Addiction, Dependence, Withdrawal, Klonopin reply to Brian

[mosspa]

Back when I was a psychopharmacology grad student in the 70s, the term "addiction" was reserved for compounds whose continual use results in physical dependence on the compound. Physical dependence was demonstrated by the production of severe withdrawal symptoms following termination of the compound. In 1976, the list of things that were truly addictive was quite short. It included opiate derrived and synthetic opiate drugs, barbiturates, benzodiazepines, and ethanol. Things that definitely were not addictive in the 70s included psychostimulants (without added barbiturates) including amphetamine and cocaine, nicotine, caffeine, most hallucinogenic compounds, and chocolate. Then, during the Reagan era, an interesting thing happened. The right wing "Just say No!" people intersected withthe left wing social humanist's "blame uncontroled behavior on a medical condition" mantra, and almost overnight changed the definition of the word addiction. Addiction became defined in terms of a much less strict definition of physical dependence. Where in the 70s, withdrawal symptoms included seizures, hallucinations, vomiting, and death, today's definition includes such things as increases in neuron firiing rate or psychophysiological reactions to withdrawal that would be would have been dismissed as psychologically mediated previously. In today's world, the symptoms of anxiety, depression and hopelesness that acompany an obese persons reaction to a strictt diet qualify as withdrawal symptios, elevating food to the same status as heroin in terms of addiction.

The point here, is the separation of the concept of addiction, as it applies to Klonopin, from the multifaceted "dependence syndromes" often observed in onsomniacs on sleep meds. Very few of the people who use the z-drugs are physically dependent on them, although they may be very highly psychologically dependent. The same is true for most sleep use benzodiazepines, although the line becomes blurred by the fact that if used long enough, most of the benzodiazepines lead to real physical dependence. The reason why real physical dependence may not develop in z-drug usage, but almost always does for benzodiazepine sleep induction usage (Halcion, may be one of the few exceptions, here) is lies in the pharmacokinetic profiles of the drugs.

While the all of the z-drugs have very low half lives (2-10 hrs), most benzodiazepines have much longer half lives. Take Valium, for example, that has a half life for active metabolites oxazepam, I think) that is expressed in days (70-100 hrs). What that means,is that if you were to take one 5 mg valium every day, everything else remaining linear, by the time you got to day 3 or 4 you would have the equivalent of 15-20 mg of valium in constant circulation and in constant interaction with benzodiazepine receptors. So what started out as an initial 5 mg dose of diazepam by day 4 becomes a steady state15-20 mg oxazepam/diazepam load plus the new 5 mg you add each day. That meand that about 2 hrs after you take the valium, your total benzodiazepine load peaks at 20-25mg on day 4. It is easy to see how tolerance develops in this situation if the 5 mg/day valium dosing schedule was continued. This is, percicely, why valium is a great drug for use in treating alcoholics who are going through alcohol detox (an acute process that usually takes only about 4-5 days in the worst case), and a horrible choice as a sleep medication. This is also why people become physically dependent after even reasonably modest long-term chronic daily usage (i.e., 20-50 mg) such as that seen in "Mother's little helper" syndrome, that was so popular in the late 60s and early 70s.

Now, about Klonopin. I do not really understand the use of Klonopin for chronic insomnia treatment. Klonopin has an average systemic hald life of 30-40 hrs. That means that you still have more than half of the original dose when you take the second dose. Depending on the individual (i.e., whether their metabolism time is closer to 30 or 40 hrs), repeated daily dosing is going to result in bioaccumulation over time. Graph it out. I'm sure you will be impressed with how mych klonopin was saturating your benzodiazepine receptors after a couple weeks chronic usage. Contrast that to what happens with a z-drug or with halcion (half life 1.5-5.5 hrs).

So, Brian, think about your tolerance to the effects of klonopin mean in pharmacokinetic/pharmacodynamic terms. When you stopped taking it, you had a whole lot more of it in your system than you might have realized. Conformational changes in the various benzodiazepine receptors have been observed as their exposure to the benzodiazepines is maintained. The curve fits well with the tolerance curve. After termination of klonopin after very long term usage, it is not surprising to see signs of true physical dependence and true 70s-style addiction. The severity of the symptoms (not rebound insomnia) determines the severity of your addiction. Never having used klonopin I really don't know much about overdose levels, etc. However, like most other things. tolerance indicates a changing set-point for negative effects of taking any drug. More than likely, the concentration of klonopin you had floating around in your system on the day you quit would have killed you if you ingested it in one dose on day 1.

