A Narrative Pharmacological Review of Buprenorphine: A Unique Opioid for the Treatment of Chronic Pain

Gudin, Jeffrey; Fudin, Jeffrey

doi:10.1007/s40122-019-00143-6

Cited by 108 publications

(120 citation statements)

References 82 publications

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“…For example, in addition to being full mu-opioid receptor agonists, tramadol and tapentadol have been shown to activate descending pain inhibitory pathways through norepinephrine reuptake inhibition, with tramadol also acting as a serotonin reuptake inhibitor [72,73]. Buprenorphine is a partial mu-opioid receptor agonist, an antagonist at the kappa-and delta-opioid receptors, and a full agonist at opioid receptor-like 1 [74]. Of the classic and atypical opioids, buprenorphine has unique partial agonism and signaling profiles at the mu-opioid receptor, which may result in a ceiling effect on respiratory depression but not on analgesia (Fig.…”

Section: Opioidsmentioning

confidence: 99%

“…Pharmaceutical and recreational agents such as barbiturates, benzodiazepines, Z drugs, opioids, and ethanol can suppress multiple steps in respiration to cause respiratory depression [79]. Full mu-opioid receptor agonists recruit (an adaptor protein) that is associated with signaling events that lead to poor outcomes such as respiratory depression, whereas the biased signaling mechanism elicited by buprenorphine limits b-arrestin recruitment, which may contribute to an enhanced safety profile [74].…”

Section: Opioidsmentioning

confidence: 99%

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The Physiology and Maintenance of Respiration: A Narrative Review

Webster

Karan

2020

Pain Ther

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Chronic pain is one of the most common reasons adults seek medical care and is often managed with opioid analgesics; however, opioids may cause respiratory depression by suppressing various components of respiration. Respiration is the physiological process that facilitates gas exchange and is mediated through the proper function of and communication among central neural control (respiratory drive), sensory input systems, the lungs, and the muscles involved in respiration. Normal respiratory function can be dampened with the use of central nervous system (CNS) depressants and/or underlying health conditions. Patients with chronic pain are often exposed to CNS depressants other than opioids, including benzodiazepines, barbiturates, nonbenzodiazepine sedative-hypnotics, and ethanol, which can function synergistically with opioids to increase the risk of respiratory depression. Some patients may also have underlying health issues, such as obstructive sleep apnea, that can be exacerbated with the use of opioids and other CNS depressants and further contribute to respiratory depression. Clinicians should have a thorough understanding of respiration, recognize how various CNS depressants suppress it, and take necessary steps to mitigate the risk of opioid-induced respiratory depression by collaborating with a multidisciplinary team (i.e., sleep and pain specialists), choosing appropriate medications, and educating patients on the proper use and storage of opioids.

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Section: Opioidsmentioning

confidence: 99%

Section: Opioidsmentioning

confidence: 99%

The Physiology and Maintenance of Respiration: A Narrative Review

Webster

Karan

2020

Pain Ther

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“…Although there have been many reviews about the pharmacological effects of buprenorphine (2,9,10,11), examination of pharmacology educational materials (12,13,15,16) revealed a very simplified MOR-centric presentation of this drug. Therefore, the goal of this review was to examine the pharmacodynamics as opioid neuropharmacology and therapeutics is an expanding field (17).…”

Section: Introduction and Historymentioning

confidence: 99%

An Examination of the Complex Pharmacological Properties of the Non-Selective Opioid Receptor Modulator Buprenorphine

