Why does methadone withdrawal last so long compared to short acting opiates?

[cj]

Hi we all know long acting opiates have a significantly longer physical withdrawal syndrome compared to short acting opiates. My question is why? What process slows down the brain from re-establishing homeostasis?

 

[adder]

I'm not able to explain it in detail (I mean how opioid dependence effects changes in opioid receptors, their internalization and changes in secondary messaging systems), but in short, long-acting opioids upon discontinuation give longer-lasting withdrawal and with a slower onset due to their pharmacokinetics and pharmacodynamics at opioids receptors. If you take a look at some plasma concentration curve in Google Images, you will see that the elimination phase is generally the longest and the concentration in that phase drops steadily as opposed to dropping steeply after the peak. Both methadone and buprenorphine don't have as sharp peaks for maximum concentration and are excreted much more slowly than morphine. When the concentration of an opioid drops below the value at which withdrawal symptoms are still counterbalanced, the withdrawal starts and one will not recover as long as there is still some opioid in their system because it still acts on opioids receptors. When an opioid is finally excreted, homeostasis can be slowly brought back in the opioid system. Post-acute withdrawal syndrome is the lack of recovery even though the drug is out of the system and it is due to some changes in opioid receptors and the opioid system in general.

 

[clubcard]

The abstinence causes less acute effects but more chronic affects. Right now I am trying to get the (S) R-4066 derivative with an acetyl ester replacing the ketone into use. If you can find an agent with a low abuse potential (8 hours to peak plasma, T1/2 42 hours) so that 3 or even 2 doses per week help people to stop using other opioids. My logic is that fentanyl and other highly potent opioids bind to a 4th site. That is why methadone doesn't deal with fentanyl dependence very well. I think people have the right to choose but I also think that we should give people the best chance of getting clean.

Drug use isn't a crime. Drug death is avoidable. Only groups like the DEA benefit and are responsible for the current status.

 

[cj]

I'm not able to explain it in detail (I mean how opioid dependence effects changes in opioid receptors, their internalization and changes in secondary messaging systems), but in short, long-acting opioids upon discontinuation give longer-lasting withdrawal and with a slower onset due to their pharmacokinetics and pharmacodynamics at opioids receptors. If you take a look at some plasma concentration curve in Google Images, you will see that the elimination phase is generally the longest and the concentration in that phase drops steadily as opposed to dropping steeply after the peak. Both methadone and buprenorphine don't have as sharp peaks for maximum concentration and are excreted much more slowly than morphine. When the concentration of an opioid drops below the value at which withdrawal symptoms are still counterbalanced, the withdrawal starts and one will not recover as long as there is still some opioid in their system because it still acts on opioids receptors. When an opioid is finally excreted, homeostasis can be slowly brought back in the opioid system. Post-acute withdrawal syndrome is the lack of recovery even though the drug is out of the system and it is due to some changes in opioid receptors and the opioid system in general.

So in theory would cleaning the receptors with naloxone for a a few half life cycles significantly speed up methodone withdrawal?

 

[Kdem]

cj,

Possibly the adaptation to longer acting opioids (that also happen to have a long half life) is more complete compared to short acting opiates that cause peaks and valleys ?

 

[clubcard]

cj - I'm not sure that an antagonist will increase the expression of opiate receptors. I could be wrong but it would surely take a long and painful time just to find out if it works. Are their no papers on the subject?

 

[cj]

cj - I'm not sure that an antagonist will increase the expression of opiate receptors. I could be wrong but it would surely take a long and painful time just to find out if it works. Are their no papers on the subject?

Yeah it's not something I am going to try personally. Just curious why half life length has stronger correlation then time addicted when it comes to withdrawal length.

 

[adder]

So in theory would cleaning the receptors with naloxone for a a few half life cycles significantly speed up methodone withdrawal?

There exists a method of detoxification employing naloxone to precipitate withdrawal in an anaesthetized patient, you can find information on it searching for "rapid detox". Precipitated withdrawal is much more intense (hence anaesthesia) but also much shorter, however, the legitimacy of this method is questioned here (1) as it doesn't offer any advantage over other methods with respect to potential relapse and carries health risks associated with very high adrenaline release during the procedure including death. Whether the actual withdrawal is shortened or not is debatable because patients after rapid detox often still experience physical symptoms of withdrawal and require additional medicines. Here is another site worth visiting as it has plenty of references to start from while further researching the topic (2).

I don't want to make a final verdict on it, but I myself would not go for a rapid detox due to the risk of cardiovascular side effects, I'm not sure if I have an actual heart disease, but it seems heavily strengthened, for the same reason I wouldn't consider ibogaine either now. But there is also the question what's next after any detox. When I was quitting methadone, I believed I was quitting for good, but apparently I went into PAWS, two months after quitting I was still experiencing withdrawal symptoms and even though they were different from acute withdrawal, they dragged on and were debilitating to the point I decided to start buprenorphine maintenance. It's been 5 years since that time and I can't picture quitting right now, there's too much stress and too much everything in my every day life and very little to hang on to in case of potential cravings (what if buprenorphine wasn't available any more in case I failed?). I'm sure you can go different routes when deciding to quit maintenance just as when you do a detox from heroin, but these are two different situations in my opinion. When you do a detox, there are options afterwards such as opioid maintenance or rehab centre, I don't think one starts opioid maintenance be it on methadone or buprenorphine to eventually find themselves in the same situation at the end of it as when quitting heroin. Thus I hope I eventually get to a point when taking another dose of bupe is not something I have on my mind and look forward to all day, then I can start tapering off and I hope it won't be nowhere near as painful as it was with methadone if it's well spaced over time.

