Need to understand buprenorphine better

[InfectedWithDrugs]

Butran patches release buprenorphine at a specific rate based on the prescribed dosage. Here's directly from Butran website regarding buprenorphine concentration in blood:

- This does not make sense because buprenorphine has a very long half-life, but based on that graph, buprenorphine doesn't seem to stay in person's blood for that long half-life period. Why is that? Each mcg release should be piling up and piling up on top of new mcg's released per hour, should it not?

- Assuming that patch is replaced every 4 days instead of every 7 days, would total plasma concentration increase 2x fold over a period of 1+ week when compared to total plasma concentration when the patch is replaced every 7 days?

- For someone who has been completely 100% opiate/opioid-free (kratom-free too) for over a month after several years of 25mcg/hr fentanyl patch use, can Butran patch / buprenorphine usage be the cause of severe anxiety? Some research indicates that while mu-receptors upregulate/downregulate depending on opiate/opioid intake/withdrawal, kappa-receptors do not recover... Since buprenorphine acts as kappa-receptor antagonist, could this mechanism be the cause of such sudden anxiety?

- Based on limited Wikipedia research, there is evidence that kappa-receptor agonism causes dysphoria/bad mood/anxiety along with analgesic effect. Is this one of the reasons why buprenorphine, kappa-receptor antagonist, is being studied as a possible treatment for depression? Its the only explanation I find as to why choose buprenorphine as anti-depressant instead of a full agonist, such as morphine, hydrocodone, etc.

- Again from Wikipedia "Activation of the KOR (kappa-receptor) appears to antagonize many of the effects of the MOR (mu-receptor)". What do they mean by "activation" ? Is "activation" = agonism or antagonism or either one? I assume "activation" = agonism. In that case, buprenorphine, kappa-receptor antagonist, actually agonizes many of the effects of the mu-receptor, does it not?

- Which full agonist opioids agonize kappa-receptor? I believe oxycodone is the only common one.

 

[endotropic]

- This does not make sense because buprenorphine has a very long half-life, but based on that graph, buprenorphine doesn't seem to stay in person's blood for that long half-life period. Why is that? Each mcg release should be piling up and piling up on top of new mcg's released per hour, should it not?

Based on that graph Bup has a half life of about 5-days, possibly a bit less depending how slowly the drug diffuses from the patch. That only measures the concentration of unchanged bup, active metabolites can have an effect even after the parent drug gets metabolized. How long did you expect the half-life to be?

- Assuming that patch is replaced every 4 days instead of every 7 days, would total plasma concentration increase 2x fold over a period of 1+ week when compared to total plasma concentration when the patch is replaced every 7 days?

The drug would reach a higher peak concentration, but not necessarily double the 7-day concentration, especially if the patch still releases drug after the 4 day mark.

- For someone who has been completely 100% opiate/opioid-free (kratom-free too) for over a month after several years of 25mcg/hr fentanyl patch use, can Butran patch / buprenorphine usage be the cause of severe anxiety? Some research indicates that while mu-receptors upregulate/downregulate depending on opiate/opioid intake/withdrawal, kappa-receptors do not recover... Since buprenorphine acts as kappa-receptor antagonist, could this mechanism be the cause of such sudden anxiety?

Maybe, but lots of other factors could play a role too.

- Based on limited Wikipedia research, there is evidence that kappa-receptor agonism causes dysphoria/bad mood/anxiety along with analgesic effect. Is this one of the reasons why buprenorphine, kappa-receptor antagonist, is being studied as a possible treatment for depression? Its the only explanation I find as to why choose buprenorphine as anti-depressant instead of a full agonist, such as morphine, hydrocodone, etc.

Pre-clinical evidence suggests that kappa antagonists will act as antidepressants, and buprenorphine is a kappa antagonist already approved for human use. It also has less abuse potential than a short acting full agonist.

The FDA will throw out most applications for antidepressant drugs if they have any abuse potential, no one would have even looked at bup as an antidepressant if it wasn't already approved for other uses. Same story with ketamine.