Moss

[ZZzzZZss]

Moss is correct here plus one additional point is also important. The short half live drugs have another advantage besides failure to accumulate as described here. Since a 2 hour half life drug is essentially gone after 5 half lives or so, it only 10 hours and its GONE. That means that your receptors are only exposed for a portion of the day and not exposed the rest of the day. They are only strongly exposed for a few half lives so they have time to begin unadapting during the off period before the next nights dose. So from the addiction point of view, the shorter the half life and the lower the potency the better.

Klonopin is both quite potent with 1mg being about equal to 10mg of Valium and has the long half life as Moss has mentioned. It also has really poor hypnotic properties so its makes little sense to take it for insomnia for all these reasons.

[sleepylady]

Wow.
Some great stuff in here and a lot to think about. Thanks, Moss!!

[bizfrob]

I recently posted about my wanting to get off long term use of klonapin and anafranil. It has been about 5 years for chronic insomnia. I have been very stable. There is a lot of information on this site. I understand that drinking alchohol is not recommended but I have been binge drinking 1-2x per week for several years, sometimes not taking the meds but most of time i do. I have a meeting with my Dr. this week to plan to get off. I know this will require some work. He has told me that alchohol doesn't really have any negative health effect with the meds. This seems like a good group. What are your thoughts?

[ZZzzZZss]

[mosspa]

Biz,

Please describe your alcohol binging, as you did to the Dr. I can't imagine a medical doctor making a statement such as that. I've been mixing bexnos (and more recently z-drugs) with alcohol for years. In reasonable dose ranges, the benzo/ethanol interaction is not too serious, and is probably of even lower risk if you take the benzo first. Most fatalities that occur from benzodiazepine and alcohol interactions involve failure of respiration. Since the z-drugs don't share the respiration effect with the benzodiazepines, the only real effect of alcohol is an additive one for sleep. Still, I'd like to know more about what you consider binge drinking. Independently from any additive health effect with benzos, binge drinking is not a healthy thing to do. The way you qualify 1- 2x per week, suggests to me that you probably aren't really binge drinking. Most drinking "binges" go on for several days. So, 2 binges of 3 days would eat up most of a week. On the other hand, I have an alcoholic friend who could be considered to be on a perpetual drinking binge (I'm not sure if he has actually been sober for over 2 years).

Moss

P.S. To anybody, how do you quote other posts using this interface?

[bizfrob]

2 x per week. 4-8 drinks.

[ZZzzZZss]

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z

[mosspa]

Zzz.., thanks for the tip.

Bizfrob, 4-8 drinks a couple of days a week does not a binge make, even if you put them back to back. If you disregard all of the politically correct crap, and the demonization of alcohol, most sane people will conclude that 3 oz absolute alcohol/day is not really problematic (I guess it counts when you consume it, like I'm not sure that heavy drinking before driving to work in the morning is a good thing). 7.5 oz of 80 proof spirits is equal to 3 oz of absolute alcohol. An average drink contains about 1.5 oz of spirits. That would equal out to 6 standard drinks made with 80 proof spirits. So, 4 drinks is a little less than what is generally considered "normal" and 8 is a little more. The fact that you you drink in this range only 2 nights a week is not a binge, nor is unsafe. As to drinking this much with Klonopin, I have to say, I agree with your physician. First, you are so tolerant of the benzodiazepine, that your system has adapted to whatever level you are carrying in steady state,. The alcohol intake you describe shouldn't bring you any closer to respiratory arrest than it would if you took .5 my Klonopin and washed it down with several drinks on the first night you took Klonopin. Actually, the more tolerant you become to the Klonopin, the effect of one night's dosing is negligible when you consider its proportionality to the load you are carrying around in steady state.

Let me guess, the nights you forget to take the Klonopin are the 8-drink nights? How would you rate your sleep on those nights? On my non-z-drug nights, I drink in that range (6 or so drinks, in my case glasses of wine). On my alcohol only nights, I sleep fine, and tests in a sleep lab show that I am slightly REM suppressed, but not much, and that I achieve REM rebound in the last few hours of the 9 or so hrs of sleep I get on the alcohol-only nights. Except that I sometimes have a mild hangover, if I drink closer to the 8 drink range (headache and maybe a little nausea) some mornings, I generally feel fine and rested the next day. As I have posted elsewhere, I consider this the price I pay for not letting my system develop tolerance to the z-drugs.

Just to put this drinking thing into perspective, by the time I graduated high school, a six-pack was pretty standard consumption for me and most of my friends on an average Fri and Sat night. By the time I finished college, 8 drinks in a night would have been considered lightweight.

