What causes massive fluctuations in tolerance and drug response ?

[Altered Perception]

For the past 3 years I've been on a crusade to desensitize myself to opiates but more specifically to Oxycodone which I use for chronic pain daily. I'm under the impression that once I succeed in achieving a good level of tolerance I feel thatmay finally have the long needed surgery with minimal risks to the anesthesia and opiates administared due to some level of cross tolerance between other types of opiates and anelgesics.

I have finally achieved my goal after 3 years, I have been living with a neurological damage and Autonomic Dysfunction for the past 11 years in which I also became stuck with a severe chemical sensitivity and adverse reaction to all substances that act on my ANS such as all sedatives, stimulants, anelgesics and opiates. I've had many visits to the ER during my trials trying to find an opiate I can tolerate and even when I thought I had achieved desensitisation I would have random adverse reactions that would suddenly reappear, last for a few months and then ease off.

If I took an extra 1 mg does of Oxycodone on top of my regular dose I would have a bad reaction, if I drank grapefruit juice I would have to cut my dose in half for at least 5 days but suddenly in the past 3 months I havent had a major adverse reaction and I feel like I have been cured, my Oxycodone dose has tripled in 3 months and I went from my usual 10mg to 30mg a day and now I find that I can even drink a glass of grapefruit juice and still not be phased too badly, I can even take a tramadol on the same day as the Oxycodne and not end up in the ER which is amazing for me.

I still get fevers from the Oxycodone but none of the other life threateneing reactions I've had but I don't want to get too comfortable as from experience the adverse reactions reappear randomly, but this whole ordeal has me curious how is it that it took so long (3 years) of daily use to achieve my current level of desensitasation and why is it that randomly my tolerance levels can change so fast? If I stop for a few days I revert back very quickly, what is the mechanics behind this? I also want to know if I have surgery now am I likely to tolerate the anesthesia better than I would have previously when I was exteremly sensitive to opiates?

I am also curious if someone like me who is exteremly sensitive to substances that act on the ANS is it likely as they get older past 60 years of age that their adverse reactions will decrease due to dulling in the senses? Especially If someone has adverse reactions to drugs and experiences hyperthermia, neuroexcitory and sedative reponses to a drug and major fluctuations in vitals causing increases and decreased blood pressure, rapid and very slow heart rates, confusion, agitation, respiratory depression and other twaeked autonomic functions is it likely that with age may reduce these symptoms because of the slowing in the body and the ANS?

 

[itsok]

hey u might be interested in these two articles:
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Pharmacogenomics
December 2005, Vol. 6, No. 8, Pages 849-856 , DOI 10.2217/14622416.6.8.849
(doi:10.2217/14622416.6.8.849)
Review: Pharmacogenetics and anesthesiologists
Helen F Galley†, Amr Mahdy & Damon A Lowes

http://www.futuremedicine.com/doi/abs/10.2217/14622416.6.8.849

Genetic polymorphisms involved in pharmacokinetics (absorption, distribution, metabolism, and excretion of drugs) and pharmacodynamics (receptors, ion channels and enzymes) can affect an individual’s response to the drugs used in anesthetic practice. In addition, genetic variation in proteins directly unrelated to drug action or metabolism can influence responses to environmental changes that occur during anesthesia. This review will summarize the current knowledge of genetic variation in response to drugs relevant to anesthesia, and how this impacts upon clinical practice.

----
Pharmacogenomics
July 2008, Vol. 9, No. 7, Pages 905-933,
Pharmacogenetics of analgesics: toward the individualization of prescription
Victoria Rollason1†, Caroline Samer1,2, Valerie Piguet1,3, Pierre Dayer1,4 & Jules Desmeules 1,5

http://www.futuremedicine.com/doi/abs/10.2217/14622416.9.7.905

After a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the µ-opioid receptor reduce morphine potency.

 

[Epsilon Alpha]

Hello,

I'm currently compiling evidence on how amphetamines and their derivatives can affect gene expression and was wondering if you had any specifics from your case. I'm currently working on my BSc honours pharmacology, and I'm hoping to gather some evidence on the topic so that one of the profs in my department will throw me some expertise on the topic.

If you could share some of the details on your condition I think it could help point me in the right direction for further research into amphetamines and gene expression. If all goes well I should probably be able to get a oncologist and neuropharmacology prof to talk a look at your case seeing as these guys are obsessed with how MDMA and various other drugs affect gene expression.

Thanks
-Epsilon Alpha

 

[Altered Perception]

Hi Epsilon Alpha,

This would also be a great oppurtunity for me to have my case looked into by people who can potentially offer me help. If possible it would be ideal if they can even collaborate with my Neurologist and Autonomic Specialist to offer treatment and managment.

What exactly did you want to know about my case? I only just received an inbox message yesterday about this so excuse the delay as I haven't been on much lately.