- Again from Wikipedia "Activation of the KOR (kappa-receptor) appears to antagonize many of the effects of the MOR (mu-receptor)". What do they mean by "activation" ? Is "activation" = agonism or antagonism or either one? I assume "activation" = agonism. In that case, buprenorphine, kappa-receptor antagonist, actually agonizes many of the effects of the mu-receptor, does it not?

Buprenorphine acts as a direct MOR agonist, that effect predominates over any small effect KOR antagonism might have on MOR.

 

[Zeds(NCO2CH2CH3)2]

This is an ideal graph presented by the pharmaceutical company, at seven day intervals (168hours), representing five day half lives, the trough concentration is 100ug/mL. The avg plasma concentration is varies by the Stat bars, overall approx 150-200ug/ml on avg.

I am unsure of your severe anxiety I feel as if you added medication on top of this. Also nyucnta is a wierd Kappa agonist/nri, do not recommend..

 

[InfectedWithDrugs]

Thank you for such prompt responses!

SWIM is probably stupid and did not understand the graph... SWIM assumed the graph shows total concentration of buprenorphine in a person's blood per day. Let's assume that in that body, buprenorphine has a 96hr half life when released from Butran patch. Wouldn't that mean that the concentration would continue to rise even after 4 days IF the patch releases buprnorphine at exactly the same rate? Buprenorphine concentration should be piling up and up for way more than 5 days because of its long half-life... For example, assume 24hr half-life drug. First dose = 100mg, 24 hours later another dose of 100mg would provide total concentration of 50mg (from previous 100mg dose 24hrs ago) + new 100mg dose = 150mg total concentration. 24hrs later, it would be 75mg + 100mg = 175mg. 24hrs later total would be 187.5mg. Afterwards increase would be negligible. So, for a 24hr half life drug, it takes at least 3 days to reach steady plasma concentration, but buprenorphine has a MUCH longer half life than 24hrs, which means it should take at least 7 days or more to reach maximum blood concentration. Instead, it shows that peak concentration is reached only within 3 days and that makes no sense to me... It does make sense if the patch releases much higher mcg/hr amounts during the first several days than during the last 3 days of the 7-day period. Even then, a 4-day half life would still result in rising concentration past 7 days if the patch releases the same exact 10mcg/hr every single hr.

Based on my Wikipedia research, buprenorphine metabolite in this situation is not very relevant because it has a hard time bypassing BBB, thus having little/limited effect on the brain, regardless of metabolite's half-life.

SWIM is bipolar and buprenorphine concentration fluctuations in blood may contribute to mood swings, which is why SWIM asked dear Pain Doctor to allow patch replacement every 4 days instead of every 7 days. Hopefully, that way, max concentration will be achieved within 7 days or so and remain more stable throughout the course of the treatment, without severe fluctuations shown when the patch was replaced every 7 days... Or is SWIM wrong about this one too?

SWIM also sees people stating that buprenorphine is not as effective for moderate to severe pain as full agonists. Is that really so? So far SWIM's post-laminectomy low-back pain has improved by just as much as it has from 25mcg/hr fentanyl patch, but without the drowsy "stoned" feeling and without depression. Yes, SWIM gets depressed on opiates, especially oxycodone, but buprnorphine seems difference. SWIM apologizes for providing personal subjective experience information - SWIM realizes this forum sub-section not a place for such a discussion, but only for objective science discussions.

 

[Mr.M.301]

Thank you for such prompt responses!

