The Quest for More Effective Analgesics with Reduced Abuse Liability and Fewer Adverse Effects: Promises, Pitfalls, and Future Perspectives of Biased Agonists at Opioid Receptors

2020 ◽  
pp. 181-192
Author(s):  
Andrea Bedini
Keyword(s):  
Adverse Effects ◽  
Opioid Receptors ◽  
Abuse Liability ◽  
Future Perspectives

scholarly journals Peripheral Tramadol in Dentistry: A New Use for an Old Drug

2016 ◽  
Vol 18 (2) ◽  
pp. 10
Author(s):  
Daniel Chavarría DDS, MSc, PhD ◽  
Amaury Pozos DDS, MSc, PhD
Keyword(s):  
Adverse Effects ◽  
Opioid Receptors ◽  
Analgesic Effect ◽  
Health Sciences ◽  
Analgesic Drug ◽  
Orofacial Region ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
New Perspective ◽  
Inflammatory Action

Tramadol is a well known central acting analgesic drug, used in a wide variety of treatments within health sciences; including dentistry. Due to its lack of anti-inflammatory action and some adverse effects related mainly to opioid receptors agonism, it is not use as a routine alternative; keeping mainly for patients allergic to non-steroideal anti-inflammatory drugs or as an adjuvant to manage severe odontogenic pain.  Since new available evidence supports the possible analgesic effect of this drug when is applied locally in different sites, recent reports have been done to explore the same effect in the orofacial region, especially to improve the local management of odontogenic pain. This new perspective article summarize some of the current efforts develop to explore the peripheral Tramadol in dentistry; “a new use for an old drug”. 

Methylnaltrexone Mechanisms of Action and Effects on Opioid Bowel Dysfunction and Other Opioid Adverse Effects

2007 ◽  
Vol 41 (6) ◽  
pp. 984-993 ◽  
Author(s):  
Chun-Su Yuan
Keyword(s):  
Adverse Effects ◽  
Opioid Receptors ◽  
Literature Search ◽  
Clinical Investigation ◽  
Bowel Dysfunction ◽  
Mechanisms Of Action ◽  
The Body ◽  
Data Sources ◽  
Advanced Illness ◽  
Sites Of Action

OBJECTIVE: To review the mechanisms of action of methylnaltrexone and its effects on opioid bowel dysfunction, as well as its effects on other opioid-induced adverse effects (ADEs), and its potential roles in clinical practice. DATA SOURCES: A literature search using the MEDLINE and Cochrane Collaboration databases for articles published between 1966 and March 2007 was performed. Additional data sources were obtained from manual searches of recent journal articles, book chapters, and monographs. An updated literature search showed no additional publications. STUDY SELECTION AND DATA EXTRACTION: Abstracts and original preclinical and clinical research reports published in the English language were identified for review. Review articles, commentaries, and news reports of this compound were excluded. Literature related to opioids, opioid receptors, opioid antagonists, methylnaltrexone, opioid-induced bowel dysfunction, constipation, nausea, and vomiting was evaluated and selected based on consideration of the support shown for the proof of concept, mechanistic findings, and timeliness. Fifty-eight original articles from preclinical studies and clinical trials using methylnaltrexone were identified. Pharmacologic action, benefits, and ADEs of methylnaltrexone were reviewed, with a focus on its effects on bowel dysfunction after opioids. Emphases were placed on its receptor binding activities and therapeutically relevant sites of action (peripheral vs central), in which peripheral opioid receptors in the body contribute to physiological and drug-induced effects. DATA SYNTHESIS: Morphine and related opioids are associated with a number of limiting ADEs, including opioid-induced bowel dysfunction. Methylnaltrexone, a quaternary derivative of naltrexone, blocks peripheral effects of opioids while sparing central analgesic effects. It is currently under late-stage clinical investigation for the treatment of opioid-induced constipation in patients with advanced illness. Reported results showed the drug to be generally well-tolerated. The rapid reversal of constipation is very encouraging. Hastening postoperative discharge may also be possible. CONCLUSIONS: Methylnaltrexone has the potential to prevent or treat opioid-induced peripherally mediated ADEs on bowel dysfunction without interfering with central analgesia. The study of methylnaltrexone leads to a greater understanding of the mechanisms of action of opioid pharmacology.