As for opioids longer-acting than methadone and buprenorphine, I don't think I would exchange buprenorphine for a longer-acting partial agonist that could be taken twice or thrice a week. Even though buprenorphine effects are very mild compared to full agonists, when you get used to taking it in a certain manner and expect certain effects, the transition itself to a different medication with different pharmacokinetics can be very disorienting. If I were suddenly to switch from taking buprenorphine twice a day to taking thienorphine for instance every two days, I'm sure I would be in some kind of mental withdrawal on evenings and days without dosing. I do agree that the frequency of dosing can play a major role in the outcome of maintenance though, so we should wait to see some comparison between sublingual buprenorphine and buprenorphine implants. On the other hand how do we know we will have safe protocols for weaning off even longer-acting opioids? These drugs also differ in pharmacodynamics one to another, additional effects of methadone and buprenorphine apart from MOP agonism/partial agonism certainly impact the withdrawal.

 

[clubcard]

adder - yow, 'Detox 5'. I've heard nothing but horror stories. I noted 1950s papers from the UNODC. They didn't directly state it but they remarked that compounds that were both ? & NMDA ligands produced the worst withdrawal. That would be ketobemidone, dipipanone, levorphanol, piritamide and so on. I've been told the kick of these is truly aweful.

 

[Cotcha Yankinov]

So in theory would cleaning the receptors with naloxone for a a few half life cycles significantly speed up methodone withdrawal?

Naltrexone/Naloxone are very likely inverse agonists, meaning that they will actually cause the opioid receptor in question (Mu Opioid Receptor - MOR) to essentially disappear/be recycled. A MOR silent antagonist may just sit on top of the receptor without causing it to be recycled, and that may help increase expression of opioid receptors, but it would surely induce some precipitated withdrawal if there is still an opioid in one's system or if the basal endogenous activity of opioid receptors isn't zero.

There is evidence that naltrexone can help with withdrawal and tolerance when given in extremely low doses (We're talking 0.125mg). This seems to be because Naltrexone/Naloxone bind to a high affinity site (Filamin-A) and thus interfere with a switch in MOR's coupling to different downstream signaling pathways that occurs after chronic opioid use.

Normally an MOR agonist binds to the MOR and activates a signaling cascade element (G-protein) called Gi/o, which causes inhibition of the cell that the MOR is expressed on and thus leads to the desirable effects of opioids. But with time, the MOR agonist causes the opioid receptors to switch their coupling to "Gs" G-proteins, which when activated by an agonist produces an increase in the cells excitability. Eventually the opioid receptors stay "stuck" on Gs.

Naltrexone/naloxone appear to be able to prevent/reverse this aberrant coupling by binding to said high affinity site Filamin-A, and therein could be the reason for the efficacy of ultra low dose naltrexone for withdrawal (higher doses would block the Gi/o coupled MORs and outweigh the blockage of the "bad" Gs coupled MORs"). But low doses would cause recycling of the "bad" MORs or reversal of the aberrant G-protein coupling.

Depending on G-protein coupling, a ligand's affinity for a receptor can change, so its possible that naltrexone has higher affinity for MOR coupled to Gs than MOR coupled to Gi/o, meaning that naltrexone would preferentially block Gs a bit.


One may have this notion of "Give me naltrexone, give me a horrible withdrawal for 2 days and just get it over with" - I'm actually not sure about that notion. Increased dynorphin release -> increased signaling at kappa opioid receptors plays a role in opioid withdrawal (ibogaine seems to block some acute opioid withdrawal by partial agonism at the kappa opioid receptors, which effectively blocks some of the dynorphin signaling), so there may also be some component of kappa blockade when it comes to taking naltrexone for opioid withdrawal

It seems to me this would be a much better idea when no opioids are actually in one's system, you could block some of the dynorphin/kappa signaling without displacing the opioid agonist and precipitating withdrawal really bad. You would mostly be blocking the endogenous MOR agonists at that point, and I believe most non-opioid dependent individuals can take some naltrexone without displaying horrible withdrawal-like symptoms (I think they tend to get some sympathetic nervous system activation, this is my experience as well).

However, the opioid withdrawing patient without an active opioid in their system may already be vulnerable to an increase in sympathetic nervous system activity when taking naltrexone. An example is the increase in locus coeruleus (LC) cell firing with opioid withdrawal - this is an sympathetic/adrenergic projection that will be causing release of e.g. norepinephrine downstream and thus causing symptoms of withdrawal.

Eventually, the adrenergic receptors downstream of the LC will start to desensitize, and maybe taking naltrexone will just mean increased LC firing/more norepinephrine release but also faster desensitization of downstream adrenergic receptors, and faster activation of other homeostatic mechanisms that would act to inhibit the stress response.

So you may be able to condense the withdrawal symptoms down to a shorter time frame, but I'm not sure if its overall less suffering. From a sleep deprivation point of view I would rather have a couple really shitty (excuse the pun) days than a week or two of zero sleep.

Any questions are welcome,
CY