SWIM is probably stupid and did not understand the graph... SWIM assumed the graph shows total concentration of buprenorphine in a person's blood per day. Let's assume that in that body, buprenorphine has a 96hr half life when released from Butran patch. Wouldn't that mean that the concentration would continue to rise even after 4 days IF the patch releases buprnorphine at exactly the same rate? Buprenorphine concentration should be piling up and up for way more than 5 days because of its long half-life... For example, assume 24hr half-life drug. First dose = 100mg, 24 hours later another dose of 100mg would provide total concentration of 50mg (from previous 100mg dose 24hrs ago) + new 100mg dose = 150mg total concentration. 24hrs later, it would be 75mg + 100mg = 175mg. 24hrs later total would be 187.5mg. Afterwards increase would be negligible. So, for a 24hr half life drug, it takes at least 3 days to reach steady plasma concentration, but buprenorphine has a MUCH longer half life than 24hrs, which means it should take at least 7 days or more to reach maximum blood concentration. Instead, it shows that peak concentration is reached only within 3 days and that makes no sense to me... It does make sense if the patch releases much higher mcg/hr amounts during the first several days than during the last 3 days of the 7-day period. Even then, a 4-day half life would still result in rising concentration past 7 days if the patch releases the same exact 10mcg/hr every single hr.

I don't think using SWIM is allowed here, or it is at least frowned upon.

Unless there is something really fancy going on, the patch does release more of the dose at the start... think about diffusion. The rate at which a substance diffuses through a membrane is proportional to the difference in concentration of the substance between the two sides of the membrane. Same/similar thing with heat (look up Newton's cooling theorem): the rate of change in temperature between two objects in contact is proportional to the difference in temperature between them, and this rate (or the derivative of the rate) is non-linear, in the same manner as half-lives.

Based on my Wikipedia research, buprenorphine metabolite in this situation is not very relevant because it has a hard time bypassing BBB, thus having little/limited effect on the brain, regardless of metabolite's half-life.

SWIM is bipolar and buprenorphine concentration fluctuations in blood may contribute to mood swings, which is why SWIM asked dear Pain Doctor to allow patch replacement every 4 days instead of every 7 days. Hopefully, that way, max concentration will be achieved within 7 days or so and remain more stable throughout the course of the treatment, without severe fluctuations shown when the patch was replaced every 7 days... Or is SWIM wrong about this one too?

SWIM also sees people stating that buprenorphine is not as effective for moderate to severe pain as full agonists. Is that really so? So far SWIM's post-laminectomy low-back pain has improved by just as much as it has from 25mcg/hr fentanyl patch, but without the drowsy "stoned" feeling and without depression. Yes, SWIM gets depressed on opiates, especially oxycodone, but buprenorphine seems difference. SWIM apologizes for providing personal subjective experience information - SWIM realizes this forum sub-section not a place for such a discussion, but only for objective science discussions.

Well, it seems to be an objective fact that people subjectively experience the effects of drugs differently. The standard dose of buprenorphine for pain if I remember correctly is 200 mcg, obviously intended for opioid-naive patients. Based on anecdotes (and personal experience), it seems that lower doses of bupe (very roughly, in the hundreds of micrograms, at maximum 1 mg) are more effective, in terms of pain relief / euphoria / typical full-agonist type effects vs higher doses (e.g. > 1 mg).

 

[anubis23]

Here is some related info you might find useful re: downstream antidepressant effects.

https://en.wikipedia.org/wiki/ALKS-5461

 

[Zeds(NCO2CH2CH3)2]

Your assumption is bupe isn't metabolized so therefore it accumulates, ever increasing plasma level. Which is wrong, bupe undergoes metabolism and is excreted through multiple routes.

I don't think switching patch to 4 days from 7 days based on bipolar mood swings to be a correct indication at all, mood can vary pain but that is a ridiculous increase, nearly doubling patches used.

I would add a non opioid analgesic I. E provigil, amphetamine, to help with the central pain syndrome(prescribed off label for fatigue in pain therapies) . Otherwise for breakthrough pain follow the regime if he prescribes narcotics, if not request gabapentin or Lyrica for breakthrough pain.