Pande¹,

Piper²

2020

Preprint

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Buprenorphine, an analogue of thebaine, is a Schedule III opioid in the United States used for opioid-use disorder and as an analgesic. Research has shown drugs like buprenorphine have a complicated pharmacology with characteristics that challenge traditional definitions of terms like agonist, antagonist, and efficacy. Buprenorphine has a high affinity for the mu (MOR), delta (DOR), kappa (KOR), and intermediate for the nociceptin opioid receptors (NOR). Buprenorphine is generally described as a partial MOR agonist with limited activity and decreased response at the mu-receptor relative to full agonists. In opioid naïve patients, the drug’s analgesic efficacy is equivalent to a full MOR agonist, despite decreased receptor occupancy and the “ceiling effect” produced from larger doses. Some argue buprenorphine’s effects depend on the endpoint measured, as it functions as a partial agonist for respiratory depression, but a full-agonist for pain. Buprenorphine’s active metabolite, norbuprenorphine, attenuates buprenorphine's analgesic effects due to NOR binding and respiratory depressant effects. The method of administration impacts efficacy and tolerance when administered for analgesia. There have been eleven-thousand reports involving buprenorphine and minors (age < 19) to US poison control centers, the preponderance (89.2%) with children. The consequences of prenatal buprenorphine exposure in experimental animals and humans should continue to be carefully evaluated. In conclusion, buprenorphine’s characterization as only a partial mu-agonist is an oversimplification. Contemporary research shows the traditional explanation of the pharmacology of buprenorphine does not take into account changes to receptor theory, pharmacological terminology, route of administration, and biologically active major metabolites.

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“…Several strategies have been pursued in the search for analgesic medications with reduced abuse liability, including drugs that target not only the μ-opioid receptor (MOR), but also the δ-opioid receptor (DOR), κ-opioid receptor (KOR), and/or nociceptin/orphanin opioid receptor (NOR) (Kiguchi et al 2020;Spahn and Stein 2017;Turnaturi et al 2019). Partial agonists, such as buprenorphine, provide analgesic effects with reduced abuse liability in part due to their low efficacy (Gudin and Fudin 2020;Walsh et al 1995). Additionally, formulations that include antagonists (e.g., naloxone and naltrexone) have been designed to reduce the abuse potential of opioid drugs (Mendelson and Jones 2003;Setnik et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA

Islam¹,

Rahman²,

Brenner³

et al. 2020

Preprint

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Rationale: IBNtxA (3-iodobenzoyl naltrexamine) is a novel μ opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, producing a unique pharmacological profile resulting in antinociception with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. IBNtxA represents an intriguing lead compound for preclinical drug development targeting truncated MOR splice variants but further evaluation of its in vivo pharmacological profile is necessary to evaluate its potential.Objective: The purpose of this study was to independently verify the antinociceptive properties of IBNtxA and to more completely examine the rewarding properties and discriminative stimulus effects of IBNtxA. These results will allow broader assessment of IBNtxA as a translational candidate or lead compound for further development.Results: IBNtxA was synthesized and compared to morphine in a variety of mouse behavioral assays. 3 mg/kg IBNtxA was equipotent to 10 mg/kg morphine in a hot plate analgesia assay. In drug discrimination testing using mice trained to discriminate between 3 mg/kg IBNtxA and DMSO/saline vehicle, the κ agonist U-50488 fully substituted for IBNtxA. Classical μ agonist morphine, δ agonist SNC162, NOP agonist SCH 221510, and μ/NOP partial agonist buprenorphine each partially substituted for IBNtxA. IBNtxA up to 3 mg/kg did not produce a place preference in CPP. Pretreatment with 3 mg/kg IBNtxA but not 1 mg/kg IBNtxA attenuated acquisition of place preference for 10 mg/kg morphine. 3 mg/kg IBNtxA attenuated morphine-induced hyperlocomotion but did not alter naloxone-precipitated morphine withdrawal. Conclusions:Overall IBNtxA has a complicated opioid receptor pharmacology in vivo. These results indicate that IBNtxA produces potent antinociception and has low abuse liability, likely driven by substantial κ agonist signaling effects.

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A Narrative Pharmacological Review of Buprenorphine: A Unique Opioid for the Treatment of Chronic Pain

Cited by 108 publications

References 82 publications

The Physiology and Maintenance of Respiration: A Narrative Review

The Physiology and Maintenance of Respiration: A Narrative Review

An Examination of the Complex Pharmacological Properties of the Non-Selective Opioid Receptor Modulator Buprenorphine

Abuse liability, antinociceptive, and discriminative stimulus properties of IBNtxA

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