Talk:Morphine

Large quotes

We cannot use large quotes so reverted.[1] This is also though of as a medication first so we should mention that first. Doc James (talk · contribs · email) 04:00, 13 October 2016 (UTC)

Fine. Seppi333 (Insert 2¢) 21:46, 13 October 2016 (UTC)

Pharmacokinetics wrong

The pharmacokinetics in the Infobox and those in the article are wrong/inconsistent. One source for the Infobox is specifically only for the rectal route, and the other for children. Peak plasma onset for oral route (PO) is, for example, widely quoted as 30–90 minutes, not 20 (Infobox) nor 30 (text). One better source (of thousands) might be PMID 2057987, though there are probably better or at least newer. — Preceding unsigned comment added by 71.93.151.83 (talk) 18:06, 22 July 2017 (UTC)

Wording

No sure why the spelling was changed from British to American or the simplification in the lead was removed?[2]

Not sure what thuis means "morphine msy affect the baby"

Doc James (talk · contribs · email) 14:47, 12 December 2018 (UTC)

Still not sure why the spelling was changed. Also it is recommended to simplify the lead per WP:MEDMOS. Doc James (talk · contribs · email) 12:43, 13 December 2018 (UTC)

Therapeutic dose and fatal dose

The concern with morphine and all opioids is the window between therapeutic and over- doses. But nowhere in the article is this made apparent. We don't know what dose is overdose?! I can't find any non-animal studies. Obviously, we can't actually conduct a study, but we could know from survey and accidental overdoses, what the fatal dose is; I think we do know. And what's the minimum therapeutic dose for acute and chronic pain? Any help? Sbalfour (talk) 17:48, 1 December 2019 (UTC)

Relatedly, it would be useful to know the naturally occurring concentration of morphine or its metabolites in e.g. blood or urine. I cannot find this information anywhere, although it must be very important in interpreting drug tests. A5 (talk) 16:26, 11 January 2020 (UTC)

Proper classification of morphine

The article for Dopamine opens with "Dopamine (...) is an organic chemical of the catecholamine and phenethylamine families. It functions both as a hormone and a neurotransmitter, and plays several important roles in the brain and body."

By contrast, the opening sentence of this article has tended to prioritize the medical and commercial applications of morphine over its function in nature. Compare the following revisions:

2008 "Morphine is a highly potent opiate analgesic drug and is the principal active agent in opium and the prototypical opioid."

2011 "Morphine (MS Contin, MSIR, Avinza, Kadian, Oramorph, Roxanol, Kapanol) is a potent opiate analgesic medication and is considered to be the prototypical opioid."

2014 "Morphine (sold under nearly a hundred trade names) is an opioid analgesic drug, and the main psychoactive chemical in opium."

2017 "Morphine is a pain medication of the opiate type which is found naturally in a number of plants and animals."

2019 "Morphine is a pain medication of the opiate family which is found naturally in a number of plants and animals."

It is apparent that the emphasis has been gradually changing, perhaps reflecting growing awareness among scientists and even medical professionals of the natural role of morphine in the human and animal body. However the current version still seems wrong to me. Why would we describe a natural signaling molecule as first and foremost a "pain medication"? And under what circumstances is it proper to emphasize the commercial and medical applications of a substance over its natural biological role? Consider the article for Human Growth Hormone, which doesn't even mention drug applications of HGH until the second paragraph. Consider the article for Water, which doesn't get into the economic significance of water until the fourth paragraph.

