Sending out Biased Signals: an Appropriate Proposition for Pain?

2019 ◽  
Vol 32 (2) ◽  
pp. 108-110 ◽  
Author(s):  
E. Besserer-Offroy ◽  
P. Sarret
Keyword(s):  
Side Effects ◽  
Acute Pain ◽  
Gold Standard ◽  
Pain Treatment ◽  
Opioid Analgesics ◽  
Mu Opioid Receptor ◽  
Clinical Development ◽  
Mu Opioid ◽  
Development Stages ◽  
The Past

In the past few years, several biased ligands acting at the mu-opioid receptor were reported in the literature. These agonists are aimed at reducing pain while having fewer side effects than morphine, the gold standard of opioid analgesics. In this mini-review, we describe and discuss the recent advances in mu-biased ligands actually in preclinical and clinical development stages, including the latest U.S. Food and Drug Administration review of oliceridine, a biased mu-agonist for moderate to severe acute pain treatment developed by the company Trevena.

scholarly journals A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates

2018 ◽  
Vol 10 (456) ◽  
pp. eaar3483 ◽  
Author(s):  
Huiping Ding ◽  
Norikazu Kiguchi ◽  
Dennis Yasuda ◽  
Pankaj R. Daga ◽  
Willma E. Polgar ◽  
...  
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Nonhuman Primates ◽  
Mu Opioid Receptor ◽  
Mu Opioid ◽  
Opioid Receptor Agonist

The role of oxycodone/naloxone in pain management

Ból ◽  
2017 ◽  
Vol 17 (4) ◽  
pp. 26-40
Author(s):  
Magdalena Kocot-Kępska ◽  
Renata Zajączkowska ◽  
Anna Przeklasa-Muszyńska ◽  
Jan Dobrogowski
Keyword(s):  
Side Effects ◽  
Pain Treatment ◽  
Treatment Options ◽  
Analgesic Efficacy ◽  
Opioid Analgesics ◽  
Bowel Dysfunction ◽  
Prolonged Release ◽  
Gastrointestinal Side Effects ◽  
Strong Opioids ◽  
Pain Patients

ABSTRACT: Strong opioid analgesics are essential for pain treatment of moderate to severe intensity, regardless of its etiology. An important factor limiting safety and efficacy of opioids are side effects, particularly gastrointestinal. Constipation as part of opioid induced bowel dysfunction is one of the most common reason for discontinuation of strong opioids. Introduction of novel oxycodone/naloxone formulation is an attempt to resolve the problem of opioid induced gastrointestinal side effects. On the basis of clinical trials from 2008-2016 the authors discuss the applicability of oxycodone/naloxone prolonged release in management of different pain syndromes in humans, in cancer patients, in neuropathic pain patients, in the elderly, in acute post-operative pain and other clinical indications for example restless leg syndrome. Presented data indicate comparable or in some cases even better analgesic efficacy of oxycodone with naloxone and lower risk of gastrointestinal side effects, especially constipation, when compared to other strong opioids. The introduction of oxycodone with naloxone significantly expands treatment options for chronic pain patients, likewise improving safety and thus the effectiveness of treatment with strong opioids.

Dilemma of Addiction and Respiratory Depression in the Treatment of Pain: A Prototypical Endomorphin as a New Approach

Pain Medicine ◽  
2019 ◽  
Vol 21 (5) ◽  
pp. 992-1004 ◽  
Author(s):  
Lynn Webster ◽  
William K Schmidt
Keyword(s):  
Side Effects ◽  
Respiratory Depression ◽  
Opioid Receptor ◽  
Severe Pain ◽  
Mu Opioid Receptor ◽  
Endogenous Opioid Peptides ◽  
Endogenous Opioid ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Abstract Objective Although mu-opioid receptor agonists have been the mainstay of analgesic regimens for moderate to severe pain, they are associated with serious side effects, risks, and limitations. We evaluate the most serious risks associated with conventional opioids and compare these with the pharmacology of CYT-1010, a prototypical endomorphin and mu-opioid receptor agonist. Results Addiction and respiratory depression are serious risks of traditional mu-opioid analgesics. Mitigation strategies have been inadequate at addressing the opioid crisis and may interfere with the effective treatment of pain. Improved understanding of mu-opioid receptor biology and the discovery in 1997 of an additional and unique family of endogenous opioid peptides (endomorphins) have provided a pathway for dissociating analgesia from opioid-related adverse events and developing new classes of mu-opioid receptor agonists that use biased signaling and/or target novel sites to produce analgesia with reduced side effect liability. Endomorphin-1 and -2 are endogenous opioid peptides highly selective for mu-opioid receptors that exhibit potent analgesia with reduced side effects. CYT-1010 is a cyclized, D-lysine-containing analog of endomorphin-1 with a novel mechanism of action targeting traditional mu- and exon 11/truncated mu-opioid receptor 6TM variants. CYT-1010 preclinical data have demonstrated reduced abuse potential and analgesic potency exceeding that of morphine. In an initial phase 1 clinical study, CYT-1010 demonstrated significant analgesia vs baseline and no respiratory depression at the dose levels tested. Conclusions CYT-1010 and other novel mu-opioid receptor agonists in clinical development are promising alternatives to conventional opioids that may offer the possibility of safer treatment of moderate to severe pain.

