Abuse-deterrent Opioids Research Articles

Opioid epidemic and the urge to discover new treatment options

The primary tools to alleviate the opioid epidemic in the USA include strict Federal and State laws on opioid prescriptions, tracking opioid medications, accountability of the opioid manufacturers and physicians, as well as boosting public awareness. Although abuse-deterrent opioids have in part lowered the incidence of opioid abuse, many post-marketing studies are still pending and some products have been recalled or terminated. Moreover, some studies show that the current deterrent opioid products might potentially force the abusers to seek more-powerful and deadly illicit drugs that can lead to toxicity and hepatitis C infections. Along with all the positive developments, there remains a strong need to discover and develop nonaddictive opioids and comparable non-opioid alternatives for acute pain management.

Abuse-Deterrent Opioids: A Survey of Physician Beliefs, Behaviors, and Psychology.

ObjectiveEvaluate beliefs and behaviors pertaining to abuse-deterrent opioids (ADFs).DesignSurvey in 2019 by invitation to all licensed physicians.SettingCommonwealth of Kentucky.Participants374 physicians.MethodsDescriptive statistics, and hypothesis test that early adopter prescribers would have greater endorsement of opioid risk management.ResultsOf all prescribers, 55% believed all opioid analgesics should have ADF requirements (15% were unsure); 74% supported mandating insurance coverage. Only one-third considered whether an opioid was ADF when prescribing, motivated by patient family diversion (94%) and societal supply reduction (88%). About half believed ADFs were equally effective in preventing abuse by intact swallowing, injection, chewing, snorting, smoking routes. Only 4% of OxyContin prescribers chose it primarily because of ADF properties. Instead, the most common reason (33%) was being started by another prescriber. A quarter of physicians chose not to prescribe ADFs because of heroin switching potential. Early adopters strongly believed ADFs were effective in reducing abuse (PR 3.2; 95% CI 1.5, 6.6) compared to mainstream physicians. Early-adopter risk-management practices more often included tools increasing agency and measurement: urine drug screens (PR 2.0; 1.3, 3.1), risk screening (PR 1.3; 0.94, 1.9). While nearly all respondents (96%) felt that opioid abuse was a problem in the community, only 57% believed it was a problem among patients in their practice. Attribution theory revealed an externalization of opioid abuse problems that deflected blame from patients on to family members.ConclusionsThe primary motivator for prescribing ADFs was preventing diversion by family members, not patient-level abuse concerns.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40122-021-00343-z.

Abuse-Deterrent Opioids: A Survey of Physician Beliefs, Behaviors, and Psychology

Abuse-Deterrent Opioids: A Survey of Physician Beliefs, Behaviors, and Psychology

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance.

BackgroundOver the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of “drug liking,” “take drug again”), which are referred to as ‘pharmacodynamic (PD)’ responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs.MethodsExtensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11th, 2010 until March 25th, 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data.FindingsFollowing oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65.InterpretationOur assessment indicates that the measure of early systemic drug exposure of opioids is the best predictor of the abuse potential response in recreational opioid users following oral or nasal administration of a single dose of an intact or manipulated abuse deterrent opioids. Our findings support FDA's recommendation of comparative PK studies with early partial AUCs as a supportive PK metric for the assessment of abuse deterrent properties of generic opioid drug products in the general and product-specific guidance's of ADFs.FundingThe study was partially funded by Fiscal Year 2017 Critical Path of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

Recent advances in pain management

Pain is one of the most common complaints for which patients approach physicians. In spite of this there is a huge unmet need for developing medications for pain that are safe and efficacious. Owing to the heterogeneity of clinical pain and complex pathophysiology, target identification for drug development is difficult. Preclinical models have also proven unreliable for the development of novel analgesics. Recent advances in understanding the physiology of nociception has enabled the development of novel analgesics including abuse deterrent opioids, drugs targeting several receptors, ion channels and enzymes. This review will attempt to cover the physiology of nociception focusing on the novel targets, the challenges in development of novel analgesics and give an overview of the recently developed drugs and those in the pipeline for the management of pain.

Modeling the potential impact of abuse-deterrent opioids on medical resource utilization

