Opiate potentiation to prevent an adverse reaction ?

[Unlucky]

I could be way off here guys but its worth taking a stab at...

If someone is experiencing an adverse reaction to opiates due to issues with their metobolism processing the drug too quickly or too slowly via the CYP450liver enzymes or perhaps due to a specific genotype or CYP2D6 enzyme, then can altering the metobolism by inhebiting the metobolism with say Tagamet HB (Cimetidine) which is a broad CYP450 inhibitor have a positive outcome in preventing an adverse reaction ?

Or if the adverse reaction is due to a slow processing then what would have an opposite effect to Tagamet, grapejuice etc. to speed up the CYP450 ?

After many years of adverse reaction to all opiates, sedatives and anelgesics due to a diagnosed Autonomic Dysfunction, metobolic issues and chemical sensitivity I feel that tampering with my metobolism and liver enzymes may be the key to allowing me to take my chronic pain meds without experiencing an adverse reaction. Am I off track in my theory ?

 

[shibireru]

Remind me. What drug classes mainly precipitate your hyperserotonaemia-like states?

When you're in these states which are caused by and which characterize your dysautonomia, do you experience vasoconstriction or vasodilation? Has a doctor ever described it as anaphylaxis or anaphylactoid?

I believe you mentioned that you had your epigenome examined and it was found that the norepinephrine transport protein was hypermethylated?

The hypothesis that I am developing here - which is readily conceived, I assume, by anyone with even the most rudimentary understanding of the CNS (e.g. me) - is that many opioids produce the aforementioned state on account of the fact that they degranulate mast cells, triggering the release of histamine which in turn promotes the release of norepinephrine (opioids also trigger serotonin release, perhaps within the hypothalamus), and that amphetaminergics and serotonergics trigger the state because they, too, of course can trigger norepinephrine release from synaptic storage vesicles. There exists a fairly intimate connection between the serotonergic system in the brain and the adrenergic (oh hell, there's a very intimate connection between almost any two monoaminergic systems in the brain). For example, the agonism of one of the beta receptors (presumably beta 3) produces serotonin release at least within the hypothalamus, the brain structure most strongly associated with temperature regulation and so forth; this may well be the source of your problem - at least as far as the hyperthermic element is concerned. 5-HT1A agonism or antagonism or 5-HT2A agonism (the literature is really not clear at this point as to which serotonin receptor lies at the root of hyperserotonaemia and whether it is agonism or antagonism of the post-synaptic form of that receptor that causes it), in turn, appears to promote the release of the catecholamines.

The solutions to your problem then, as I see it, would be one of the following: (I do not mean to imply that any of the following is safe or well-informed.)

1. Avail yourself of a gene therapy - namely the insertion of an extra non-methylated copy of the norepinephrine transporter gene into your genome

2. Take inhibitors of DNA methyltransferases and maintenance methyltransferases as well as histone deacetylase inhibitors for some time and see if that has a positive effect on your condition.

3. Take an alpha 2 adrenergic receptor agonist (preferably one that bonded covalently with the receptor. I'm not sure that anything like this exists as yet.) (The relief that this would provide would only be temporary and could exacerbate your condition in the long run.)

4. Make use of nepicastat which prevents the conversion of dopamine into norepinephrine.

5. Try an opioid that doesn't trigger degranulation of mast cells. (Make sure you're near a hospital and some sympatholytic drugs at the time.)


Do make sure to take my advice with a grain of salt. And do make sure to toss your hypothesis out the window. I don't mean to be rude, but that is quite a long shot there. I mean, it is way way out there, what you suggested.

/When you say that sedatives cause issues for you, do you mean benzodiazepines and barbiturates? I ask because those indirectly modulate opioidergia. Have you ever received an injection of propofol? What physiological and psychological effects ensued, if so?

//Forgive the quasi-stream-of-consciousness style of writing in my post here. The longer I take these fucking benzos, with that much less facility do I formulate thoughts and write with articulateness.

 

[Unlucky]

WOW, very impressive work there and to top it off you remembered I had methylation of the NET gene

Yes I often experience vascular related problems which are a common trait of my Autonomic Dysfunction whereby change of posture results in significant vasoconstriction resulting in symptoms and the heat intolerance and fevers due to adverse reactions causes vasodilation and only makes things worse.