Mu Opioid Receptor (OPRM-1) Polymorphisms among Patients with Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3804-3804
Author(s):  
Sharmila Mehta ◽  
Nicholas Campbell ◽  
Lakiea Bailey ◽  
Ferdane Kutlar ◽  
Dedrey Elam ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Allele Frequency ◽  
Sickle Cell ◽  
Opioid Analgesics ◽  
Mu Opioid Receptor ◽  
Wild Type ◽  
Cell Disease ◽  
Opioid Use ◽  
Mu Opioid ◽  
Pain Frequency

Abstract Opioid analgesics form an important component of the management of acute and chronic pain in patients with sickle cell disease (SCD). Chronic opioid use, sometimes associated with dependence and addiction in a subset of patients, may pose difficult management problems. This adds to the sometime antagonistic relationship that can develop between providers and patients with SCD. Pain management can become a sociological and psychological issue in the management of SCD. The Mu opioid receptor (OPRM-1) is the primary site of action of endogenous opioid peptides (enkephalins and endorphins) and of opioid analgesics, such as morphine, methadone, fentanyl, heroin, and related compounds. Rapid activation of the mu receptor results in a euphoric effect, conferring the reinforcing or rewarding effects of opioids and thus contributing to the development of addiction. It has been known that there is variation between individuals in sensitivity to opioids suggesting potential variation in the receptor protein and the gene. Some recent data have shown that polymorphisms in the OPRM-1 gene affect pain threshold and tolerance as well as opioid requirements for optimal pain control. In an effort to unravel the complex issues surrounding pain frequency, pain tolerance, opioid usage, and opioid addiction in this patient population, we conducted a study of our adult sickle cell patients for the frequency of the two common cSNPs and another SNP in the IVSII (G691C) of the OPRM-1 gene. DNA samples from randomly selected patients were used in this study. The OPRM-1 gene was PCR amplified and subjected to cycle sequencing on an ABI Prism automated sequencer. The results showed that of the 97 adult SCD patients screened for the C17T polymorphism (GenBank accession #AY292291 and 292290), 67 (69.7%) had the wild type (CC), 28 (29.1%) were heterozygous (CT), and 11 (11.4%) were homozygous (TT) for the SNP. This represents an allele frequency for the T of 0.26. Of the 39 sequenced samples for the A1189G, all (100%) showed the wild type (AA). These results closely resemble those reported by Bond et al (PNAS, 95;9608,1998) for the frequency of the two cSNPs in the African-American population (allele frequency of 0.21 for the C17T and 0.016 for the A118G). Of the 16 samples screened for IVS II G691C polymorphism (GenBank accession #AY299483), 6 (37.5%) had the wild type (GG), 9 (56.3%) were heterozygous (GC), and 1 (6.2%) was homozygous (CC). Our results among SCD patients show a high frequency of C17T polymorphism in the OPRM-1 gene. Detailed studies in higher numbers of SCD patients and clinical correlations with pain frequency and threshold, opioid usage, opioid abuse and drug seeking behavior will be undertaken. It is expected that these studies will clarify the role of OPRM-1 polymorphisms as a genetic modifier associated with pain frequency, with tolerance as well as opioid use and abuse.

scholarly journals Biased mu-opioid receptor agonists confer analgesia with reduced side effects

2018 ◽  
Vol 87 (1) ◽  
pp. 62-64
Author(s):  
Chloe Gui ◽  
Sean Wong
Keyword(s):  
Side Effects ◽  
Respiratory Depression ◽  
Opioid Receptor ◽  
Drug Application ◽  
Mu Opioid Receptor ◽  
Therapeutic Effects ◽  
Opioid Use ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Opioids are considered mainstay treatments for acute and terminal pain. In recent decades, however, overprescription and the increasing prevalence of illicit opioids has propelled North America into a state of “opioid crisis.” Along with the analgesic benefits, opioid use also commonly induces a number of side effects. Respiratory depression is an especially dangerous and potentially lethal example. The development of painkillers with improved safety profiles is thus a priority. Downstream to the mu-opioid receptor, which is responsible for the analgesic effects of opioids, β-arrestin-2 signaling has been suggested to be important for the manifestation of side effects, including respiratory depression. Two novel mu-opioid receptor agonists, TRV130 and PMZ21, have recently been reported to preferentially promote G protein-coupling over β-arrestin-2 signaling, thereby promoting analgesia with reduced side effects. TRV130 has been found in clinical trials to be more potent than morphine but safer in the setting of acute moderate-to-severe pain and is currently under New Drug Application review in the U.S. PMZ21 has shown promising and unique pain-relieving effects in mouse models, but further investigation is warranted to examine whether its therapeutic effects and safety profile are translatable to humans.

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