However, I'm wondering what is the correct description to use. Is morphine a hormone or a neurotransmitter or both (like dopamine)? Are these terms even very precise? I've found a number of scientific papers talking about the synthesis of morphine in the body, but none of them seem to adopt a terminology for describing its function. A5 (talk) 16:26, 11 January 2020 (UTC)

I was under the impression that morphine is a secondary metabolite produced by a few plants and not by animals in which case it is not a neurotransmitter. PMID 22578954 describes it as a homeopathic regulator which immediately raises alarm bells. PMID 23266549 which provides more details concerning the biosynthesis in animals is more plausible, but I am still skeptical that morphine can be classified as an endogenous neurotransmitter. In general, I am in favor of describing the natural role of endogenous hormones and neurotransmitters first and their use of drugs second, but in this particular case, the role of morphine as an endogenous neurotransmitter is somewhat dubious. In contrast, the application of morphine as a medication derived from plant sources is not at all in doubt. Boghog (talk) 17:47, 11 January 2020 (UTC)

Thanks @Boghog:. I saw those papers, but what does "homeopathic concentrations" mean? Based upon my understanding of homeopathy, I thought that meant "less than one molecule" which is why I stopped reading the paper at that point. And what do you mean by "alarm bells"? Is there a suggestion of bad faith or just that the researchers don't know what they are doing? On p. 9786 of PMID 3467337, from 1986, it describes measuring morphine concentrations of 5-25 pmol/g, which seems like 1-7 parts per billion, in the cow's brain. This corresponds to a total of several micrograms, indeed small compared to the dosage of morphine as a drug, but maybe not small given what could be expected to cross the blood-brain barrier when injected as a typical 2mg dose for humans? And for example this article describes reference HGH concentrations in humans of 5 parts per billion, which is in the same range. Here is a paper PMID 26123500 describing dopamine concentrations in the brain of 1.5 parts per billion (0.3 - 8 ppb), which is again similar. Is there some criterion for deciding whether a molecule is important in the body in this concentration? Are you suggesting that morphine only exists in the body as a metabolite of some more important molecule? What other molecules are known to activate the same receptors? Let me know if I'm reading these wrong, but the only difference I see is that morphine is much more profitable than the other molecules - which seems hardly relevant to its biological classification. A5 (talk) 07:26, 13 January 2020 (UTC)

but what does "homeopathic concentrations" mean? is an excellent question which I am not sure of the answer myself. If they mean it in a literal sense, then I completely agree with you ("alarm bells" ≡ "why I stopped reading the paper"). But what I suspect they meant is very low concentrations, but still more than one molecule. Please keep in mind that the binding of morphine to its receptor is completely reversible and hence its activity is thresholded. If the level of endogenous morphine never reaches its threshold value, the receptor will not be significantly occupied and hence the endogenous morphine will have no pharmacologic effect, in which case it cannot be classified as a neurotransmitter. So the critical question is does the concentration of endogenous morphine ever get close its EC₅₀ value (i.e, EC₅₀/10 = 1.8 nM/10 = ~0.18 nM)? The literature that you quote is signficantly below that value. Boghog (talk) 11:03, 13 January 2020 (UTC)

Another important consideration is that neurotransmitters get concentrated synaptic vesicles that are released into synapses. In addition, the neurotransmitters are either quickly degraded or reabsorbed into neurons, so that transient concentrations can be quite high, but quickly return to a low level. This type of regulation is essential to signal transduction. Is there any evidence of similar regulation of morphine? Without signal transduction, morphine cannot be considered a neurotransmitter. Boghog (talk) 19:19, 13 January 2020 (UTC)

@Boghog: is there a reference for this EC₅₀ value of 1.8 nM? Thanks. A5 (talk) 01:37, 14 January 2020 (UTC)

This article contains one (see Morphine#Pharmacodynamics first table, μ-opioid receptor reference #54). Boghog (talk) 04:16, 14 January 2020 (UTC)

PMID 15917730, 19456354 provide evidence that morphine functions as a neurotransmitter. However both of these reviews describe this as a hypothesis. The previously mentioned PMID 23266549 also discusses the possibility that morphine is a neurotransmitter, but stops just short of concluding that it is. From the sources, I think it is fair to conclude that endogenously produced morphine may have physiological roles, but so far, this is unproven. Boghog (talk) 06:42, 14 January 2020 (UTC)