Always use low doses of pain medication and do not chase euphoria
Zedz

 

[adder]

As for the anxiety while on buprenorphine, I was searching for some info on this some time ago. Generally speaking (pharmacology is just my hobby and I don't really have a deep enough understanding of pharmacodynamics and how "stuff" is interrelated), kappa agonism inhibits the synthesis of catecholamines. Buprenorphine is a kappa antagonist, signalling through kappa receptors obviously happens all the time via natural kappa ligands, so it's regulatory for catecholamine synthesis in this respect. When buprenorphine blocks kappa receptors, more catecholamines may be synthesized, hence anxiety from increased adrenaline/noradrenaline levels. However, it's far from being as simple as that, both kappa agonists and antagonists were researched as possible treatment solutions for conditions like addiction and depression. Kappa agonists generally have sedative properties, yet there are rebound effects when the effect of a kappa agonist wears off.

I'm on Suboxone and I do experience a sort of adrenaline rush after taking my dose before any morphine-like opioid effect kicks in, it is actually quite dysphoric to some extent and it certainly is reminiscent of anxiety. It could as well be due to naloxone though. Buprenorphine itself can feel very drowsy once it exerts enough effect, so I somehow doubt that the initial anxiety is actually due to its kappa antagonist properties if MOP-mediated effects take at least 30 minutes to fully kick in. On the other hand buprenorphine itself may be slightly anxiogenic. I can sometimes feel some anxiety hours after taking my dose, yet it's no proof it's related to buprenorphine, if I don't take my dose at all, I'm anxious too. Anyway, you can find articles on this on Google or Google Scholar if you can understand enough of scientific language.

- Which full agonist opioids agonize kappa-receptor? I believe oxycodone is the only common one.

I don't believe oxycodone might be any more active at kappa receptors than morphine analogues like hydromorphone, oxymorphone, or even morphine itself. I remember reading an article where it was stated that oxycodone's analgesia was mediated via KOP receptors as opposed to morphine's MOP-mediated analgesia. I think it's wrong, it just can't be true as it's against any SAR for morphinans, certainly oxycodone isn't more active at KOP receptors than it is at MOP, certainly it isn't more active at KOP receptors than morphine is. Perhaps they tested it against some splice variant, I don't know. Both 3-O-methyl and 14-hydroxy generally decrease activity there, some very potent kappa antagonists were synthesized in the series of 6-ketolevorphanol analogues with 14-hydroxy substituent. I actually think that more stimulatory nature of oxycodone and oxymorphone is due to reduced activity at kappa receptors vs. morphine for instance.

 

[InfectedWithDrugs]

Thanks! I already take gabapentin, acetominophen, BP drugs (lamotrigine, tiagabine), hydroxyzine, and I am prescribed Vyvanse 20mg BID, but it drives me super-anxious these days. In the past, fentanyl 25mcg/hr patch was prescribed ti take every 3 days and mood did fluctuate - good mood on day 1 and 2, but worse mood on day 3, likely due to fentanyl blood concentration decrease on the 3rd day. This is why Butrans are now prescribed every 4 days to make blood concentration as stable as possible. I can't take any other opiates because of my past *no self-incrimination* "proper use" and buprenorphine patches were the "last chance" at narcotics for pain from pain doctor, but fentanyl + Vyvanse felt really good and without anxiety. Subutex and Suboxone are not covered by my insurance for the use as pain medicine and Butran patches supposedly work better for pain anyway.

Anxiety improved. I also forgot to mention that for post-fentanyl WD I had severest of anxiety and was prescribed trazadone 50mg QD, quetiapine 200mg QD for 1 month, which I quit cold-turkey since I wanted to feel some mild dopamine/endorphin-rush from buprenorphine and anxiety was mostly post-fentanyl WD, which means Butran patches should have taken care of that. I also was Xanax dependent over 2 years ago when I took Xanax 4mg for a year. I had to quit cold turkey, which made it impossible for me to ever have a drink, even 2 years later because 1 shot of alcohol restarts benzo WD's for some 4-5 days (itch!!!) before it goes away. To alleviate post-fentanyl WD, I also had some low-dose phenobarbital that I took for 3 weeks and stopped, which I think also restarted some mild benzo WD's. I smoked tobacco for a whole month (non-smoker before), which also made me itch like crazy and also quit cold turkey after Butran patches. I take hydroxyzine for allergies, but that did not prevent the itch. So it looks like there are too many factors, medicine/drug discontinuations, and etc. to really tell what is causing what. I just need to take it easy for 2 weeks before making conclusions.

