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Ouch! Abrupt opioid withdrawal increases pain sensitivity

By Spucky, May 30, 2010 | Updated: May 30, 2010 | | |
  1. Spucky
    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 neurophysology 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 This study proves for the first time that opioids also leave a "memory trace" in the pain system if they are withdrawn abruptly.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 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 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. 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 Pain- without any nasty surprises once they are withdrawn.

    Source: http://www.physorg.com/news166449845.html

    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


  1. chillinwill
    Red Rock knows he has felt a sensitivity to pain when he is in withdrawal, and even during PAWS. Even today, he feels like he is more susceptible to pain than before, but that might be because all he can remember for the longest time is feeling no pain. There have been several threads on this subject here on DF, but it is good to see a study done on this proving the theory.
  2. Spucky
    AW: Ouch! Abrupt opioid withdrawal increases pain sensitivity

    I was looking for this article a few times in combination with the Nigella Sativa
    This is very interesting!

    Opioid dependence is a chronic disorder that produces changes in brain pathways that remain long after the patient stops taking the drug. These protracted brain changes put the dependent person at greater risk of relapse. Detoxification can be successful in cleansing the person of drugs and withdrawal symptoms; it does not address the underlying disorder, and thus is not the adequate treatment. Maintenance with methadone or naltrexone is the usual practice in the long-term management of opioid dependence but both drugs have their own disadvantages because no single medication is appropriate for every individual for treating their opioid dependence, it is important that clinicians have a variety of the therapeutic agents available to them.

    Calcium channel blockers, such as verapamil, diltiazem, nifedipine, nimodipine, and felodipine are useful drugs being used in cardiovascular disorders, such as hyper-tension, arrhythmias, and ischaemic heart disease. Research on calcium channel blockers has proved their therapeutic potential in a variety of disorders such as asthma, diarrhoea, premature labour, and diseases of central nervous system such as epilepsy, and opioid dependence. Modern drugs are not only expensive and beyond the reach of majority of the population of world but also have multiple side effects. Hence there is a need to explore such drugs from indigenous sources and to observe if combination of desired therapeutic efficacy exists in nature.

    Nigella Sativa is in use for the treatment of variety of ailments since ancient times. Research has based its many effects on their efficacy of blocking calcium channels. As calcium channels have been tried for the treatment of opioid dependence, so Nigella Sativa was used in this study. This study was carried out on 50 patients who were divided into two groups. Patients were admitted for 12 days and then weekly followed up for 12 weeks.

    Each patient received placebo orally during day-1 and day-2 of admission. Thereafter Nigella Sativa was given to the patients from day-3 of admission to eighth week. Then the dose of each drug was tapered off during 9th and 10th weeks and then no treatment was given during last two weeks.

    It was observed that Nigella Sativa showed a rapid improvement in signs and symptoms of acute opioid abstinence. It was also observed that Nigella Sativa prevented the development of significant craving and relapse. It is concluded that Nigella Sativa is effective in long term management of opioid dependence and it is suggested that further long term follow up studies may be designed with greater number of patients.
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