What I have been diagnosed with is "Autonomic Neuropathy" and " POTS (Postural Orthastatic Tachycardia Syndrome) which both are classified as a neurological based Dysautonomia, also called autonomic dysfunction.

One of the causes in both cases is toxic exposure to chemicals. But more comonly people develop these conditions due to physical trauma, to viral illness attacking the brain, autoimmune disorders, degenerative neurological diseases, and brain injury.

In my case the only thing I did prior to the day developing this condition was to have a drug overdose on a coctail of methamphetamine, ecstacy tablet and mda and ended up losing conciousness, I was treated in hopital for severe hyperthermia and I left the hopital with this new life changing condition which I have now had for 11 years consistently. All my Autonomic functions have been messed up since the day of my overdose. I constantly overheat with high temperatures, even in winter.

I don't know what exactly gene expression is so I could not offer you specific information relating to your study however I did have one specific gene test during investigations for a blood test to check for Norepinephrine transporter deficiency is thought to cause POTS in some patients, The study below was conducted by my autonomic specialist who has now published it online, his name is Professor Murray Esler ....

http://potsville.wordpress.com/2011/02/05/norepinephrine-in-fibromyalgia-chronic-fatigue-syndrome/

These patients have an abnormality in the clearance of norepinephrine from the synaptic cleft. The body normally recycles norepinephrine. The protein that recycles norepinephrine doesn’t work well in people with the norepinephrine transporter deficiency (Grubb, 2002). Excessive amounts of norepinephrine is spilled over. These people soon become depleted of norepinephrine if the neuron is continually stimulated (Grubb, 2002). They go from having excessive amounts of norepinephrine to having no norepinephrine, at which point they crash. Read More

Other researchers have reportedly discovered hypermethylation of the norepinephrine transporter (NET) gene promoter in POTS patients (Esler, Alvarenga, Pier, Richards, El-Osta, Barton, Haikerwal, Kaye, Schlaich, Guo, Jennings, Socratous & Lambert, 2006) In these patients, the gene for the protein that transports norepinephrine (NET) is turned off because its promoter is turned off. Further studies are being conducted to determine whether hypermethylation of the NET gene promoter is a mechanism or cause of POTS.

If there is anything more specific you want to know please get back to me, I apreciate you taking an interest in this, my case is very unique and I have been told by my specialists that even for Dysautonomia the ongoing fevers I have is one of the worst they have seen and there are not many people out there like myself who develop this ilness due to neurotoxic effects and hyperthermia from a recreational drug overdose, so there arent many others I can compare my unique symptoms with out there or anyone reseraching specificaly in to my condition.

 

[23536]

Hello,

I'm currently compiling evidence on how amphetamines and their derivatives can affect gene expression and was wondering if you had any specifics from your case. I'm currently working on my BSc honours pharmacology, and I'm hoping to gather some evidence on the topic so that one of the profs in my department will throw me some expertise on the topic.

If you could share some of the details on your condition I think it could help point me in the right direction for further research into amphetamines and gene expression. If all goes well I should probably be able to get a oncologist and neuropharmacology prof to talk a look at your case seeing as these guys are obsessed with how MDMA and various other drugs affect gene expression.

Thanks
-Epsilon Alpha

this is very interesting stuff

 

[Epsilon Alpha]

Hi Epsilon Alpha,

This would also be a great oppurtunity for me to have my case looked into by people who can potentially offer me help. If possible it would be ideal if they can even collaborate with my Neurologist and Autonomic Specialist to offer treatment and managment.

What exactly did you want to know about my case? I only just received an inbox message yesterday about this so excuse the delay as I haven't been on much lately.

What I have been diagnosed with is "Autonomic Neuropathy" and " POTS (Postural Orthastatic Tachycardia Syndrome) which both are classified as a neurological based Dysautonomia, also called autonomic dysfunction.

One of the causes in both cases is toxic exposure to chemicals. But more comonly people develop these conditions due to physical trauma, to viral illness attacking the brain, autoimmune disorders, degenerative neurological diseases, and brain injury.

In my case the only thing I did prior to the day developing this condition was to have a drug overdose on a coctail of methamphetamine, ecstacy tablet and mda and ended up losing conciousness, I was treated in hopital for severe hyperthermia and I left the hopital with this new life changing condition which I have now had for 11 years consistently. All my Autonomic functions have been messed up since the day of my overdose. I constantly overheat with high temperatures, even in winter.