Objectives: To extend a previously published manuscript on a model for estimating potential avoided medical events and cost savings in the US associated with the introduction of extended-release abuse-deterrent opioids and incorporate new methods of evaluating abuse deterrence using human abuse potential studies.Methods: A model was developed to estimate reductions in abuse-related events and annual savings in the US. Model inputs included: opioid abuse prevalence, abuse-deterrent opioid cost and effectiveness at deterring abuse, and opioid abuse-related events and costs. Direct (medical and drug) and indirect (work loss) cost savings (2017 US$) and abuse-related events were estimated assuming the replacement of the entire extended-release opioid market (brand and generic) by brand abuse-deterrent opioids.Results: Replacing the extended-release opioid market with abuse-deterrent opioids is estimated to lower annual abuse-related medical events by ∼13–31% (e.g. 78,000–186,000 emergency department visits) and lower annual medical costs by ∼$640 M–$1,538 M, depending on the abuse-deterrent technology (physical/chemical barrier or agonist/antagonist). Replacement of extended-release oxycodone with extended-release abuse-deterrent oxycodone is associated with the largest amount of cost savings and highest number of avoided medical events, followed by replacing extended-release morphine with an extended-release abuse-deterrent opioid. Replacement of transdermal fentanyl is associated with the smallest amount of cost savings and lowest number of avoided medical events.Conclusion: Agonist/antagonist abuse-deterrent opioid technology is associated with higher annual medical cost savings and more avoided events than physical/chemical barrier technology. Total net savings are dependent upon the abuse-deterrent opioid price relative to non-abuse-deterrent opioids.

The Role of Pharmacists in Safe Opioid Dispensing

Opioid misuse, abuse, and diversion continues to be a public health issue. Pharmacists (particularly those who work in the community setting) form the vanguard of health-care providers facing the opioid crisis because they have the opportunity to interact with patients more frequently than primary care or specialty medical providers. These frequent interactions give pharmacists more opportunities to properly counsel patients on prevention and to reinforce appropriate use of opioid medications. Pharmacists should be aware of the strategies for reducing opioid misuse, abuse, and diversion, including understanding mandates on prescription limitations; knowing how to use prescription drug monitoring programs; knowing when drug take-back programs are occurring; educating patients on the risks of opioid abuse, safe storage, and proper disposal of unused medications; identifying “red flag” behavior that may indicate opioid misuse; using assessments that help identify a patient’s risk for opioid abuse; interacting with other health-care professionals to discuss a patient’s care; understanding how abuse-deterrent opioids work and their limitations; preparing for opioid overdose management and understanding the local regulations on naloxone availability; and knowing when to refer patients to addiction services. Using these strategies, pharmacists have an opportunity to potentially reduce opioid abuse and improve patient outcomes.

Three Years Down the Road: The Aftermath of the CDC Guideline for Prescribing Opioids for Chronic Pain.

The 2016 CDC guidelines for opioid prescribing by primary care physicians have exposed some shortfalls in our thinking about opioid use and stranded many chronic pain patients with inadequate analgesia. Opioid prescribing rates started to decline in 2012, but still remain high. The response from providers to the 2016 guidelines have led to unintended consequences. Some of the CDC guidance seems arbitrary and not supported by evidence (the 90 MME per day cutoff). Patient and prescriber education, the role of buprenorphine (an atypical Schedule III opioid), and abuse-deterrent opioids are not mentioned at all but could play crucial roles in reducing abuse. Opioid use disorder (OUD) is not defined by the guidance which calls on primary care physicians to recognize and treat it. Opioid withdrawal syndrome is not mentioned and tapering plans, although advised, are not described in a practical way. While the morbidity and mortality associated with OUD are public health crises, so is untreated pain. Chronic pain patients deserve consideration, yet emerge as the silent epidemic within the opioid crisis. To be sure, there is much good in the CDC guidance or any guidelines that urge caution and care in opioid prescribing. Pain specialists must speak out to advocate for patients dealing with pain, to educate patients and prescribers about analgesic options, and to make sure that pain is adequately treated particularly in vulnerable populations.

Abuse-deterrent opioids prevent abuse at substantial cost

Abuse-deterrent opioids prevent abuse at substantial cost

Regulatory and evidence-based considerations for abuse-deterrent opioids.

Regulatory and evidence-based considerations for abuse-deterrent opioids.

Supply-Side Drug Policy in the Presence of Substitutes: Evidence from the Introduction of Abuse-Deterrent Opioids.

Overdose deaths from prescription opioid pain relievers nearly quadrupled between 1999 and 2010. We study the consequences of one of the largest supply disruptions to date to abusable opioids - the introduction of an abuse-deterrent version of OxyContin in 2010. Supply-side interventions which limit access to opioids may have the unintended consequence of increasing use of substitute drugs, including heroin. Exploiting cross-state variation in OxyContin exposure, we find that states with the highest initial rates of OxyContin misuse experienced the largest increases in heroin deaths. Our results imply that the recent heroin epidemic is largely due to the reformulation of OxyContin.

A Summary of Newer and Safer Opioid Formulations

The review provides a brief summary of newer and safer opioid formulations that are currently on the market. The FDA currently has on the market seven opioid formulations that have abuse-deterrent properties. While prescription opioid abuse continues to be a problem today, the development of abuse-deterrent opioids may mitigate the incidence of abuse.

An overview of abuse-deterrent opioids and recommendations for practical patient care.