@Boghog: Thank you for checking those out. You said "The literature that you quote is signficantly below that value" but I get (1.8nmol/liter)*(285 g/mol)/(1g/mL) = 0.513 ppb... The 1-7 ppb I quoted for naturally occurring levels in cow brain is significantly above that level. Have we made a mistake somewhere? As for the other articles, it seems we are finding the same thing. I could check a textbook at the library, but I couldn't find anything online which comes out and says morphine is a hormone, or morphine is a neurotransmitter. Your (implied) suggestion of comparing the EC₅₀ with the natural background in one animal species, finding it lower, and concluding morphine's natural role as a signalling molecule, is probably going to be considered synthesis. Let me know if you can see a way around though. A5 (talk) 22:45, 15 January 2020 (UTC)

@A5: Opps, I misread pmol/g as pmol/L. Since it is mostly water, 1 g of brain homogenate is approximately 1 mL. Hence pmol/g = pmol/mL = nmol/L = nM. But this causes a new problem since it is above the EC₅₀ of the mu receptor which would imply it would be permanently switched on and therefore incapable of transmitting signals. The overall concentration of morphine in homogenate may not represent the synaptic concentration however if it the morphine were concentrated in vacuoles like other neurotransmitters and transiently released for signaling. But the evidence for this is not conclusive. It is also quite possible that the overall concentrations in disrupted brain homogenate may not reflect the concentrations in an intact living brain. Again, I think a fair to concluded from the available secondary sources, that endogenously produced morphines may have a biological function, but this has not been proven. Hence I believe that the order of presentation, starting with drug (whose effects are not in doubt) followed by endogenously produced morphine (whose function is still in question) is appropriate . Boghog (talk) 06:07, 16 January 2020 (UTC)

I added Morphine#Human biosynthesis a while back. I concur with Boghog's conclusion that it appears to have a biological function, though not necessarily as a neural signaling molecule, but this hasn't yet been established in the literature. Seppi333 (Insert 2¢) 00:25, 16 January 2020 (UTC)

@Seppi333: Thank you. After some thought, I'm inclined to WP:BB and put the facts that we do know in the order of their importance. Boghog's linked Zhu and Stefano 2009 (PMID 19456354) says in conclusion "Furthermore, endogenous morphine participates in physiological processes transcending pain, making it an important chemical messenger" which "functions as an information transmitter in plants, invertebrates, and mammals". So it is at least a "chemical messenger" and "information transmitter" in "plants, invertebrates, and mammals". I would argue that these facts about morphine take precedence to its use by humans as a pain medication, and should therefore be stated first. I'll probably think about it for a few more days, but would encourage anyone who is interested in doing so to take a stab at reorganization of the first paragraph along these lines.

I would also like to see a historical context paragraph including this data about morphine biochemistry research from Zhu and Stefano's abstract: "For many years it has been believed that animals cannot make morphine. However, within the last 30 years scientific documents have emerged reporting on endogenous animal opiate synthesis, including morphine biosynthesis in animals and specific tissues". I think this data would be helpful in reorienting readers who may be confused by the proposed reclassification. Thanks. A5 (talk) 02:44, 16 January 2020 (UTC)

I agree, a paragraph on historical context would be a useful addition. There's probably more on that in the article itself; it's been a few years since I last read Stefano's 2011 review on it (see "Historical perspectives"), so I don't remember what it says about that beyond what I originally cited. Seppi333 (Insert 2¢) 02:51, 16 January 2020 (UTC)

I'm reading through this paper right now; it's an RCT investigating the involvement of neural morphine signaling in mindfulness-induced increases in pain tolerance, since that apparently isn't associated with endogenous opioid peptide signaling. It appears to be one of the newest research papers which investigated this topic.

