The opioid epidemic: a central role for the blood brain barrier in opioid analgesia and abuse

Schaefer, Charles; Tome, Margaret E.; Davis, Thomas P.

doi:10.1186/s12987-017-0080-3

Cited by 67 publications

(62 citation statements)

References 96 publications

(122 reference statements)

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“…The BBB, formed by the brain microvascular endothelium, regulates molecular movement into and out of the brain. It is important to establish the rate and extent of BBB transport of these agents to evaluate their potential as central nervous system (CNS) therapeutics, mainly for pain and management of opioid withdrawal, especially at a time when use and abuse of opioids are epidemic (Schaefer, Tome, & Davis ).…”

Section: Introductionmentioning

confidence: 99%

Rate and extent of mitragynine and 7‐hydroxymitragynine blood–brain barrier transport and their intra‐brain distribution: the missing link in pharmacodynamic studies

et al. 2018

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Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (K ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.

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Section: Introductionmentioning

confidence: 99%

Rate and extent of mitragynine and 7‐hydroxymitragynine blood–brain barrier transport and their intra‐brain distribution: the missing link in pharmacodynamic studies

et al. 2018

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“…The signals travel to the dorsal root ganglion, are transmitted through the spinal cord and synapse on the somatosensory cortex and limbic system. The modification of this pathway by medications aims to reduce or eliminate pain [5].…”

Section: The Era Of Opioid Analgesics and The Discovery Of Anesthesiamentioning

confidence: 99%

“…With the impression that there was very little risk, particularly of addictive potential, in prescribing opioids for chronic pain, the demand for opioid use increased in clinical settings. However, by 2000, attitudes are beginning to shift and a reduction of opioid use is becoming the trend [5].…”

Section: The Public Health Issue Of Prescription Opioid Abusementioning

confidence: 99%

From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain Management in Surgery

Yim¹,

Parsa²

2019

From Conventional to Innovative Approaches for Pain Treatment

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Pain is a physiologic mechanism of the human body. Early cultures believed pain to have demonic and spiritual origins. In the early nineteenth century, morphine was first isolated by the German pharmacist Friedrich Wilhelm Adam Ferdinand Serturner. Since then, synthetic opioids and other derivatives of morphine have been developed for a wide variety of purposes, including pain relief during surgery. Opioids mainly act through the stimulation of μ-receptors, which has inhibitory effects on the propagation of pain signals to the brain. However, opioids also have unwanted side effects like nausea, vomiting, constipation, postoperative sedation, dizziness, and addiction, and are associated with significant morbidity, prolong hospital stays, increase use of medications needed to reverse side effects, and decrease patient satisfaction. Furthermore, use and abuse of opioids have contributed to an opioid epidemic, especially in the United States since the beginning of the twenty-first century. Opioid-free anesthesia is an alternative aimed at providing pain relief without the opioid-related adverse effects and to enhance recovery. Non-opioid alternatives and preoperative patient education strategies have been shown to be superior in the management of postoperative pain and opioid requirements. Clinicals have embraced these concepts enthusiastically and have begun to incorporate an opioid-free pain management approach in surgery.

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“…Loperamide is a potent μ‐opioid receptor agonist sold over‐the‐counter under the brand name Imodium and as generic antidiarrheal medicines. It is peripherally acting with limited central nervous system (CNS) activity . It was first marketed in the United States of America in 1977 and classified as Schedule II.…”

mentioning

confidence: 99%

“…In normal physiological settings, P‐gp can effectively efflux loperamide from the cytosol of the endothelial cells lining the vasculature in the brain to the lumen of the vasculature, effectively preventing access to the brain. However, overdoses of loperamide have shown CNS activity as the P‐gp is overwhelmed, allowing intracerebral absorption and thus facilitating euphoric CNS effects .…”

mentioning

confidence: 99%

Loperamide as a Potential Drug of Abuse and Misuse: Fatal Overdoses at the Medical University of South Carolina

Powell

Presnell

2019

Journal of Forensic Sciences

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Loperamide is an over‐the‐counter, μ‐opioid receptor agonist commonly used as an antidiarrheal agent. Loperamide was thought to have minimal abuse potential due to its low bioavailability and limited central nervous system activity; however, there have been increasing reports of loperamide misuse in supratherapeutic doses to achieve euphoria and/or avoid opioid withdrawal. A literature review suggests a rise in loperamide abuse was inevitable, with substantial increases in reported cases over the last decade. Five fatal cases of toxic medication use where loperamide was listed as a primary or contributory cause of death were identified at the Medical University of South Carolina. The characteristic autopsy demographics and findings are described, and the mechanisms of abuse and toxicity of loperamide are reviewed. Loperamide overdoses are a growing concern from both a forensic and clinical standpoint, and the frequency of reported cases will likely increase as awareness grows within the medical and toxicological communities.

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The opioid epidemic: a central role for the blood brain barrier in opioid analgesia and abuse

Cited by 67 publications

References 96 publications

Rate and extent of mitragynine and 7‐hydroxymitragynine blood–brain barrier transport and their intra‐brain distribution: the missing link in pharmacodynamic studies

Rate and extent of mitragynine and 7‐hydroxymitragynine blood–brain barrier transport and their intra‐brain distribution: the missing link in pharmacodynamic studies

From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain Management in Surgery

Loperamide as a Potential Drug of Abuse and Misuse: Fatal Overdoses at the Medical University of South Carolina

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