But these have never been described as a anaphylaxis type reaction, primarily because the Autonomic Dysfunction is a permanent syndrome I now live with but the adverse reaction to psychoactive agents is a side effect of my illness which only occurs when I try to take substances. The adverse drug reactions have been described as more of a Pharmacological nature with symptoms causing supression and neuroexcitation to my vitals rather than an anaphylactic nature.

Yes by sedatives I meant benzo's, all though the adverse reaction varies to each drug the fever is the common trait between all of them. Unfortunately due to my adverse reaction I have to be cautious so I declined propofol during my gastroscopy and colonoscopy, I had the procedure unsedated and let me tell you it was exteremly unpleasant

I actually thought my metobolism and liver enzymes were to blame because the adverse reaction is worse during the daytime then at night perhaps because of the changes in my metobolic state, also when I went overseas this was reversed due to the time difference. Im also finding that the effects of tramadol (ultram) always take 3 - 5 hrs to come on along with the adverse reaction so theres something not quite right there. Ive also read adverse effects may be linked to liver enzyme and an abnormally fast or slow breakdown of the drug in the liver.

I apreciate your suggestions and believe me I wish I was healthy enough to give them a try but however it sounds like most of it involves substances, that may or may not have the potential aggrivate my condition ?

I was more willing to trial natural or more subtle drugs like the ones that are used in opiate potentiation but maybe you are right about it has nothing to do with my metabolism but Im working with the process of elimination to detect the problem and somwehere down the line if all else fails I will try some of the substances you mentioned despite the consequences.

 

[shibireru]

I actually thought my metobolism and liver enzymes were to blame because the adverse reaction is worse during the daytime then at night perhaps because of the changes in my metobolic state, also when I went overseas this was reversed due to the time difference.

This certainly implies the strong involvement of serotonin, as I'm sure you're aware. The closer one gets to his wonted bed-time and/or the less light (especially blue-wavelength light) reaches his retina, the less serotonin the brain produces and the more melatonin it produces from serotonin - or, if it's not so, at least melatonin production increases, regardless of whether the rate of serotonin production decreases or increases. (In either case, of course, serotonin levels decrease within the hypothalamus.)

I'm also finding that the effects of tramadol (ultram) always take 3 - 5 hrs to come on along with the adverse reaction so theres something not quite right there. Ive also read adverse effects may be linked to liver enzyme and an abnormally fast or slow breakdown of the drug in the liver.

Okay, well, then it does indeed look to be the case that you are a poor metabolizer of cyp2d6-substrate substances.

So, from that I gather that, while serotonin and norepinephrine are definitely involved in your condition, re-uptake inhibitors of these substances will not necessarily produce the effect. (Perhaps because the tramadol doesn't reach the hypothalamus, and because NET ligands are practically non-functional in your brain since there are so few NETs to bind to.) Mu-opioid agonists, however, seem to be able to do so without fail. What's strange about this is that opioids normally modulate serotonin and norepinephrine release in such a way as to decrease body temperature and induce sympatholysis - the exact opposite of what happens. ...............Hence, 'dysautonomia'. Hurr durr. Forgive me I'm a bit slow.... always.

Have you ever taken naloxone or naltrexone?

Anyways, it's just quite hard to buy your theory about enzymatic dysregulation being a core or even peripheral part of the pathophysiology of your condition. This on account of the fact that a diverse range of benzos and opioids trigger it. Some benzos are prodrugs; others are not. Some have complex, non-linear pharmacokinetics; others have linear. Some depend upon cytochrome p450 enzymes like cyp3a4, while others are simply glucuronidated. It can't really be said that there's a great deal of homogeneity across the pharmacokinetics of all benzodiazepines. The metabolites and the precursors of those metabolites are always at least slightly different from one to the next. (And the same goes for opioids.) There is, however, a great deal of homogeneity in the pharmacodynamics of all benzodiazepines - the point of homogeneity being the binding of the alpha1gamma2 allosteric site on the GABA-A receptor and from that the positive modulation of mu-opioidergia downstream.


Sorry not to be able to be of any help here.

