Veritatem said:
I can not possibly ever imagine taking those doses ever again. I'm just curious if the half-lives of the various benzos have any correlation to the half-life of the medicine.
I'm not sure what you're asking in this thread if it's the correlation between the half-life of a benzodiazepine or its GABA-A subtype selectivity and its propensity to cause paradoxical effects. As for the answer to the question quoted above, I suppose you ask if the half-life of a benzodiazepines correlates with the duration of effects. The half-life of a benzodiazepine drug does correlate with the duration of effects, however, it's not the only factor that comes into play. Any centrally active drug must pass the blood-brain barrier first, this barrier is a membrane separating the blood in the brain from the cerebrospinal fluid. This membrane can be crossed by lipophilic drugs, but it can be crossed in both ways obviously, and depending on the structure and properties of a drug capable of crossing the blood-brain barrier, it may spend more or less time in CNS. Some benzodiazepines despite having long half-life have shorter duration of effects because they being more lipophilic cross the BBB faster and once they travel back from the CNS into the periphery, they get accumulated in the fat tissue, diazepam is an example. To compare, take lorazepam which is more polar than diazepam, once it crosses the blood-brain barrier, it stays for longer in the CNS and has longer duration of anticonvulsant effect than diazepam even though diazepam has ~4x longer half-life. So the half-life of a drug is not the only thing that determines how long they effectively exert their effects.
As for the GABA-A receptor subtype which may be particularly responsible for causing paradoxical effects, I have no information if there is any correlation. There's certainly a lot of literature on GABA-A receptor subtype roles and how selectivity impacts overall effects. Alpha-1 containing receptors are the most abundant in the brain and depending on their location they may have a different role, generally they are responsible for sedative and amnesic effects of benzodiazepines, but they also modulate anticonvulsant effects. Hypnotic benzodiazepines typically have some selectivity for alpha-1 and alpha-5 over alpha-2 and alpha-3, the problem is all classic 1,4-benzodiazpines bind to alpha-1 containing receptors, so all classic benzodiazepines can cause amnesia. Talking about subtype selectivity of classic 1,4-benzodiazepines, you always have to assume they all bind to alpha-1, -2, -3, and -5 containing subtypes despite having some selectivity for certain subtypes. Anyway, hence the idea to design more subtype-selective drugs so we can have anxiolytics and anticonvulsants without sedation and amnesia as side effects.
Benzos aren't very effective after 14 days and useless at 28 days. Your body adjusts. The effects you feel are RELATIVE calm i.e. it staves off abstinence syndrome. It took me 16 months to drop from 24mg diclazepam a day to zero and it was hard work all the way. It looks like doctors are repeating what they did with barbs. People who are physically dependent are just being kept on the same dose. That's why Seconal & Tuinal are still in the BNF.
I think it's more complex than that. Tolerance does kick in very fast with benzodiazepines, that's true. I've been on alprazolam for 4 months now, I started at 0.5mg a day, now I'm at ~1.5mg a day. I've been at 1.5mg for 3 weeks now and I can manage without further increasing my dose, but it's time to start tapering down for sure. I can feel the difference in effects when I drop my daily dose by 0.25mg, also, when I wait too long with my first dose in the day, then around noon I already start feeling shaking inside and fear of imminent withdrawal, the same thing happens when I try not to take my 0.5mg evening dose. However, the drug still works for my anxiety, it doesn't eliminate it fully, it never did in the first place, but I don't get panic attacks after taking my morning dose during the day and I started taking it last December because panic attacks made it impossible for me to sit through obligatory classes at the uni. I certainly function better taking it than I did in December without it, so it still does its job although I have developed tolerance. What I feel when I wait too long with the next dose is not just my pre-existing anxiety or rebound anxiety. The problem with taking benzodiazepines for over a month is IMO rebound increased glutamatergic neurotransmission, part of the tolerance may simply be adjustments of the GABA-A receptors to increased GABA neurotransmission (structural/conformational changes at the benzodiazepine binding site making them less effective), but rebound glutamate is probably the culprit in rebound anxiety in the short-term benzodiazepine treatment. Still, as long as you increase the dose, benzodiazepines retain their efficacy for anxiety in my experience (and long-term treatment with clonazepam for its anticonvulsant properties is also common, often at quite high doses) although certainly much of the dose is "used up" to counter glutamate stimulation and there is indeed a ceiling where in spite of further dose increase, anxiety can't be helped. That's a real danger but it concerns people who take very high doses of benzodiazepines for a long period of time. Still, the longer you take benzodiazepines, the harder it is then to quit and the longer the tapering process takes. I'm not sure if totally pain-free taper off is possible no matter how slowly one reduces their dose, I think not.
Not that I condone prescribing or taking benzodiazepine for longer periods of time, I certainly do not. Having been addicted to them for 9 years and having gone through hellish withdrawal after that despite tapering down, I certainly advise against taking them for anxiety unless absolutely necessary.