Anxiety decreased, but now I get this odd head-ache I never had before Butrans or with any other opiates... I might try ibuprofen for it. Its not as much headache and jaw-pressure, like TMJ, which full-agonist opiates always treated completely.

 

[aced126]

Wouldn't catecholamine synthesis not only mean increased NE levels, but also increased dopamine levels leading to euphoria? Also I read that kappa agonism has dysphoric effects

 

[Nagelfar]

- Which full agonist opioids agonize kappa-receptor? I believe oxycodone is the only common one.

Norbuprenorphine, I believe, antagonizes the K-opioid receptor, and unlike common bupe, is a full agonist of the mu-receptor (instead of being a mixed agonist/antagonist). Quite a potential compound by itself, that one is, if it were ever indicated for anything stand alone.

 

[adder]

Wouldn't catecholamine synthesis not only mean increased NE levels, but also increased dopamine levels leading to euphoria? Also I read that kappa agonism has dysphoric effects

I only mentioned noradrenaline as potentially linked to anxiety. Kappa antagonism has actually been shown to increase dopamine levels in nucleus accumbens (link 1, link 2, link 3. link 4; these are actually all about kappa agonists increasing DA uptake thus lowering DA levels, but I'm almost sure that I read an article about some kappa antagonist increasing DA in NAc). I suspect indirect dopaminergic effects of buprenorphine are responsible for its antidepressant properties even in a combination with samidorphan, a mu antagonist with higher affinity than buprenorphine. From my own experience I think monoaminergic activity plays some role in overall buprenorphine effects. While one of the symptoms of opioid withdrawal from classic mu/kappa agonists like morphine is agitation, I noticed that with buprenorphine it's quite different, one of the first symptoms of buprenorphine withdrawal is weirdly cloudy mind and this could be rebound kappa activity after buprenorphine wears off. I don't know how kappa antagonistic properties compare to mu partially agonistic properties, but the former shouldn't be underestimated in my opinion. The mu/kappa affinity ratio of buprenorphine is much lower than that of widely used opioids like heroin/morphine or oxycodone/oxymorphone. Morphine is a mu/kappa/delta agonist, but it exerts its effects through mu receptors most strongly, kappa agonistic effects are secondary, and orvinols are a much more balanced mu/kappa ligands.

I have a feeling N-methylnorbuprenorphine, which I named tebutorphine (analogues with longer branched chains at C19 may be interesting too), might be a very enjoyable opioid, a full mu agonist and kappa antagonist/partial agonist. Norbuprenorphine appears to be a partial kappa agonist, so N-CPM in buprenorphine lowers efficacy at kapp, I'm wondering what plain methyl group would do, it might not be as effective at lowering efficacy but tebutorphine could still have such a low intrinstic activity at kappa that it would essentially behave like an antagonist and I suppose it wouldn't be a p-glycoprotein substrate.

 

[serotonin2A]

Norbuprenorphine, I believe, antagonizes the K-opioid receptor, and unlike common bupe, is a full agonist of the mu-receptor (instead of being a mixed agonist/antagonist). Quite a potential compound by itself, that one is, if it were ever indicated for anything stand alone.

Norbuprenorphine is a kappa partial agonist (1), which would probably limit its usefulness. It does have 13-fold higher affinity for mu vs kappa, but that probably isn't enough selectivity to prevent it from producing effects via kappa activation.

I have a feeling N-methylnorbuprenorphine, which I named tebutorphine (analogues with longer branched chains at C19 may be interesting too), might be a very enjoyable opioid, a full mu agonist and kappa antagonist/partial agonist..

The compound you are describing is the tert-butyl isomer of dihydroetorphine and is a known compound. It is a mu and delta agonist with higher potency than buprenorphine (2).


1= https://www.ncbi.nlm.nih.gov/pubmed/11303059

2 = Husbands et al., Bioorganic & Medicinal Chemistry Letters 9 (1999) 831-834