Ouch! Abrupt opioid withdrawal increases pain sensitivity

July 10, 2009
Bio-Chemistry of pain: Too much calcium may hurt.

(PhysOrg.com) -- 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. 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 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 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 , 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 This study proves for the first time that opioids also leave a "memory trace" in the pain system if they are withdrawn abruptly.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 Professor Jürgen Sandkühler. "Until now, we had assumed that only strong or sustained pain could induce LTP in the pain system." On making this discovery, Prof. Sandkühler 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 LTP, calcium ions flow into the brain's 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. Sandkühler. 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. Sandkühler. 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 - without any nasty surprises once they are withdrawn.

More information: Ruth Drdla, Matthias Gassner, Ewald Gingl and Jürgen Sandkühler. Induction of synaptic long-term potentiation after opioid withdrawal, Science 325 (2009), July 10th. DOI: 10.1126/Science/1171759.

Provided by Austrian Science Fund

Related Stories

Recommended for you

Scientists find key to regenerating blood vessels

November 23, 2017
A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies a signaling pathway that is essential for angiogenesis, the growth of new blood vessels from pre-existing vessels. The ...

Researchers find infectious prions in Creutzfeldt-Jakob disease patient skin

November 22, 2017
Creutzfeldt-Jakob disease (CJD)—the human equivalent of mad cow disease—is caused by rogue, misfolded protein aggregates termed prions, which are infectious and cause fatal damages in the patient's brain. CJD patients ...

Surprising roles for muscle in tissue regeneration, study finds

November 22, 2017
A team of researchers at Whitehead has illuminated an important role for different subtypes of muscle cells in orchestrating the process of tissue regeneration. In a paper published in the November 22 issue of Nature, they ...

Study reveals new mechanisms of cell death in neurodegenerative disorders

November 22, 2017
Researchers at King's College London have discovered new mechanisms of cell death, which may be involved in debilitating neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

Cinnamon turns up the heat on fat cells

November 21, 2017
New research from the University of Michigan Life Sciences Institute has determined how a common holiday spice—cinnamon—might be enlisted in the fight against obesity.

How rogue immune cells cross the blood-brain barrier to cause multiple sclerosis

November 21, 2017
Drug designers working on therapeutics against multiple sclerosis should focus on blocking two distinct ways rogue immune cells attack healthy neurons, according to a new study in the journal Cell Reports.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.