidenced by decreasing the opioid dose required for analgesia (i.e., opioid sparing) and extending the duration of the opioid analgesia. In contrast, controlled human laboratory studies and clinical trials have not demonstrated robust analgesic or opioid-sparing effects from opioid-cannabinoid combinations. Meta-analyses of the literature (clinical trials, controlled laboratory studies; some non-controlled studies/case reports) have examined the effects of cannabis/cannabinoids for pain relief in those taking a wide variety of analgesics, including prescription opioid medications. These data do not strongly support the use of cannabinoids for chronic pain nor do prospective studies demonstrate significant cannabinoid-mediated opioid-sparing effects. Preclinical studies have also suggested a role for cannabinoids for the treatment of opioid withdrawal. Controlled laboratory and clinical studies suggest that there may be a modest signal for Δ9-THC to suppress some opioid signs and symptoms but they are not completely ameliorated and there may also be concerns around safety of Δ9-THC administration in a state of heightened autonomic arousal as occurs with opioid withdrawal. Despite anecdotal and correlational reports suggesting a benefit of cannabis on reducing opioid overdose, there is no strong data supporting this contention and emerging reports have conflicting results. In summary, there is a groundswell of public advocacy supporting the use of cannabis and cannabinoids to replace opioid analgesics or to reduce opioid use; however, the extant controlled clinical data do not support the role of cannabinoids for opioid replacement or opioid-sparing effects when treating opioid use disorder or chronic pain.
Outpatient opioid addiction treatment with sublingual buprenorphine pharmacotherapy has rapidly expanded in the United States and abroad, and, with this increase in medication availability, there ...have been increasing concerns about its diversion, misuse, and related harms. This narrative review defines the behaviors of diversion and misuse, examines how the pharmacology of buprenorphine alone and in combination with naloxone influence its abuse liability, and describes the epidemiological data on buprenorphine diversion and intravenous misuse, risk factors for its intravenous misuse, and the unintended consequences of misuse and diversion. Physician practices to prevent, screen for, and therapeutically respond to these behaviors, which are a form of medication nonadherence, are discussed, and gaps in knowledge are identified. Outpatient opioid addiction treatment with sublingual buprenorphine pharmacotherapy experiences from other countries that have varied health care systems, public policies, and access to addiction treatment are shared to make clear that diversion and misuse occur across the world in various contexts, for many different reasons, and are not limited to buprenorphine. Comparisons are made with other opioids with known abuse liability and medications with no known abuse. The objective was to facilitate understanding of diversion and misuse so that all factors influencing their expression (patient and provider characteristics and public policy) can be appreciated within a framework that also recognizes the benefits of addiction treatment. With this comprehensive perspective, further careful work can help determine how to minimize these behaviors without eroding the current benefits realized through improved addiction treatment access and expansion.
Buprenorphine treatment for opioid use disorder may be improved by sustained-release formulations.
To determine whether treatment involving novel weekly and monthly subcutaneous (SC) buprenorphine ...depot formulations is noninferior to a daily sublingual (SL) combination of buprenorphine hydrochloride and naloxone hydrochloride in the treatment of opioid use disorder.
This outpatient, double-blind, double-dummy randomized clinical trial was conducted at 35 sites in the United States from December 29, 2015, through October 19, 2016. Participants were treatment-seeking adults with moderate-to-severe opioid use disorder.
Randomization to daily SL placebo and weekly (first 12 weeks; phase 1) and monthly (last 12 weeks; phase 2) SC buprenorphine (SC-BPN group) or to daily SL buprenorphine with naloxone (24 weeks) with matched weekly and monthly SC placebo injections (SL-BPN/NX group).
Primary end points tested for noninferiority were response rate (10% margin) and the mean proportion of opioid-negative urine samples for 24 weeks (11% margin). Responder status was defined as having no evidence of illicit opioid use for at least 8 of 10 prespecified points during weeks 9 to 24, with 2 of these at week 12 and during month 6 (weeks 21-24). The mean proportion of samples with no evidence of illicit opioid use (weeks 4-24) evaluated by a cumulative distribution function (CDF) was an a priori secondary outcome with planned superiority testing if the response rate demonstrated noninferiority.
A total of 428 participants (263 men 61.4% and 165 women 38.6%; mean SD age, 38.4 11.0 years) were randomized to the SL-BPN/NX group (n = 215) or the SC-BPN group (n = 213). The response rates were 31 of 215 (14.4%) for the SL-BPN/NX group and 37 of 213 (17.4%) for the SC-BPN group, a 3.0% difference (95% CI, -4.0% to 9.9%; P < .001). The proportion of opioid-negative urine samples was 1099 of 3870 (28.4%) for the SL-BPN/NX group and 1347 of 3834 (35.1%) for the SC-BPN group, a 6.7% difference (95% CI, -0.1% to 13.6%; P < .001). The CDF for the SC-BPN group (26.7%) was statistically superior to the CDF for the SL-BPN/NX group (0; P = .004). Injection site adverse events (none severe) occurred in 48 participants (22.3%) in the SL-BPN/NX group and 40 (18.8%) in the SC-BPN group.
