neuropathic pain research pinpoints new role for microglia
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THE LANCET Neurology Vol 2 October 2003 http://neurology.thelancet.com 587
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AstraZeneca postpones discontinuation of MysolineAstraZeneca will extend the supply of the antiepileptic drug(AED) Mysoline (primidone) until August 2004 afterpressure from neurologists and epilepsy charities about theproposed withdrawal of the drug in December 2003.
After the anouncement that Mysoline would bewithdrawn, Ley Sander and John Duncan (UCL, Institute ofNeurology, London, UK) wrote to AstraZeneca with theirconcerns that patients with epilepsy, who rely on mysolinefor symptom control, were not being given enough time tosafely come off the treatment by the time the drug supply ranout in January 2004.
“This is a drug that you cannot withdraw very easilybecause it is a barbiturate”, Sander told The LancetNeurology. There is a high risk that withdrawal symptomswill appear. “The worst case scenario would be statusepilepticus”, says Sander.
About 4000 patients with epilepsy take Mysoline in theUK; 6000 more with essential tremor use the drug. As anolder-generation drug, many patients who use Mysolinereceive prescriptions from their family doctor and have littleor no interaction with epilepsy specialists. “Those old timerswho had their epilepsy well controlled and are looked afterby their GPs who carry on taking the prescription will findthe drug is not available anymore, and that could have majorimplications for those people”, warns Sander.
After pressure from Duncan and Sander and the charityEpilepsy Action, AstraZeneca announced that they plan to
continue the supply of Mysoline until August 2004.Neurologists recommend a withdrawal period of 18 monthsfor Mysoline, so this extension should be sufficient.However, Sander urges drug companies to tell people3–4 years in advance of drug withdrawals, to tell familydoctors, and to recommend replacement drugs.
AstraZeneca say they informed the Department ofHealth in accordance with best practice guidelines for drugdiscontinuations. Owing to the concerns of the epilepsycommunity the company are trying to sell the rights tomysoline to ensure its long-term availability.
Mysoline and generic primidone are widely used in theUSA. According to William Theodore (NINDS, Bethesda,MD, USA), “Mysoline is an effective and useful AED for aproportion of people with seizures. Were it to be taken offthe market, some patients might experience a loss of seizurecontrol, especially if supplies were not adequate for aprolonged taper and transition to other AEDs.”
Donna Bergen (Rush Medical College, Chicago, IL,USA) pointed out that “not many neurologists will mournits passing. But older physicians may still use it a lot.” Bergenalso stresses the importance of psychological implications forpatients who have seizure control with one drug and do notwant switch to to a possibly unsuccessful one. The USAmanufacturers of Mysoline, Xcel pharmaceuricals, do notplan to stop production.Peter Hayward
The pathogenesis of neuropathic painhas proved as hard to understand as itstreatment. Now, researchers from Japanand Canada have implicated aparticular receptor on activated glialcells, which was not previously linkedwith pain processing.
Most research on neuropathic pain has tried to elucidate howcommunication among neuronsinvolved in pain signalling could beincreased over long periods, commentsEdwin McCleskey (Oregon Health andScience University, Portland, OR,USA). The “minority view” is that theimmune system and related glial cellssomehow influence neural connections,a view that “now gains considerablesupport”, he notes.
The researchers focused on P2Xreceptors—a class of ATP-driven ionchannels—because some subtypesoccur commonly on nociceptiveneurons. Makoto Tsuda (NationalInstitute of Health Sciences, Tokyo,
Japan) and colleagues investigated therole of these receptors in a standard ratmodel of tactile allodynia, in which ratswith a peripheral nerve injury withdrawtheir paws in response to a light touch.
By use of P2X-receptor antagonists,the researchers found that blockade ofP2X receptor-subtype 4 (P2X4R)reversed tactile allodynia. Moreover,concentrations of P2X4R increased inthe rats’ spinal cord ipsilateral to theinjury, matching the time course of theemerging allodynia. The receptor wasupregulated on microglia, but not onneurons or astrocytes. “If the mech-anism is the same in humans”, arguesauthor Michael Salter (Hospital for SickChildren, Toronto, Ontario, Canada),“we have a good lead on a whole newclass of agents to target chronicneuropathic pain”. Because P2X4Rs didnot change after acute painful stimuli,the authors speculate that, in interferingwith P2X4Rs, “normal pain sensitivitywould be unaffected”.
The “broader importance” of thework, notes McCleskey, “is the cleardemonstration of a function formicroglial cells. The authors elegantlytested this idea by injecting microgliadirectly into the spinal cord of normalrats. This by itself induced allodynia—but only if the microglia had first beenincubated with ATP, thereby(presumably) activating them” (Nature2003; 424: 729–30, 778–83).
Salter hypothesises that pain hyper-sensitivity could be mediated by factorsreleased by microglia, such as cytokinesthat increase synaptic transmission inspinal pain pathways. While the teamexplore the steps between P2X4Rinduction and microglial activation,Salter hopes that this report will promptother researchers to look for activatedmicroglia in patients with neuropathy.Other groups are starting to discoverthe importance of such cells inneurodegenerative diseases and stroke.Kelly Morris
Neuropathic pain research pinpoints new role for microglia