I don't know what exactly gene expression is so I could not offer you specific information relating to your study however I did have one specific gene test during investigations for a blood test to check for Norepinephrine transporter deficiency is thought to cause POTS in some patients, The study below was conducted by my autonomic specialist who has now published it online, his name is Professor Murray Esler ....

http://potsville.wordpress.com/2011/02/05/norepinephrine-in-fibromyalgia-chronic-fatigue-syndrome/




If there is anything more specific you want to know please get back to me, I apreciate you taking an interest in this, my case is very unique and I have been told by my specialists that even for Dysautonomia the ongoing fevers I have is one of the worst they have seen and there are not many people out there like myself who develop this ilness due to neurotoxic effects and hyperthermia from a recreational drug overdose, so there arent many others I can compare my unique symptoms with out there or anyone reseraching specificaly in to my condition.

Thanks! I'll ask the prof who specializes in drugs of abuse and changes in gene expression (which decides how much of a gene should be turned into a protein) and show him this study and see if anything comes of it.

He's done several studies on hyperthermia in rats with BZP and MDMA though I'm not sure he's published them all aside from abstracts. But, without getting my ass fired for spilling too much info, most of his interest is proving that serotonin syndrome really isn't all about serotonin.

But, my primary interest in your case is functional changes brought on by amphetamine induced changes in gene expression. The NET protein promoter methylation and possible changes for other genes is what I'm primary interested in. If you have any other information like that I'd be glad to try and get him to take a look at your case. Right now he's busy with his grad students but he did seem interested in this case.

I'm sorry for avoiding giving specifics in this message, but I was told never to mention findings outside the lab before papers are published and to not mention him by name, lest I jeopardize my job.

 

[Altered Perception]

my primary interest in your case is functional changes brought on by amphetamine induced changes in gene expression.

I don't want to bore you with my life story and I don't know how much you know about me already so I'm uncertain what will relevant information to give you..

I was in perfect health before the overdose, I was going to raves and clubs almost every weekend taking ecstacy, lsd and amphetamines, I kept this routuine up for 5 years without a single bad incidence..

The day of my overdose I had come back from a big drug fuelled night at rave party , went to a friends house took more drugs and engaged in sex, a few hours into sex I just began to burn up severely. The situation escalated very quickly turning into hyperthermia and I found my whole body from head to toe feeling that same uncomfortable tingling you get in your foot from paraesthesia or limbs 'falling asleep "pins and needles sensation" I ran to the shower instinctively to cool down, I sat under the cold water waiting for the ambulance thinking how warm the cold water actually felt and that was the last thing I remember. When I woke up in hopital I was no longer the same person as the incidence had left me with the damage and disability I have now been living with for the past 11 years.

Upon release from the hospital I began to live a new life spending the following years in front of a cooling system unable to go out into the sun or warm areas. I found I could no longer tolerate any drugs or substances that acted on my autonomicc system, I had to immedeatly quit the cannabis and diazepams I was on prior to the incidence as it was now causing me severe adverse reactions. I was horrified to find my first sexual arousal following the incidence resulted in painful muscle spasms, cramps and twitching and attempt to enage in sexual activity resulted in hyperthermia. I realised that whatever had happened to me during the overdose had also caused a malfunction in my sexual reponse and thermoregulation. Perhaps because the overdose happened whilst i was engaged in sexual activity I felt that the damage I sustained had somehow also now influneced my sexual response. For example like being punched in the face whilst having your hand in front of your face my leave an imprint of your fingers on your face, so I felt that that being hit by an overdose whilst in a vulnerable"sexual mode" flooded with dopamine, sex hormones vasopressin etc somehow left an imprint with this odd and uncommon symptoms I now live with.

Sexual acivity causing hyperthermia, nauseau and sexual arousal causing painful spasms and twitching is unheard of. I have ended up in hopital dozens of times following sexual arousal where they found my body temperatures at a hyperthermic level. Doctors were stunned at my symptoms but no one could offer a solution.

Furthermore following the overdose I fopund everytime I stood up or moved my heart would race , which later I discovered was a symptom of POTS (postural orthastatic tachycardia syndrome) all my automatic functions had become unstable causing digestive problems, loss of sweat function, blood pressure problems, thermoregulatory problems, sexual dysfunction. vertigo, fainting, diziness and one of the most annying ones...intolerace and hypersensitivity to all psychoactive substances. I could no longer drink alcohol, caffeine, take muscle relaxants and even second hand cigarette smoke triggered reactions.

I went from beinga drug fiend to bubbleboy overnight from one single overdose. Even though some of my symptoms are common with others who have Dysautonomia, the majority of my symptoms are unlike anything anyones ever heard of in the medical world. after 11 years I can confidently say that I seem to be an exteremly isolated case. When something as rare as this happens people began to question the authenticity of my situation, I even had people on this board suggest and insisted that my situation maybe anxiety or psychosamatic even though i dont get anxiety and I dont suffer from panic attacks or any other mental health problems, so there is no question of that being the case and all of my specialists who have done various tests dont seem to think so either. Just for the sake of it I even had about 5 different pychiatric and pychological tests over the years from various shrinks and every one of them concluded supporting the findings of my specialists for Dysautonomia and no other psychosamatic condition.