Emerging pharmacologic mechanisms of buprenorphine to explain experience of analgesia versus adverse effects

2021 ◽  
Vol 17 (7) ◽  
pp. 21-31
Author(s):  
Jeffrey Bettinger, PharmD ◽  
Himayapsill Batista Quevedo, PharmD ◽  
Jacqueline Cleary, PharmD, BCACP
Keyword(s):  
Adverse Effects ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Partial Agonist ◽  
Clinical Trial Data ◽  
Receptor Activation ◽  
Cellular Mechanisms ◽  
Μ Opioid Receptor ◽  
Addictive Potential

Buprenorphine’s unique pharmacologic mechanisms of action lend itself to a higher level of complexity than its typical characterization as a partial agonist at μ-opioid receptors. It is well-documented that its additional activity at Δ- and κ-opioid receptors, and opioid receptor ligand 1 may be associated with varying degrees of analgesia and usual opioid-related adverse effects. However, novel downstream molecular and cellular mechanisms from μ-opioid receptor activation contain potential new insights into its overall unique effects. These include buprenorphine’s peculiar ability to induce analgesia at escalating doses, while exhibiting a plateaued effect on respiratory depression, euphoria, gastrointestinal (GI) motility, depression, anxiety, and addictive potential. Thus, this review aims to discuss several of these emerging mechanisms to gain a better understanding of these curious actions, as well as support much of this in vitro evidence with various human clinical trial data to further support buprenorphine’s place on the analgesic ladder.

scholarly journals Peripheral Tramadol in Dentistry: A New Use for an Old Drug

2016 ◽  
Vol 18 (2) ◽  
pp. 10
Author(s):  
Daniel Chavarría DDS, MSc, PhD ◽  
Amaury Pozos DDS, MSc, PhD
Keyword(s):  
Adverse Effects ◽  
Opioid Receptors ◽  
Analgesic Effect ◽  
Health Sciences ◽  
Analgesic Drug ◽  
Orofacial Region ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
New Perspective ◽  
Inflammatory Action

Tramadol is a well known central acting analgesic drug, used in a wide variety of treatments within health sciences; including dentistry. Due to its lack of anti-inflammatory action and some adverse effects related mainly to opioid receptors agonism, it is not use as a routine alternative; keeping mainly for patients allergic to non-steroideal anti-inflammatory drugs or as an adjuvant to manage severe odontogenic pain.  Since new available evidence supports the possible analgesic effect of this drug when is applied locally in different sites, recent reports have been done to explore the same effect in the orofacial region, especially to improve the local management of odontogenic pain. This new perspective article summarize some of the current efforts develop to explore the peripheral Tramadol in dentistry; “a new use for an old drug”. 

scholarly journals Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sandeep Dembla ◽  
Marc Behrendt ◽  
Florian Mohr ◽  
Christian Goecke ◽  
Julia Sondermann ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Opioid Receptors ◽  
Dorsal Root ◽  
Trp Channels ◽  
Signaling Cascade ◽  
Central Component ◽  
Mu Opioid Receptors ◽  
Cellular Mechanisms ◽  
Mu Opioid

Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral µORs are not well understood. Here, we show in neurons of murine dorsal root ganglia that pro-nociceptive TRPM3 channels, present in the peripheral parts of nociceptors, are strongly inhibited by µOR activation, much more than other TRP channels in the same compartment, like TRPV1 and TRPA1. Inhibition of TRPM3 channels occurs via a short signaling cascade involving Gβγ proteins, which form a complex with TRPM3. Accordingly, activation of peripheral µORs in vivo strongly attenuates TRPM3-dependent pain. Our data establish TRPM3 inhibition as important consequence of peripheral µOR activation indicating that pharmacologically antagonizing TRPM3 may be a useful analgesic strategy.