Another primary study (PMID 26350413) also mentions this: Endogenous morphinergic signaling, in concert with NO-coupled signaling systems, has evolved as an autocrine/paracrine regulator of metabolic homeostasis, energy metabolism, mitochondrial respiration and energy production. Basic physiological processes involving morphinergic/NO-coupled regulation of mitochondrial function, with special emphasis on the cardiovascular system, are critical to all organismic survival. Key to this concept may be the phenomenon of mitochondrial enslavement in eukaryotic evolution via endogenous morphine. Addendum: there are 8 review articles that cite this study.

We should cite reviews that cover the discussion and/or findings from these papers if/when any are published though. Seppi333 (Insert 2¢) 03:06, 16 January 2020 (UTC)

@Boghog: you said "Hence I believe that the order of presentation, starting with drug (whose effects are not in doubt) followed by endogenously produced morphine (whose function is still in question) is appropriate". But we have a reputable source stating that morphine is a chemical messenger in plants, invertebrates, and mammals. What else is required? Did you find someone questioning this fact in the (recent) scientific literature, or is the doubt all coming from your own speculation? A5 (talk) 03:01, 17 January 2020 (UTC)

What else is required? Specifics as to the function and mechanism. The quote that you mention is from Zhu & Stefano (2007) PMID 19456354 which contains a lot of self citing. Laux-Biehlmann (2013) PMID 23266549 which is more extensive and up-to-date and contains much less self-citation, is more cautious in its conclusions:

“ Although no clear function has yet been attributed to EM [endogenous morphine] and EMM [endogenous morphine metabolites] in the CNS, their presence in specific neurons and astrocytes cannot be considered as fortuitous. ”

There is another issue of WP:WEIGHT and WP:PRIMARYTOPIC. The scientific literature on the medicinal uses of morphine significantly outweigh the function of endogenous morphine. Most readers are probably coming here to read about the drug and not it endogenous counter part. Both the policy and guideline would argue that most of the article should be about the drug and treatment of the drug should come first. The only other option would be to split the article into two, one focusing on the drug, and the second on endogenous morphine and for the reasons already stated, the drug would have to be considered the primary topic. Boghog (talk) 17:00, 17 January 2020 (UTC)

@Boghog: thank you for your perspective, which I value. I still think your request for more specifics is a red herring, since we will never know everything there is to know. Laux / Laux-Biehlmann does not cast doubt on the chemical messenger status of morphine, and in fact supports its role as a neurotransmitter in Purkinje cells, citing himself (Laux 2011, PMID 21456021), where he mentions that morphine may be "cosecreted with other neurotransmitters in the CNS"; and Muller 2008 PMID 18327293, which states "The presence of morphine in the brain and its localization in particular areas lead us to conclude that it has a specific function in neuromodulation and/or neurotransmission". As I said - we will never know everything, which means that certain aspects of this topic will always be under debate - is it a neurotransmitter, a neuromodulator, a hormone? - but there are quite a few basic facts which seem to be undisputed in 2020. One of these facts is that morphine is a chemical messenger in mammals.

However, you do have a point about undue weight. A Google search for "morphine research" turns up not a single result in the top 100 about endogenous morphine. In fact there is even a recent article about UC San Francisco medical researchers studying "the body's 'natural opioids'", which makes it apparent that the researchers are unaware that morphine is one of them. No doubt most of the visitors to this article are looking for information about morphine as a drug, whether legal or illegal. Splitting this into two separate articles is an intriguing idea. Is there a precedent for having two articles about two different roles for the same chemical substance? I can think of certain inorganic compounds which have separate articles for the mineral form. A5 (talk) 18:27, 18 January 2020 (UTC)

The available evidence certainly suggests morphine acts as a neurotransmitter, but what precisely is its function? This still has not been established. Examples of articles that were split are Testosterone/Testosterone (medication) – discussion and Insulin/Insulin (medication) – discussion. Boghog (talk) 08:55, 19 January 2020 (UTC)

