The Opioid Epidemic in the United States

The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700 fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development.

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“…46,47 Indeed, the recent rise in opioid overdose in the United States has been referred to as “epidemic”. 48,49 …”

Section: Pharmacological Results and Discussionmentioning

confidence: 99%

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

et al. 2016

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“…The United States is in the midst of an opioid epidemic that began in earnest 15–20 years ago, primarily with prescription opioids. Most first time users, between 66% and 97% among various non‐medical use populations, initiate such use by swallowing a pill/tablet whole .…”

Section: Introductionmentioning

confidence: 99%

“…2 However, users must eventually determine how to cope with the development of tolerance that is inevitable with the persistent use of any opioid. The literature is primarily devoted to two consequences of tolerance: (1) progressing to non-oral routes of administration such as injection and inhalation, which provide a more rapid response with less drug [2][3][4][5][6] or (2) shifting to stronger opioids (prescription or illicit) to replace a weaker one to which tolerance has developed. [7][8][9][10] What is often overlooked and little understood is a seemingly obvious third pathway for coping with tolerance: increasing the number of pills/tablets ingested at one time.…”

Section: Introductionmentioning

confidence: 99%

Understanding multi‐pill ingestion of prescription opioids: Prevalence, characteristics, and motivation

Ellis

Cicero

Dart

et al. 2018

Pharmacoepidemiology and Drug

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Purpose Oral use is the primary route of administration among non‐medical prescription opioid users. While progression to non‐oral routes and shifts to stronger opioids have been previously studied as ways to cope with tolerance, the prevalence and patterns of those who cope by increasing the number of pills/tablets ingested at one time (ie, multi‐pill use) has not been assessed. Methods A subset (N = 231) of treatment‐seeking opioid users from a national opioid surveillance system, participating in the Researchers and Participants Interacting Directly (RAPID) Program, completed an online survey centered on multi‐pill use. Results Over two‐thirds of non‐medical prescription opioid users had a history of multi‐pill use (67.7%), defined as ingesting four or more of the same pill, intact and at the same time. Among these (n = 154), the median maximum number of pills taken at one time was eight, with over 20% ingesting 11 or more pills in a single instance. Nearly half engaged in multi‐pill ingestion more than once a day in the past month (43.8%), with accessibility to lower dose pills being the primary motivator (85.4%). Hydrocodone immediate‐release (IR) compounds were by far the most frequently endorsed (90.3%), followed by oxycodone IR tablets with acetaminophen (76.0%) and oxycodone IR tablets containing no acetaminophen/ibuprofen (56.5%). Conclusions These results indicate that the ingestion of multiple opioid pills/tablets is extremely common among treatment‐seeking opioid users. This, and other forms of non‐medical oral use of prescription opioids, should be taken under consideration when developing prevention and intervention efforts targeting the opioid epidemic.

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“…In fact, there has been an alarming increase in prescription opioid use, abuse and illicit use; and according to the National Center for Health Statistics, the total number of deaths related to opioid overdose has more than tripled from 2011 to 2014 2–5. Although representing 5.0 % of the global population, studies report that Americans consume 80% of the global opioid supply,3 and the United States is experiencing an opioid abuse epidemic 6. Considering this unprecedented rise in opioid consumption, the United States Centers for Disease Control and Prevention has listed prescription opioid overdose among one of the 10 most important public health problems in all the 50 states 7…”

mentioning

confidence: 99%

Pain in the management of opioid use disorder

Sirohi

Tiwari

2016

JPR

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The Opioid Epidemic in the United States

Cited by 141 publications

References 85 publications

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

Understanding multi‐pill ingestion of prescription opioids: Prevalence, characteristics, and motivation

Pain in the management of opioid use disorder

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The Opioid Epidemic in the United States

Cited by 141 publications

References 85 publications

Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment

Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment

Understanding multi‐pill ingestion of prescription opioids: Prevalence, characteristics, and motivation

Pain in the management of opioid use disorder

Contact Info

Product

Resources

About

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment