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Structure-Activity Relationships of the Benzimidazole Opioids: Nitazenes and Piperidinylbenzimidazolones (Cychlorphine, Brorphine, Bezitramide Derivs) [Vol 1]

2024.03.09 08:04 jtjdp Structure-Activity Relationships of the Benzimidazole Opioids: Nitazenes and Piperidinylbenzimidazolones (Cychlorphine, Brorphine, Bezitramide Derivs) [Vol 1]

Structure-Activity Relationships of the Benzimidazole Opioids: Nitazenes and Piperidinylbenzimidazolones (Cychlorphine, Brorphine, Bezitramide Derivs) - [Vol 1: Nitazenes]

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By: Oxycosmopolitan X.com/DuchessVonD
Patreon.com/Oxycosmopolitan
u/jtjdp
AskChemistry
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The world of chemistry pulsates with the creative energy of its practitioners. It is a realm where imagination takes flight, conjuring new molecules with the potential to revolutionize how we treat disease, understand life, or even alter the course of human history. However, the journey from conception to tangible reality is fraught with difficulty. Unexpected hurdles lie in wait. Transforming a dream molecule into a practical therapeutic is far from guaranteed. Failure awaits most ventures. These failures are studied, formulas improved. Failure breeds success. Success is founded in failure.
“If you aren’t frustrated, you aren’t doing hard science.” Repeatedly beating one’s head against the wall is a hallmark of great scientists. Those with unmarred foreheads, like my own, are usually just mediocre. I’m too vain to be anything but mediocre.
The modern chemist operates within a complex landscape. Gone are the days of unfettered exploration, where ideas could blossom unhindered. Instead, regulations and obligations hold sway, demanding careful consideration and responsible practice. Yet, amidst these constraints, a multitude of approaches exist to guide the design of these coveted molecules.
One particularly reliable approach involves drawing inspiration from the success of existing structures. By studying molecules with established efficacy, the chemist embarks on a quest to improve upon their therapeutic potential through targeted molecular modifications. This journey of optimization, fueled by both creative vision and scientific rigor, lies at the heart of this fascinating field.
Fifteen years ago, at the beginning of my chemical career, an era when I spent more time hitting on boys than I did the books, I was inspired by the resonant beauty of a different type of beau. It was neither furbaby, frat boy, or the cute nerd from the library: it was benzimidazole – my bundle of aromatic joy!
More specifically, I was attracted to the NOP/ORL1 and μ-opioidergic potential [http://dx.doi.org/10.1021/bk-2013-1131.ch008] of the relatively niche 2-benzimidazolone derivatives that were first pioneered by Paul Janssen in the early 1960s. The marriage of 2-benzimidazolone resonance with the C4 position of piperidine gave birth to a scaffold with diverse pharmacology: the 4-(2-keto-1-benzimidazolyl)piperidines. Also referred to as piperidinylbenzimidazolones or the more “Charmed” nomenclature, 4-benzimidazolonepiperidines.
The 4-(2-oxo-benzimidazolyl)piperidine scaffold was first utilized by Janssen to grow his portfolio of antipsychotic-neuroleptic agents. Janssen coupled the piperidinylbenzimidazolone moiety with a halogenated N-butyrophenone to form the dopamine antagonists benperidol, droperidol and domperidone. Concurrent with the discovery of neuroleptics of the benzimidazolone series were opioidergic members based on the same scaffold. There is significant overlap in Janssen’s diverse portfolio of dopamine antagonists with those of his opioid portfolio. Most of Janssen’s classical neuroleptic scaffolds are readily converted to highly selective μ-opioid receptor agonists by replacing the butyrophenone moiety with an opioactive moiety. The most active of these include:
p-Halogenated benzyl (brorphine; clorphine)
N-cyanoethyl + p-halo benzyl (cychlorphine, cybrorphine): analgesic activity up to 230 x morphine
p-Methyl benzyl (warorphan): 130 x morphine
Methadyl (R4847; etodesitramide): up to 200 x morphine
Diphenylbutyronitrile (bezitramide, desitramide): 10-15 x morphine
Diphenylpropyl (R5460): 60 x morphine
Additional opioid-activating moieties are found in the following diagram (not a comprehensive list).
[https://i.imgur.com/Lb3lHYE.jpg]
[REFS: Janssen - Drugs Affecting the Central Nervous System, Vol 2 (1968) - A Burger, ed.; https://doi.org/10.1016/0014-2999(83)90331-x; https://doi.org/10.1016/0014-2999(77)90025-5; https://doi.org/10.1208/aapsj070234; https://doi.org/10.1016/s0960-894x(03)00665-6; https://doi.org/10.1248/cpb.49.1314]
Janssen’s 2-benzimidazolone odyssey culminated in the clinical development of the long-acting analgesic bezitramide (100 x pethidine). Despite its potential, bezitramide was poorly soluble with low bioavailability and did not see widespread adoption. He would continue to utilize the scaffold in his psychiatric portfolio, but bezitramide was the last commercial venture in its class.
Other members of the class, especially those derived from N-despropionyl bezitramide, are highly active opioid analgesics with potencies ranging from 10-230 x morphine. Research into the scaffold was revived by Kennedy et al. as a platform for developing biased μ-opioid receptor (μOR) agonists. [https://doi.org/10.1021/acs.jmedchem.8b01136] Several of the ligands from the 2018 study have appeared as designer drugs, including brorphine and the 5,6-dichloro congener SR-17018.
The piperidinylbenzimidazolone series was initially developed alongside fentanyl – the most successful of Janssen’s opioid discoveries. The 2-benzimidazolones can be imagined as closed-ring analogs of the propionanilide substructure within the fentanyl molecule (see red arrow in the diagram below).
The evolution of the piperidinylbenzimidazolones from their humble methadylic and fentanylic roots and their latter-day ethylenediamine derivatives is outlined in the following diagram:

https://preview.redd.it/ptocngnmz8nc1.jpg?width=2402&format=pjpg&auto=webp&s=fdc327a99ef9c5a74a1aab830a293197e0eb24fd
[https://i.imgur.com/4Qy3RRl.jpg]
Members of the piperidinylbenzimidazolones, such as cychlorphine and its congeners, will be more fully explored in the second volume of this two-part series.
The first volume is dedicated to members of the nitazene series: 2-benzylbenzimidazoles.
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Karma is a Benzimidazole, who doesn't play with balls (Deandra’s Version)

Benzimidazole stands out as a prominent player in the realm of heterocyclic pharmacophores, earning the reputation as a privileged structure due to its frequent presence in bioactive molecules [https://doi.org/10.1016%2Fj.jscs.2016.08.001]. This unique aromatic scaffold emerges from the fusion of two aromatic rings: benzene and imidazole. As an amphoteric moiety, benzimidazole embodies characteristics of both acids and bases. Additionally, benzimidazoles have the ability to form salts, further broadening their potential.

https://preview.redd.it/x3mldahxz8nc1.jpg?width=955&format=pjpg&auto=webp&s=6edae983dd7da7d0ca86b503866d355e27a9b839
[https://i.imgur.com/coC3yjd.jpg]
This unique structure imbues its derivatives with interesting properties and diverse chemical reactivity. [https://doi.org/10.1016%2Fj.apsb.2022.09.010]
The benzimidazole structure offers a unique combination of aromatic character and planarity, contributing significantly to its properties and reactivity. [https://doi.org/10.3390%2Fmolecules28145490] Both the benzene and imidazole rings exhibit aromaticity, granting them stability due to delocalization of π-electrons throughout the conjugated system. [https://doi.org/10.1039/B40509] This aromaticity also translates to a planar structure for the molecule, enabling crucial interactions with biological targets. This planarity facilitates π-π stacking, where the π-electron clouds of the benzimidazole ring overlap favorably with aromatic moieties present in the active sites of target receptors. These interactions, driven by transient electrostatic forces, contribute to the stabilization of the complex and enhance the binding affinity of the benzimidazole moiety to its target. [https://doi.org/10.1107%2FS1600536809027391]
While the aromatic framework confers stability, the presence of nitrogen atoms in the imidazole ring introduces a degree of polarity. This polarity arises from the uneven distribution of electrons, rendering the molecule slightly basic. These nitrogen atoms also contribute to the amphoteric nature of benzimidazole. Depending on the reaction environment, the molecule can act as an acid by donating a proton (H+) from the NH group, or as a base by accepting a proton from an acidic species.
The unique electronic distribution within the benzimidazole structure influences the reactivity profile of this versatile substrate. [http://dx.doi.org/10.2174/1570179420666221010091157] The positions 4, 5, 6, and 7 (relative to the imidazole ring) are electron-rich. This electron-rich character makes these positions susceptible to attack by electrophilic reagents, leading to reactions like nitration, halogenation, and sulfonation. Conversely, the 2-position exhibits electron deficiency due to the electron-withdrawing nature of the adjacent aromatic ring. This electron deficiency makes the 2-position a favorable target for nucleophiles, facilitating nucleophilic substitution reactions. This specific reactivity is particularly relevant in the context of 2-benzylbenzimidazoles, where the 2-position serves as the anchor point for the para-substituted benzyl moiety present in compounds like etonitazene. Benzimidazole generally displays resistance towards both oxidation and reduction reactions. However, under harsh conditions, the benzene ring can be susceptible to oxidation. Conversely, the aromatic character of the molecule contributes to its resistance towards reduction. The acid/base properties of benzimidazoles are due to the stabilization of the charged ion by the resonance effect.
The substitution pattern of benzimidazole derivs (such as nitazenes) influences the reactivity of different regions of the molecule and alters its physicochemical properties. [https://doi.org/10.2174/1389557519666191122125453]
The two nitrogens of benzimidazole have different properties and acidities, increasing the ring system’s electronic diversity and utility as a synthetic scaffold. The pyridine-like nitrogen, aza (–N=), is an electron donor (labeled N1 in diagram), while the pyrrole-like nitrogen, an amine (–NH–), acts as an electron acceptor (labeled N2).
Benzimidzole’s nitrogens are somewhat less basic than the corresponding pair in plain vanilla imidazole. This makes benzimidazoles more soluble in polar solvents and less soluble in organics. Unsubstituted benzimidazole, for example, is soluble in hot water but poorly soluble in ether and insoluble in benzene.

https://preview.redd.it/gcil3y0zz8nc1.jpg?width=878&format=pjpg&auto=webp&s=16f814d564613672a9e31534a74f991c11b8dffc
[https://i.imgur.com/9DjyBfU.jpg]
In unsubstituted benzimidazole, a rapid proton exchange occurs between the nitrogen atoms (–NH– and =N– see above figure). This phenomenon, known as tautomerism, gives rise to two equivalent forms of the molecule that exist in an equilibrium. The transformation can occur either between individual benzimidazole molecules or with the help of protic solvents like water. This exchange makes substituents at the C5 and C6 positions chemically identical. However, the magic fades once you introduce a substituent to the N1 nitrogen (N-substituted benzimidazoles). This disrupts the dance, locking the molecule into two distinct and isolatable forms, like twins that can finally be told apart. [https://doi.org/10.1016/0169-4758(90)90226-t90226-t)]
As the nitazene species are highly substituted benzimidazoles, the position of the substituent along the C5-C6 benzene axis is just as critical to bioactivity as the nature of the substituent itself. The opioidergic activity of the C5-C6 regioisomers of the nitro nitazenes varies substantially. In the case of the series prototype etonitazene (5-nitro), shifting the nitro group from C5 to C6 results in an activity loss of nearly 100-fold. [https://doi.org/10.1039/J39660001511]

[ABOVE: Anatomy of 2-benzylbenzimidazole prototype, etonitazene, featuring optimal substituents: 5-nitro (electron withdrawing group = EWG), 2-benzyl (p-ethoxy optimal), ethylenediamine side chain (diethylamino optimal)]
[https://i.imgur.com/dF1ZnXz.jpeg]
As with chemical reactivity, the solubility of substituted benzimidazoles varies. The aliphatic side chain (blue in diagram) and 2-benzyl substituent (green) of etonitazene contribute to a very high lipid solubility. The ionization constant of the diethylaminoethyl side chain (branching from the pyrrole nitrogen) contributes to greater acidic character compared to the unsubstituted benzimidazole. Combined with the increased lipophilicity, this translates to lower aqueous solubility and increased solubility in organic solvents. The ionization constants (pKa) for the nitrogens in etonitazene are as follows: pyrrole-type (N2) is 2.86 and that of the aminoethyl side-chain (N3) is 6.36. [https://doi.org/10.1111/j.2042-7158.1966.tb07782.x]

https://preview.redd.it/9ky1ghx309nc1.jpg?width=3551&format=pjpg&auto=webp&s=5cb67cf4a5a1a5bb6a0a0bb928c8a8eca9d3eb66
[https://i.imgur.com/39pQFP9.jpeg]
[ABOVE: The anatomy of piperidinylbenzimidazolone opioid analgesics. The 2-benzimidazolone core of series prototype (brorphine) attaches to C4 of the piperidine ring, forming the crucial 4-piperidinylbenzimidazolone core]
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History

The path to fully synthetic opioids began with the elucidation of the chemical structure of morphine. [Mem. Proc. Manchester Lit. Philos. Soc. 1925, 69(10), 79] Before the vast array of analytical tools we take for granted today, pinpointing the exact structure of complex natural products like morphine was a major challenge. Gulland-Robinson (1925) and Schopf (1927) independently proposed the structure we now accept, but only the 1952 total synthesis of morphine by Gates and Tschudi [https://doi.org/10.1021/ja01124a538] confirmed it definitively. Just two years later, Elad and Ginsburg reported an intermediate convertible to morphine, solidifying the picture
With a rudimentary framework of morphine’s structure, researchers sought an improved drug with better oral activity and less addiction potential. In 1929, a US National Research Council program embarked on this mission, systematically modifying the morphine molecule and establishing the structure-activity relationships (SAR) of the 4,5-epoxymorphinan class. This small group included Nathan B. Eddy and EL May, who would later become leaders in the field of addiction research. The aim of their 11-year odyssey was to discover improved analgesics through elucidation of simpler fragments of the morphine molecule. While contributing greatly to the structure-activity relationships of morphine derivatives, their ultimate goal of discovering less addictive narcotics was elusive. Two morphine analogs resulting from the project, desomorphine and metopon, demonstrated reduced dependence potential. Based on the recent emergence of Krokodil (homebake desomorphine) on the Russian exotic reptile market, it seems doubtful that the reduced addiction liability of desomorphine observed in rodents translates to humans. [NB Eddy, “The National Research Council Involvement in the Opiate Problem, 1928-1971” (1973)]
Before the spindly 11-year odyssey of their American colleagues concluded, a series of discoveries at German pharma firm Hoechst AG would rock the field of analgesics like a blitzkrieg bukkake. Eisleb introduced the first fully synthetic opioid when he synthesized pethidine (meperidine) in 1937 [https://doi.org/10.1055/s-0028-1120563], followed by Schaumann’s elucidation of its morphine-like mechanism of action a year later. Later that same year (1938), Hoechst’s chief of R&D, Max Bockmuhl, and his eventual successor, Gustav Ehrhart, discovered morphine-like analgesia in a series of straight-chain diphenylpropylamine derivatives [https://doi.org/10.1002/jlac.19495610107]. The prototypes of this class, methadone and its α-methyl isomer isomethadone, would go on to inspire many of the first synthetic opioids introduced to the clinic (dipipanone, phenadoxone, dextromoramide, normethadone, LAAM, dextropropoxyphene). Aspects of this 3,3-diphenylpropylamine scaffold, such as the ethylamino side chain and the methadyl moiety, would be incorporated into the design of 2-benzylbenzimidazole and 2-benzimidazolone opioids.
To learn more about the chemistry and pharmacology of methadone, isomethadone and other 3,3-diphenylpropylamine opioids, see my review here: [https://www.reddit.com/usejtjdp/comments/11jbjmy]
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Percocet in Peacetime

The immediate postwar period ushered in an explosion of research dedicated to the elusive "Holy Grail" of analgesics: a pain reliever devoid of the dark side. These ideal analgesics would have fewer side effects, such as respiratory depression, constipation, sedation and dependence liability. In this “morphine python quest for the holy grail,” several key discoveries stand out.

https://preview.redd.it/hya6t67b09nc1.jpg?width=5981&format=pjpg&auto=webp&s=6e8261d7228e5914df9ead6e0f0524fbe1baf40a
[https://i.imgur.com/0hHsSz6.jpeg]
The structural complexity of morphine presents a significant challenge to the natural product chemist. The cis-(1,3-diaxial) geometry of the iminoethano bridge (the top half of the piperidine; ring D) frustrated early attempts at total synthesis of this molecule and its relatives. Much of the early work, in fact, focused on construction of a “model hydrophenanthrene” scaffold containing the important quaternary center (corresponding to C13 in the morphinan skeleton). A cyclodehydration reaction developed in the course of this research provided a necessary tool for much of the subsequent work.
The speculative scheme for the biological origins of morphine, as proposed by Robinson and Schopf in the mid-late 1920s, is likely to have inspired the successful synthetic scheme for prep’n of simpler versions of the morphine nucleus. These proposals detailed the cyclization of a benzylisoquinoline into the desired morphinan nucleus. Another 40 years would pass before these postulates were confirmed by studies involving the (in vivo) conversion of radiolabeled norlaudanosoline into morphine (in plant tissue).
Using the postulates of Robinson-Schopf as templates, the young chemist Rudolph Grewe prepared a substituted 1-benzyloctahydroisoquinoline (known in industry as “octabase”). Grewe spent the better part of a decade (1942-49) tinkering with different cyclization conditions in order to convert octabase into the cis-(1,3-diaxial)-fused morphinan structure observed in morphine. This ring closure was accomplished via a carbonium ion mechanism and effected by heating octabase in concentrated phosphoric acid, yielding the morphinan nucleus – see (14R)-levorphanol in the above figure. Levorphanol was a useful addition to the clinicians toolkit. It was the first analgesic to pair supra-morphine potency with substantially reductions in dependence liability. Levorphanol has been used for decades as a tolerance-attenuation agent in high-dose morphine patients (attributed to levorphanol’s `incomplete cross-tolerance’ with other opioid analgesics).
For a detailed review of Grewe Cyclization, see my reddit post: [https://www.reddit.com/AskChemistry/comments/p4z5sx/]
While the holy grail of opioid analgesics devoid of side-effects remained elusive, the outlook among opioid researchers was one of optimism.
The year 1952 saw the formal synthesis of morphine by Gates & Tschudi [https://doi.org/10.1021/ja01124a538]. Their achievement holds a distinguished position in the annals of organic chemistry, not just for being the first, but also for its impact on the field of natural product chemistry. This synthesis marked a pivotal moment in the field of total synthesis by showcasing the potential of the Diels-Alder reaction for the construction of complex structures. [https://doi.org/10.1021/ja01630a108] This powerful reaction, forming a cyclic structure from two simpler molecules, became a cornerstone in organic synthesis, employed in numerous subsequent syntheses of natural products and pharmaceuticals. A decade after Gates’ total synthesis, KW Bentley utilized [4+2] cycloaddition [https://doi.org/10.1016/j.ejmech.2020.112145] to systematically explore a series of Diels-Alder adducts of thebaine, i.e. 6,14-endoethenooripavines (“orvinols”). His discoveries in this class were so numerous, that they have been given their own class: the aptly named “Bentley Compounds.” [doi.org/10.1111/j.2042-7158.1964.tb07475.x] Bentley’s research resulted in several currently marketed drugs, including buprenorphine and dihydroetorphine (used primarily for opioid maintenance), and etorphine/diprenorphine (used in veterinary medicine). [https://doi.org/10.1016/B978-0-08-010659-5.50011-1] The Bentley series is noteworthy for high analgesic potency and their ability to substitute for opioid dependency with minimal side effects. Dihydroetorphine, upwards of 10,000 fold more potent than morphine, is used extensively in China as a maintenance medication and has an exemplary safety record. [https://doi.org/10.1111%2Fj.1527-3458.2002.tb00236.x]
Total synthesis provided researchers access to the synthetic dextro-antipodes of morphine and the inactive enantiomers of related 4,5-epoxymorphinans. [https://doi.org/10.1039/JR9540003052] Access to the unnatural (+)-morphine enantiomer helped researchers elucidate the complex stereochemistry of the 4,5-epoxymorphinan nucleus, which remains the most popular class of opioids in modern pharmacopeia. [https://doi.org/10.1021/acschemneuro.0c00262]
For a review of the history and chemistry of the morphinan superfamily, see my reddit post: [https://www.reddit.com/AskChemistry/comments/opnszl]
In 1954, AH Beckett and AF Casy published one of the most influential theories of the early opioid era: the Beckett-Casy Postulate [https://doi.org/10.1111/j.2042-7158.1954.tb11033.x]. The researchers analyzed the structure-activity relationships of morphine-like agents and proposed a set of structural, steric, and electronic requirements that were shared among the opioid ligands of the era. This became a proto “opioid pharmacophore,” that is, a rough template of the structural requirements for high activity at the proposed “Morphine Receptor.” The existence of a common site of action among morphine-like agents was supported by what was known at the time: stereotypical “narcotic cues” demonstrated by animals upon administration of both semi-synthetic and fully synthetic analgesics (Straub tail, anti-mydriasis, respiratory depression, antidiarrheal, cough suppression). While the quantitative potency varies widely (i.e. fentanyl vs codeine), the qualitative effects of analgesia and the side-effects following drug administration are consistent across natural and synthetic morphine-like agents. This formed the basis of the theory of a common site of action.

1954 Beckett-Casy Postulate - early Model of the mu Opioid Receptor
[https://i.imgur.com/epFABkr.jpg]
While the proposed pharmacophore held a more humble understanding than modern receptor theories, the Beckett-Casy Postulate (also known as the “Morphine Rule”) was impressive given that the “analog models” of the era were still crafted by hand and often molded out of papier mache. The hypothesis provided a convenient rule of thumb used by drug designers to quickly determine the likelihood of a compound having morphine-like activity. Compounds conforming to the rule were explored further, while structures that didn’t obey were made to sleep in the doghouse until they learned proper manners. Their theory combined the earlier SARs of morphine derivatives elucidated by NB Eddy during the 1930s with those of the newfangled fully synthetic analgesics, such as methadone and pethidine.

Core features essential for strong opioidergic activity (Beckett-Casy Postulate)
[https://i.imgur.com/hEjeDlg.jpg]
The following core structural features were determined to be essential for strong analgesic activity:

An aromatic ring system: provides a platform for π-π stacking interactions with amino acid residues at the μ-receptor active site.
The aromatic ring is attached to a quaternary carbon.
Ethylene bridge. The quaternary carbon is linked to a basic amine via an ethylene bridge, that is, a two carbon chain. This flexible linker allows for the conformational freedom necessary for optimal receptor binding.
Basic amine separated from the quaternary center by a two carbon spacer. The amine forms a critical salt bridge with the Asp149 residue in the human μ-receptor (Asp147 in the murine sequence). The amine requirement remains true for virtually every class of opioid. Exceptions to the rule emerged in the early 2000s when Prisinzano et al. discovered non-nitrogenous Salvinorin A analogs with high μOR affinity (i.e. herkinorin).

Beckett & Casy developed their theory by comparing the shared structural features of morphine analogs with those of early synthetic opioids, including levorphanol, pethidine and methadone.
The figure below shows the structural features common to morphine (pentacyclic 4,5-epoxymorphinan) and prototypes from three important synthetic opioid classes: levorphanol (tetracyclic morphinan), pethidine (4-phenylpiperidine) and methadone (3,3-diphenylpropylamine).

https://preview.redd.it/i54h2chp09nc1.jpg?width=3487&format=pjpg&auto=webp&s=9f0d22653daa1b44da5319307d22d973569d6d2b
[https://i.imgur.com/hE0eAp4.jpeg]
While the morphine rule offers a valuable framework for understanding opioid activity, there are exceptions and limitations. One of the first challenges to the universality of the Morphine Rule came from a key structural feature of the nitazenes: the diamine side chain.
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Enter Nitazene…

In 1957, researchers at CIBA (Hoffmann, Hunger, Kebrle, Rossi) found that a minimally substituted 2-benzylbenzimidazole, 1-(β-diethylaminoethyl)-2-benzylbenzimidazole, induced a Straub tail response in mice. The Straub tail reaction is a highly sensitive narcotic cue that is indicative of morphine-like mechanism of action. Despite lacking the potency-enhancing accouterments of etonitazene (5-nitro and p-ethoxybenzyl substituents), this homely-looking structure demonstrated analgesic activity on par with codeine (one-tenth morphine). This finding was of sufficient interest to spur elucidation of the structure-activity relationships of this novel series. And so the ugly duckling benzimidazole became the proteus of a dynasty.

https://preview.redd.it/7734j43s09nc1.jpg?width=2116&format=pjpg&auto=webp&s=8972f550794ffeb2662aa14d9347f20d2ff81a49
[https://i.imgur.com/RoTsrOO.jpg]
At the time of the discovery of the nitazenes, the diamine system was an uncommon structure within the opioids.
Most clinical opioids are monoamines. One nitrogen to rule them all. In the morphinan class, nitrogen functionalization outside of the 17-amine position (the iminoethane bridge) is rare. The addition of multiple nitrogens into the morphinan nucleus has a deleterious effect on activity.
At the same time as the discovery of the 2-benzylbenzimidazoles, researchers at American Cyanamid discovered a series of morphine-like diamine analgesics based on the N-(tert-aminoalkyl)-propionanilide scaffold, including phenampromide and diampromide (Pat # US2944081A; https://doi.org/10.1021/jo01061a049]. As with nitazenes, the design of the ampromide class was influenced by lessons learned from the 3,3-diphenylpropylamine series [https://doi.org/10.1002/jps.2600511131].

https://preview.redd.it/nwemwk5u09nc1.jpg?width=4375&format=pjpg&auto=webp&s=48c1e75b753a7a7d5956be815d9456a51a032200
[https://i.imgur.com/WEhPd6w.jpg]
The nitazenes were the first opioid analgesics to successfully incorporate the diamine into a highly active μ opioid pharmacophore. This dynamic amine system contributes to the high activity observed in the series. It consists of two basic moieties: the pyrrole-like nitrogen incorporated into the aromatic benzimidazole system and a tertiary amine in the side chain. This diamine function endows them with the ability to exhibit both acidic and basic character depending on the surrounding environment. This is known as amphoterism.
The benzimidazole ring system experiences a reduction in apparent basicity due to the electron-withdrawing nitro group substitution. In etonitazene, the benzimidazole amine has a pKa of 2.86. This translates to an estimated 22% of the molecule being protonated at physiological pH (7.4). Conversely, the side chain amine boasts a higher pKa of approximately 6.36.
Furthermore, the nitazenes are highly lipid soluble, indicating rapid absorption and a distribution that favors the lipid rich CNS. This is exemplified by their lipophilic Log P range of approx 4.1 to 5.1, highlighting a pronounced preference for nonpolar environments. The nitazenes have greater lipid solubility than fentanyl, which possesses a Log P of 4.05.
A comprehensive understanding of the acid-base properties and lipophilicity of these molecules is crucial for elucidating their pharmacological behavior. Their dual acidic and basic character allows for interactions in diverse environments, while their high lipophilicity facilitates penetration through biological membranes, contributing to their potent CNS-mediated effect.
NITAZENE CHEMISTRY
Of the variety of routes to benzimidazole derivatives, the most popular are modifications of the classical acid-catalyzed cyclocondensation of 1,2-phenylenediamine.derivs (first devised in the late 19th century). The Ladenburg-Phillips reaction is a versatile and efficient method for synthesizing benzimidazoles. It involves the condensation of an o-phenylenediamine with a carboxylic acid, ester, acid chloride, or anhydride, followed by cyclization. This reaction was first reported in the 1870s and has since been used to prepare a wide variety of benzimidazoles with different substitution patterns. Carbonyl equivalents such as carbonitriles, imino-ethers, or amidines can also be used. The reaction is catalyzed by HCl, polyphosphoric acid or boric acid. The Weidenhagen reaction can be adapted using Cu(II)-mediated oxidative cyclocondensation to prepare benzimidazoles.
Synthesis of Nitazenes:
[For a full review of nitazene synthetic methodology, see the full version of this article at Patreon.com/Oxycosmopolitan]
-------------------END OF PART I-----------------
To read the full version of this article, visit Patreon.com/Oxycosmopolitan

submitted by jtjdp to AskChemistry [link] [comments]

2024.02.19 23:12 Peaceb2all My clinic going from 90 to 50 mmes. I'm currently on 70.5. Which of these 3 meds is best in my case?

I've been on Methadone 15mg / 70.5 mmes for a while now. I found out my clinic is now forced to take us all down to 50 mmes in the next 60 days. My Dr said most of her patients are 50-60 except me. That I take methadone & it was 4 times stronger than other patients meds and had to figure out something for myself & my strange narcolepsy case. I had no idea Methadone was so strong honestly but I found out she's not a methadone fan saying it's hard to convert. I have another med I take (Modafinil) that's for my narcolepsy type 1 that decreases absorption of opioids so now the Dr is very determined to switch my meds up to help with this transition. I was given 3 med options and told to do my research Feb. Month too and return to give her my findings on what I think is best at tomorrow's appt. We are both leaning towards Dilaudid since it looks like modafinil doesn't cause as much of a decrease as the other two meds. I was also offered to switch to Fentynyl and buprenorphine as an option in place of Methadone 15g a day. They want patches or one pill a day (so can't sell I guess) but with my narcolepsy, I take a prescription called Xyrem that makes that impossible. The Xyrem nurse line said any med is fine in pill form no patches as expected. My pain Dr asked me to call to ask that but we knew the answer already. I'm guessing she'll let me do 50 mmes but which would you think would be the smoothest transition in my situation? Methadone has always helped prevent my pain and not made me loopy which I appreciate. I'm scared of any new drug and the fact that it will decrease with all 3 options is not a good feeling either. I'm only getting older and my pain has worsened in the past few years for sure. Any advice is appreciated. Also has anyone else in GA heard of this 50 mme limit drop from 90 mme or is it just my clinic? Thanks in advance friends.

submitted by Peaceb2all to PainManagement [link] [comments]

2024.02.08 20:49 sadallthetimeagain [1104] Listen To The Wind Blow

Fire's still burning. This is becoming a mini habit waking up and writing to start my day.
I had a session with one of my clients from Groups who rejoined me. Obviously not speaking to specifics, but they launched into the pattern I've been seeing with regard to the "professionals" I've been attempting to hire. In recovery, there's any point along the way you might think you've done "enough" or "deserve" to indulge here and there. It's all relapsing. It's all excuse-making. It's all distancing yourself from taking responsibility and building that larger context of consequences.
I just fielded an email from one of the potential hires who claimed to have sent me an email (you know, that thing we can immediately search our inboxes for) that she didn't. She put the idea out there that it's not "best practices" to be submitting for grants or asking for donations. She said we're at "the very beginning" and didn't have "enough on paper." Now, she's one person of 8 or so that I've got writing grants, fundraising, or who've had a look under the hood. None of them have said what she's said, and if they had questions regarding what stage we're in, they asked them, I sent along the info, or they told us how to procure and dress it up.
Financial statements, for example, given that I haven't paid myself or anyone else anything, exist, as a series of zeroes. I can find and .pdf that form if you need. "Data" on who we've helped when it's a handful of people over the last few years as we've worked full-time jobs is not going to be a robust sales tool. Do you want me to convert and tell you my caseload numbers at those jobs? That then sounds like we're cross-pollinating inappropriate things. If both the federal and state government say we're a nonprofit and have all the rights and responsibilities associated with that status, I'm hard pressed to entertain your distance-excuse-making email on its face.
I'm happy to report that I'm less discouraged, reactive, and defensive about that stuff with each instance, but it's so telling and often just exhausting enough to need pointing out. To my client's credit, as they decided to go into more detail regarding complaints at previous methadone clinics they utilized and the clientele they were interacting with, they were receptive when I pointed out the complaints were a 1 to 1 parallel. If someone comes to you and behaves poorly and then blithely says, "Well, you know, I'm an addict!" and it's like a cheeky sitcom throwaway excuse, we can all see pretty clearly why that doesn't hold water. If you say, "Well, you know, I was never as bad as xyz…and have been clean for 5 years!" You're doing the same thing.
So it goes if we're not talking addiction or crisis situations. If your impulse is, "Well, YOU did that and didn't do that" and not, "My perception is this or that and here's my contribution to resolve or fix it" you're not talking about anything. You're not helping. You're not being honest about where you're coming from. You're doing a dance. Don't lay my ignorance or start-up struggles at the feet of "best practices." If you presume to be the holder of those keys, unlock a piece of knowledge for me or I don't trust you actually know what you're talking about. It's a subtle and feeble-minded attempt to retain or grasp power you don't otherwise feel you have.
Again I can only contrast this behavior with my own life. When I have resources, power, options, or knowledge, I try to share it and make it freely available. I commit to the work it's going to take to do so. Even something as silly and easy as sharing music. I told my dad I'd populate his old phone with all of his music so he could break the bonds of shitty radio. It took me over a week, hours a day, to get it all downloaded and organized. I didn't say, "You know, just buy Spotify Premium. I anticipated you having shittier music tastes with less prolific bands, and this is taking sooooo loooong." The project doubled my overall music inventory, which I've been building for 20 years.
It's occurring to me that this is a pretty precise means of accounting for how burnout exists in this field. How emotionally and "spiritually" exhausting it can be to field an endless waterfall of people's excuses. It's almost worse when it's people who occupy a higher financial or credential class because you think to yourself that person must be cynically indulging. If you grew up dumb, broke, or just generally inculcated in a culture of "ratchet" shit, okay, that's less on you. If you have the time, money, or access to be carrying on like you're above the hoi polloi with regard to your field or experience and then you're anything less than gracious and patient and eager to contribute? Yeah, I can't entertain that level of selfish insecurity.
If we're ever to understand "class warfare," we have to grasp that Warren Buffet's son sent $500 million directly to Ukraine, and in contrast, Warren Buffett signed a pledge that he'd donate his money when he dies. I'm not going to pretend I have an intimate understanding of either man and their or efforts/reasoning or financial games. What I will suggest is that Warren Buffet has $500 million dollars, and the headline addressing intervention in a potentially world-destabilizing conflict wasn't about him or the European countries who contributed less.
There's people who are looking for the things they can best do to help. There will always be a fire, conflict, missing piece or reasonable and compelling situation that you might be drawn to influence. Then, there's the rest of people who are playing along, looking for every reason to escape any responsibility, and who wish to build bubbles and blame. Rich or poor. Ph.D. or GED. Young or old.
To the idea that anyone who proves themselves willing to engage in that behavior wishes to suggest to me what "best practices" are is laughable if it didn't hurt so much to think about and experience sometimes. Do they even know what they're doing? I can't believe so if I'm going to be bothered to "forgive" or confidently continue to navigate their input. I have to check my impulse to bargain with the universe in questions like, "Why can't they just tell me they don't want to work with me without all the extra judgment, condescension, and inevitable "good luck" sentiment?" The fact that they defaulted to that tells me everything I need to know. They weren't the one speaking. They don't have accountability built in. I don't want to work with them regardless of what they'd pretend to be contributing.
I've learned that all you need is specifics. You ask someone for specifics, their whole world blows up. Detailed understandings, accounting, or effort is the kryptonite for the excuses, defensiveness, and empty judgment. Ask a politician to define anything, you get the broad feel-good catch-all qualified language. Your average person is a shitty politician. They use the cliches afforded to them. They're not used to being punished or pressed. They will demand you go away, leave them alone, stop talking or engage in, "I know you are, but what am I." You'd think with my knowledge of this I'd be able to better weaponize or utilize it. I'm not blindly stepping into it when I double-down on the shitty email and illicit the obvious response, but I'm not helping myself by doubling-down ever. That's something to move on from and improve on.
I can't keep your ego fluffed about the work you haven't shown me. I can't play the pleasantry game when I've invested money and you're mostly committed to your feelings. I have to prevent my "desperation" at the idea of not finding anyone worthwhile translate into retaliatory or antagonistic pissing matches with those people. The more vigilant and less hopeful I can be that anyone I'm working with is actually worth a damn is how I'll get through these interactions. But that just sucks lol, right? It sucks that people suck, and are liars, and children, and might spend their whole life crashing into and throwing mud at the things you're building.

submitted by sadallthetimeagain to self [link] [comments]

2024.01.22 07:50 obblonge The Gospel Of Saint Patricia, Digest Edition

Your grandmother Joan and I at her kitchen table. Tommy Tiny Penis fumbles for something, gum perhaps, in his pocket, spilling out a baggie of cocaine. All of a sudden the beads of sweat on his brow and his anxiousness stand out even more. Joan and I both look at something on her wall - a plaque? Its round, maybe it wassa plate. A single word in black lettering across the diameter. It was positioned near the ceiling, along the kitchen wall, almost to the front room. Was it in German? We had been trading jokes with our beers. I observe that Priscilla and I would eventually be buying some of the same and heroin as well downtown, and that we're always happy to share if anybody wants some. This information seems to give the sweaty, uncomfortable man indigestion and grunting, he briskly stumbles to the restroom without adding to the jovial conversation. Later, I overhear Joan speaking to her three daughters, relating that " guys like me always beat guys like him - its specifically what they do. "
I've been using the Truecaller app to handle my calls and texts forra bout four years now. Its one of those programs that is endearing - buggy, subject to crashes. My favorite p2p Frostwire is also included in this category. Every time - and I do mean every single time - its updated something is noticeably fixed and something else is broken. I've been using p2p programs since the original Napster, have many fond memories of KaZaa, Morpheus, and Limewire. I won't stop using Frostwire until its abandoned and rendered obsolete. I'll even wear their logo t-shirts and paste their stickers on random car bumpers. Itsan exciting event when it updates, immediately searching through the screens and menus seeking the functionality that says it's still there but isn't. Some peoples watch sitcoms to pass their time I'm told.
Truecaller has the amusing habit of being a somewhat permanent record of text threads. Both conversationists can edit and delete their phone's text messages all they want. And the next time that text thread is opened they'll be downloaded in their original form from Truecaller's servers and right back in their original places in line. It's been referred to as the snitch app, as it has been used in court as evidence. The only way to delete SMS permanently is if the original speaker in the thread deletes the entire thread. Otherwise, it'll just keep resending at intervals. I've made use recently of E2PDF as well - it pairs nicely with Truecaller and tuna. Also, a courtroom approved program, it converts entire text threads to - you guessed it - PDF files. My continuing epic saga also updated at intervals on the Internet Archive - The Gospel of Saint Patricia - was recorded this way. I have a four-year long text thread on my 4th generation Moto G. I am not willing to entertain the notion that it may beea partial cause of my third-party calling app's intermittence. Assof tonight it's at 791 pages, growing organically and digitally every day.
Truecaller also hassan other habit that's entertaining - crowdsourcing its ID information, which pops up and replaces whatever corrections a user has made on their device every time it updates. It usually reverts back to whatever the user's labels were after a bit of usage. Usually. More than 72% of the time.
I have come to anticipate with smiling glee the new round of mysterious contacts that may be hiding behind that icon when MBs are being added.
(I also enjoy typing questions with lots of adjectives and detail into the Amazonian search engine. I'm sitting alone on someone else's barely too small futon onna Saturday night if anyone else is lonely...)
So. I have been texting and calling the phone numbers that my missing fiancé and best friend Patricia Ann Roberts implored me to contact her on, day or night, for years. A few months ago two were disconnected permanently after I managed to hear an extremely short, stressed, frightened few words from my love before the line went dead. Earlier that month I had discovered that Tommy Tiny Penis's line had been changed in its response - the blocking of my number removed and a robokiller screen installed. It immediately let me through, and I left eight voicemails. The next day that one cancelled of service as well. That's how I had named his number in my Truecaller contacts list - Tommy Tiny Penis. There issan other number I still am calling, a 313 landline, probably paid for by his company. Shortly after the cell lines were removed, I noticed briefly after an app update that the contact header had changed. No longer wassit Patty Landline, but Turkey Bone. Which only makes sense if one understands just how infantile and utterly void of useful knowledge Thomas Wayne Randle truly is. I imagine someone availed him, finally, to the fact that his number came up as Tommy Tiny Penis in Truecaller, er something. So in childish protest he renames the remaining number Turkey Bone, probably meaning to say Turkey Neck, which would at least almost make sense, if you were five and this was your first day of first grade. But no. Instead he invokes an image of two children at the folding legged card table on Thanksgiving, each holding a vaguely Y-shaped glossy and greasy object between them in their fingers. One sneezes and wipes its oozing nostrils, inadvertently snapping the thin, fragile wishbone.
Even the largest turkeys have bones at max the circumference offa dime. I will refrain from making a pun using the word " fowl " here. Sixty-three years old, and an embarrassment to the species.
Complete refusal to learn from mistakes or accidental successes. Step on the head of the one in front of you and sink it underwater as you ford the brook. Take and immediately destroy and irresponsibly dispose of. Replacing the sadistic pain and suffering caused to others in the place where happiness from accomplishment and empathy could have been fostered. A wannabe demon. Not real evil. Real evil is actually a threat onna mass scale. That can only occur with the stealth of hiding in plain sight while wearing a sandwich ad sign. Being able to shove packaged food into one's mouth does not impress the recruiters on either side of the moral conflict. If demons exist and eat souls, then Tommy and his lookalikes are still quite safe. Nothing to see here, just plaster garden gnomes.

Patty is the most beautiful and intelligent sister nextdoor. One of the only people I don't have to modify my choice of words in speech to so they may understand part of what I'm saying. Anyone who claims that this is anything but a horrendous crime punishable by jury trial is insulting her. Suggesting that she is as ugly, selfish, weak, and sadistic as they themselves are.
Today is my missing fiancé's fifty-sixth birthday.
She is ten years, six months, ten days, and one minute older than I.
We were both born to the same delivery room staff and certificate signing doctor, on the Air Force base in Abilene, TX.
Both of our mothers were having planned, scheduled births at full term, and we were both the first of the day.
Next to me and one on one in conversation she is completely confident, an amazing listener and orator, comprehending information spoken atta percentage I've never imagined could actually exist. Patient enough to maintain an attention no matter how demanding the thoughtful exercise. Knowledgeable about how a human body works and disciplined enough to maintain it. Imaginative, with the creative vision that the Makers of our species possess, to invent and produce the cutting edge of human wisdom and knowledge. That is the Artist's goal: to take the collected knowledge farther.
A truly breathtaking, amazing person. Who has spent the past eighteen years living with a talentless possessor of people; a follower who hates new ideas and actively tries to destroy them. A hollow shell with no created self, only robotic repetition of irrational and self-defeating tradition.
Patricia's voice in my earbuds is stereophonic and the slightly lower pitch offa woman who has been smoking for decades. Dark like tinted glass, as John McCrea says.
" I wassat a party and he was wearing a Hello! My name is... sticker that had Fugazi written onnit. I thought that was clever and he told me he had made it up. Then two days later I saw it written onna cassette case you pulled out of your leather's jacket pocket that had your joints innit!
Fugazi issa French word meaning " fake ", and also the moniker offa noisy Do It Yourself work ethic espousing band, I had informed her, Tommy Tiny Penis glaring at me and sniffling, oily perspiration sheening his brow. Like wow, man. Whata fucking born loser; a phrase truly only applicable to him. The conversation ensuing would reveal that he has also been taking the credit the past twenty years for writing at least four lines directly stolen from the long, spoken introduction to the track " Chemical Imbalance " by the SkateNigs, which, if you haven't heard, you should totes stop reading this and go listen to. I will not be offended. I recommend playing a full set of air drums in sync upon the inevitable second listen. The air ride cymbal you are not hitting with a drumstick I predict will give that arm an especially fine workout. Also up on his plagiaristic docket are the Butthole Surfers, one of the best bands to ever call San Antonio a home, however briefly. Both Gibby Hanes and Paul Leary have degrees from Trinity University, the most expensive per semester college in Bexar County and surrounding area, and home to 91.7 KRTU - jazz and other not popular music! I have contributed enough monetary donations to this station's pledge drives that my torso has been adorned with their logos often.
We should have known. There's that word " should " again. Tommy's taking credit for work not his own was not an isolated incident but an embedded, lifelong pattern. According to my fair lady love the man hasn't stopped bitching about how much fucking cooler I am than him since the day we met. Even to people who have never been to Texas nor met me nor ever will meet me I come up in his conversations. Twenty years later, give er take. Wow. I hadn't hadda thought involving him since the last time he was ineptly attempting to insult me. If my memory hadn't been inspired by Patty's voice his name and face would have disappeared forever in favor of more useful and fun data.
Like this industrial sewing machine service manual, I could only find an online copy of in German. All forty-five plus pages offit. That was way more entertaining than the pathetic coward narcissist loser Thomas Wayne Randle has ever been, even to itself.
He only buys porn with brand names like Penthouse and Hustler. Even though he has cohabitated, in separate rooms of course, with a goddess for eighteen years. Even though she hates it, and she pleads with him that its degrading he still insists on never getting a blowjob. Instead, he'll pretend, like he always does, that he's someone else, someone he thinks is cool, and insists on masturbating in her hair and on her face. Because sex to him, everything to him - and I speak of the pathetic coward narcissist loser Thomas Wayne Randle - issa desperate lie where he pretends, he has power and is somehow important, even though the " man " has never once had an original thought in his entire wasted existence. A waster of life and time. Twenty-eight years of Rogaine with Minoxodil, an ingredient found in laboratory rat urine. Both crying for and resenting his mumma, sexually stimulated by his memories of when she'd spank him.
Does Ira Glass still do This American Life?
She listens to NPR. We were both listening tooit when an interview with the Temptations was playing, that day at Pam's when we met yet again, and assi entered the building I laid a warm, wet hand upon her bare pelvic bone, she emitting an exciting " oooohhh ". Two days after she and Tommy Tiny Penis hooked up. He would later fuck Pam, at her then current boyfriend's house, who was present, on the couch in the living room, in the ass I hear, while I was locked outside with Paula by a mischievous Patty, and my then girlfriend Prissy was at work assa waitress at IHOP. She suggested our little new in-law holiday group each say something defining of themselves assan introduction to each other. I offered a quote I had recently heard from one of the Temptations on NPR. And her eyes continued to sparkle, hazel reflecting blue. Later, Tommy Tiny Penis attempted to earn brownie points with the girls' parents, Ken and Gloria - my next door neighbors, by taking the group out to dinner at Olive Garden, saying he knew the head chef working. So. Filing into our seats at the table, Patty launches a convincing argument to her father Ken, insisting that she sit in the chair he was about to plop down upon. Winning convincingly, she seats herself not next to Tommy, but directly in front and across from me. Smiling conspiratorially. She issin full information gathering mode. She remembers to this day what I ordered. Not the most expensive nor the least expensive menu items, as someone being treated has a tendency to do. But selections based on the nutrient content and healthiness of the meal. Dark leafy greens, lean protein, only a bit of oil instead of heavy calorie content dressing. Beers, multiple, selection based on how well the brew recipe paired taste-wise with the food ordered. While eating, her father attempted to pass the salt in my direction, after being handed it from Tommy, who had just immediately doused his large steak with the saline grains. I told him, apparently in my default radio announcer voice, that I never added seasoning to food until I had tasted it, my reasoning being that it was an insult to the person who had prepared it, in this case a paid professional. Preparing a meal issan artform, and assan artist I recognize the sweat and effort of the cook or chef. The food as placed with purpose upon a plate by another is a finished product - the last stage of producing art is the presentation to the audience. It is now up to the audience to appreciate the finished work. To apply seasoning without tasting issan insult by an uncultured, unaware, and unappreciative person. If modifications need be applied after tasting to match an individual's preferences, then so be it - it's their food. Unbeknownst to me, the actual person who had prepared the food, the actual head chef on duty who obviously Tommy did not know at all, was standing directly behind me when I said this. He announced his presence, and I was rewarded with a complimentary meal, including the beers. Three beers, most likely. Tommy would attempt over and over that week to catch me in acts of verbal plagiarism, or insult me, only to always be bested by my quick and always razor honed intellect. I had already been practicing my craft for more than a decade by that point. The coward even uttered a " faggot " in my direction as Prissy and I left, under his breath, only to have my sharp ears pick it up. So, spinning with overdramatic flair and facing the opponent as always, I pointed out why that isn't an insult, and indeed that I could never be insulted by him, adding a well-placed and accredited quotation by Tom Waits, in French. Much to the confusion of the attacker and the delight of Patricia. I make memories, man. I even blew Patty a kiss, 'til we meet again, which we would, of course.
To backtrack a bit, when mischievous Patty locked me outside with the youngest sister Paula, who I almost always sat next to on the school bus if I rode it, she never speaking to me, I had immediately postulated that since we were so rudely confined all night to the expansive backyard that she and I had a duty to retaliate in kind and consume every single beer. Which we did, triumphantly. Paula grew up to be a big girl, and a voracious consumer of alcohol. Taking me up on the challenge, she matched me beer for beer until they were all gone. 108 each, in five hours. That's one 12oz bottle of various brands every five minutes. And at no time, as mischievous Patty observed, mischievously, did I ever hit on Paula in any way. Come morning we were in someone's car listening to her CD collection. I inquiring about any I didn't recognize. I put in 10,000 Maniacs' Our Time In Eden album, informing her that I had all of their catalog on cassette, including the earliest collected demos. Much to her surprise. I would continue to confound that woman over the coming decades. Upon daybreak, Prissy returned and released us from the walled backyard that her younger sister and I would have escaped in someone's vehicle had we could in pursuit of more beer. She had to go get her daily dose of methadone from a clinic downtown. Patty cringed as she threw the van keys assa softball pitcher would, directly at my face, as was our custom. And I, wearing the leather jacket my grandmother had given me on my eighteenth birthday a decade earlier, caught them without thinking or flinching with a swooping downward arm movement. Prissy's dealers lived in the neighborhood behind the clinic. She was into heroin and cocaine, and I was into her. We went back to my house and I grabbed my guitar, always the disposable emergency income, and a Seymour Duncan JB pickup I had purchased new but not installed yet. I pawned those and used the extra cash for more cocaine than the planned amount, which I would divide into two nice-sized lines on the bathroom countertop for Patty and myself. Tommy, I was informed later, didn't want to share the baggie of coke and meth mixed he carried. With us or her. Ugh. How fucking uncool is that? I guess Pam got some. Eew. I smile now, writing this, remembering Patty playing footsies with me under the table at Olive Garden, and again at Christmas a year or so later under her grandmother's kitchen table, with her grandmother and aunts sitting around us. I customarily wear steel toed boots, ankle high. But that day at grandmother's I had some cushy old man sandals my aunt had given me on, leaving my feets open this time to return the playful gestures.
Tommy Tiny Penis sounds like a cameo antagonist inna children's cartoon. Maybe one oriented for a more adult audience, now that I read what I just wrote. Because obviously, Tommy Tiny Penis is notta suitable babysitter. I mean, ultimately pathetic and harmless because of his malformed pudenda and obvious lack if skills and knowledge concerning sex, but notta character that garners a kind of sympathy or even pity. Too arrogant, inept, and stupid to learn and grow from his experiences. Just a big, fat, butt of jokes for the protagonists to constantly spew victoriously. Entertainment forran audience with a sense of righteousness and morals that find continuously masturbating to lolita porn nauseating. Maybe midway through the episode a brief subplot could be introduced wherein his dear, dear mumma is explained through a brief but hilarious montage to be an additional inspiration for his stunted and fruitless attempts at child rape. Nevertheless, slobby Tommy Tiny Penis ends his villainous vignette as he began it, a corny throwaway uninspired hack piece filling midseason space while allowing a slower character story arc to peak in the season finale for Our Heroes.
Tommy Tiny Penis's cartoon theme song is performed by the band Extreme, guest soloist Yngwie Malmsteen. Oooh. And the gay singers from Boston that married each other. They even include lyrics about how he didn't support their right to wed, supporting further his miniscule antagonist role. And an endorsement from Pantene, for hair that rocks leopard print.

submitted by obblonge to story_telling [link] [comments]

2024.01.14 12:46 obblonge Ken Paxton's Corrupt Attorney General's Office

043: Margarita
CSLive, Customer Support Specialist
Chat window
You are No.1 in the queue. The estimated wait time is about 10 minute(s). Thank you for your patience.
Agent 043: Margarita has joined the chat.
043: Margarita
12:27
Thank you for contacting the Office of the Attorney General. May I have your name and the name of the other party to your case.
12:27
Michael Mackenzie, regarding Priscilla Bratton/Roberts
043: Margarita
12:28
May I have your OAG Case ID number or your date of birth to locate your case please?
12:29
0013512981 DOB 06/15/1978
043: Margarita
12:30
Thank you. To ensure that we have the current and correct information in our system, does your address, telephone number or email address need to be updated?
12:34
No. I replied to an email sent earlier this week and have not received any information in return, nor has Priscilla's name appeared on the Guadalupe county jail roster. I want to make sure that the following message has been seen: Priscilla Roberts/Bratton is not employed to my knowledge. She is most likely still paying at least $12 every morning for a 100ml+ dose of methadone. The last clinic she was supplying with daily payments was at San Pedro and Lorene, in the strip mall behind the former Maggie's restaurant. Previously her official daily supplier was on E. Commerce.
In over ten years Priscilla has not paid one penny of child support, although I was informed by mail that during the initial Covid outbreak a $1200 check or checks was/were confiscated and used to pay the state for its services in its/their entirety.
Where she is staying is in a converted commercial kitchen building in the backyard of her former parents house, now owned by her son Wesley who just turned 18. Her sister Pamela Daby resides there as well and is very much aware she is harboring a fugitive. Wesley's father Mark Handte is often at the residence, his large dark colored pickup truck parked on the road. It has a red vinyl decal adhered to the back window that reads " I'm reMARKable ". If I'm not mistaken he has recently been released from prison for a methamphetamine manufacturing charge and may be on parole. Priscilla is most likely still a daily user of methadone, heroin, cocaine, methamphetamine, and marijuana.
On October 30th my recently founded record label Obblonge Box released five of my albums - two music and three spoken word. I am known professionally as The Prophet Obblonge and have also received in the past year and a half two daily spotlights on DeviantArt for 114,100 and 431,300 reads respectively, my near 600 copyrighted works on the site drawing over 1.5 million views in the same amount of time. A few months ago I was published on the "Top 100 Writer's Digest" rated site SixSentences blog, which to date is at over 1,036,000 reads. I have produced 149 videos on my official YouTube artist channel, none of which are selfie films. These have been released on TikTok, Likee, LinkedIn, Facebook, Twitter, Instagram, Threads, the Internet Archive, and three separate Reddit groups. Three manuscripts are currently being typeset into the Amazon Kindle format for release on the platform, possibly before the end of the year. Another album or perhaps several EPs may drop in the same time period.
A majority of my artistic output is autobiographical in nature - the intended category being comedy, memoir, or religious parable. I have published continuously Priscilla's current exact whereabouts on every previously mentioned site since pressing charges years ago as well as many other disturbing acts involving the four sisters I moved next to when I was eight. I am now 45.
Priscilla's oldest sister Patricia asked me to marry her five years ago and I accepted. She was then cut off from all communication by the white supremacist narcissist abuser she was attempting to leave who began and still maintains a public and private gaslighting campaign documented using the guidelines of the National Domestic Abuse Hotline. Patty Ann Roberts, 55, was last seen in the company of Thomas Wayne Randle, 64, at 2164 Craigend Lane, Lake Orion, Michigan - a property he has been in trial with an Oakland County federal court for more than seven years over, owing at least $86,000 in taxes on and possibly being guilty of perjury. The Lake Orion police failed to bother to even make visual confirmation of Patricia's presence at the residence during two welfare checks. Free and paid online records searches have been obviously scrubbed and altered with an extreme amateur's skill, containing many white supremacist racist references. His home refinance paperwork, which removes Patty, claims he is the "Sheriff of Oakland County". An explanation of this can be found on the Southern Poverty Law Center's website.
Private investigators and personal injury/mental anguish attorneys have refused to take the case. All I had was $10,000 after selling my property.
Currently I have three crowdfunding fundraisers on different sites to pay for a ticket north and whatever tools are necessary to find and rescue my fiancé, if she is still alive.
If no one will do their job or even qualify as a human being, then I will.
I am begging you. For the fourth time.
Please do yours.
Please tell me that my father spent his entire working life as an Air Force Chaplain after leaving the seminary to safeguard the rights of the Good People of the Earth, not hypocrites and psychopaths.
043: Margarita
12:34
Thank you. Allow me a few minutes to assess your case please.
It's been a while since your last response. Please respond within the next few minutes or this chat will be ended.
12:36
Okay
043: Margarita
12:37
I am still assessing your case. I will be right with you.
It's been a while since your last response. Please respond within the next few minutes or this chat will be ended.
12:39
This is to appease the message that wants to kick me off
043: Margarita
12:39
Would you happen to know if Ms. Roberts is working or if she has a source of income?
12:42
That is exactly what the email I was responding to said. Priscilla Bratton/Roberts has no intention of working for a paycheck for the rest of her life. She is a former high dollar adult entertainer and is well practiced in the manipulation of others to provide her with the only thing she cares remotely for: heroin.
043: Margarita
12:43
We issued a delinquency letter to her on 12/14/23. We do need to allow 30 days for her to respond.
12:51
I have been pressing charges now for years. How many such letters have been mailed before? It is a crime to knowingly harbor a fugitive that owes at least over $60,000, probably more, correct? What about all of the other information I just provided? Not one penny in over a decade. Her older sister has quite possibly been murdered while her jealous younger sister engages in a public and private documented gaslighting campaign to cover it up. I am communicating with a live operator representing the Texas State Attorney General's Office. At a certain point, after years of reprinting dialogues like this one, when does a citizen accept that no one will do anything, even if it is their job, and be forced to act alone?
043: Margarita
12:51
You do have the option to consult with a private attorney if you believe that the processes available to the Attorney General's Office are not working for your case.
043: Margarita
12:53
Please keep in mind that the Attorney General's Office represents the interest of the State of Texas. It does not represent any of the parties on the case.
12:56
Would I be allowed the tax dollars not used by the official, actual prosecuting arm of the people? Why would I expect a civil lawsuit to be used in an obvious criminal matter? The law has been broken and their is ample evidence. A person is missing and suspicious parties have court admissable evidence posted publicly for the entire world to examine. What more constitutes a better usage of these offices?
043: Margarita
12:57
Those are legal questions that I am not authorized to answer. You may need to consult with a private attorney. Please allow 30 days for Ms. Roberts to respond to the delinquency letter that was sent to her. That is the process that we need to take at this time.
12:57
She owes the State money. Those letters have been sent before, multiple times.
12:58
I even have copies you sent me as well
043: Margarita
12:59
Mr. Mackenzie, this is the information that I can provide at this time. With all do respect, I am going to leave the chat as the additional questions you have I am not able to answer. Have a nice day.
Indeed. 043: Margarita has ended a communication by refusing to answer pertinent questions, telling me that a private attorney should be consulted. Since this these are proven, documented criminal matters and this is the correct office that prosecutes such, she is overtly telling the taxpayer that this office is refusing to perform its duties and should be sued for inexcusable incompetence as well as damages incurred to all abandoned parties involved. An absolute disgrace. Blatant corruption at a State level perpetrated by psychopaths who care nothing for human life - only money that can be wasted openly in contempt of the Commonwealth.

submitted by obblonge to lakeorionhippies [link] [comments]

2024.01.14 12:45 obblonge Ken Paxton's Corrupt Attorney General's Office

submitted by obblonge to u/obblonge [link] [comments]

2023.08.03 00:41 syfyb__ch Involvement of spinal NMDA receptors in LC pain: An anecdote from a LCer

The paper below shows an unusual mechanism in which innocuous sensations (touch, tickle, prick, heat, etc) can be turned into hypersensitive pain. Imagine, whether it be constant exercise, inflammation, histamine (a pain modulator), etc. upregulating these glutamate NMDA receptors! PAIN. If you look up the receptor Pharm of NMDA, the direct agonist is glutamate, while glycine/D-serine and ammonia are positive modulators that potentiate effects.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2043493/
Anyway....what does this have to do with my anecdote? Well, I have a bunch of mutated neurotransmitter genes so I'm super sensitive to a lot of supplements, as I've learned the painful way after COVID infections. Anyway, as many of you know, nerve/muscle/rib/etc pain is a chronic issue of PEM. We commonly think of it as 'hypersensitization'. Something hypersensitized our nervous system.
Well, being the guinea pig that I am. I was recently testing magnesium supplements due to a low/normal blood potassium reading. K+ and Mg+ tend to correlate; Mg+ wasting causes K+ excretion.
Anyway, Magnesium malate works fine, no issues.
Magnesium glycinate....fook me! Took it in the evening, only 50mg elemental Mg, and I couldn't sleep. Pain, felt like my spine and ribs were squeezing me. I also noted muscle tightness in the abdomen, and an anxious/sob sensation. I got the usual shooting/stabbing neuralgias in the other usual places.
I've also noted that I can no longer tolerate collagen (lots of glycine). Less so theanine (somewhat relaxing but it stimulates glutamate/glutamine/GABA. So it elevates glutamate/NMDA). In fact, skipping the intermediates and using GABA directly works better (no pain).
This will not apply to many of you...glycine seems to be very relaxing. But it may be that your genes or neuro sensitization is different, or not part of your LC.
Would be cool to see if any of you here used an NMDA receptor antagonist or modulator and found some success.
Here are some antagonists/blockers of NMDA receptors:
Kynurenic acid -- tryptophan metabolite and S. cerevisae (beer yeast) metabolite
Syrian Rue, Cat's Claw, Berberine, Ginko, etc - herbals
Guaifensin, Dextromethorphan -- cough suppressants
Mg/Zn/Se/B12/ALA/NAC -- help regulate/convert glutamate or block receptor
Progesterone - indirect, actually pregnenolone is the blocker, which is a metabolite of progesterone
Huperzine A
Taurine - indirect via GABA
Amantadine - antiviral used for neurodegen diseases
Agmatine - naturally produced by gut microbes and in fermented foods
Lithium
Dantrolene/orphenadrine - muscle relaxers
Methadone/dextropropoxyphene - opiates; interesting as LDN is an opioid receptor antagonist and will, over time, upregulate opioid receptors
Ketamine
Riluzole - ALS drug
Memantine
Ibogaine

Quick note: salicylates (aspirin and various foods) or Vitamin C can increase NMDA receptors (upregulate) or increase functioning. In combination, the effect is even greater. I know some are hypersensitive to various foods now...and yes the gut has neurotransmitters and nerves and they go to your spine and brain (the spinal afferents more relevant here, probably).

submitted by syfyb__ch to LongCovid [link] [comments]

2023.04.01 01:34 Ok-Gas-6786 My experience having a flipphone for the past three months

been seeing way too much incel shit lately so I want to post this before all of the reasonable people stop browsing the subreddit. I got my flipphone in december of 2022 and this has been my personal experience living with one since then. As a disclaimer I do have an iPad that i use to do work and browse r*ddit etc so I'm not really off the internet but i still think that my experience might interest some of you. I sincerely reccommend getting a flipphone to anyone who has been considering it.
first off, a flipphone will not fix your problems. an addictive or generally poor relationship with technology/the internet is the fault of the user and their underlying psychological problem. however i have found having a flipphone rather than a smartphone to be very helpful in overcoming problems such as a lack of self control in terms of my constant consumption of media (constant social media use, constant music listening etc.) Also helpful in terms of lowering screen time generally, alleviating feelings of dissociation/not feeling like the world is real, and reducing my egotism/sense of the world revolving around me. I think that a lot of these problems were aggravated by excessive screen time with my smartphone.
not sure if this is a cope or a real concern but a lot of you cite lack of acess to music streaming as a downside of a flip phone. first of all, you really don't need acess to a massive music library at all times and you will find that music sounds a lot better when you've been yearning to hear it for a whole day. also, a lot of people don't actually listen to music as a form of art and just use it to block out their thoughts but that is a whole other post. REGARDLESS my phone does have a function where I can upload music files to it using anything with a usb port. just find the shit you want on youtube and use a website that lets you convert the video to an mp3 then drag and drop baby(i grew up in the age of streaming so i don't know shit about torrenting or whatever. if i can do it you can too.)
yes, i have no acess to navigation or maps. I challenge you all to just develop spatial awareness. if you're going someplace that you've never been before, look up directions for where you need to go and write them down on a piece of paper beforehand. as a last resort you can stop and ask someone for directions. its not hard. if you want to find gas or a place to eat you can just walk or drive until you find someplace. if i lived in a rural area where there was a real concern of getting lost and dying this wouldn't be so easy for me to write but I live in a major city and as long as you do too there shouldn't be a problem. if you're going someplace rural you can switch the sim card from your flipphone to your old smartphone for a day. Also, my flipphone has the capability to set up a hotspot which i can use my ipad with but I rarely do this because it sort of defeats the whole idea.
one concern that I had before I got my flipphone/off social media was that it would socially isolate me because so much goes on on the internet nowadays(at least in my generation). This was not the case for me as I was saved by my friends who would alert me to things that were being posted about online. so the only instance in which I would not recommend for someone to get a flipphone is if they have NO FRIENDS irl bc I really would not know about community events without my friends. Besides this I think that having a flipphone actually helped me to feel more connected to people and to have less social anxiety. I remember I always used to revert to going on my phone and ignoring the real world when I was uncomfortable but since I can't do that anymore i have realized that really there is nothing to be uncomfortable about.
Here are some journal entries I made about my mental state with the flipphone:
Tuesday January 17: One month
Everything is a thousand times less exhausting. I mean, just stuff like walking back from class and taking out the trash is easier. The easy metaphor of “carrying the weight of the world in one’s pocket” tempts me but I think that things that I have to do seem easier now not because of my condition in the moment of action but because of the contrast between the moment of action and how I spend my leisure time. Before getting rid of my smart phone, as soon as I gained a moment of rest from some sort of effort-requiring endeavor, I would immediately immerse myself in an alternate reality: social media, youtube, any type of moving entertaining soul sucking thought blocker. Say, getting back from class on an average day, I’d just lay in my bed for thirty minutes to an hour and probably go on social media. I’d think, I need this, I’m tired. Now, since I don’t have access to that type of thing at immediate hand, I remain in the ambivalent twilight between the dreadful real world of task and accountability and the comforting, bright, LED tones of escapism. I’m coming to realize that it was never a twilight after all - now, there is just my day, my real world, my good and bad, all in the light, and an insignificant place that I used to spend my time that no longer appeals to me. I was able to realize this only once I forced myself to be with only my flip phone outside of my dorm. Now, I get back from class and instead of anticipating the mindnumbing barrage of bullshit that I used to put into my mind, I want to read a book or write or play guitar or even do those very effort-requiring things that I had been using alternate realities to avoid. This new condition would have sounded quite impossible to the me of even just two or three months ago, but it is real.
Saturday Feb 4th:
I have gotten a lot better at guitar. I’ve been playing for about three years and I had sort of plateaued at a certain skill level but over the past month I’ve actually gotten better. I can read now with much more focus than I used to. I see things with my eyes shut. I recall memories that I thought had been forgotten. I read through long sections of writing without wondering how far I have gone and how far I have yet to go.
When I walk to class or stand about on campus, I look at the other students. It’s hard to find someone who doesn’t have earbuds in or isn’t looking at their phone. How are they not miserable and in a dissociated state? I don’t know anyone else who puts as much effort into avoiding dissociation by consumption as I do. Are they all just miserable and don’t care to change? Or do they somehow manage to go about their lives in such a careless manner while still feeling and thinking as I only wish that I could? I am weak in the sense that I cannot stand much stimulation. I died because I was overwhelmed. Even considering that other people have a higher tolerance for stimulation than I do, it still seems to me that they are drowning themselves.
I don't really know why I developed an averse relationship with technology, maybe it's just a natural human instinct of maybe it's my complexes speaking. I spent too much time in wierd places on the internet in my formative years and as a result I think its damaging in a pyschological sense. I think tons of people are digging around on the internet for something that's not there. The comfort of the online collective unconcious is about as much of a replacement for the things that you're lacking in real life as methadone is for heroin. I used to find myself caring intensely about things that had nothing to do with me, clinging on to parasocial emotional warmth. It rips you from the folds of reality into some sick hellscape where you could seriously spend a lifetime rotting away. At the same time as the world is so intensely individualistic, constant connection via technology has appeared to balance it out but its in a very sick way. I just feel like I'm much more of my own person now.
Thank you for reading this if you got to the end. This could be all be a total delusion but I'm still taking the chance in writing this out as it might help some of you. If you've had a similar experience I'd like to talk about it.

submitted by Ok-Gas-6786 to redscarepod [link] [comments]

2023.03.01 18:29 Several-Town4142 Please help me

So stressed out please help me it’s been over 10 days since I got a swab test 4am two sundays back and still haven’t heard from them they’re taking my upt hours I’m down 6 hours left :( I smoke weed and I am on methadone 15 mg I’m detoxing off that ain’t the problem but got prove and it’s very low I had a month to go and I have prescriptions and even will quit to stay at my job. No one called me no lab no job I had great attendance my rates everything I was about to convert I had one bad night mother of four little ones I work nights I was so sleepy couldn’t keep my eyes open it was my bday week went to ac so I didn’t get much sleep that week I got home I hadda work after 6 months working great I had one night and got drug test they hired me with the same swab result im disappointed and worried why haven’t they called me??! Is there any email or way I can reach someone it said o my a and z I got work and I can pick shifts up but they told me to wait on an email what should I do I wanna know by tonight I’m post to start work tomorrow or need know if I got a job mom of four kids just brought a house in nj I can’t afford to be jobless we just moved here i didn’t cause no harm or didn’t anything not bad for safety I don’t understand why they’re taking my upt I got 6 Hrs then from there I’m fired I bet. Anyone has a way I can email someone and my test would be clean from weed. Nj u can work here and I have my medical card wasn’t even high so upset n scared

submitted by Several-Town4142 to AmazonFC [link] [comments]

2023.01.28 21:52 iofdastorm How does everyone convert methadone dose to other opioids?

submitted by iofdastorm to AddictionMedicine [link] [comments]

2022.10.29 10:59 That1TrainsGuy The Great TS Classic Humble Bundle Review Roundup - 2022, Extra Bourbon Edition

[Warning: Corase language ahead.]
Alright, it is time once again. The Humble Bundle has a Train Simulator bundle out, and today we're going to talk about all the DLC which is available to you in each of the tiers, since I own nearly all of the DLC for this simulator.
I will be moving from tier to tier, adding things which are in each, and speaking about them individually. I will also be giving a brief review of Train Simulator Classic and the routes included with this year's edition, just so you know if that, in and of itself, is worth picking up. Note, I will not be providing a "rivet-counter" review of anything, wherein I tell you if, for example, horns and sounds and the likes are off. This is focused more on basic functionality, bang for your buck, and how good it "feels" in a simulation sense. I will also be making note of whether or not any of the trains included come with scenarios for the routes included. This is important because it means you won't have to make your own.
Regarding the rivet-counting...I mean, after all, this is DTG-produced material. The sounds are probably not very accurate and the physics are all over the place by default. If that bothers you, then this pack is definitely not for you.
Here goes.
Tier 1:

1. Train Simulator Classic (RailWorks/Train Simulator 2022):
The base edition comes with three routes. I will be surmising them here in brief because, frankly, they're all painfully mediocre. There is nothing outstanding about any of them, nor are they particularly worth the full price. But in a bundle like this? They're really worth the money.
a) Tehachapi Pass: I am the first to confess that I am no great fan of the average US Class I railroad. Anyone who knows me can attest to this. Therefore, I cannot speak to how good of a representation this is of actual US Class I operations, nor how accurate what is depicted actually is. Some of the trains sound weak, and the engines sound underpowered. The signallisation is okay, and the scenarios are bug-free, as far as I can tell.
b) WCML South: London - Birmingham New Street: This route received a LOT of flak when it was first released because of its propensity to exhibit really, really, really poor framerates. This comes down to DTG's asinine insistence on rendering a large amount of distant scenery, and their overuse of 3D trees in places where no living human would ever notice them. However, as it stands, it runs...relatively well. The rolling stock is particularly good, albeit repeated from previous packs and iterations, with some notable improvements. Especially salient is the Pendolino, whose inclusion I welcome. Its sounds are all off and everything, but it is quite lovely to drive. On the whole, very good route.
c) Bahnstrecke Leipzig - Dresden: This one I have the least positive to say about. I drive UK almost exclusively, but when I drive German, I prefer to drive without a HUD, relying on trackside speed limit markers because that way, my attention is not divided between the PZB and the HUD. However, on this route, I found notable errors in both the PZB placement and the placement of speed markers. Advance speed limit markers are absent, and several of the high-gain 500 Hertz magnets are also missing, but only visually. This is a BIG problem as you may end up running a red by accident. The rolling stock, however, is the worst offender. Everything on this route is ancient German stuff. Back from the Cologne to Koblenz days. We are talking Dostos that have interiors made of greyness and putty, and the classic BR 101 with less functionality with a potato. However, speaking from extensive experience, the landscape is nicely modelled and this is definitely Dresden. I would not recommend this route as a stand-alone at all, though, and only bought it as such because, well...let's say that there's a certain someone in Dresden I like to be reminded of a lot. Anyway, moving on.

2. BR Class 170 Turbostar DMU
Oh boy, back at it again with the trash. This is a Thomson Interactive classic locomotive, and you can get it by buying the old Glasgow to Edinburgh route. It contains a handful of scenarios for some other classic routes, like the old York ECML and the Paddington to Oxford route. It has no cab lights, and extremely minimal functionality. It sounds like absolute wank and drives even worse. It is simply...dated. Horrendously dated. When it came out over a decade ago, it was more than serviceable, but the world has moved on. None of the routes included feature scenarios for it, nor is it driven on any of the routes included. However, as a bit of a silver lining, this thing is the AK-47 of AI traffic for a lot of scenario creators, so you'll see it a lot in workshop-related content. Just...don't bother driving it.

3. Thompson Class B1 Loco
Oh shovelware, my beloved. This was in the last Humble Bundle for TS as well. I am fairly sure that, when the average simulator fan dies, a code for one of these will be automatically deposited into their casket. This thing is around 12 years old at this point. It is so old, you could teach someone younger than it how to drive it, not least of all because it is as simple as mud. It comes with scenarios for the Woodhead Route, which is not included in this pack. It is incredibly simple, has very poor physics, and is generally extremely dated. Would not buy for 30 cents. Mostly because I wouldn't need to. It would fucking apparate into my postal code.

4. DB BR 648
This is a mistifying inclusion into this pack. This is a not-so-old DMU unit for the Hamburg to Lubeck line, that has a few notable errors. It sounds rather poor, and it generally performs in a sub-par way. But it isn't atrocious. It is most certainly driveable. I even saw one or two in Dresden, where they serve some local, non-electrified branchlines. However, this one comes with scenarios for the (quite old) Hamburg to Luebeck route, so unless you intend to quick-drive it, you won't see a lot of use out of it. Still, not a bad locomotive.

5. Grand Central Class 180 Adelante DMU
My God, what a strange inclusion. This one is properly weird. I love it, personally, and I am glad to see it, but it is incredibly weird. This is part of a very limited set of extremely luxurious diesel multiple units that are run on the UK's East Coast Main Lines. They're basically rolling hotels. This one comes with scenarios for the (superb, essential, superlatively good) London to Peterborough route. For the price, it's a steal. Sadly, no scenarios included for anything in this pack, but if you run it on the WCML South, it isn't entirely out of place, especially if you just quick-drive it from end to end. These are express trains after all.

6. Peninsula Corridor: San Francisco - Gilroy
Oh fuck me running, not this. Don't do this to me, DTG. Please. I beg of you. I cry and pee as I beg. This route is infuriatingly good. It's brilliant. My God, the scenery is fucking gorgeous. And I feel myself wanting to do a double somersault up my own anus because the rolling stock for this route is a war crime. The F40s included come with the horrible, awful advanced braking script which, in this instance, is *completely and utterly shagged.* The brakes will loop the release sound as you pull them back past their limit until your headphones explode. And they never release fully. It is such a buggy mess for what is otherwise a tremendous route. My God.
Listen to me. Carefully, okay? Searchlight Simulations sells a sound enhancement for these babies for like 5 American smackaroonies. Get yourself that and TS-Tools. Convert the scenarios to standard, edit them in the in-game editor to include the Searchlight asset pack, and convert them back to the actual career mode. And you'll fix the brakes.
And you will get an amazing, ball-shatteringly good route. Fuck. So good. How did they fuck up the rolling stock so badly?
Okay, another shot of bourbon, and we move onto the next tier...

Tier 2:

7. Mittenwaldbahn
Hey, you! Yes, you! ~~Stand still, laddie!~~ No, but seriously, do you enjoy German railroads? Do you like the hustle and bustle of them, the speed, and the intense signallisation, or the winding mountain paths at rather fast speeds? Well, if so, forget all about it because this route has none of it. Yep, the Mittenwaldbahn lives up to its literal name - this is a bit of track in the middle of the sodding woods. It is a single line. That's it. There's some really nice buildings and very lush trees and a gorgeous valley on one side. You'll be driving a Talent 2 so you'll have all the peripheral vision of a horse with blinders and a methadone habit. Oh, unless you do the one cargo scenario that comes with it and drive the world's most wheel-slippy EuroRunner! Oh, and to make matters even more fun - the scenarios are a straight line, often seeing you shuttle between stops, and the Innsbruck main station has a...problem.
Or, well, the BR 340 has a problem. See, her LODs are fucked. Which, if you do not know what those are, they're the geometric simplifications the sim implements at distance so that faraway trains - or numerous trains - do not launch your GPU into low-Earth orbit. In the case of the DTG BR 340...there are no LODs! None! So the train is rendered at ball-slapping ultra-HD at any distance, even if there are 40 of the fucking things in a station. There are several scenarios at the Innsbruck Hbf which see framerates in the literal single digits as a result.
No/10

8. DB BR 605 ICE TD
Another perplexingly decent addition, this is a surprisingly good rendition of an odd duck - a diesel multiple unit version of the high-speed ICE train. On Steam, this thing retails for 17 euros instead of the usual 13, and I am not sure why. And, Habemus Papam, it comes with scenarios for a route included within this very pack! My God, dare we dream? Yes, it comes with THREE scenarios for the Hamburg to Hanover route! And it is quite well done. The sounds, of course, are arse, and the physics, of course, are arse. The visuals are...not great, but hey, they're a step up from the usual ICE 3's which look like dog vomit with luminescent dials. It is very decent and actually has some expanded functionality, like real tilting! I would lukewarmly recommend this on a Steam sale and thus definitely recommend it here.

9. Amtrak E8
Ugh. Yeah it's...it's not great. Visually? Fucking superb. Great looking thing. Very googie. Very 1950s. It even has two scenario packs out on the marketplace to expand the amount of places you can use this thing, as it served the US everywhere. However, the train itself? It sounds poor. The horn especially sounds poor, and you know that means business coming from someone who gives as much of a fuck about that as I do. The physics are also...really not great. Do you mean to tell me that a l950s era diesel train hauling some wide-ass early Amfleet cars could stop that quickly? No way. Scenarios are for the (incredibly boring but competent) Miami route. I will say this about said route: It is a bit like driving through a combination of a Lowe's warehouse, a vaporwave music video without the colours, and some sort of slum consisting entirely of semi-detached condos. Pink flamingo depression town, ahoy. This one's definitely a pass from me, and it belongs on NONE of the routes included in this pack what so ever.
And finally, as my bottle doth run dry...

Tier 3:

10. Chatham Main Line - London-Gillingham Route
Buy it.
Fuck you, buy it. It's the best route in Train Simulator. In fact, it's so good, it's two routes! Oh my GOD this is good. This is the best DLC for Train Simulator Classic DTG have ever put out. I shit you not. Holy shit, listen to me. The Gillingham Main Line? So lush. So green. Fucking hell, mate, there's boats. Boats! They sway with the wind! And the stock is scrumptious. The signallisation is spot on. You can drive the entire thing from end to end with no HUD perfectly. There's metric fathoms of DLC for this route. Buy the whole fucking pack just for this route. If I could, I'd crush this DLC up and snort it. This isn't sarcasm. This isn't an exaggeration. If you love UK trains, you NEED this. Do you feel me here? Are you picking up what I am laying down here?
Buy. It. Now.

11. DB BR 407 New ICE 3
This one is a pro range German engine, and the most advanced ICE which we currently have in sim. I, personally, really quite enjoy it, despite some notable shortcomings like international voltage changes. The latter is not that important, however, as the total number of Dutch, French, and Belgian routes which do not require you to own almost all of Dovetail's catalogue is tiny. The safety systems are simulated well, the sounds are quite okay, and it is probably the best modern ICE we have. Not, mind you, that it has much competition, because the other ICE 3 is - as I said before - comparable to a war crime. I think you get it with the Hamburg to Hannover route on this. You get it with most German electrified routes longer than a postage stamp. But anyway, this is a good one. Scenarios for the Frankfurt High Speed route, which is not included. It does, however, fit nicely onto the Dresden route, if you don't mind quick driving it.

12. Hudson Line: New York - Croton-Harmon Route
Oh boy, this one's another mixed bag. On the one hand, more New York stuff is always welcome, and I won't lie, the scenery is nice. It is also buggy. In winter, the platforms are untextured. Don't fucking ask me what galaxy brain at DTG forgot to put that in, but they did. Other than that, the rolling stock is...okay. The M2s are nice, and the P42DC is older than the Bible and has about as much train simulation functionality. Both of them support in-cab signalling, which is very important on this route, but...
Okay, brief aside about the way that ATC and ASCES work in TS Classic and why their implementation fucking blows ass. And this will be relevant to both this review, and the review of the Washingnton to Baltimore track. You ready, kids? Here goes:
ATC and and ASCES work as follows: you see the signal aspects in cab, and two values, track speed and signal speed. You generally always follow the lower of those two speeds, which is generally always signal speed. In the event of a speed change, be it signal or track, you get an *advance notice* during which you have to press the alerter, push the brakes to suppression, and slow down to the new limit within...I think it was 30 seconds? Not doing so gets you emergency braked.
In the quaint little universe DTG inhabits, where the scoring systems are designed by fucking lunatics, the area where you're first told of the speed change is where the route actually changes the speed. This is bad because, if you play without a HUD, driving solely through ATC and ASCES, you are going to be speeding literally all fucking day, every single fucking time. You may also notice that ATC and ASCES equipped rail and routes have NO TRACKSIDE SIGNS FOR SPEED. Care to guess why that is? So yeah, ATC and ASCES are hopelessly, comically broken in the bizzaroworld that DTG inhabits. And the same is true both of this and of...

13. NEC: Washington DEC - Baltimore
...this. I wanna preface this by saying I love the NEC. The classic NEC, from Philadelphia to New York, retails for basically dick these days and is really very good still. Nice, cozy, AMERICAN high speed. Never thought you'd hear it, eh? And we have THREE NEC's to choose from. New York to New Haven, New York to Philly, and Washington to Baltimore. The astute geographers among you, however, may notice that the Baltimore route is a bit...short? I mean, yeah, it is. Very. This is a snippet of the NEC that was included with the original MSFS back in the day. Fortunately, it comes with a good bit of rolling stock, which - whilst being a mixed bag - is nice and diverse. Some of the local services are unbranded, presumably due to issues with the branding itself. The physics and sounds are nice, the ACS-64 is okay (even if the speedo is fucking microscopic), and there's a decent few scenarios.
The most glaring issue is in the Acela Express, which is a shame, because most of you may buy this route solely for it. The cruise control keymappers are broken, so you can't set them using Y and C, and trying to do so manually by clicking and dragging the lever is a bit like trying to have sex with a person on a mechanical bull if your penis were attached to a carnival claw machine. Also, the ATC has a problem, wherein - if you pass around 200 miles per hour - it will begin to beep incessantly. You won't on this route, but on the classic NEC, you will, and the only way to defeat this bug is to hold the alerter down. Last but not least, it still uses destinations from the New York to New Haven route, so everything on this route is missing from your destination blinds. Fun! I'd say this is a mixed meh from me.

14. BR Regional Railways Class 101 DMU
Why the fuck is this in the final tier? I don't get it. This is a very, very, very old DMU. In fact, it is one of the oldest pieces of stock in Train Simulator. It is a gear-driven DMU, which does make it fun to drive, if tricky, but visually, it is extremely dated. The back of the cab has a problem with the mipmaps which causes sunlight to piss through the back of it whenever the Sun is behind you. The horn is laughable and the sounds are very meh, and in general, it feels...mediocre. Which is understandable, becuase it was great when it first came out, back in the days you could still buy a PS2 at MediaMarkt. It comes with scenarios for the Liverpool to Manchester route, which is not included, but even then, it only comes with two. Luckily, this oldd thing is at home on every railway in the UK, so if you want to quick-drive something nice and gear-driven, go for it. It is also very often used by workshop designers. Just...don't expect it to blow your gonads out your bum.

15. LNER Peppercorn Class A2 "Blue Peter"
Finally, some good fucking ~~food~~ steam trains. This is a standard edition steam locomotive, the very famous A2, of the same lineage as the later A4 Flying Scotsman. These are nice, chunky, powerful locomotives. The cab is nice, and it has fully featured wheel slip, and proper water injection and everything. The whistle is not quite right, I think, but I frankly couldn't give a shit. It even has AWS! It comes with three scenarios for the London to Peterborough route (which you need to own, I know where you live, I will write the steam gift code on your forehead in sharpie if you don't buy it.) Very worth it even for quick drive's sake.

Amtrak P42 DC 'Empire Builder'

SHOVERLWARE, MY BELOVED. Before DTG shut down their webstore, this thing was on a permanent 4 euro sale. It comes with scenarios for the old Marias Pass route, and it is the same P42DC that is included in every pack which includes one. This is actually patient zero, the original version. Nothing has chnaged since. Even the 2D sunglasses resting on the brakeman's desk are the same. Pants sounds, pants physics, generally pants, and also does not fit on any route included within this pack. Scenarios for Marias Pass, which is not included.

17. Semmeringbahn
Oh this is an oldie. A blast from the past. This was DTG's first Austrian route, way back in the day. It is very pretty, and very short, and sadly, sort of one note. Double tracks with up and down grades, and the odd yard or two, but you're mostly confined to the insides of one valley. Having been to said valley, it's fairly faithful to the original article. The OB1116 that comes with the route as the only supplied loco is also quite passable, and so are the scenarios. I would heartily recommend this route for one reason, and that is that everything Austrian under the Sun comes with scenarios for it. It is very represented in that sense, and very worth the asking price here.
Conclusion: Given their last Humble Bundle offering, I expected far worse from DTG. The previous one was absolute garbage, consisting of random, ancient stock, tossed together like salad into a tumble-dryer. This one also has some...notable infamous mentions, but on the whole? It contains a very good crop of routes, and a very good crop of good rolling stock.
But I will say again, for the price? Literally just get it for the Chatham and Gillingham routes. Everything else is a bonus at this point because for that price, those two routes are a steal, and I think none of you need another treatise from me on just how much this route slaps absolute titties.
That's it from me, and now I go back to languidly drinking.

submitted by That1TrainsGuy to trainsim [link] [comments]

2022.10.27 23:28 CooperHChurch427 How the abortion pill actually works... (An education response to people who are not educated on how it works) [Resource for both Pro-Choice and Pro-Life debaters]

I don't usually post responses on here back to back, however I think we need to clear things up about the aboriton pill, aka misoprostol, Carboprost, and the most commonly used Mifepristone.
So Mifepristone and Misoprostil are some of the most heavily researched and tested drugs in history, pretty much the only drugs we know more about are opioids. However, there was one claim made a few minutes ago that was blatantly wrong:

No, seriously, it's a pill that produces a miscarriage. I understand that people take this voluntarily, and under normal circumstances it won't kill you, but it's still a poison.

So here is the thing about Mifepristone and Misoprostil. They are not poisons. A Poison is a susbtance that is toxin that when turned into a metabolite (broken down) version of it's self, it interferes with the bodies ability to metabolize hormones or interferes with things such as the electron transport chain (energy production). A drug can be toxic however when taken in large dosages, such as lidocaine or even vitamin k and potassium (which cause bleeding and the body to be relax to much).
So to define what Mifepristone is I need to explain a few terms an analogue is a substance that is structurally similar or identicle, a antagonist is a substance that acts against. Progesterone is a naturally occuring female sex hormone that is a steroid (phospholipid) that the body releases to lower immune response, relax the uterus and converts the endometrium lining into the placenta. A Prostaglandin is a sex hormone as well.
So, what is Mifepristone and Misoprostil and the others I labeled? Mifepristone is a anatogonist to progesterone while misoprostil is a analogue to a prostaglandin. The way they work to end a pregnancy is by interfering with the hormone progesterone which prevents the pregnancy from continuing.
Essentially the drugs bind to the progesterone receptors in the uterus which causes a sudden and dramatic drop in progesterone. When this happens the body goes through the exact same process that happens in natural miscarriages and during the a persons menstruation cycle.
Essentially during a persons natural menstruation cycle in preperation for pregnancy the body increases progesterone to signal the uterine lining to get thicker for implantation. When no implantation occurs after (normally) 21 days the progesterone drops and the uterine lining is shed. If pregnancy does occur within those 21 days the body continues to produce progesterone for the next nine months, at the end, the body has a sudden decrease in progesterone and then proceeds to release prostaglandins to cause the uterus to contract.
So, the same thing happens using mifepristone and misoprostil together. The first drug taken causes the bodies progesterone level to drop and the body goes through like a normal period. When paired with Misoprostil which is common it causes uterine contractions and the ZEF is expelled.
However, it is not a poison to either the mother or the zygote or embryo. Because the drugs are both analogues to drugs that are naturally produced in the body, they do not harm them. If it was poisonous to the embryo the drug would have to go throug the exact same metabolic pathways and would cause the mother to become ill.
The drugs are also not given in very large dosages. Essentially the drugs we use to end pregnancies are commonly used to end pregnancies that are wanted (to cause labor) to treat uterine fibroids and endomytriosis and are about the same dosage as what our body natural secretes. Drugs that interfere with Prostaglandin EP1 receptors also are being used for pain research as well. The drug does metabolize via the liver so a drug overdose is possible, but it needs to be done in a large dose.
Similarly before the modern version of these drugs, it was common to use 3 or 4 packs of birth control pills to end a pregnancy which could cause liver damage as the dosaging then was much, much higher.
So no, they are not poisonus and no harm is really being done. When the body miscarries (50% of all miscarriages) the body goes through the exact same process at what ever stage it happens.
However, there is one thing. When Mifepristone is taken, and a person changes there mind there are drugs that can essentially act as an antagonist to mifepristone. But when paired with Misoprostil there is no going back. It's not to say there aren't issues and risks like all drugs, but usually it's when these drugs are used at the end of a pregnancy, and if a person doesn't expell the fetus it can cause very serious birth defects and sepsis. The drug combo also has been found to work up to 24 weeks as well which is also safer than D&C and surgical abortions.
Note I am not a doctor but this information is included in my Human Development Class Notes and my Anatomy and Phsyiology Textbook which explains how prostaglandins and inhibitors work. However you can find this information just about everywhere. Here are resources where you can better understand this.
Further Readings
MIFEPRISTONE+MISOPROSTOL: Uses, Side Effects and Medicines Apollo Pharmacy
download (fda.gov) ( Mifepristone U.S. Post-Marketing Adverse Events Summary through 06/30/2021)

This one does clarify that:

Seventeen of the 18 remaining U.S. deaths involved two cases of homicide, two cases of combined drug intoxication/overdose, two cases of ruptured ectopic pregnancy, two cases of drug intoxication, and one case each of the following: substance abuse/drug overdose; methadone overdose; suspected homicide; suicide; delayed onset toxic shock-like syndrome; hemorrhage; bilateral pulmonary thromboemboli; unintentional overdose resulting in liver (hepatic) failure; and a case of natural death due to severe pulmonary emphysema

A similar FDA report also did say that pretty much no fatal cases have been linked to proper usage and without any pre-existing conditions that make you high risk. Also I might add that 12 of the reported deaths are from external countries where a person might not have the ability to get proper follow-up care.
How Does the Abortion Pill Work? Abortion Pill Function (plannedparenthood.org)
Misoprostol and mifepristone medicine: What is the abortion pill? (usatoday.com)
Mifepristone And Misoprostol: Understanding The Medical Abortion Pill. (womenscenter.com)
Mifepristone - Wikipedia
Misoprostol - Wikipedia
Clinical Review Report: Mifepristone and misoprostol (Mifegymiso) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 May. PMID: 30512905. (Via online medical database access)

submitted by CooperHChurch427 to Abortiondebate [link] [comments]

2022.05.12 07:32 PeachySpleen101 I'm afraid I'm becoming an addict....idk what to do...

So...I'm in palliative care. I'm terminally ill, but my conditions are really rare, a lot is unknown, it's progressive but we don't know exactly how long I have. Maybe a year if I'm lucky? It may come down to how much time I *want*, because I'm already at the point where I have a feeding tube, less and less able to eat or drink, and there's been lots of complications with that (including severe, constant pain) and they want me on TPN, but I have made it clear I'm not interested in going back on TPN. But I also have a tracheostomy now. Use a ventilator daily. More and more. Chronic respiratory failure. So on, so on. My quality of life is shit. Several docs that I've had for a long time, before we knew I was sick like this, have talked to me about how they really think I should sign a DNR. Palliative dr said that because of my issues, treatments, ventilator reliance, etc, that "hospice" for me would be being admitted to the palliative wing in the hospital, treatments withdrawn, "made comfortable" (in other words, sedated), then removed from life support and I'd pass away. He said that's open to me at any time - as he put it, if I "wake up one day and think 'I just want to be comfortable now'"...which honestly is terrifying, but something that may come to pass when I hit a point where I'm near to being locked into a body, unable to even communicate well. But we don't know how long I have if I keep slogging it out and patching myself up - 6 months? A year? 16 months? Who knows.
Anyway, that's the situation. That complicates it a bit. I was never on opiates until I entered palliative care in July 2020. We didn't know then that I was quite as sick as I turned out to be. But still real bad. I initially refused pain meds but my primary care doc actually begged me to reconsider. I was puking from the pain daily by that point - mainly my back, it was right before I got my permanent feeding tube and that painfest started. I was afraid I'd be judged for being on them. But I finally did start them in I think August 2020.
Now I'm on like 270 MMEs a day. Methadone 5mg 3x a day and Oxycodone 25mg every 4 hours as needed. But now I need it every 4 hours, always. The pain has gotten worse, worse, worse, and then new pain came on board, even nerve pain, which was never an issue before. And the pain is still so damn bad. When I try to back off the meds, it's unbearable. But even on them, the pain rules every second of my life. I'm so worn down. I can't keep this up. I'm weary to my core, weary of the struggle, of hurting pretty much ALL OVER, every second, of every day. I always had a high pain tolerance, I never complained, I rode out kidney stones at home with tylenol. But this is worse, it never goes away. And now I keep taking extra. I used to be so anal about not taking extra. Lately, I do. Often. Extra oxy. Like an extra 5, sometimes even 10mg. I try not to, but sometimes the pain is so bad. It scares me that I'm doing this. I tried to stop. But I hurt so damn much that I can't stand it. I don't crave these meds or anything. They don't make me feel anything. I'm a "poor metabolizer" of CYP2D6, so Oxycodone (and fentanyl patches, which I was on before I switched to methadone) doesn't do a whole lot, I have to take a lot more - I don't convert Oxycodone into oxymorphone very well. I don't drink alcohol, I don't smoke, I actively dislike feeling altered or not right....so I'm not chasing some high, which I never felt from any of these meds anyway. I just want the pain to be something close to tolerable, to where it isn't so painful to be conscious. To where it doesn't just zap all energy from my soul from dealing with it day after day. So I've been taking extra - and it only helped a tiny, tiny tad, because I don't dare take too much more and risk running out of my meds early. I tried messaging my palliative doc about that my pain wasn't tolerable, in addition to telling him about something else. Didn't tell him about taking extra, and absolutely won't. But he didn't say much. Or, anything at all, really, about the intolerable pain.
IDK. It scares me that I'm taking extra. And I tried to put my foot down - tell myself no, don't do that anymore, only what you're prescribed and no more. But that didn't work. I still ended up going back an hour and a half after my dose to take more because I was still in so much pain. Then I tried telling myself I'd skip a dose. Or, that I'd wait an extra 2 hours, do 6 hours until the next dose instead of my normal 4hrs. But I couldn't. I caved. It's like I don't have self control. I feel like I must be an addict or something. I can't always tell myself no. I always could before. But it's like the pain has worn me down. I can't tolerate it like this anymore. I'm so tired, goddamn.
What should I do? I wish I could quit the pain meds completely. Be done with them. But I know for darn sure that all the severe pain I have, without these meds.... I would almost certainly be begging for hospice within a few days. I'd be ready to just be done with my life - such as it is, despite how hard I've fought to hang on, all I've endured....because this pain is just straight unreal. It hurts like hell lately to even turn the pill crusher to crush my meds, especially tylenol....funny that it can be so painful to crush meds I take for pain...lol...

submitted by PeachySpleen101 to ChronicPain [link] [comments]

2022.05.12 05:44 Jaded-Wafer-6499 Information About Effective Medications for the Treatment of Anhedonia / Low Hedonic Tone

• Pramipexole (Mirapex, Mirapexin, Sifrol) - [Non-Ergot Dopamine Agonist] - Mechanism of Action (MoA): Non-Ergot Dopamine Partial / Full Agonist Selective for the D2-like Receptors, with Special High Affinity for the DRD3
Pharmacodynamics: “Pramipexole is a non-ergotamine full agonist at the D2 subfamily of dopamine receptors, with higher selectivity for D3 than for D2 and D4 dopamine receptors (Mierau and Schingnitz 1992; Svensson et al 1994; Mierau 1995; Mierau et al 1995; Bennett and Piercey 1999). Thereby, pramipexole is able to simultaneously excite the direct striatopallidal pathway (by D3 stimulation) and to inhibit the indirect striatopallidal pathway (by D2 stimulation), alleviating PD symptoms by mimicking dopamine’s effects in the striatum. Since the D3 receptors enjoy greatest predominance in the limbic system (Bouthenet et al 1991), pramipexole has the theoretical potential to also have an impact on psychiatric symptoms in PD (Bennett and Piercey 1999). In addition, pramipexole has a very low affinity for 5-HT2A, 5-HT2B, and D1 receptors, partly explaining its beneficial effects in the context of cardiac valvulopathy and dyskinesias, as discussed later.”
Pharmacokinetics: “Pramipexole has an absolute oral bioavailability greater than 90%, indicating good absorption and little first pass metabolism. It exhibits linear pharmacokinetics and less than 20% is protein bound; more than 90% of the absorbed dose is eliminated unchanged and almost exclusively by the kidneys, motivating a dose reduction with low creatinine clearance. Its elimination half-life is 8 hours in young, healthy volunteers (Häselbarth 1994a, b; Wright et al 1997; Bennett and Piercey 1999).”
“In contrast to other DA, Pramipexole has been found to exert no strong cytochrome P-450 inhibition in vitro, minimizing the risk for drug-drug interactions (Wynalda and Wienkers 1997).”
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518382/#:~:text=Pharmacodynamics,%3B%20Bennett%20and%20Piercey%201999)
Clinical Experience With High-Dosage Pramipexole in Patients With Treatment-Resistant Depressive Episodes in Unipolar and Bipolar Depression - https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2015.15060788

• Phenelzine (Nardil), Tranylcypromine (Parnate), Isocarboxazid (Marplan), High Dose Transdermal or Buccal Selegiline (EMSAM / Zelapar) - [Irreversible and Non-Selective Monoamine Oxidase Inhibitors (MAOIs)]
Treatment of Depression with MAO Inhibitors: “The profound antidepressant action of MAOI inhibitors was discovered by chance (Lehmann and Kline, 1983) in tuberculous patients treated with iproniazid, a derivative of the hydrazine compound isoniazid. Further developments led to the introduction into clinical use of several non-subtype-selective irreversible MAO inhibitors including the hydrazines Phenelzine (Nardil) and Isocarboxazid (Marplan), the propargylamine pargyline, and the cyclopropylamine Tranylcypromine (Parnate), but these compounds can all lead to potentiation of the cardiovascular effects of the dietary amine tyramine (“cheese effect”). Following realization that the cheese effect can be avoided by dietary counseling, and that MAO inhibitors are in fact excellent drugs for treatment of drug-resistant and atypical depression, use of certain non-subtype-selective inhibitors, in particular tranylcypromine (Parnate), is now seen with increasing frequency. Tranylcypromine has pharmacological properties in addition to inhibition of MAO, in particular inhibition of lysine-specific histone demethylation type 1, and interaction with the endogenous cannabinoid system (Lee et al., 2006; Hill et al., 2008). Phenelzine also has an additional pharmacological property which may be involved in its antidepressant actions, namely blockade of GABA and alanine transaminases (Baker et al., 1991; Todd and Baker, 2008). In a recent review (Heijnen et al., 2015) of a small number of clinical trials, tranylcypromine was found to be an efficacious and safe drug for the treatment of bipolar depression, when administered with correct dietary counseling. Although cheese effect is a potentially serious reaction, the limitations it imposes on treatment of psychiatric patients have been much exaggerated, because the amounts of tyramine occurring in foodstuffs are quite low, and only a gross violation of normal dietary directions would be likely to cause a fatal, or damaging, reaction (Gillman, 2011). The management of such a hypertensive reaction if it does occur has also been well-documented (Gillman, 2011). In addition to cheese effect, another potential danger is serotonin toxicity syndrome (ST), which can occur following the combination of irreversible MAOI with a drug which has the potential to elevate 5-HT synaptic levels, such as a serotonin-selective reuptake inhibitor (SSRI) (Gillman, 2006). In this context, the relatively long period required for return of MAO activity following cessation of therapy with an irreversible inhibitor is important when a change in therapy is required. If therapy with a SSRI is to be used, there is a danger of ST if these drugs are instituted before MAO activity has returned to normal levels. Following cessation of tranylcypromine administration in healthy subjects, a period of 30 days was required for complete normalization of the pressor response to oral tyramine challenge (Bieck and Antonin, 1988). In the case of rasagiline, using platelet activity of MAO-B as the index, enzyme activity returned to baseline levels 2 weeks after cessation of drug administration in healthy subjects (Thebault et al., 2004). The time required for return of enzyme activity in the brain however, is considerably longer than in the periphery. Using (Denney and Denney, 1985) C-labeled selegiline together with positron emission tomography (PET) the half-time for return of MAO-B binding in the brain following complete blockade of binding by an initial injection of selegiline in a baboon was 30 days (Arnett et al., 1987), and using similar technique, following initial MAO-B inactivation by rasagiline in human subjects, was 40 days (Freedman et al., 2005). Recommended periods (by manufacturer) for wash-out after cessation of tranylcypromine range from 7 to 10 days (Gahr et al., 2013). The antidepressant effect of MAOI has focused interest on the possibility that altered expression levels of the MAO enzyme could be the cause of some forms of depressive disorders. Polymorphisms in the MAO-A gene have been associated with a number of behavioral traits. Reduced enzyme activity is associated with violent behavior and aggression, whereas over-expression may be linked to depression (Alia-Klein et al., 2008). These facts, together with the well-known biogenic amines hypothesis, provide theoretical background in support of the use of MAOI for treatment of affective disorders. Several studies have attempted to link the MAOA-uVNTR polymorphism, which leads to increased enzyme transcription, with suicidal tendency, but a meta-analysis including 1452 psychiatric patients and 1198 control subjects did not find a significant association (Hung et al., 2012) with this particular trait. In a recent study in which MAO-A expression level (total distribution volume, Vt, of 11C-harmine by PET) was determined in borderline personality disorder (BPD) patients, the MAO-A brain content was correlated with symptom severity (Kolla et al., 2015). Interestingly, MAO-A Vt was increased in prefrontal cortex and anterior cingulate cortex by 43 and 42% respectively in severe BPD subjects in relation to controls. One of the main restrictions to the clinical use of MAOI for treatment of depression is the cheese effect. In preclinical and clinical studies it was shown that potentiation of the pharmacological effects of tyramine occurs following selective inhibition of MAO-A but not MAO-B (Lader et al., 1970; Finberg and Tenne, 1982; Finberg and Gillman, 2011). This can be attributed to the localization of MAO-A to noradrenergic (as well as serotonergic) neurons (see Finberg, 2014) for detailed review). A corollary to this selective localization of MAO subtypes is that selective inhibitors of MAO-A but not MAO-B are effective antidepressants (Youdim and Finberg, 1983), however no irreversible selective MAO-A inhibitors are in use for treatment of depression.”
https://www.frontiersin.org/articles/10.3389/fphar.2016.00340/full

• Low Dose of Buprenorphine (Subutex) - [Atypical Opioidergic Antidepressant] - Mechanism of Action (MoA): “Buprenorphine is a partial agonist at μ-receptors, an antagonist of kappa (κ) receptors, and also displays affinity for delta (δ) opiate receptors. Buprenorphine has a favorable safety profile with low risk of respiratory depression, and the pharmacokinetics are not affected by advanced age or renal dysfunction, supporting its use in both mid-life and older adults with TRD. The combination of μ-agonism and κ-antagonism produces less dysphoria than methadone (9), and animal studies suggest that κ-antagonism may exert antidepressant effects (10). Buprenorphine may also interact with serotonergic systems and the hypothalamic-pituitary-adrenal axis (11). Rapid improvement in mood has been observed in both younger non-opioid abusing patients with TRD (12) and opioid-dependent patients treated with buprenorphine (13). Of particular relevance for TRD, especially in older adults in which cognitive impairment is often comorbid with depression (14), is that the effects of buprenorphine on cognition may be minimal (15, 16). The unique mechanism of action, potential for early effect, and acceptable safety profile make buprenorphine an intriguing molecule to test in older adults with TRD. In this proof-of-concept, unblinded clinical trial, we describe the clinical effect, safety, and tolerability of low-dose buprenorphine for TRD in older adults.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157317/

• Tianeptine Sulfate / Sodium (Stablon / Coaxil) - [Atypical Opioidergic Antidepressant] - Mechanism of Action (MoA): Mainly a MOR Agonist, Glutaminergic Modulator, Neuroplasticity Promoter on Amygdala / Hippocampus by BDNF Proliferation.
“Tianeptine, and its active MC5-metabolite, behave as Mu-Opioid Receptor (MOR) Agonist, and acts to a lesser extent on the Delta opioid receptors without affecting the Kappa receptor. A noteworthy fact is that tianeptine, despite its affinity for these receptors, did not cause tolerance, as it does not lose its efficacy after continued treatment, or physical dependence, as after suppression or administration of naloxone no withdrawal syndrome was observed. These two characteristics clearly differentiate tianeptine from the other opioids, such as morphine. In all likelihood, tianeptine, despite acting on the Mu receptor, will trigger mechanisms of neuronal transduction that are different to those induced by morphine and other opioids, since these cause tolerance and withdrawal syndrome after they are discontinued. This differential fact has raised the possibility that antidepressants could be developed that act on the transduction mechanisms modified by tianeptine. On the other hand, we should point out that the potency of tianeptine on Mu receptors is 6 times less than that of morphine, and that addiction to the antidepressant has been limited to a few isolated cases, essentially polydrug-dependent individuals. In fact, tianeptine does not cause tolerance or withdrawal syndrome, two inescapable characteristics of opioids that cause dependence. Furthermore, along the same lines, it has been demonstrated that supratherapeutic doses of tianeptine showed low potential for abuse. Thus, tianeptine significantly decreased morphine tolerance and suppressed the withdrawal syndrome caused by the administration of naloxone in the mouse, and therefore it can be claimed that tianeptine, despite having affinity for the opioid receptors, behaves as an inhibitor of morphine tolerance and dependence. In fact, these authors point out that the administration of tianeptine could benet patients who require prolonged administration of morphine. These pharmacological properties of tianeptine have aroused great interest, not only in the eld of depression, but also for the potential development of Mu receptor agonists that modify transduction mechanisms in a similar way to tianeptine, in order to obtain analgesics that cause less dependence than the classic opioids.”
https://www.sciencedirect.com/science/article/abs/pii/S1888989118300971?via%3Dihub

• Rasagiline (Azilect) - [Irreversible MAOI] - Mechanism of Action (MoA): Irreversible MAO Inhibitor with Very High Selectively for MAO-B; Boost significantly DA and PEA levels in the brain; Highly Neuroprotective Against DAergic Neurotoxicity; \In contrast to Selegiline it has no amphetamine-like metabolites ([Finberg et al., 1999](https://www.frontiersin.org/articles/10.3389/fphar.2016.00340/full#B39)) ; Is available in the EU, the US and in several other countries worldwide, including Canada and Israel*
https://www.frontiersin.org/articles/10.3389/fphar.2016.00340/full

• Selegiline (Deprenyl, Eldepryl, Emsam, Zelapar) - [Irreversible MAOI] - Mechanism of Action (MoA): Selective and Irreversible Inhibitor of the Enzyme MAO-B at Low / Moderate Doses; At high doses inhibits significantly MAO-A losing its selectivity in large part; Weak CAE Substance (Catecholamine Activity Enhancer); Neuroprotective Substance Against DAergic Neurotoxicity.
https://www.frontiersin.org/articles/10.3389/fphar.2016.00340/full
\Available and FDA approved in the USA for the treatment of Major Depression Disorder on it's Transdermal Patch version known as EMSAM.*

• Very Low Dose of Amisulpride "VLDA" at 12.5 mg; (Solian) - [Atypical Antipsychotic / Atypical Antidepressant] - Mechanism of Action (MoA): Selective Antagonist of DRD2 / DRD3 (Pre-Synaptic) Autoreceptors.
“Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity) for these receptors with dissociation constants of 3.0 and 3.5 nM, respectively.[37] Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low-dose amisulpride has also been used to treat dysthymia.[5] The effectiveness of Amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynaptic dopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse.”
https://en.wikipedia.org/wiki/Amisulpride
Subjective Effects: Significantly increase on hedonic tone, improve focus/cognition, enhance color vividness, improve symptoms of social anxiety, improves confidence, improves mood, more positive mindset, enhance physical coordination and responsiveness, etc. \[Starts working very fast and usually without side effects, with a fast onset of action from ~ 2 hours up to a few days depending on the individual response. It takes ~ 2 - 4 weeks to reach full effectiveness.]*

• Low Dose of Aripiprazole (Abilify / Aristada) - [Atypical Antipsychotic] - Mechanism of Action (MoA): Mainly a Partial Agonist of the DRD2 / DRD3 at Low Doses of ~ 1 - 2.5 mg.

• Brexpiprazole (Rexulti) - [Atypical Antipsychotic / Serotonin–Dopamine Activity Modulator "SDAM"] - Mechanism of Action (MoA): Partial Agonist of the 5-HT1A / DRD2 / DRD3
https://en.wikipedia.org/wiki/Brexpiprazole

• Cariprazine (Vraylar / Reagila) - [Atypical Antipsychotic] - Mechanism of Action (MoA): Acts primarily as a DRD3 / DRD2 Partial Agonist, with a High Selectivity for DRD3.
https://en.wikipedia.org/wiki/Cariprazine

• Armodafinil (R-Modafinil) - [Atypical Stimulant and Eurogenic Substance] - Mechanism of Action (MoA): Mainly a Long Acting and Moderately Strong Dopamine Reuptake Inhibitor (DRI); “Armodafinil is an indirect dopamine receptor agonist; it binds in vitro to the dopamine transporter (DAT) and inhibits dopamine reuptake. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels. In genetically engineered mice lacking the dopamine transporter, modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent.”
https://en.wikipedia.org/wiki/Armodafinil

• Lisdexamfetamine (Vyvanse) - [Psychostimulant] - Mechanism of Action (MoA):"Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound which is responsible for the drug's activity. After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine. The conversion of Lisdexamfetamine to Dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times; Dextroamphetamine is a potent full agonist of the trace amine-associated receptor 1 (TAAR1) and interacts with vesicular monoamine transporter 2 (VMAT2). Combined action on TAAR1 and VMAT2 results in increased concentrations of dopamine and norepinephrine in the synapses, which stimulates neuronal activity.”
https://en.wikipedia.org/wiki/Lisdexamfetamine

• Dextroamphetamine (Adderall) - [Psychostimulant] - Mechanism of Action (MoA): "Dextroamphetamine exerts its behavioral effects by increasing the signaling activity of neurotransmitters norepinephrine (NE) and dopamine (DA) in the reward and executive function pathways of the brain. The reinforcing and motivational effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway. Dextroamphetamine is a potent full agonist of the trace amine-associated receptor 1 (TAAR1) and interacts with vesicular monoamine transporter 2 (VMAT2). Combined action on TAAR1 and VMAT2 results in increased concentrations of dopamine and norepinephrine in the synapses, which stimulates neuronal activity."
https://en.wikipedia.org/wiki/Dextroamphetamine

• Methylphenidate (Ritalin) - [Psychostimulant] - Mechanism of Action (MoA): “Methylphenidate primarily acts as a Norepinephrine–Dopamine Reuptake Inhibitor (NDRI). It is a benzylpiperidine and phenethylamine derivative) which also shares part of its basic structure with catecholamines. Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE).[105] Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET).[106] Variability exists between DAT blockade, and extracellular dopamine, leading to the hypothesis that methylphenidate amplifies basal) Dopamine activity, leading to nonresponse in those with low basal DA activity.[107] On average, Methylphenidate elicits a 3–4 times increase in Dopamine and Norepinephrine in the striatum and prefrontal cortex.[108] Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed.[102] A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5HT1A receptor, but no significant activity on the 5HT2B receptor was found.[118]”
https://en.wikipedia.org/wiki/Methylphenidate

submitted by Jaded-Wafer-6499 to anhedonia [link] [comments]

2022.01.06 11:03 MagzalaAstrallis Those In Power, Government, Banks, Pharmaceutical Companies And Certain Other Jobs Do Not Want A World Without Sickness, Addiction, Crime etc.

This thought has been sitting with me for a while... The realisation that we are pretty much equal to animals and cattle, we are not superior to animals/cattle at all, we are one in the same.
Farmers, breeders, supermarkets, butchers etc would not want everyone in the world to become vegan. If everyone became vegan, these workers would lose money and potentially their jobs, and also likely that a lot of animals would be put down because if farmers, breeders etc were no longer making money from selling meat and produce, they wouldn't have the money to be able to feed, care for, look after, breed and keep animals.
If a farmer had 1000 cows, all which he fed, paid for vet bills, looked after, breed etc and over night, everyone in the world became vegan, the farmer would lose money/stop making money and he would no longer have enough to feed every cow and look after them all, the money he made from meat and produce was enough to feed them all and look after them, so without that money, they'd be neglected and probably starve, so the only options would be to put down the animals that he couldn't afford to look after, or just let them starve to death.
They give the illusion that they care for these animals by feeding them, treating sickness, grooming them, looking after them, but they don't do these things because they care and because the animals need these things, they only do all the fake caring because these animals are making them money ..
And we are exactly the same.
"They" don't want us to all be healed from our sicknesses and illnesses because doctors, nurses would lose their jobs, pharmacy's and the companies that produce and sell meds would lose their jobs.
Drug and alcohol counselors/support workers don't want all of us to be sober and free from addiction because they too, would lose all their jobs, the companies that produce and sell methadone, subutex etc would lose their jobs.
The police do not want a world free from crime because they too would lose their jobs.
They don't want us all to become vegan because farmers, breeders, butchers, meat sellers, milk, cheese and yoghurt companies, egg companies would all lose their jobs.
There are people in this world that want and need us to be sick, to be addicted to drugs, to be criminals, killers and abusers, that want us eating meat and drinking milk and eating cheese, because that's how they make money and earn a living.
If someone in or with power had a cure for every cancer, a cure for every disease and every illness, if they had the ability to stop all drug and alcohol addiction, do you really think they would allow us to have these things? Do you really think they would heal the world and cause the loss of thousands of jobs?
Even if they had some miracle, magical, cure to stop all crime and to make all humans moral and never do anything illegal, never murder, rape or steal.. even if they had that, would they use it? Would they give us the gift of peace and safety for the loss of a thousand more jobs?
If something that would benefit the human race as a whole, benefit all of us, but would cause some to lose jobs and money, they would rather us suffer and fail than cause the loss of money.
We are just like the cattle... They pretend to care about us, they feed us, give us jobs, money, give us things to enjoy, give us nice things to buy, they look after us, ensure we all breed and try and keep us all alive, not because they care for the human race but because as long as we are alive, we are making someone money, just like the cows and the pigs...
And it would probably be the same situation as the farmer with 1000 cows ... If we no longer had sickness or disease, no longer had addictions, no longer committed crimes, they would probably put us all down too because they wouldn't be able to afford looking after everyone in the human race anymore with the loss of so many jobs and so much money ..
We are all just a pay check to someone.. we are just something that earns someone else money...
Free energy? Free electricity for us all? Would they give it to us? Absolutely not because all the companies like British gas and all the gas and electric companies, again, would lose jobs and money ...
When you think about all of this, you have to wonder, our lives are in the hands of people that clearly do not care about a single one of us...
And then also ask yourself, why do they sell medicine to us, why do they encourage veganism and healthy leaving, why do they encourage soberiety, why do they put warnings all over cigarettes, why do they give us boosters and vaccinations, why sell condoms, if in reality, if these things were 100% effective, so many jobs would be lost... Again, these things are just something which makes somebody else money...
But .. if they need us to be sick, addicted etc to continue the economic flow of things and make sure there are always jobs and people earning money, do you really think the medicines and treatments and cures and vaccinations they give us, actually work?
We are more equal to cattle and animals than we realise... We always see things as humans being on top as superior, and animals underneath us, but we are on the same step as the animals, with just a few, powerful, controlling, wealthy people above us all, pulling the strings...
Even littering and global warming and pollution makes jobs and money... Think of how all this lead to the mass production of electric cars...
But yet again, they tell us to get electric cars to save the earth and to stop global warming, but they don't care about that stuff, they don't care about pollution, they don't want to improve climate change, because they will never want us to stop using cars and buying petrol, petrol is one of the biggest money makers, presidents have literally gone to war for oil, so do you really think they want us all converting to electric? If we all stopped using petrol, MAJOR money would be lost, this is one of the big things which would affect people's wealth BIG TIME... They would probably choose to allow a cure for cancer and have some doctors lose their jobs than have everyone convert to electric and lose oil/petrol money...
How did the world get like this? Has it always been this way? Have we always just been cattle and slaves to make someone else their money?

submitted by MagzalaAstrallis to TrueOffMyChest [link] [comments]

2021.12.12 13:24 IHateBackPain30 How effective is the fentanyl patch?

It feels like considering the mme of it, it doesn’t seem super effective but maybe I’m just more opioid tolerant. It’s 60mme or supposed to be equivalent to 6 10mg hydrocodone, 12 50mg tramadol, 4 10mg oxy and 13 1/3 Tylenol #3 for reference. Yes mme is flawed but that’s my only way of comparison and converting so I’d like to get the most effective painkiller for the lowest mme if that makes sense.
I’m on the 25mcg fentanyl patch. Tbh the biggest issue rn is it doesn’t last 3 days and I’m gonna ask my pain doc to switch it to 2 days (not sure why he even wrote it for every 3 I feel like he made a mistake bc he literally forgot to send 3 of my other prescriptions too smh). The reason I think it’s a mistake is he himself said it often doesn’t last 3 days when I said I’m not a big fan of it bc it doesn’t last 3 days and said yeah it doesn’t and “thankfully it’s approved for q72 and 48” so I figured he would’ve wrote it for 2. I actually should’ve asked how he was gonna write it my mistake. After the appointment I had to go to the bathroom and forgot to use it then and so went back to ask them and I meant to ask if I could go inside and ask the doc a quick question being how he wrote the patch but I didn’t wanna intrude I can be too nice to others at the expense of myself like that. Tbh If he isn’t willing which I doubt to write it for 2 days at my next appointment I’m gonna ask for another long acting opioid.
I have good insurance so any long acting opioid works. Maybe hydro er or mscontin to balance out the energizing effects from the ir opioids. I’m already on oxy so OxyContin is an easy choice. I would rather avoid xtampza bc last time I had Cigna with express scripts they’d cover OxyContin but not xtampza and I’ve heard reports of it not being as effective as OxyContin and I personally don’t trust abuse deterrent reformulations or versions after they always have so many complaints of working less. I mean they can’t all just be addicts or placebo complainers. Methadone is an option but it’s messy and not 12 hours.
Also there’s the question of do I want 60mg hydro er once a day or half that twice a day. For a long time I was of the belief that er opioids acting while you sleep is stupid and increases tolerance and wastes your limited supply of opioids for no reason but if I take it maybe 2 hours before I plan to sleep it can work a bit to get rid of that be pains I have that it’s too late to take a Percocet and waste it since I should be asleep in half an hour. Also can help me sleep by reducing that pain and discomfort that often keeps me up where it’s not quite high enough to take a Percocet and it would be wasted due to time but if it’s just a bit of the er opioid working than yeah good. Also some extra sedation from the opioid may help I worry that oxy energy will keep me up if take it too close to sleeping.
But being on the fentanyl patch changed my mind a bit. I think I sleep better although my sleep is still awful that’s something me and my psych have to work on. Also I wake up less in pain and less anxious I do take my kratom within 10 minutes of waking up but often wait an hour or so to take my Percocet unless the pains bad for some reason like I barely slept then I’ll take it with my Kratom. So idk thoughts on one er vs 2 er tablet? I’d be nice if they could be different dosages like 40mg hydro during the day since your active you need more painkiller and 20mg at night but I imagine that would be a prescribing, pharmacy, and insurance nightmare.
What I like about the fentanyl patch: I don’t feel a buzz or high and I don’t have to think too much I just write a note when I changed it on my phone and change it every 3 days sometime between afternoon and evening on alternating upper arms and that’s it. I do have to shave and my arm hair but not too much work. So easy. It also works while I sleep so while I do wake up with pain it seems muted and I think I sleep better with it even if I do have trouble getting to sleep or waking up early but tbh I think my ambien er dose needs to be increased.
What I don’t like: the pain is not at a level where I can function I need additional analgesia 24/7 which currently is mostly Kratom (I’m tapering already taking 2 grams less a day but it’s about another 10-12 weeks left on my taper) and I’m prescribed 4 10mg oxy which I only take usually 1 a day sometimes 2 due to the kratom there’s not much need and I don’t wanna overdo it opioid wise or waste them. Idk how I’ll turn out pain wise when I’m kratom free and if 4 10mg Percocet will work out well or great or meh or bad who knows.

submitted by IHateBackPain30 to ChronicPain [link] [comments]

2021.07.16 04:34 theloyguy Prozac treatment for anx/dep & substance use

Hi all, First time posting here I’ve been taking 20mg Fluoxetine for about 3 weeks (started with 10mg for one month, then the 20mg daily, so almost 2 months into treatment). While I do have diagnosis of both generalized anxiety and depression, I was actually prescribed the Prozac by my Suboxone (Buprenorphine) doctor to assist in my opioid addiction maintenance.
He recommended the drug awhile back due to my inability to fully convert to a Buprenorphine-only daily schedule. I remain unable to stay on suboxone. It’s just not doing what my choice of opioid would do for me, my preferences being heroin, fentanyl… really any mu-agonist in a high enough dose: my tolerance is massive. Think: “I could take 100 of those 5mg Percocet tablets from the dentist and still drive to work without suspicion or reasonable impairment” (…of course, I could not ACTUALLY take all of the Tylenol that would be in those percosets without liver failure… I mean to say that 500mg of oxycodone wouldn’t hardly phase me.
It’s terrible. I want to quit so bad. My grandmother (biological / maternal) was a heroin addict. She was able to quit after detox/rehab, but unfortunately committed suicide pre-my-existence. I believe she was being prescribed new antidepressant / antipsych type meds or switching them when it happened, but the family all remember her just not being herself after rehab. Her depression was treated but not always, plus her personality said to have been dulled. My grandmother was diagnosed bipolar. I’m not sure which one. I have a feeling that if I were to spend the time with a psychologist, they’d likely slap a similar diagnosis into my chart.
I use opioids because they’re all that works for my depression (mild to moderate) and my constant anxiety (moderate to severe). Benzodiazepines could do the trick for social anxiety, but I don’t LIKE to be an idiot all the time. I ENJOY having memories. Sure, 0.25Mg of Xanax might take the edge off but I’d need 1mg to really feel comfortable in any social setting outside of my family.
The Prozac seems to be helping, and the ultimate goal is for it to help me get off of opioids. Should I just give it more time? I really don’t want to up my dose any more. I’ve read the horror stories and it took me hitting somewhat of a “rock bottom” to actually agree to start taking an SSRI-type drug. (Long story, but essentially had taken ~2 to 3 mg of etizolam and was unresponsive for a minute or two after smoking a bit of fentanyl. Never lost heartbeat or anything, just scared the living fuck out of my mother who I love too much to feel ok with doing that to. We truly have a great relationship outside of my opioid dependency bothering her, as I’m sure it would any mother. I’m sorry for the giant ramble. I’m looking for advice from someone who’s maybe been in some shoes that look like mine. I’m very high functioning. Straight A’s until high school when I kind of stopped caring: some trauma with ex girlfriend cheating likely kicked that off but nothing crazy for a 16 year old to experience at that time in life.
Substance record: -Smoked weed constantly 15 to 20yrs old, now I can’t do THC hardly at all w/o panic. -Psychedelics used infrequently, maybe 4 of each acid and psilocybin trips. Nothing recent. Too scared. -Recent small MDMA phase before the Prozac because I know I’ll probably never feel that magic fully again (actually benefitted from it mindset wise!) -Oxy addiction started around 17, also hydrocodone or morphine or any other painkiller i got my hands on. -Maintained on Kratom (herbal leaf, mild opioid effect, plant in the coffee AKA rubiaceae family) for about 3 years. 15 to 30 grams/day every day. -Started smoking heroin (bth/west coast gear) around 19/20. Had another bad breakup, got pretty drunk (for me, at least) with the wrong person, rest is history. -IV user within a year after. 0.5 to 1g daily. -Mild alcohol drinker since 18 ish. Never to excess, nor daily for the most part. -ADHD; Script 30mg Dexedrine daily (3x 10mg IR) for 3-4yrs. Sometimes I take breaks because it makes me sweat like a sonofabitch. Have tried the big M once or twice. Felt amazing for a day, then stayed up popping my acne for another day, paranoid as hell required mass sedation to get to sleep… SERIOUSLY: why does ANYONE rly like (let alone be addicted to) street meth????? Dm me, I actually want to try and understand this ! -Did some shitty blow at parties (maybe .5G a total of 5 separate times ? Don’t rly get this 1 either.. -Occasional 25 or 50mg seroquell to sleep (prescribed) -(former) inconsistent benzo use, 18 to 22. Therapeutic ranges only, or at least not far passed that. Maybe few binges of 4-8mg tops (can’t seem to remember any of those though. Weird right.) Still might take a .5mg Xanax, but rly don’t like to for many reasons outlined. For reference, I’ve never used benzos enough to suffer serious WD (never had a seizure or needed a major taper)
I’m healthy. IV use is always done with extremely clean practices. I never over-do it anymore. No HIV/Hep or anything like that. I’ve had lots of tests done as of prettty recently. (No MRI’s/CAT scans or anything like that, but EKG’s, blood analysis, all the standard stuff. It’s all logged into my apple health app and everything within norm. I had Mono at 16 if that means anything, some say it messed them up Permanente. I don’t think that’s the case with me but it was around the time of my diagnoses.
Opioids are seemingly all that is keeping me sane. Is anyone in this boat? Perhaps a similar vessel? I’m 22, I know, but really considering going on methadone :( I’m just almost positive that I’d be stable mentally on something like that. I am 110% far too terrified to enter a detox. Been kicked out of an outpatient They always thought I was sober but fentanyl urine concentration was off the charts and they felt I was a liability due to the fact that I was well over the lethal threshold for someone twice my size. I don’t blame them.
I do have days where bare minimum dose (so no bad opioid withdrawal but also no euphoria / mood boost) will keep me myself but it’s RARE and typically would be due to something specific making me happy, and doesn’t last maybe 12 hours.
Man. If anyone out there can live happy without drugs, but enjoys experimentation, maybe experiment with trying to convince yourself that there’s no such thing as an opioid. You would thank me, unless you’re one of those people who just doesn’t like mu agonists. In that case you are who I envy most in this world.
Thanks to anyone who read all of this crap. Truly.
I’m sorry that only maybe 10% of it related to the actual SSRI that I’m taking. Just figured that if, by chance, a very caring and concerned practicioner were to read my stupid depressing autobiography, the painfully specific details might provide a quicker path to insight of some kind previously missed by my therapist, docs or my minimally-informed self

submitted by theloyguy to antidepressants [link] [comments]

2021.07.12 05:21 SeriousNep2nian Causes and remedies of ED

I got tired of answering the same questions, so I thought a sort of summary might be helpful.
Erectile dysfunction (ED), causes and remedies
The basics
ED refers to a persistent problem with not getting an erection, especially when attempting to have intercourse. Men want to know if their ED is psychological or physical. That’s not always clear-cut, and of course it can be both – someone whose erections are less reliable because of a physical problem may also develop anxiety about it, perhaps making the situation worse.
Penile erection is a wonderful thing, and the process is wonderfully complicated. Erection occurs when the nervous system is stimulated, either locally by touching the penis, or through the brain, by sex-related perceptions, or thoughts. The local nerves secrete nitric oxide, which activates cyclic GMP, causing the small blood vessels in the penis to relax, so that cavities in the penis (the “corpora cavernosa”) become engorged with blood. This compresses the drainage veins against the outer lining, blocking outflow temporarily. Although the brain is involved, the process is not under voluntary control, so one can’t get an erection by “trying harder.”
Some posters have been concerned that the head of their penis doesn’t get hard. This is normal. The underside of the penis, and the head, are made up of the “corpus spongiosum,” which doesn’t get hard, otherwise it would choke off the urethra and the semen could not come out.
Psychological factors and treatment
The most common issue, especially in younger men, is performance anxiety (“stage fright”). Worrying, “will I be able to get it up?” interferes with “getting it up.” Sometimes when an expected erection does not happen, it can set up a pattern of being anxious about it. Performance anxiety is about meeting one’s partner’s expectations, and not disappointing them. During masturbation, partner’s expectations are not an issue, so erections are good. Erections are also good in sleep, especially as the night goes on, hence “morning wood.” Generally the rapid eye movement (REM) phase of sleep is associated with penile erection, and these erections are a strong indication that the physical systems are working well. Absence of morning wood suggests a physical problem, or serious depression.
A first step in dealing with performance anxiety is to discuss it with one’s partner; having the partner’s support will take a lot of pressure off. Accepting that erections are not guaranteed to happen every time is helpful. If the problem persists, the usual treatment is specific psychotherapy. It might involve “sensate focus,” learning to keep attention on the sensory experiences of feeling, smelling, and hearing one’s partner, as opposed to worrying or anxiously monitoring whether the penis is getting hard. In another approach, the man resolves to have sexual encounters without attempting intercourse, whether or not he happens to get an erection. Obviously this needs to be coordinated with the partner.
Pornography-induced ED (PIED). Pornography and masturbation alone don’t cause a problem. But excessive masturbation may. How much is excessive? There’s no way to give a number, but functionally speaking, it makes sense to masturbate when feeling a sexual need. Some people additionally masturbate because they are bored, or anxious, or just looking for an orgasmic reward. (Some people eat only when they are hungry; others eat when bored or depressed, or because the food looks good.) It becomes excessive when the sex drive itself diminishes. It becomes harder to get an erection or reach orgasm. To compensate, men may increase the intensity of manual stimulation (“death grip syndrome”) or, if they use pornography, increase the intensity of the porn they use. The content used in masturbation may become linked to arousal and orgasm. A sexual encounter in real life will be different in content and intensity, and may fail to trigger an adequate sexual response.
The usual recommended treatment is abstinence from porn and masturbation—for how long? Suggestions from internet sources range from 2 to 26 weeks. My suggestion: if you need to masturbate, go ahead, but don’t use porn while doing so.
Other psychological issues. Acute stress from work or family issues can interfere with sex, but this is usually temporary. There may be specific sex-related issues, when a man is angry at his partner, or he feels guilty or unattractive. People who have been sexually abused can have anxiety about sex. Or, they can have active sex lives most of the time, but then a particular event can trigger new anxieties related to the abuse. Severe depression can cause a lack of interest in sex, food, hobbies, and social interaction. The diminished sex drive can be extreme; even “morning wood” may not occur.
Physical causes are numerous. The presence of anxiety and worry doesn’t mean it’s in your head, because men with physically based ED can get anxious about it. Adequate sleep, nutrition and exercise are important. Both underweight and overweight have been associated with ED.
(https://www.webmd.com/sex-relationships/news/20110707/size-counts-when-it-comes-sex)
Diabetes can damage small nerves and blood vessels, and lower testosterone.
Heart and blood vessel problems, like high blood pressure, can cause ED.
Smoking can constrict blood vessels.
Bicycle riding has been reported to increase the risk of ED.
Normal aging can reduce sex drive and erectile function. Even a younger man may notice a change from being “extremely horny” as a teen to merely “horny” in his 20’s, with fewer spontaneous erections.
Low testosterone (T) interferes with sex drive; replacement may or may not help. Low T is more common in older men. T is mostly bound to proteins like SHBG. A small portion is not bound, called "free T.” Free T is a more accurate measure of functional T than the usual measure, total T.
Various neurological and hormonal conditions can contribute to ED.
“Venous leak,” officially “venogenic ED,” is often mentioned in this subreddit. In most situations, venous drainage is a good thing, but during erection we need some blockage. Normally, when the spaces in the penis become engorged with blood, the veins are compressed against the tough lining called the tunica albuginea, closing them off temporarily. When this doesn’t work, it’s not always clear what the cause is. Sometimes, due to trauma or other causes, the tunica itself is scarred or misshapen, as with Peyronie’s disease, and that interferes with venous closure. In one study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306031) venous leakage was not seen in any of 25 men with ED aged 25-45, but in 8% of 51 men aged 45-69. So it’s uncommon in younger men but not unheard of.
Drugs and alcohol
Alcohol. Shakespeare on drink: “Lechery, sir, it provokes and unprovokes. It provokes the desire, but it takes away the performance.” One drink will most likely not create a problem. Long-term heavy drinking can cause liver damage, with higher estrogen and lower testosterone levels.
Some people experience stimulants (amphetamines, cocaine) as enhancing sexual performance, but many others find they have the opposite effect. People who abuse stimulants often use high doses, and this can cause damage to small blood vessels (especially with cocaine).
Opioids (narcotics) can reduce sex drive. And large doses, such as would be given in a methadone clinic, can reduce T as well.
Blood pressure medications can be associated with ED. It's not easy to tell whether the problem is due to the high blood pressure itself and the accompanying changes in the blood vessels, or to the medications.
Antidepressants of the SSRI or SNRI type (Prozac/fluoxetine, Paxil/paroxetine, Zoloft/sertraline, Celexa/citalopram, Lexapro/escitalopram, Effexovenlafaxine, Cymbalta/duloxetine) can lessen sex drive. The usual side effect is delayed or absent orgasm, but ED can occur.
Remedies (other than psychological)
Viagra-type drugs (PDE5 inhibitors is the technical name). Viagra/sildenafil and Cialis/tadalafil are the most used; Levitra/vardenafil and Stendra/avanafil are others. They block the enzymes that break down cGMP. So, they don’t actually create an erection, but if the conditions for an erection are present, the erection will be stronger and last longer. Thus they work if the man has a sex drive and relatively intact nerves and blood vessels. The great advantage of these drugs is that they do not cause an erection in the absence of sexual stimulation; one can mow the lawn without embarrassment.
Viagra is absorbed, like most drugs, over the course of an hour, then it is eliminated gradually. The maker says the half-life is 4 hours, but their graph suggests that it’s closer to 2 hours. At 4 hours after dosing the level is less than half of the peak (which occurred at 1 hour). The half-life can vary from one person to another, and is longer in older men. Available doses are 20, 25, 50 and 100 mg.
The timing on Cialis is much more forgiving; the average half-life is 17.5 hours, but this can vary. Note, although the drug is described as lasting 2 or 3 days, the level after 1 day is about half of the peak level. The peak is reached after 2 hours (range ½ to 6 hours). Smaller doses taken daily create a near steady level of the drug after the first 5 days. Available doses are 2.5, 5, 10 and 20 mg.
Apart from the timing, Viagra and Cialis differ in side effects. Which drug gives more side effects varies by individual. Common side effects include dizziness or faintness, flushing of the face, headache or backache. Rarely, priapism can occur, an unwanted erection lasting for hours. If it lasts for 4 hours or more, emergency medical attention is recommended.
Pricing is insane, at least in the US. Figures are from GoodRx for 30 tablets, at Wal-Mart, accessed April 2021. Viagra, 100 mg, brand, $2014, generic $852, with GoodRx $26. Cialis, 20 mg, brand, $2171, generic, $1789, with GoodRx $32. Levitra, 20 mg, brand, $1610, generic $1189, with GoodRx $408.
Drugs for injection. Blood vessel dilating drugs like phentolamine can be injected into the penis, giving an erection that lasts an hour or so. The advantage here is that it bypasses the nervous system, so it will work regardless of mental state, and even in the presence of nerve damage. Intact blood circulation is still required. One disadvantage, the erection persists for an hour or so even with no sexual stimulation. (Phentolamine apparently can work by mouth as well, but the maker never sought approval in the US.) Other drugs used for injection are papaverine and prostaglandin; sometimes all 3 drugs are combined as “Tri-mix.” Prostaglandin is also available as a pellet (MUSE/alprostadil) to be inserted into the tip of the penis.
Supplements. Supplements in the US are not regulated by the FDA, so you need to trust your manufacturer. There is often limited information about effectiveness and risks. For instance, some “herbal” remedies have been found to contain Viagra, which could create a problem when taken with prescription Viagra. When studies show no effect, it is possible that some individuals will benefit from a supplement anyway. Conversely, a single study that shows a benefit may be due to chance.
L-arginine is an amino acid present in the body. It is used to make nitric oxide, so it has some blood vessel dilating properties. In theory it should help with ED, but studies have given conflicting results. People don’t have deficiencies of arginine, but it is safe to take extra. Citrulline is a related amino acid. It is converted to arginine in the body and vice versa. Again, safe, with limited evidence of effectiveness.
DHEA (dihydroepiandrosterone) is a hormonal substance in the body. It is made into testosterone and estrogen, but has weak hormonal activity on its own. With aging, DHEA levels go down. Supplementation may increase testosterone levels in women, but did not in men. Studies have not shown any benefit to muscle mass or sex drive. Again, it appears to be safe (though women may have unwanted side effects like body hair growth.)
Vitamin D is also present in the body. It is difficult to get adequate amounts in the diet; the other source is sun exposure. Deficiencies are common in people living at northerly latitudes, especially those with darker skin, and can be identified with a blood test. Vitamin D is clearly important for bone health, especially in children. In recent years, there has been great interest in using it to treat other conditions, but the evidence is not persuasive, in particular for ED. It is generally safe (toxic at high doses, probably much greater than 4,000 IU per day).
(There are many proprietary herbal preparations. Typically they are a mixture of ingredients, each with little or no convincing information.)
Mechanical remedies. Cock rings are elastic rings worn on the base of the penis, to restrict outgoing blood flow. They are not to be worn beyond 30 minutes or so. (Metal or rigid plastic rings are available, but they may be difficult to remove if the erection does not subside, so they are not really safe.) Vacuum pumps are used to induce an erection, using a cock ring to maintain it. Surgical implants can be inflatable or semi-rigid.

submitted by SeriousNep2nian to erectiledysfunction [link] [comments]

2020.10.22 16:45 JeffreyBoswell NFL Week 7 Predictions

Nashville is the big game hot spot as the Steelers and Titans engage, while the Chiefs channel “Jake the Snake From State Farm.” Jimmy Garoppolo seeks another notch in his bed post in Foxboro, and the Cardinals host the Seahawks in a huge NFC West showdown.
Note: the quotes in this article are fictional.

NY Giants @ Philadelphia (-3½)

The Giants nipped Washington, 20-19, foiling Kyle Allen's two-point conversion pass to secure the win. It was New York's first win of the season, and they are 1-5 in the NFC East.
"Daniel Jones only had one turnover," Joe Judge said. "That's a small victory. We're thinking about trademarking the 'Danny Dimes' nickname. That way, people will see ™ and not necessarily associate it with 'Turnover Machine.'
"We're 1-5, and try not to snicker when I say this, firmly in the NFC East race. It's not entirely impossible for us to win the NFC East. It is entirely possible that a NFC East team qualifies for the playoffs as a wild card."
The Eagles rallied late at Baltimore, but failed to convert a late two-point conversion and lost, 30-28.
"I give my guys an 'A' for effort," Doug Pederson said, "and a 'D-minus' for result.
"We were a playoff team last year. Now, we're 1-4-1. It's like we fell off a cliff and landed on Zach Ertz. Suffice it to say in contract negotiations, Zach's agent and our management are not on the same page. They differ on a lot of things, like the number of zeros."
Eagles win, 27-24.

Detroit @ Atlanta (-2½)

The Falcons throttled the Vikings 40-23 for their first win of the season. Matt Ryan passed for 371 yards and 4 touchdowns, two to Julio Jones.
"We embarrassed the Vikings," Ryan said, "and almost became the first team to get a coach fired two weeks in a row.
"This was our first game without Dan Quinn. We all wish Dan the best, in life and in his search for another job. He's got a good resume, so I hear he has some good 'leads.' But I'm sure he'll blow every last one of them."
The Lions beat the Jaguars 34-16 in Jacksonville, led by a rushing attack that accumulated 180 yards and 3 touchdowns.
"That's a win we really needed," Matt Patricia said. "And one I really needed. It probably saved my job. So, everything has consequences."
Falcons win, 30-27.

Cleveland @ Cincinnati (+3½)

The Bengals blew a 21-0 lead at Indianapolis and eventually lost, 31-27. Cincy fell to 1-4-1, last in the AFC North.
"Obviously," Zac Taylor said, "we're not used to playing with a lead. That's because we're not used to having a lead. And those we do have, we don't keep long enough to garner enough experience of having. It's a vicious cycle."
The Browns were smoked 38-7 by the Steelers in Pittsburgh.
"We just got physically manhandled," Kevin Stefanski said. "And I hesitate to use the word 'manhandled,' because it contains the word 'man.'
"We got down early, and soon after had to go to a different game plan. So, you could say the Steelers 'tore us a new one.'"
Browns win, 31-24.

Pittsburgh @ Tennessee (+1½)

The Steelers crushed the visiting Browns, 38-7, holding Cleveland to just 220 total yards.
"No helmets were forcefully removed during the game," Mike Tomlin said. "Just souls. And dignity. And hearts. And confidence. And any remaining belief that Baker Mayfield is a franchise quarterback.
"But moving on, our first order of business against the Titans is stopping Derrick Henry. Our second order of business is not getting stiff-armed into oblivion in the process. Trust me, no one wants to be the next Josh Norman."
The Titans beat the Texans 42-36 in overtime, led by 212 yards rushing and 2 touchdowns from Derrick Henry, including the game-winner in overtime.
"Derrick has redefined the stiff arm," Mike Vrabel said. "And redefined Josh Norman's reputation as a tackler.
"We expect to be fined by the NFL for breaking some of the league's COVID-19 protocols. So be it. We're 5-0, so when all is said and done, we just might be Super Bowl champions, despite our issues. And, we could also be voted by our peers as the NFL's 'Outbreak Performer of the Year.'"
Titans win the battle of undefeated, 27-24.

Carolina @ New Orleans (-7½)

The Saints had a Week 6 bye and are 3-2 with NFC South rival Carolina due up. Michael Thomas is expected to play for the first time since suffering an opening day ankle injury.
"Michael's ankle is fine," Sean Payton said, "but he just needs to remember that the team comes before himself. We've made Michael an appointment with not a chiropractor, but a 'Me, Myself, and I-ropractor," for an 'attitude adjustment.'
"Now, our next order of business is to get Taysom Hill an appointment with a urologist, so we can find out why he's been so 'impotent' this year."
Saints win, 28-24.

Buffalo @ NY Jets (+12½)

The Jets began the post-Le'Veon Bell era with a 24-0 loss to the Dolphins in Miami. New York is 0-6, last in the AFC East.
"Believe what you will," Adam Gase said, "but I think I'm the right coach to take this team to where it needs to go. And that's to the 2021 NFL Draft with an 0-16 record.
"We released Le'Veon, but we still have to pay him. I'm not sure how much, but I hear we're calling Le'Veon the '$6 Million Man-child.'
"There's some beef between me and defensive coordinator Gregg Williams. We don't agree on anything. One thing we can agree on is that the other is the biggest douchebag."
The Bills lost their second straight, falling 26-17 at home to the Chiefs on Monday. Buffalo surrendered 245 rushing yards, less than a week after giving up 139 in a loss to the Titans.
"That was a big loss," Josh Allen said. "But the biggest 'L' went to Josh Norman in the Titans game. He got stiff-armed into orbit by Derrick Henry. Josh got hang time that would make Ray Guy jealous. Josh is still floating. In fact, we sent him to a methadone clinic, because he still hasn't 'come down.'
"I have a feeling we'll get our rush defense issues figured out. After all, we're playing the Jets, the most dysfunctional organization in professional sports history. So, we're going to stack the box and force the Jets to throw games so they can get the No. 1 pick in the draft."
Bills win, 29-13.

Dallas @ Washington (+3)

With Andy Dalton running the show, the Cowboys offense struggled mightily in a lopsided 38-10 loss to the visiting Cardinals.
"If there's a 'new sheriff in town,'" Mike McCarthy said, "he should have Andy Dalton arrested for failure to appear. We signed Andy to be the 'Red Rifle.' What we got was the 'Red Badge of Discourage.'"
Washington lost 20-19 to the Giants at MetLife Stadium. Kyle Allen's 22-yard TD pass to Cam Sims cut the lead to one, but Allen's two-point conversion pass for the win fell incomplete.
"There's a reason they call me 'Riverboat Ron,'" Ron Rivera said, "and it's not because I was conceived on one. That was Ken Stabler. They call me 'Riverboat' because I'm not afraid to take chances. Like, taking the head coaching job of a team owned by Daniel Snyder.
"I certainly don't take full blame for all of our struggles. Jay Gruden left me a mess here in Washington. I know it's a hot-button topic in this year's election, but the 'pre-existing condition' is a big deal for me, too."
Dallas win, 27-18.

Green Bay @ Houston (+3½)

The Buccaneers blasted the visiting Packers, 38-10, as Tampa's defense got the best of Aaron Rodgers, with 4 sacks and 2 interceptions.
"Aaron really took a beating in Tampa," Matt LaFleur said. "He was sore, but he's doing much better now. So, he just wants to say to all the Packers fans out there: '(Muscle) R-E-L-A-X-ers.'
"I can promise you'll see a different Rodgers in Houston. Aaron will be in the zone. He'll be locked in. He'll be laser-focused. And he won't be stopped, especially by fans seeking autographs."
DeShaun Watson's 4 passing TDs weren't enough, as the Texans fell 42-36 in overtime to the Titans.
"I'm not sure what Romeo Crenel has against an 8-point lead," Watson said. "Has he ever heard of win probabilities? All I can say is, 'Romeo, Romeo, wherefore art thou analytics?'"
Rodgers throws 4 touchdown passes, out-duels Watson, and the Packers bounce back with a 42-35 win.

Jacksonville @ LA Chargers (-8)

The Chargers had a Week 6 bye and while last in the AFC West, the teams appears to have found its quarterback of the future in Justin Herbert.
"We're so pleased that drafting Justin in the first round worked out," Anthony Lynn said. "If you listen closely, you can even hear the sighs of relief. Or, that may just be the sound of a lung deflating."
The Lions pounded the Jaguars, 34-16, in Jacksonville. The Jags rushed for only 44 yards, while Detroit racked up 180 yards on the ground.
"We obviously have some defensive issues," Doug Marrone said. "And that falls on our defensive coordinator Todd Wash. If you'd need to reach Todd for comment, try looking 'under the bus.' I'll say this: it helps to have a last name of 'Wash' when you know you'll soon be 'done dirty.'
"Offensively, we're also not in a good place. Gardner Minshew has struggled with consistency. We still don't know if he's our quarterback of the future. All we can say for certain about him is that his parents were Lynyrd Skynyrd fans."
Chargers win, 30-17.

Seattle @ Arizona (+4)

The Seahawks emerge from their Week 6 bye with a two-game lead over the Rams and Cardinals in the NFC West.
"We spent our bye week addressing some issues on defense," Pete Carroll said. "Because it took us 14 days to cover them all.
"As long as we have Russell Wilson, we can get by. I've said for years, 'The best defense is an offense that scores more than your actual defense surrenders.'"
The Cardinals pummeled the Cowboys, 38-10, at AT&T Stadium, led by Kyler Murray's 3 total touchdowns.
"I'm still undefeated when playing at AT&T Stadium," Murray said. "What does that tell you? That I'm not a Cowboy."
Seattle wins, 27-24.

Kansas City @ Denver (+9½)

The Broncos shocked the Patriots 18-12 in Foxboro, powered by Brandon McManus' 6 field goals.
"Brandon is clearly our most valuable player," Vic Fangio said. "But you hardly ever read about him. It's the epitome of a player 'out-kicking his coverage.'
"You've probably heard about Melvin Gordon III's DUI a couple of weeks ago . Here in Denver, they're calling Melvin's DUI incident 'The Drive II.'"
The Chiefs beat the Bills 26-17 on Monday. Patrick Mahomes passed for 2 touchdowns, and the Chiefs rushed for 245 yards, including 161 from rookie Clyde Edwards-Helaire.
"This team is more than just Patrick," Andy Reid said. "Patrick is the shiny object that everyone notices, but we have an offensive line and running backs who aren't afraid to get filthy. If Patrick does commercials with 'Jake From State Farm,' our OL and RB's hobnob with 'Jake The Snake From State Farm.'
"We signed Le'Veon Bell after the Jets released him. I see that less of an acquisition and more of a rescue. I hear Le'Veon had an $8 million injury guarantee that the Jets didn't want to risk. We didn't have to offer Le'Veon anything like that. All we had to say was, 'You'll be playing on natural 'grass.'"
Chiefs win, 28-16.

San Francisco @ New England (-3)

The 49ers beat the visiting Rams 24-16 on Sunday night. Jimmy Garoppolo passed for 268 yards and 3 touchdowns.
"Jimmy is headed back to New England for the first time since the Pats traded him," Kyle Shanahan said. "And he wants nothing more than to go into Gillette Stadium and leave with a win. Of all the notches in his bedpost, and there are many, that's one he doesn't have."
Three costly turnovers doomed the Patriots in an 18-12 loss to the visiting Broncos. New England dropped to 2-3, the first time the team has had a losing record in October since 2002.
"You don't win championships in October," Bill Belichick said, "except for the NBA, NHL, and MLB this year.
"Like Cam Newton said, we're not pressing the panic button. This is New England; we don't have a panic button. We did have an eject button, which Tom Brady used when he felt threatened."
Patriots win, 24-21.

Tampa Bay @ Las Vegas (+3)

The Bucs hounded Aaron Rodgers into a miserable day on their way to a dominating 38-10 win over the Packers. Tampa improved to 4-2 and leads the NFC South by a half-game over the Saints.
"Our defense was really pumped up to face Rodgers," Brady said. "Especially Ndamukong Suh. Suh certainly made his presence known. Trust me, Rodgers heard footsteps. Heck, Suh sometimes makes you feel footsteps.
"I'm looking forward to playing in Allegiant Stadium and facing Derek Carr. Derek's a good quarterback, but he has problems with consistency. I can relate, because, at 43 years of age, I have my own problems with irregularity."
The Raiders had a Week 6 bye and trail the Chiefs by just one game in the loss column in the AFC West.
"We took down Drew Brees and the Saints," Carr said. "And I fully expect us to take down Brady and the Bucs. Those would be my two biggest wins as an NFL quarterback. Notice they didn't come in the playoffs."
Bucs win, 28-21.

Chicago @ LA Rams (-5½)

The Rams lost 24-19 to the 49ers at Levi's Stadium and fell to 4-2 and remain a game behind the Seahawks in the NFC West.
"Kyle Shanahan had a brilliant game plan," Sean McVay said. "When applied at Levi's Stadium, it was downright 'jean-ius.'
"My offense isn't the quick strike offense that people often associate with the Rams. Believe it or not, we're actually among the league leaders in time of possession. Call it the 'Slo Cal' offense."
The Bears beat the Panthers 23-16 in Charlotte, led by a defense that sacked Teddy Bridgewater 4 times and forced 3 turnovers.
"After a slow start," Matt Nagy said, "our defense is coming together. They really look strong. Heck, even Buddy Ryan is sitting up and taking notice, and he's dead.
"Nick Foles is proving his worth as a leader. How do I know Nick is a leader? Because he's putting up stats comparable to those of Mitch Trubisky, and we're still winning."
Rams win, 28-20.

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2020.04.22 09:46 NathanSlothchild The most "anti-depressive" minerals I know (with a few hormones).. and I've tested them all. There are 6 I've found help me most.

**This is extremely long ***Scroll down then commit to reading this mess I refuse to neatly format for anyone, as it took me that long to write.
This could help a few people in a big way.
The most anti-depressive minerals I know. Where lithium is important to talk about, I'd still start with Boron.
Boron from sodium tetraborate, yes, from regular cheap Borax is the best I've tried & I've tried them all! I don't like this form because it's cheaper. I don't really care about the price I just notice it actually works the best.
I like it better than the "TripleBoron" bottles too. Or the chelated versions from GNC that sometimes made me a bit fuzzy or irritable. They just don't process cleanly at any dose. The "3mg" chelated I'm talking about, which they don't even name the actual chelated version on the bottle. Don't take that type of Boron. That's my own recommendation.
Pure, natural borax is very clean & your body appears to assimilate it much better for hormones, pain & energy. The fact that certain people also seem to hate this recommendation, makes me believe the boron conspiracy could be real. Maybe I do believe that certain biochemical investors have stocks in big pharma, suboxone, methadone, fentanyl, and are trying to steer arthritic / pain dependent prospects away from effective minerals like boron.
People older than 30 need about 30-50mg of Boron from Borax everyday for proper hormone production, balance, enzymatic function, bone function, pain, arthritis. Something close to this was cited by a doctor in a YT video I saw who knew more about Boron than any other person in the world. Unfortunately did not bookmark it. It's still up there somewhere.
Boron is sooo underrated & most people don't get the right form at the right dose. That's around 300-500mg of actual borax for that % of boron.
It's not just "safe" but your body craves boron in this form & dose. Don't go too much higher. Yes it can also push down riboflavin (slightly) but that's why I throw a multi-vitamin at the end.
Certain minerals just aren't smart at higher doses & can be toxic. Many redditors already know this. Boron is a good example like selenium. Your body needs both, too high of either can become toxic, but too high of anything can be toxic, so I never go "unreasonably high" with any of my doses of anything. That's likely Rule #1 of Supplement Club. Even the Boron, personally I only do 200mg a day. Which I worked up to from 100mg a day for 1 week. The higher I go the better I feel in every respect. I will likely slow down at 300mg.
Then Iodine. Normal liquid potassium iodide solution is highly underrated when taken with HIGH PROTEIN meals & boron at the same time. I find that higher doses of iodine not taken with lots of protein, it just gives you lots of catalysts in the blood with nothing to charge. This state of too much iodine & too little food can drive you into anxiety. That's all I'll say about iodine & anxiety because it helps me a lot more for anxiety just by keeping my mood elevated.
Lets not forget that iodine is also what converts ephedrine into methamphetamine. Iodine is a very special catalyst. But very strong. So keep the dose lower, start with 225mcgs, but see how quickly you can get to 550mcgs (as you likely won't feel 225mcgs at all, it's low)... then 1100mcgs. Don't go any higher unless you really feel you need it would be my advice. If I do 1100mcgs at once I become a fair bit too wired. Like I am right now. In production mode. But when spaced throughout the day with food in smaller doses I never get sleepy after I eat, I digest better, my food seems to be used to actually improve my mood, rather then just make me feel sluggish afterward. Boron also has this effect in me. Never eat any food without a low dose of iodine & boron together at every meal. Seriously.
I've experimented with lower doses of iodine in the past, I left, then came back to slightly higher doses & now I see why various people never shut up about it. And they shouldn't shut up. And I won't either. Iodine is awesome & so is Boron.
ps. I know people do much higher doses but seriously, 1000mcg should be plenty high enough to get most peoples levels back up, or "feel" them coming up the first few days. I see other people doing 12.5mg (miligrams) iodine, some doing 50mg... personally I think that's insane & overcharging the thyroid with too much iodine. This is how good meth is destroyed & I suspect also a good thyroid.
On to lithium.
Now if you add 2mg of lithium orotate on top with just 8mg of iron, these 2 also help a lot with mood. You can surely take lithium by itself. But I just take my low dose with iron. And only take it the first 3 days of every week. It seems to wear off after 3 more days, I spend 1 day feeling a bit lithium deficient... then add a low dose back in on Monday again.
The combination of boron, iodine & lithium are unbelievably powerful for mood.
Now to prevent other electrolytes from being thrown off, that also impact mood (synergistically) add 2000 mg potassium citrate. Why? I can only say that until adding potassium I never realized how key it is for simply battling stress. It really keeps my heart in check like I know for that full day if I start off with a good dose of potassium.. my heart just behaves "properly". No speedy beats, no skipped beats, my heart relaxes, slows down & beats nice & normal.
And to prevent sodium imbalance from too much potassium I always throw a bit of sodium in there from table salt, usually around 1gm is perfect for me.
Magnesium for me is not that anti-depressive. If you're deficient you'll definitely feel better getting your levels up. That's how I felt the first half year or so. When your levels get up, around 1-2 yrs taking higher doses of magnesium I noticed it was making me too lethargic & tired... and rather than boost my mood it started making me depressed. I could have veered into "hypermagnesia" or too much magnesium for a short period.
So I dropped the dose a lot and now that's what I take. You can play with magnesium dosing, see how lower vs higher doses of calcium effect your mood. I always rely on my mood to change dosing and it seems to never fail me. I understand the lower / upper limits, costs / rewards, and make very basic, reasonable calculations.
Some people might do 6gms potassium citrate a day, or 10gms, I really think 2-4gms is plenty for most people.
Let me mention I also workout / run 5 days a week. If you don't, maybe test half all these doses then double them a month down the road. I don't know. Personally I think regardless of age that we all pee out these things way more than we take them in. That's my suspicion.
Now if you add these last 3-4 things on top of this, it will supercharge everything to a different stage.
DHEA I would not experiment with unless I was over 30. You really shouldn't need DHEA at a much younger age unless you have a history of abusing opiates. As opiates can cause OPIAD, opiate induced androgen deficiency syndrome. DHEA helps correct this. It also seems to help correct just getting past the age of 30.
Add in 12.5mg sublingual DHEA. Test this dose for a month. Then raise to 25mg sublingual after 1 month. 12 months of low dose sublingual DHEA can boost your endorphins / enkalphalins by a level of >>>4. This is very significant in terms of depression. After 12 months levels won't go much higher. But those very power morphine compounds in your brain.. that are 19xs stronger than morphine itself... are also very powerful anti-depressants. More powerful than other basic hormones DHEA helps boost like testosterone (through androstenediol), estrogen, pushes cortisol levels down, fires up endorphins & nitric oxide that make you relaxed & happy.
If you presently do a higher dose of oral DHEA, you're totally doing it wrong imho.
I also keep pregnenolone around the house too. I use to do a low dose but like DHEA better for now. I'm not gonna rant about this.
7,500IUs vitamin D stacked with a multi-vitamin, the last 2 ingredients.
If you suffer from minor depression, moderate depression, severe depression, that you think is being caused chemically... consider targeting everything I mentioned above.
This is most of what I do everyday & the strongest are really the Boron, Iodine, Lithium, DHEA, vitamin D & Iron. Those 6 taken the right way at the right dose should really be able to shed most your depression. Anyone with mood problems, focus on those 6 before you crawl too deep into the supplement hole.
After many many years taking supplements, those 6 are consistently the best anti-depressants I've come across. SAMe is also great but I want to avoid amino acids for the sake of avoiding a very large rabbit hole. We can avoid that rabbit hole by most people just eating enough protein.
Good luck to anyone suffering mood or motivation problems I should also mention that I've become productive to a level I never thought possible. Just by learning to supplement right. CHEERS!

submitted by NathanSlothchild to Supplements [link] [comments]

2020.01.20 07:50 Dirtclodkoolaid Individual Variation in Opioid Metabolism by Zyp Czyk

Though this article is a decade old by now, the biological processes of opioid metabolism haven’t changed, so it’s still entirely valid. It points out several reasons why prescribing standard doses of opioids is not a valid medical practice.
Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability.
Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids.
However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified.
For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease).
This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management.
Articles selected for inclusion discussed
general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events. Experienced clinicians are aware that the efficacy and tolerability of specific opioids may vary dramatically among patients… I would have thought that the CDC would listen to “experienced clinicians”, not just self-appointed “experts”, to confirm that standard doses for opioids are not medically appropriate, no matter how politically desirable (and idiot-proof) they may be.
…and that trials of several opioids may be needed before finding one that provides an acceptable balance of analgesia and tolerability for an individual patient.
Pharmacodynamic and pharmacokinetic differences underlie this variability of response.
Pharmacodynamics refers to how a drug affects the body, whereas pharmacokinetics describes how the body alters the drug. Pharmacokinetics contributes to the variability in response to opioids by affecting the bioavailability of a drug, the production of active or inactive metabolites, and their elimination from the body. Pharmacodynamic factors contributing to variability of response to opioids include between-patient differences in specific opioid receptors and between-opioid differences in binding to receptor subtypes. The receptor binding of opioids is imperfectly understood; hence, matching individual patients with specific opioids to optimize efficacy and tolerability remains a trial-and-error procedure. This is another factor that makes standard doses an ignorant political stance that has nothing do to with the practice of medicine.
BASICS OF OPIOID METABOLISM
Metabolism refers to the process of biotransformation by which drugs are broken down so that they can be eliminated by the body.
Some drugs perform their functions and then are excreted from the body intact, but many require metabolism to enable them to reach their target site in an appropriate amount of time, remain there an adequate time, and then be eliminated from the body.
This review refers to opioid metabolism; however, the processes described occur with many medications.
Altered metabolism in a patient or population can result in an opioid or metabolite
leaving the body too rapidly, not reaching its therapeutic target, or staying in the body too long and producing toxic effects. Opioid metabolism results in the production of both inactive and active metabolites.
In fact, active metabolites may be more potent than the parent compound. Thus, although metabolism is ultimately a process of detoxification, it produces intermediate products that may have clinically useful activity, be associated with toxicity, or both.
However, several general patterns of metabolism can be discerned. Most opioids undergo extensive first-pass metabolism in the liver before entering the systemic circulation. First-pass metabolism reduces the bioavailability of the opioid. Opioids are typically lipophilic, which allows them to cross cell membranes to reach target tissues.
Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P450 (CYP) enzymes. Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione. Opioids undergo varying degrees of phase 1 and 2 metabolism. Phase 1 metabolism usually precedes phase 2 metabolism, but this is not always the case. Both phase 1 and 2 metabolites can be active or inactive.
FACTORS INFLUENCING OPIOID METABOLISM
Metabolic Pathways
Opioids undergo phase 1 metabolism by the CYP pathway, phase 2 metabolism by conjugation, or both.
Phase 1 metabolism of opioids mainly involves the CYP3A4 and CYP2D6 enzymes.
The CYP2D6 enzyme metabolizes fewer drugs and therefore is associated with an intermediate risk of drug-drug interactions.
Drugs that undergo phase 2 conjugation, and therefore have little or no involvement with the CYP system, have minimal interaction potential.
Phase 1 Metabolism
The CYP3A4 enzyme is the primary metabolizer of fentanyl and oxycodone, although normally a small portion of oxycodone undergoes CYP2D6 metabolism to oxymorphone (Table 1).
Tramadol undergoes both CYP3A4- and CYP2D6-mediated metabolism.
Methadone is primarily metabolized by CYP3A4 and CYP2B6; CYP2C8, CYP2C19, CYP2D6, and CYP2C9 also contribute in varying degrees to its metabolism.
The complex interplay of methadone with the CYP system, involving as many as 6 different enzymes, is accompanied by considerable interaction potential.
TABLE 1. Metabolic Pathway/Enzyme Involvement
Each of these opioids has substantial interaction potential with other commonly used drugs that are substrates, inducers, or inhibitors of the CYP3A4 enzyme (Table 2).
TABLE 2. Cytochrome P450 3A4 Substrates, Inhibitors, and Inducers
The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone,codeine, and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation.
These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors, tricyclic antidepressants, β-blockers, and antiarrhythmics; an array of other drugs are substrates, inducers, or inhibitors of the CYP2D6 enzyme.
TABLE 3. Cytochrome P450 2D6 Substrates, Inhibitors, and Inducers
Although CYP2D6-metabolized drugs have lower interaction potential than those metabolized by CYP3A4, genetic factors influencing the activity of this enzyme can introduce substantial variability into the metabolism of hydrocodone, codeine, and to a lesser extent oxycodone.
Allelic variants altering CYP2D6-mediated metabolism can be associated with reduced efficacy of hydrocodone or increased toxicity of codeine, each of which relies entirely on the CYP2D6 enzyme for phase 1 metabolism.
Phase 2 Metabolism
Morphine, oxymorphone, and hydromorphone are each metabolized by phase 2 glucuronidation and therefore have little potential for metabolically based drug interactions.
Oxymorphone, for example, has no known pharmacokinetic drug-drug interactions, and morphine has few.
However, the enzymes responsible for glucuronidation reactions may also be subject to a variety of factors that may alter opioid metabolism.
The most important UGT enzyme involved in the metabolism of opioids that undergo glucuronidation (eg, morphine, hydromorphone, oxymorphone) is UGT2B7.
The activity of UGT2B7 shows significant between-patient variability, and several authors have identified allelic variants of the gene encoding this enzym
…at least 2 allelic variants (the UGT2B7-840G and -79 alleles) have been linked to substantial reduction of morphine glucuronidation, with resulting accumulation of morphine and reduction in metabolite formation.
Clinical Implications of Metabolic Pathways
Most opioids are metabolized via CYP-mediated oxidation and have substantial drug interaction potential.
The exceptions are morphine, hydromorphone, and oxymorphone, which undergo glucuronidation
In patients prescribed complicated treatment regimens, physicians may consider initiating treatment with an opioid that is not metabolized by the CYP system.
However, interactions between opioids that undergo CYP-mediated metabolism and other drugs involved with this pathway often can be addressed by
careful dose adjustments, vigilant therapeutic drug monitoring, and prompt medication changes in the event of serious toxicity. Response to individual opioids varies substantially, and factors contributing to this variability are not clearly understood. This is why standard doses of opioids are so stupid and medically inappropriate. Of course, this doesn’t prevent ignorant politicians from coming up with their own uninformed ideas about some “standard” regulations.
Because an individual patient’s response to a given opioid cannot be predicted, it may be necessary to administer a series of opioid trials before finding an agent that provides effective analgesia with acceptable tolerability
In some patients, the most effective and well-tolerated opioid will be one that undergoes CYP-mediated metabolism.
In short, for some patients, selecting an opioid without considerable potential for drug interactions may not be possible. Again, it’s clear that there are no standard rules possible because our bodies are all so different.
Under such conditions, an understanding of opioid metabolism can guide dose adjustments or the selection of a different opioid when analgesia is insufficient or adverse events are intolerable.
PRODUCTION OF ACTIVE METABOLITES
Altered metabolism due to medical comorbidities, genetic factors, or drug-drug interactions may disrupt the balance of metabolites, thereby altering the efficacy and/or tolerability of the drug.
Moreover, opioids that produce metabolites chemically identical to other opioid medications may complicate the interpretation of urine toxicology screening. This is a huge problem with urine drug screens because the opioid you are prescribed may show up as a different one in the drug screen after it’s been metabolized.
TABLE 4. Major Opioid Metabolites
Codeine
Codeine is a prodrug that exerts its analgesic effects after metabolism to morphine. Patients who are CYP2D6 poor or rapid metabolizers do not respond well to codeine.
Codeine toxicity has been reported in CYP2D6 poor metabolizers who are unable to form the morphine metabolite and in rapid metabolizers who form too much morphine
Morphine
In addition to its pharmacologically active parent compound, morphine is glucuronidated to 2 metabolites with potentially important differences in efficacy, clearance, and toxicity:
morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). The M3G metabolite of morphine lacks analgesic activity, but it exhibits neuroexcitatory effects in animals and has been proposed as a potential cause of such adverse effects as allodynia, myoclonus, and seizures in humans
In a clinical trial, however, low-dose M3G exhibited no analgesic effects, did not potentiate the analgesic effects of morphine or M6G, and did not produce adverse effects
Hydromorphone
The primary metabolite of hydromorphone, hydromorphone-3-glucuronide, has neuroexcitatory potential similar to or greater than the M3G metabolite of morphine.
hydromorphone is available only in short-acting formulations and extended-release formulations are recommended in patients with chronic pain requiring long-term therapy.
Tramadol
Like codeine, tramadol requires metabolism to an active metabolite, O-desmethyltramadol (M1), to be fully effective.
The parent compound relies on both CYP3A4 and CYP2D6, with metabolism of M1 relying on CYP2D6
Both tramadol and its M1 metabolite exert analgesic effects through opioidergic mechanisms (μ-opioid receptor) and through 2 nonopioidergic mechanisms, serotonin reuptake inhibition and norepinephrine reuptake inhibition
tramadol-mediated analgesia appears to depend on the complementary contributions of an active metabolite with a route of metabolism that differs from that of the parent compound.
Oxycodone
Oxycodone is metabolized by CYP3A4 to noroxycodone and by CYP2D6 to oxymorphone.
The central opioid effects of oxycodone are governed primarily by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites
OPIOIDS WITHOUT CLINICALLY RELEVANT ACTIVE METABOLITES
Fentanyl, oxymorphone, and methadone do not produce metabolites that are likely to complicate treatment.
Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite
An active metabolite of oxymorphone, 6-hydroxy-oxymorphone, makes up less than 1% of the administered dose excreted in urine and is metabolized via the same pathway as the parent compound, making an imbalance among metabolites unlikely.
Methadone does not produce active metabolites, exerting its activity—both analgesic and toxic—through the parent compound
ADHERENCE MONITORING: THE IMPORTANCE OF ACTIVE METABOLITES
Opioids that produce active metabolites structurally identical to other opioid medications can complicate efforts to monitor patients to prevent abuse and diversion.
Current urine toxicology tests do not provide easily interpretable information about the source or dose of detected compounds.
Thus, in a patient prescribed oxycodone, both oxycodone and oxymorphone will appear in toxicology results
Patients treated with codeine will have both codeine and morphine in urine samples.
The urine of patients treated with morphine may contain small amounts of hydromorphone (≤2.5% of the morphine concentration).
Similarly, those treated with hydrocodone may test positive for both hydrocodone and hydromorphone.
POPULATION PHARMACOKINETICS
Opioid metabolism differs with individual opioids in populations stratified according to age, sex, and ethnicity (Table 5).
Reduced clearance of morphine, codeine, fentanyl, and oxymorphone has been reported in older patients.
Oxycodone concentrations are approximately 25% higher in women than in men after controlling for differences in body weight, making it important for physicians to consider the patient’s sex when prescribing this opioid.
As already stated, altered opioid metabolism in ethnic populations is also a byproduct of allelic variants of the gene encoding CYP2D6.
TABLE 5. Demographic/Medical Factors Influencing Opioid Metabolism
Given the genetic variability of metabolism in specific ethnic populations, it may make sense for patients with an unexplained history of poor response or an inability to tolerate a particular opioid to be switched to an opioid that relies on a different metabolic pathway.
MEDICAL CONDITIONS
Hepatic Impairment
The liver is the major site of biotransformation for most opioids (Table 4). It is therefore not surprising that the prescribing information for most frequently prescribed opioids recommends caution in patients with hepatic impairment.
The pharmacokinetics of fentanyL and methadone, 2 of the frequently used opioids, are not significantly affected by hepatic impairment.
Renal Impairment
The incidence of renal impairment increases significantly with age, such that the glomerular filtration rate decreases by an average of 0.75 to 0.9 mL/min annually beginning at age 30 to 40 years.
Because most opioids are eliminated primarily in urine, dose adjustments are required in patients with renal impairment.
CLINICAL IMPLICATIONS OF MEDICAL CONDITIONS
The selection of an opioid analgesic may be affected by comorbidities and diminished organ reserve.
Health care professionals need to be especially cautious when dealing with patients with diminished metabolic capacities due to organ dysfunction. In general, dose reduction and/or prolongation of dose intervals may be necessary depending on the severity of organ impairment.
Moreover, clinicians should adopt a “start low and go slow” approach to opioid titration when hepatic or renal impairment is a factor. This is nothing new since that’s how opioids should always be prescribed: tailored to the individual patient. Only lately has the misguided idea of “standardization” invaded the medical treatment of pain.
CONCLUSION
Patient characteristics and structural differences between opioids contribute to differences in opioid metabolism and thereby to the variability of the efficacy, safety, and tolerability of specific opioids in individual patients and diverse patient populations.
To optimize treatment for individual patients, clinicians must understand the variability in the ways different opioids are metabolized and be able to recognize the patient characteristics likely to influence opioid metabolism. This information directly contradicts any standardization of opioid dosages, but that hasn’t stopped more and more politicians and “medical groups” from implementing policies that reject, and sometimes forbid outright, the proper medical care for pain.

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2019.12.09 19:21 kittybikes47 If someone is kind and helps you out a few times, do not decide that gives you clearance to stop by their house unannounced every time you blow your life up (again) to beg that person for stuff.

FFFFFFFFUUUUUUUCCCCCCCKKKKKK!
I am a friendly person, I talk to strangers. I saw a woman sitting on the curb crying a couple months ago, so I stopped and asked her if she was ok. She had a meltdown, told me her life story, plus a bunch of crazy lies. (I don't think she is actually Aleister Crowley's daughter, has a PhD in genetics, or a bunch of other absolutely bonkers claims.) I asked her to wait there and ran to my nearby house. (Don't like people to know where I live.) I made her a sandwich, grabbed a little weed and a few bucks (I'm poor af, it's all I could spare.) and went back and gave it to her. Then I made a mistake and gave her my #.
She started texting constantly. Mostly just to talk about nothing important, but often asking for $ or weed. I'm a student, my hubby works but we live paycheck to paycheck. We are not wealthy, or even close. The worst was the lies though. She's clearly on meth constantly. I've been around the block, I know what tweekers are like. Also, the first time I stopped by her house she greeted me with a piece of tinfoil, a lighter, and a cut off straw in hand. Yet she swears she's not on meth. I mean, do your thing, I'm not your mom, but don't lie!
Then one day I was leaving for class and she was leaving the tweeker hovel across the street. She saw me and hence found out where I live.
She started coming by unannounced at all hours. I explained that my husband has PTSD and severe anxiety and strange knocks on the door set him to panic mode. The visits slowed down but some highlights include...
Sticking her head in my bedroom window at 6 a.m. because her methadone clinic refused to dose her because she was clearly drunk. Asked us for $30 so she could buy heroin.
Again, coming by because methadone clinic won't dose her. They breathalyzed her, even though she smelled like a distillery and a breathalyzer was unnecessary. She had a Capri Sun pouch in hand, claimed she doesn't even drink, her body converted the Capri Sun to booze.
And then just now, stuck her head in my window, crying about something. I finally had enough. My husband is home sick, I have school soon, I am not up for humoring her lying are this morning.
But now I feel like an asshole. So I made this post to get it out. If you made it this far, thanks for reading.

submitted by kittybikes47 to Vent [link] [comments]

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