Ive even had experimental tests where I was administered low dose of oxycodone and then my vitals documented by a neurologist who found unusual response and adverse reaction to the substance and had this test been repeated for every stimulant, sedative, anelgesic it would have the same outcome.

Sometimes I feel like the only thing that can help me is if an advanced extraterestrial life were to try and repair me because i just feel like everything else has been insufficent so far. I've really badly damaged myself and the most frustrating part is that the damage I caused is just so dam odd, uncommon and bizarre, its liek Ive hit some crazy formula that is difficult to repeat and all I know is it has something to do with the type chemical involved during the overdose, the sexual activity at the time, the loss of electrolytes from the excessive partying the night before, the hyperthermia during the overdose which seems to have fried some specific parts of axons, neurons and possibly hypothalamus and preoptic area that has now left me with thermoregulatory problems and I feel like I should have died at that day but sitting under the cold shower as an immedeate intervention , the dantrolene they administered and, ice bath at the hopital saved me.. but also brought me back from a bad point of return due to damage sustained that has left me with uncommon complications.

So I really apreciate your offer to help after everything Ive been through and all my hopeless attempts, your a godsend to me right now. Thank you.

 

[Epsilon Alpha]

Interesting you should mention LSD in this combo, as its been shown to increase levels of c-fos after ingestion as well as potentate amphetamines. I'll do some more research on my own time before I head back to the lab on the 18th (we're doing fructose fed rats now so my research has to wait until we're back to normal rats).

But, suffice to say a massive upregulation of c-fos could in theory caused some of the genetic changes you experienced.
http://www.ncbi.nlm.nih.gov/pubmed/11927188

Out of curiosity what class of drugs do you respond the worst to and have you noticed any new allergies to non-drug compounds?

 

[Epsilon Alpha]

Interesting you should mention LSD in this combo, as its been shown to increase levels of c-fos after ingestion as well as potentate amphetamines. I'll do some more research on my own time before I head back to the lab on the 18th (we're doing fructose fed rats now so my research has to wait until we're back to normal rats).

But, suffice to say a massive upregulation of c-fos could in theory caused some of the genetic changes you experienced.
http://www.ncbi.nlm.nih.gov/pubmed/11927188

Out of curiosity what class of drugs do you respond the worst to and have you noticed any new allergies to non-drug compounds?

 

[Altered Perception]

I respond worst to stimulants. I only tried stimulants twice in the 11 years following the overdose to realise I could never take them again. In both instances the response was very severe and I ended up under the cold shower again with hyperthermia for the entire duration of the its effects.

Next in line would be opiates but specifically a class of opiates that have a strong sedative effect like morphine and fentanyl. I assume heroin would be the worst had I tried it.

I dont have any allergies to non-drug compounds although at my most sensitive point soon after developing Dysautonomia I was having reactions to passive cigarette smoke and some of the artificial food colorings and additives found in packaged chips and other junk foods but that seems to have subsided.

EDIT> I should mention my LSD use wasnt as frequent as the ampetamines and ecstacy, in the 5 years of going to raves and taking drugs on a weekend basis I used to take LSD about once every 2 months or so and mushrooms twice a year, but with ecstacy and meth it was every weekend as dancing all night was my primary interest.

 

[Epsilon Alpha]

I respond worst to stimulants. I only tried stimulants twice in the 11 years following the overdose to realise I could never take them again. In both instances the response was very severe and I ended up under the cold shower again with hyperthermia for the entire duration of the its effects.

Next in line would be opiates but specifically a class of opiates that have a strong sedative effect like morphine and fentanyl. I assume heroin would be the worst had I tried it.

I dont have any allergies to non-drug compounds although at my most sensitive point soon after developing Dysautonomia I was having reactions to passive cigarette smoke and some of the artificial food colorings and additives found in packaged chips and other junk foods but that seems to have subsided.

EDIT> I should mention my LSD use wasnt as frequent as the ampetamines and ecstacy, in the 5 years of going to raves and taking drugs on a weekend basis I used to take LSD about once every 2 months or so and mushrooms twice a year, but with ecstacy and meth it was every weekend as dancing all night was my primary interest.

Thanks for the details.
My main thought on the combination though is that amphetamines and LSD both produce a increase in c-fos which interacts with a large number of other proteins involved in DNA expression and transcription. Of course I could be wrong on this, but it does seem to be a probable cause, well that and massive increases in prolactin from extended sex.

I'll do some more research and post back if I find anything.

 

[Epsilon Alpha]

Hello,

I talked to the neuropharm prof and he wants to know if you've tried gabapentin or pregabalin. He mentioned that if you do have a hypermethylation of the NET promoter perhaps reducing NE release would be of some help.

Thanks

-EA