 

[shibireru]

Wait... (sorry stream of consciousness again)

So, let's suppose that opioids increase serotonin levels within the hypothalamus (and other brain regions). This would normally have the effect of promoting wakefulness and an increase in body temperature. In normal individuals, however, opioids have some considerable sympatholytic effect by decreasing the activity of the locus coeruleus (or whatever). Since your intrasynpatic levels of norepinephrine are pratically ungovernable (at least in a negative direction), then this increase of serotonin on the part of opioids produces an unopposed increase in body temperature. The serotonin thus released may also, then, increase the efflux of norepinephrine into the synapse through downstream modulation producing vasoconstriction, hypertension, and tachycardia... or something.

Let me try again. On account of your high intrasynaptic norepinephrine levels, basal beta 3 receptor activation is high, which results in an increase of serotonin within the hypothalamus. Opioids can't considerably decrease the amount of norepinephrine in your synapses, but they can increase serotonin levels within the hypothalamus, which are already high on account of your inordinate beta 3 stimulation, causing or aggravating your hyperthermia/pyrexia. And so on....

I wish I had a better understanding of the mind, because I'm really grasping at straws here and it shows.

BTW, are you depressed? I would guess, no? But perhaps you have a bit of a blunted affect or some apathy going on?


It seems to me, I'm afraid, that you are going to have to await the advent of safe, reliable, and affordable gene therapy.


Edit: I'm not a religious or spiritual person, and I doubt you are, but maybe you could take some consolation in thinking of this condition as sort of a "blessing"? Not a blessing vouchsafed by providence but one doled out by fortuity. You see, I am currently dependent upon lorazepam; I have to take at least 4 mg a day to feel somewhat normal and the slightest decrease makes me feel awful (not anywhere near as badly as you feel whether on or off benzos, I'm sure. I don't mean to trivialize your problems.) I hardly even remember how I got here; in the blink of an eye I found myself a dependent upon benzos, though I had always sworn that I would never put myself through that, that I would exercise enough caution in my use of them to forestall such a thing. Currently, I am contemplating killing myself to avoid the withdrawals.

The unfortunate, lamentable, hair-pullingly obnoxious thing about the brain, or about the pleasure center(s) of the brain anyway, is that homeostasis wields a despotic sort of control over the goings-on within it. Because of homeostasis, you get either to have your pleasure now and your pain/emptiness later or to have your pain/emptiness now and your pleasure later. There's no free lunch, really. Neuropharmacology being in the state that it is, you can sidestep here and there the forfeiture of some piddling portion of what you owe to hemostasis, but you can't avoid payment completley. All receptors downregulate, as far as I can tell. Drug addicts are those who choose to take out a mortgage for a very large amount, which allows them to live in opulent abodes and repast on sumptuous feasts, but which also necessitates paying back what is due over an agonizingly long period of time; while teetotalers are those who don't live luxurious lives, but neither have to pay back colossal debt. With your condition, you're not able to overextend yourself financially, as it were; you get [are forced] to avoid the agony of toiling endlessly in observation of the intolerable conditions of an inclement contract.

 

[Unlucky]

I wish you were my doctor lol, Im sure you would eventually have this figured out through meticulous testing and experiments

Im going to take your theories to my neurologist and hope he tackles it with the same enthuisasm, but so fas his only shown how confused he is by my condition.

Naloxone or naltrexone was an option I explored years ago, but no matter which specialist I suggested it to refused to give it to me believeing that it could also cause unwanted reactions for someone with autonomic problems and chemical sensitivity.

I am not depressed in the slightest, been there done that many years ago when I was first confronted with the bizarre illness, nor do I have any sort of anxiety or panic attacks. I am a calm person that uses logic to guide me in my life, unwarrented anxiety seem illogical and pointless when I have no fear of death, and I cant affor to be anxious when I already have a condition that requires staying positive. However I recently took my case to a team of neuropsychologists at a leading hospital here after someone suggested it, after weeks of cognitive tests and evaluation they released me saying they were unable to help me as they had not seen a case like mine wherby someone had suffured pure physical damage from a drug overdose and abuse without any cognitive or mental changes. Big waste of time for me as they only confirmed what I knew all along.

but maybe you could take some consolation in thinking of this condition as sort of a "blessing"?

