EndocrinologyAbrupt Opioid Withdrawal Increases Pain Sensitivity
The abrupt withdrawal of morphine-like analgesics - opioids - can
increase sensitivity to pain. Experiments have now shown that this
effect is caused by a memory-like process, the long-term potentiation of
synaptic strength in the spinal cord.
The study, which was supported by
the Austrian Science Fund FWF, also found ways of avoiding this increase
in pain sensitivity. These pioneering results have now been published in
the prestigious journal Science.
Opioids are the oldest and most effective analgesics. They are often
used, for example, during operations or when other forms of treatment
fail. This is because opioids - unlike other analgesics - bind to opioid
receptors, which are highly effective in depressing the activity of
nerve cells responsible for transmitting information about pain.
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On abrupt withdrawal, e.g. after surgery, this can lead to an abnormal, excessive increase in pain sensitivity. A research project conducted by the Department of Neurophysiology at the Center for Brain Research at the Medical University of Vienna has now been able to explain what causes this phenomenon.
Painful "Cold Withdrawal"
The abrupt withdrawal ("cold withdrawal") of opioids leads to "long-term
potentiation" (LTP) of synaptic strength in the spinal cord"s pain
pathways. This in turn leads to sustained and increased sensitivity to
pain. In the brain, LTP is a physiological mechanism for learning and
memory. An activity-dependent increase in synaptic transmission between
the nerve cells at their contact points, the synapses, can be very
long-lasting. For example in the spinal cord, pain stimuli can trigger
LTP and lead to a long-lasting "pain memory". This study proves for the
first time that opioids also leave a "memory trace" in the pain system
if they are withdrawn abruptly.
"We were rather taken aback ourselves by
the results," said project manager Prof. JÃørgen SandkÃøhler. "Until now,
we had assumed that only strong or sustained pain could induce LTP in
the pain system." On making this discovery, Prof. SandkÃøhler and his
team set about deciphering the molecular mechanisms of this process. Dr.
Ruth Drdla and Matthias Gassner, the two main authors of the study, were
able to show that abrupt withdrawal - similar to a pain stimulus -
increases the concentration of calcium ions in the spinal cord"s nerve
cells.
Excessive Calcium Ions
Calcium ions are important intracellular messengers that activate
numerous enzymes and consequently also lead to LTP. With memory LTP,
calcium ions flow into the brain"s nerve cells via NMDA receptor
channels. Therefore, the research team conjectured that blocking these
calcium channels could also prevent LTP in the spinal cord. "To test our
theory, we used selective blockers that only close off NMDA
receptor-type calcium channels," explains Prof. SandkÃøhler. The results
showed that these blockers, which are also available as drugs, did
indeed reliably prevent LTP on the withdrawal of opioids. "However, the
blocker has to be administered in good time before the start of the
withdrawal," adds Prof. SandkÃøhler. The team also made another discovery
that is important for the treatment of pain: If the opioid is reduced
slowly and in a controlled manner instead of being withdrawn abruptly,
it is quite straightforward to prevent the LTP caused by opioid
withdrawal and, therefore, the onset of withdrawal symptoms.
This latter result of the FWF-supported project in particular shows that
fundamental medical research can indeed provide concrete recommendations
for everyday medicine. These new findings mean that essential opioids
can be applied even more reliably in the treatment of pain - without any
nasty surprises once they are withdrawn.
Original publication:
"Induction of synaptic long-term potentiation after opioid withdrawal"
Ruth Drdla, Matthias Gassner, Ewald Gingl and JÃørgen SandkÃøhler.
Science 325 (2009), July 10th. DOI: 10.1126/Science/1171759.
Austrian Science Fund FWF