Photoresponsive Delivery Of Nanovectors: A Review Of Concepts And Applications

2021 ◽  
Vol 17 ◽  
Author(s):  
Manisha Lalan ◽  
Maanika Menon ◽  
Pranav Shah
Keyword(s):  
Drug Delivery ◽  
Adverse Effects ◽  
Therapeutic Efficacy ◽  
Drug Targeting ◽  
Biomedical Applications ◽  
Future Perspectives ◽  
Delivery Methods ◽  
Therapeutic Outcomes ◽  
Precise Diagnosis ◽  
Exogenous Stimulus

: Stimuli-triggered nanovectors for drug delivery enhance the clinical efficacy and decrease the toxicity by specifically conveying the drugs to the site of target with higher specificity and efficiency. Several stimuli have been regarded, but light as an exogenous stimulus renders several benefits in clinical usage, like elevated spatial and temporal control. A number of photochemical mechanisms have been exploited in the design of photo triggered nanocarriers for biomedical applications. Light in conjugation with photosensitizers or imaging agents in nanovectors can help ensure precise diagnosis, drug delivery and improve therapeutic outcomes. Nanomedicine plays a key role in enhancing therapeutic efficacy and limiting the adverse effects. The review evaluates the multiple nanocarriers such as liposomes, polymersomes, micelles, nanogels etc., which have leveraged the advantages of phototargeting via photothermal, photochemical, photo isomerization and upconversion based activation strategies for efficient drug targeting to intracellular and other regions. An overview of the significant benefits and constraints, and the latest developments in the most popular and recent photoresponsive drug delivery methods is provided to critically judge the prospectives for success and limitations and delve upon the possible future perspectives in the field.

scholarly journals Peripherally-Acting Opioids

2008 ◽  
Vol 2s;11 (3;2s) ◽  
pp. S121-S132
Author(s):  
Howard Smith
Keyword(s):  
Spinal Cord ◽  
Adverse Effects ◽  
Opioid Receptors ◽  
Opioid Analgesic ◽  
Opioid Analgesics ◽  
Endogenous Opioids ◽  
Term Therapy ◽  
Endogenous Opioid ◽  
Key Words Pain ◽  
The Brain

Opioids are broad-spectrum analgesics with potent pain-relieving qualities but also with potential adverse effects related to both short-term and long-term therapy. Researchers have attempted to alter existing opioid analgesics, utilize different routes/ formulations, or combine opioid analgesics with other compounds in efforts to improve analgesia while minimizing adverse effects. Exogenous opioids, administered in efforts to achieve analgesia, work by mimicking the actions of endogenous opioids. Endogenous opioids and their receptors are located in the brain (supraspinal areas), spinal cord, and periphery. Although opioids and opioid receptors in the brain and spinal cord have received much attention over many years, peripheral endogenous opioid analgesic systems have only been extensively studied during the past decade. It has been known since 1990 that following injection into the rodent hindpaw, d-Ala2 , N-Me-Phe4 , Gly5 -ol-enkephalin (DAMGO) [a muopioid receptor agonist] probably exerts its antinociceptive effects locally, since the doses administered are too low to have an effect in the central nervous system (CNS). This notion has been supported by the observation that the quaternary compound morphine methyliodide, which does not as readily cross the bloodbrain barrier and enter the CNS, produced antinociception following intradermal administration into the hindpaw, but not when the same dose was administered systemically (subcutaneously at a distant site). With a growing appreciation of peripheral endogenous opioids, peripheral endogenous opioid receptors, and peripheral endogenous opioid analgesic systems, investigators began growing hopeful that it may be possible to achieve adequate analgesics while avoiding unwanted central untoward adverse effects (e.g. respiratory depression, somnolence, addiction). Peripherally-acting opioids, which capitalize on peripheral endogenous opioid analgesic systems, may be one potential future strategy which may be utilized in efforts to achieve potent analgesia with minimal side effects. Key words: Pain, opioids, immune cells, peripherally-acting opioids (PAO), leukocytes, inflammatory pain, peripheral analgesia

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