I agree , I have often thought the same thing many times, if it wasnt for this condition I'd be still going to rave party's every weekend taking a smorgosboard of drugs to help me dance for unnatural lengths of time. This was my wake up call, actually it was more than that, more like straw that broke the camels back.

I can see no one else wants to touch my topic with a ten foot pole, I cant blame them really, I ve had my share of debates with the rest here but I was hoping if I kept my initial query theoratical and with fresh approach they would be willing to speculate on my topic title alone which is an actual possibility that I felt I needed to explore.

 

[shibireru]

Naloxone or naltrexone was an option I explored years ago, but no matter which specialist I suggested it to refused to give it to me believeing that it could also cause unwanted reactions for someone with autonomic problems and chemical sensitivity.

This is in all probability true. I really don't recommend trying it.

I can see no one else wants to touch my topic with a ten foot pole, I cant blame them really, I ve had my share of debates with the rest here but I was hoping if I kept my initial query theoratical and with fresh approach they would be willing to speculate on my topic title alone which is an actual possibility that I felt I needed to explore.

Don't hold you're breath. The regulars here are a fickle bunch. Once they conceive an ill appraisal of you for whatever reason - and that happens very easily and for capricious reasons - they will never redact or revoke it. They seem also to have a tendency to hold contempt for those who aren't on their level in terms of both fluid and crystallized intelligence. For these individuals they have nothing but their deafening silence. To wit, Nuke, one of the more intelligent and knowledgeable people here - more in a position to offer help and guidance than almost anyone - has yet to utter a single word to me and in his aloofness and refusal to speak to me has told me precisely what he thinks of me. One can imagine that they withhold their counsel so as not to encourage people coming here routinely for help, "clogging up" ADD with what is in their opinions a waste of time to read and a waste of space. It's for this very reason that I'm still here. It'd be a shame if they got what they pleased through what amounts to sociopathy.

 

[Unlucky]

Well thumbs up to you for being mature, compasionate and kind enough to offer me help. I wasnt too sure what "Sociopath" meant so I looked it up and it was described as... "Sociopaths are unable to experience emotional responses for other people outside of their own personal interests".... which made me laugh because it seem you have described some of the people here so accurately within one word.

Well... maybe Im a sociapath too beacuse I couldnt care less about their personal interests or wether Im taking over their space by posting here .... because my number one interest and priority in life is to overcome my disability so I can continue on with where I left my life 10 years ago following my overdose.

Im not here to make friends or socialise, all I want is to get back my independence and health back so I can get out of the house and do simple tasks by myself again without having to rely my parents for almost everything, I want to be fit enough to work, to be healthy enough to socialise , make some friends and to find that special someone and to be able to have the ocassional beer without ending up feverish and ill and not having to worry about how Im going to react to substances that may be given to me during surgery, emergency and to relieve pain. But for now none of that is possible.

Im sorry to hear they've also given you the silence treatment but take pride in knowing that it takes a better person to share their knowledge and there is greater achievement and honor in someone who helps others. I dont want to disrespect all the people here because there are a few who have genuinly helped me many times in the past but they just dont seem to be around or active at the moment.

As for the others If they dont want to help another person get their life back on track then shame on them and I'm certain my good old friend karma will take care of that if anyone is genuinly holding back on information that could potentially change my life. %)

 

[QuasiStoned]

I just wanted to say holy shit shibireru. I have enjoyed reading your hypotheses, you seem like a smart guy. You excuse yourself for being inarticulate from benzos, but really I like the way you express yourself and think its awesome that you spent the time to offer so much insight to another bluelighter.

As for you Unlucky, I really do wish you the best. I wish I could be as much help as Shibireru but my knowledge of the brain is very basic. I don't offer any real insight to anyone over here in ADD, I just lurk and love to learn from those smarter than me.

 

[Unlucky]

I like the way you express yourself and think its awesome that you spent the time to offer so much insight to another bluelighter.

Ye he is really great isnt he! Rest of the people here could sure learn from his kindness.

The best people in the world are the ones who have both the skills and the willingness to share them. Makes me laugh at the ones who fall victim to thinking their actually worthy of arrogance from a little knowledge they gained

As for you QuasiStoned its the thought that counts as well, Im sure you would have helped if you could, that means a lot to me as well. Thanks.