@Boghog: Interesting. I dimly recall (sorry, no references) that the function of morphine must have something to do with regulating body temperature and digestion, and I recall some kind of connection to insulin as well. And pain, and immune function. These are its properties as a hormone, however, and I would agree with you that its function as a neurotransmitter is not so well understood. But there is still a lot of endogenous morphine research to summarize, which I think would be easier without questions of "undue weight". I would therefore support splitting the article following the other examples, into Morphine/Morphine (medication). The main disadvantage I can think of is that there is a lot of overlap, particularly since much of what we can surmise about the effects of morphine as a hormone comes from our understanding of its effects as a medication. I need to look at Testosterone and Insulin more carefully, to see how overlap issues are resolved there. A5 (talk) 19:36, 20 January 2020 (UTC)

The drug is what most people coming here would be looking for, and as you have already pointed out above, there is much more coverage of the drug than there is of the endogenous neurotransmitter in reliable sources. Hence according to WP:PRIMARYTOPIC, if there is a split, the daughter articles should be entitled Morphine (covering the drug) and Morphine (neurotransmitter) (covering the putative endogenous role). If the precise function of endogenous morphine is in doubt, then it is not even clear what to call the daughter article which is a very strong argument against the split. Before doing anything as drastic as an article split, I would suggest that we first work on adding a neurotransmitter to section to this article. Another open quesetion is morphine's role in plants. It has suggested in the reviews mentioned above that it acts as signaling molecule, but no proof has been provided. It turns out that morphine production in poppy plants is a relatively recent evolutionary event (PMID 30166436), and therefore it much more likely that morphine's role in plants is to ward off hungry herbivores (ingestion of large quantities of poppy would be lethal to animals) as opposed to acting as an intrinsic signaling molecule. Boghog (talk) 18:57, 21 January 2020 (UTC)

@Boghog: I think most of the visitors to the Insulin article are interested in Insulin (medication), so that would be a precedent for just calling endogenous morphine "Morphine", in spite of the traffic bias towards "Morphine (medication)". Anyway what about "Morphine" / "Morphine (endogenous)"? After all, we've been calling it endogenous morphine in this discussion, and that's a good search term for digging up scientific papers on the subject. Alternatively, "Morphine (medication)" / "Morphine (endogenous)". A5 (talk) 00:36, 25 January 2020 (UTC)

Need for expert attention

@Doc James: I would recommend you find a good chemist to look at the chemistry section of the Morphine article. I moved the chemical synthesis out, because that description is okay (better, were it based on reviews, but at least it is sourced). But the real issue is that the chemistry section—which reads as naive—is, moreover, completely unsourced. (I removed the only two prior citations, one to a high school web page, and the other to a college class handout, as inapproproate for such an important substance with such a rich literature.) Were I a logging editor, I would have taken the whole thing out, as suspected plagiarism, and on the basis of its misstatements (so rampant it is with vagaries and inaccuracies). Instead, I "hid" 2-3 glaring examples (not even the most glaring), and indicated the problem with a section tag. [ a former prof.] 2601:246:C700:19D:E50A:9B38:6680:3C78 (talk) 20:59, 7 February 2020 (UTC)

Feel free to keep working on it :-) Not really my area of interest. If you see stuff that is unreferenced and incorrect feel free to remove it. Doc James (talk · contribs · email) 00:30, 8 February 2020 (UTC)

Minor nomenclature issue

The stereochemical descriptions of the intermediate enantiomers in the biosynthesis sections are presented in two different styles. I leave it to the experts to decide between the two styles (with or without parens/italics), and propagate just one for the sake of student readers. Also, the PD table mentions the dextro- and levo- forms alongside "Morphine", which here, alongside the two, implies what... activity data on the racemate? (I am not sure I believe this, but it is possible that such was formulated.) I would clarify this, and recommend 2-3 other sourced sentences, placed appropriately throughout, including in the lead, making clear the stereochemical form of what most know as morphine, the poppy- and human-derived molecule. Merci. 2601:246:C700:19D:E50A:9B38:6680:3C78 (talk) 21:07, 7 February 2020 (UTC)