Despite advances in the treatment of severe intractable pain, opioids remain a critical and appropriate component of treatment. However, abuse, misuse, and diversion of prescription opioids are significant public health concerns. Opioid abuse-deterrent formulations (ADFs) are one component of an opioid risk management plan to manage patient’s pain relief and quality of life while offering some protection against potentially harmful consequences of opioids from misuse and abuse. Opioid ADFs are designed to make manipulation more difficult and administration via non-oral routes less appealing. There are currently nine extended-release and one immediate-release opioid pain medications with US Food and Drug Administration-approved ADF labeling. All use physical/chemical barriers or agonist/antagonist combinations to deter manipulation and abuse. Evidence suggests that opioid ADFs decrease rates of abuse and diversion of opioids in the USA; however, some opioid ADFs are not yet commercially available or have not been on the market long enough to undergo post-marketing data analyses. Opioid ADFs along with the use of prescription drug monitoring programs, clinical assessment tools, toxicology testing, and co-prescribing of naloxone are all tools that can be used to reduce opioid abuse. Patient education on the risks of abuse and diversion is vital and includes a discussion of appropriate use of medication and proper storage. Physician assistants and nurse practitioners are on the “front lines” in battling opioid abuse and serve a key role in recognizing and mitigating the risks of prescription opioid diversion, abuse, and misuse (intentional and unintentional) and in identifying patients at risk for abuse while still providing pain relief to patients.

Adverse Health Effects of Abuse-Deterrent Opioids: Evidence From the Reformulation of Oxycontin

The US is currently in the midst of the worst drug overdose epidemic in its history, with nearly 64,000 drug overdose deaths in 2016. In response, pharmaceutical companies have begun introducing abuse-deterrent painkillers, pills with properties that make the drug more difficult to misuse. The first such painkiller, a reformulated version of OxyContin, was released in 2010. Previous research has found no net effect on opioid mortality, with users substituting away from OxyContin toward heroin. This paper explores health effects of the reformulation beyond mortality. Exploiting variation across states in OxyContin misuse prior to the reformulation, I find large relative increases in the spread of hepatitis B and C in states most likely to be affected by the reformulation. In aggregate, the estimates suggest that absent the reformulation we would have observed between 66-75% fewer cases of hepatitis C and 46-60% fewer cases of hepatitis B. I document further evidence that points to the likely cause of these effects: the reformulation led individuals to substitute from OxyContin to heroin, which is substantially more likely to be injected, increasing exposure to blood-borne diseases.

Supply-Side Drug Policy in the Presence of Substitutes: Evidence from the Introduction of Abuse-Deterrent Opioids

Overdose deaths from prescription opioid pain relievers nearly quadrupled between 1999 and 2010, making this the worst drug overdose epidemic in U.S. history. In response, numerous supply-side interventions have aimed to limit access to opioids. However, these supply disruptions may have the unintended consequence of increasing the use of substitute drugs, including heroin. We study the consequences of one of the largest supply disruptions to date to abusable opioids – the introduction of an abuse-deterrent version of OxyContin in 2010. Our analysis exploits across state variation in exposure to the OxyContin reformulation. Using data from the National Survey on Drug Use and Health (NSDUH), we show that states with higher pre-2010 rates of OxyContin misuse experienced larger reductions in OxyContin misuse, permitting us to isolate consumer substitution responses. We estimate large differential increases in heroin deaths immediately after reformulation in states with the highest initial rates of OxyContin misuse. We find less evidence of differential reductions in overall opioid-related deaths, potentially due to substitution towards other opioids, including more harmful synthetic opioids such as fentanyl. Our results imply that a substantial share of the dramatic increase in heroin deaths since 2010 can be attributed to the reformulation of OxyContin.Institutional subscribers to the NBER working paper series, and residents of developing countries may download this paper without additional charge at www.nber.org.

Abuse-Deterrent Opioid Formulations: A Key Ingredient in the Recipe to Prevent Opioid Disasters?

The US Food and Drug Administration (FDA) is encouraging the innovation of long-acting opioid formulations that are manipulation-resistant. The purpose of this commentary is to assess the benefits and limitations of abuse-deterrent opioid formulations (ADFs) and discuss their role in mitigating the current opioid epidemic. ADFs have been created with chemical properties that make it difficult for people who non-medically use prescription drugs to crush and dissolve opioid tablets, as well as by combining opioids with antagonists such as naloxone or naltrexone, which are released only when the dosage form has been manipulated or the drug is taken by a non-intended route. Despite these and other technologies, consensus regarding the effectiveness of these formulations in preventing non-medical use is lacking given the difficulty in obtaining post-marketing data. Researchers also question if the creation of abuse-deterrent drugs will have a positive effect on those struggling with a severe opioid-use disorder, fearing that current opioid users will simply find a new - perhaps more dangerous - drug of choice. Abuse-deterrent opioids are still opioids, and although they may make manipulation more difficult than non-ADF formulations, they are not "abuse proof." The introduction of ADFs could provide a false sense of security among prescribers and dispensers, and we fear that ADFs may have a minimal impact on non-medical use of prescription opioids. Further epidemiological studies will be required to determine the large-scale impact of abuse-deterrent opioids in preventing opioid use disorder and its downstream consequences.

