First Posted 12/31/2013
Buprenorphine is relatively unique among opioids in having a ‘ceiling’ to mu opioid effects. There are other known molecules that act as partial agonists at mu opioid receptors, but buprenorphine is the most useful, at this point, because of other traits of the molecule– such as having few side effects from actions at non-mu receptors.
As most opioid users soon realize, opioid agonists increase tolerance over time to what appears to be an infinite degree. The mechanisms of tolerance are complicated. I often describe tolerance as a process where receptors become less and less sensitive to opioids with stimulation, to the point where native opioids (endorphins and enkephalins) no longer activate opioid pathways. Some of the change in sensitivity is caused by the binding of phosphate molecules to the intracellular portion of receptors, causing changes in conformation. Tolerance development is likely far more complicated, though, and includes other changes in synaptic transmission through different mechanisms.
The best model to understand the effects of buprenorphine, in my opinion, is to plot the curve with ‘mu effects’ on the y axis and ‘blood drug level’ or ‘dose’ on the x axis. Opioid agonists yield a straight line with a slope that correlates with drug potency. Buprenorphine yields a straight, sloped line in microgram doses and low blood levels, but a horizontal line in high doses. At a sufficient blood level, buprenorphine essentially sets the tolerance at the degree of opioid effect predicted by that horizontal line.
We could also graph the development of tolerance over time, to high doses of opioids. Agonists would yield a sloped line that eventually flattens, providing the dose of drug is held constant. In increase in dose of agonist would cause the line to slope upward for more time, and flatten at a higher level. With buprenorphine, on the other hand, the slope would flatten at a level that remains constant, even if dose of buprenorphine was increased.
This second graph answers the question of whether buprenorphine or Suboxone stop working at some point in time. From a theoretical standpoint– which is mirrored by clinical experience– tolerance from high-dose buprenorphine does not change beyond the increase in tolerance over the first few weeks of use—- or beyond the decrease in tolerance that was caused by higher amounts of an opioid agonist. If we graphed the development of tolerance to high dose buprenorphine (say 16 mg per day) vs. time, the graph would be different for opioid-naive persons than for people taking high doses of agonists. In the former group, the line would slope upward and flatten in days to weeks. In people taking high doses of opioid agonists, the line would slope steeply downward over the course of minutes, and flatten at the same level as for the first group of patients. The steep, downward-sloping line would represent the forced-lowering of tolerance by buprenorphine, which is experienced as precipitated withdrawal. In precipitated withdrawal, buprenorphine is ‘yanking’ tolerance down suddenly. The graph would be similar for the mu antagonists naltrexone or naloxone, but the point of leveling off would be lower– theoretically at the level of zero, if enough antagonist is used.
I realize that it is difficult to develop mental images from another person’s written descriptions… but I encourage people who want a better understanding of buprenorphine to give the mental images a try. Once a person can picture the flattening of opioid effect with increased dose or blood level of buprenorphine, the mechanism of action of buprenorphine is easily understood. As long as the blood level remains above the point where the line becomes horizontal, the opioid effect does not decrease– and so from the brain’s perspective nothing wears off, and nothing ‘comes on’. Tolerance develops to that level of opioid effect within days to weeks, removing any subjective opioid effect.
After the initial days to weeks on buprenorphine, the tolerance level remains constant– even if the dose of buprenorphine is raised or lowered, as long as the dose remains above the critical level that yields the ceiling effect of the drug.
For those who want ‘just the facts’, the response of opioid receptors to high-dose buprenorphine does not change over time. Buprenorphine and Suboxone therefore do NOT stop working over time, and there is no need for the dose to change over time. If anything, my patients tend to move to a lower dose with time, as they find the minimum dose necessary to produce the ceiling effect of buprenorphine throughout the entire dosing interval.
The graphs also explain why there is no truth to the common internet comment that ‘the longer you take buprenorphine, the harder it is to stop’. Tolerance remains constant, so from a physical standpoint the journey off buprenorphine is the same in three months or three years. My own clinical experience suggests that people find it progressively easier to stop buprenorphine the longer they take the medication. I have no proof for if or why that occurs, but I suspect that a number of psychological factors are responsible—including the transformation to a new, non-using identity that allows withdrawal symptoms to act aversively and remind people of their desire to stop opioids.
In other words, I suspect that being on buprenorphine for a long time reduces the cravings during withdrawal, instead causing cravings
First Posted 12/31/2013