Moss

[Brian]

ZZzzZZss:

11 years ago my neurologist told me that Klonopin was non-habit forming, and that "at low doses" -- smaller than the dose they prescribe for panic -- it caused drowsiness. All I can say is that he was right. After about 20-30 minutes, I can feel myself struggling to stay awake. The problem is that you grow tolerant to it, and need ever increasing amounts to get the same affect. And no other doc I spoke to can believe any MD would say it wasn't habit-forming. You cannot simply stop taking it after you have gotten accustomed to downing 5 mgs a night for 5 or 6 years.

What I don't understand is why it is so difficult to find a drug that actually works. I see where the big names have helped a lot of people on this board, and I envy anyone who writes that they got 6-9 hours of uninterrupted sleep. I'd settle for 4 - 6 hours anyday! My use of Klonopin really concerned me, and I decided I should get off of it. But finding an effective substitute has been difficult. After trying Remeron, Restoril, Lunesta, Sonata, and regular Ambien, I'm taking Ambien CR, and about 50% of the time, when I wake up at exactly 3:19AM (no matter what time I go to sleep) I am able to fall back to sleep for about an hour and a half. The other half of the time, I can't fall back to sleep and I just slog through the day like a zombie. I'm concerned about the comments I'm reading, however, about taking Ambien on a long-term basis. My GP prescribed it, saying that I shouldn't build a tolerance for it, like I did with Klonopin. My ears pricked up on that comment, given that I was told that about Klonopin, and it didn't prove to be true.

If I thought I was substituting one drug for a less effective one--just to end up developing a tolerance for it and having a difficult time getting off of it--, I'd just as soon go back to taking Klonopin at high doses. I wonder: Is there ANYTHING out there that doesn't become less effective after a long time? Is there ANYTHING out there that can be taken on a multi-year basis without causing some sort of physical dependence? I'm seeing a rather young, green GP, who I believe will give me just about anything I ask for, but really, I don't know WHAT to ask for! The only sleep medications I know of are basically the ones I've seen on TV, and so far, they have all been a major disappointment.

b/

[ZZzzZZss]

Brian said:

[mosspa]

ZZz:

From what I've read about Xyrem, it is nearly impossible to get because the DEA has scheduled gamma-hydroxyburyrate (GHB) as a Class 1 drug (i.e., no medical use). As far as I can tell, in order to get GHB as Xyrem you need to, somehow, become part of a Phase III trial of the compound, which apparently involves getting a cataplexy diagnosis. If the drug can only be gotten if you enter a cataplexy/narcolepsy trial, how do you get to qualify as a simple insomniac? Possession of Schedule 1 drugs can be a felony depending on the quantity. Isn't it just easier to get gamma-butyrolactone (GBL) from some legal source, and use that? I fully intend to start a thread on the pharmacology of Xyrem/GBH but I want to get all of the political/social ducks in a row before I do it.

I managed to knock myself out with GHB one time when I trying to observe the underpinnings of the date-rape phenomenology, when we were looking at it as part of our epilepsy research program. If nothing else, it has got to be a great drug for use before long stretches of late night highway driving. That feeling of wakefulness you get after the 2 or so hrs sleep is, simply, amazing. What I find even more amazing (per your prior posts on the subject) is that you can get back to sleep during it.

Moss

[ZZzzZZss]

Xyrem is FDA approved for Narcolepsy under schedule 3 and off label use is allowed. They dispense from a central pharmacy to control it well. Any doctor can prescribe it and its soon to be approved for fibromyalgia. My doctor approved it because of such severe insomnia I was disfunctional and my sleep study showed no stage 3/4 delta sleep. Xyrem has been shown to improve/induce stage 3/4 sleep. She treats fibro patients and has prescribed it off label for that so was familiar with its use and effectiveness and being a non-benzo or z-drug like option. Only doctors familiar with either Narcolepsy or Fibro will likely not be worried about its bad reputation but its being trialed for other things too. Trials for Fibro are underway.

z

[michaelw]

I had to shop around for a couple of months before I could find a physician willing to prescribe Xyrem for my chronic insomnia. Neither my regular GP nor the sleep specialist I was seeing were willing to do it. However, since then the sleep doc has done more research and has started prescribing it for a few of his insomnia patients (including me). ) I suspect the biggest obstacle for most patients is the obscene price -- something like $250 for a two week supply. (I'm not sure of the exact figure because I'm lucky enough to have pretty good health insurance and they pick up nearly the entire cost.) It's hard to believe that twenty years ago you could purchase this for a few bucks in any health food store. More "collateral damage" from the insane war on drugs, I guess.

[sleepnscream]

I have had experience with both Klonopin and Xyrem. Please search my name and read for more info. I would have to argue some statements made here. I have also taken Xyrem with Klonopin. My doc talked with Stanford before alowing me.The worst drug by far I have ever had to withdraw from is Klonopin!!!