Compared with SL buprenorphine, depot buprenorphine did not result in an inferior likelihood of being a responder or having urine test results negative for opioids and produced superior results on the CDF of no illicit opioid use. These data suggest that depot buprenorphine is efficacious and may have advantages.
ClinicalTrials.gov Identifier: NCT02651584.
Opioid use disorder (OUD) is a chronic relapsing disorder that, whilst initially driven by activation of brain reward neurocircuits, increasingly engages anti-reward neurocircuits that drive adverse ...emotional states and relapse. However, successful recovery is possible with appropriate treatment, although with a persisting propensity to relapse. The individual and public health burdens of OUD are immense; 26.8 million people were estimated to be living with OUD globally in 2016, with >100,000 opioid overdose deaths annually, including >47,000 in the USA in 2017. Well-conducted trials have demonstrated that long-term opioid agonist therapy with methadone and buprenorphine have great efficacy for OUD treatment and can save lives. New forms of the opioid receptor antagonist naltrexone are also being studied. Some frequently used approaches have less scientifically robust evidence but are nevertheless considered important, including community preventive strategies, harm reduction interventions to reduce adverse sequelae from ongoing use and mutual aid groups. Other commonly used approaches, such as detoxification alone, lack scientific evidence. Delivery of effective prevention and treatment responses is often complicated by coexisting comorbidities and inadequate support, as well as by conflicting public and political opinions. Science has a crucial role to play in informing public attitudes and developing fuller evidence to understand OUD and its associated harms, as well as in obtaining the evidence today that will improve the prevention and treatment interventions of tomorrow.
Research on the impact of Medicaid expansion on buprenorphine utilization has largely focused on the Medicaid program. Less is known about its associations with total buprenorphine utilization and ...non-Medicaid payers.
Monthly prescription data (June 2013-May 2018) for proprietary and generic sublingual as well as buccal buprenorphine products were purchased from IQVIA®. Population-adjusted state-level utilization measures were constructed for Medicaid, commercial insurance, Medicare, cash, and total utilization. A difference-in-differences (DID) approach with population weights estimated the association between Medicaid expansion and buprenorphine utilization, while controlling for treatment capacity.
Monthly total buprenorphine prescriptions increased by 68% overall and increased 283% for Medicaid, 30% for commercial insurance, and 143% for Medicare. Cash prescriptions decreased by 10%. The DID estimate for Medicaid expansion was not statistically significant for total utilization (−19.780, 95% CI = −45.118, 5.558, p = .123). For Medicaid buprenorphine utilization, there was a significant increase of 27.120 prescriptions per 100,000 total state residents (95% CI = 9.458, 44.782, p = .003) in expansion states versus non-expansion states post-Medicaid expansion. Medicaid expansion had a negative effect on commercial insurance (DID estimate = −37.745, 95% CI = −62.946, −12.544, p = .004), cash utilization (DID estimate = −6.675, 95% CI = −12.627, −0.723, p = .029), and Medicare utilization (DID estimate = −1.855, 95% CI = −3.697, −0.013, p = .048).
The associations between Medicaid expansion and buprenorphine utilization varied across different types of payers, such that the overall impact of Medicaid expansion on buprenorphine utilization was not significant.
•Medicaid expansion’s impact on total buprenorphine utilization is understudied.•Medicaid expansion was not associated with a significant increase in total buprenorphine utilization.•Medicaid expansion was positively associated with utilization reimbursed by Medicaid.•Medicaid expansion was negatively associated with commercial insurance, Medicare, and cash utilization.
Background and objectives: Cannabis is the most used federally illicit substance. Due to widespread medicinal use and state-level legalization, public perceptions of cannabis have shifted toward the ...assumption that cannabis is safe. However, cannabinoids can cause adverse medical complications that may lead people to seek treatment. This study characterized cannabinoid poisoning-related medical encounters, poisoning involving cannabinoids and other psychoactive substances, and cannabinoid poisoning-related cardiac complications. Methods: Administrative billing data for emergency department visits and inpatient hospitalizations in acute care facilities with a discharge date from January 1, 2017 to December 31, 2019 were used to characterize cannabinoid poisoning events in Kentucky, identified by ICD-10-CM diagnosis code T40.7X. Results: There were 1,490 encounters of cannabinoid poisoning; patients were primarily non-Hispanic White males, ages 15-44, who had Medicaid and lived in a metropolitan area. Of those, 31.21% involved poisoning with a second psychoactive substance, primarily stimulants and/or opioids, and 17.72% experienced a cardiac complication. Cannabinoid-polydrug poisoning was associated with inpatient treatment (χ
2
=199.18, p < 0.001) and cardiac complications (χ
2
=4.58, p < 0.001). Discussion and Conclusions: These results are consistent with other state-level data. Patients who were diagnosed with cannabis-polydrug poisoning, compared to cannabis alone poisoning, had greater odds of hospital admission and cardiac complications, and longer length of hospital stays. Scientific Significance: The health risks of cannabinoid use must be more broadly recognized, while timely and accurate data need to be shared to guide policies on cannabis access. Future research on cannabinoid poisoning should consider the involvement of other psychoactive drugs.
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