Characterizing Abuse Progression of Immediate-Release Hydrocodone Combination Products

This study examined patterns of hydrocodone combination product (HCP) abuse and their potential role in abuse progression of prescription opioids and other drugs. An Internet survey was administered to 472 adult opioid users in the United States who used HCPs nonmedically. Alternate routes (33%) and concomitant drug use (45%) were indicated more frequently during respondent’s most recent HCP nonmedical use compared with their initial use (20% and 24%, respectively). Those initiating HCP nonmedical use during adolescence used alternate routes (e.g., chewing, snorting) throughout their lifetime more frequently (69.5%) compared with those older when initiating HCP nonmedical use (51.0%). A different abuse pattern was observed from first to most recent HCP use, starting with oral administration of intact tablets followed by use of alternate routes and concomitant use of illicit drugs, sometimes use of heroin. These data may inform future public health interventions, including the potential development of abuse-deterrent immediate-release opioids.

The opioid crisis: a 21st century pain.

The opioid pain market is a lucrative one, but is experiencing significant challenges in the U.S. as the country grapples with prescription opioid addiction, overdose and fatalities. The situation has been declared a national Public Health Emergency and the Food and Drug Administration (FDA) has introduced several measures intended to reduce opioid abuse. The development of abuse-deterrent prescription opioids is one such measure, but although abuse-deterrent formulations of opioids reduce drug liking and abuse, concerns have been highlighted by an Institute of Clinical and Economic Review (ICER) report regarding the insufficiency of currently available data to determine the effects of these formulations at the population level. However, the low abuse liability but effective analgesic efficacy reported for drugs such as NKTR-181 and difelikefalin highlight the potential of novel abuse-deterrent opioids.

Principles and Methods of Statistical Assessment of Abuse-Deterrent Opioids.

The FDA Guidance for Industry: Abuse-Deterrent Opioids-Evaluation and Labeling was published in April 2015. Since then questions have been raised regarding how to determine the relative abuse-deterrent (AD) effect of an AD formulation (a test product) compared to an immidiate release (IR) or NonAD extended release (ER) formulation of the same opioid (a positive control) and how to define a responder for responder analysis in clinical abuse potential studies. These questions are reasonable and important for the assessment of AD effect of an AD formulation. This article discusses the principles of the statistical assessment in this area and gives details on how to calculate sample size for the primary comparison in the study and how to perform the statistical analyses. In addition, the article also discusses the reason why the non-inferiority test is not proper for the comparison between a test product and an approved AD version of the same opioid product. Finally, a gatekeeping testing procedure is proposed for this comparison with an example.

Opioid tolerance and urine drug testing among initiates of extended-release or long-acting opioids in Food and Drug Administration's Sentinel System.

A risk evaluation and mitigation strategy for extended-release and long-acting (ER/LA) opioid analgesics was approved by the Food and Drug Administration in 2012. Our objective was to assess frequency of opioid tolerance and urine drug testing for individuals initiating ER/LA opioid analgesics. Retrospective cohort study. Sentinel, a distributed database with electronic healthcare data on >190 million predominantly commercially insured members. Members under age 65 initiating ER/LA opioid analgesics between January 2009 and December 2013. We examined the proportion of opioid-tolerant-only ER/LA opioid analgesic initiates meeting tolerance criteria: receipt of ≥30 mg oxycodone equivalents per day in 7 days prior to the first opioid-tolerant-only dispensing. We separately examined the proportion of new users of extended-release oxycodone (ERO) and other ER/LA opioid analgesics with a claim for a urine drug test in the 30 days prior to, and separately for the 183 days after, dispensing. We identified 79,824 ERO, 7,343 extended-release hydromorphone, and 91,778 transdermal fentanyl opi-oid-tolerant-only episodes. Tolerance criteria were met in 64 percent of ERO, 64 percent of extended-release hydromorphone and 40 percent of transdermal fentanyl episodes. We identified 210,581 incident ERO and 311,660 other ER/LA opioid analgesic episodes. Use of urine drug testing for ERO compared with other ER/LA opioid analgesics was: 4 percent vs 14 percent respectively in the 30 days prior to initiation and 9 percent vs 23 percent respectively in the 183 days following initiation. These results suggest potential areas for improving appropriate ER/LA opioid analgesic prescribing practices.