Anti Epileptic Drugs For Neuropathic Pain

Today's post from pallimed.org (see link below) will be of interest for those neuropathy patients being treated with anti-convulsion, anti-epileptic or seizure medications. The information using case studies, is meant for student or colleague doctors and nurses and as such is slightly more technical in nature but is nevertheless quite easy to follow. It's always interesting to know how your doctor is thinking when he or she prescribes a certain type of drug for your complaint. It also helps you understand why that particular drug has been chosen. Remember too, anti-epilepsy drugs are on the treatment list for neuropathy and if you aren't taking them now, they may well be prescribed for you in the future - it's worthwhile knowing what you may be dealing with.

Cases: Anti-epileptic Medicines for Pain Management
Posted by Christian Sinclair on Friday, August 30, 2013

 
Personal details in the case have been altered to protect patient privacy. These cases may reflect a composite image of many different cases to illustrate a teaching point.

Case: Mr. LF is a 58 year-old gentleman with a history of metastatic lung cancer with metastases to the bone including the sacrum. He is seen in a palliative care clinic for severe right lower extremity burning pain lasting several months. Noting LF’s pain appeared to be neuropathic in nature, LF’s primary care physician prescribed, in succession, duloxetine and then amitriptyline. Unfortunately, neither of these interventions decreased his pain. His oncologist prescribed a fentanyl patch and oxycodone 5-10mg as needed. LF reports the opioid pain medications make him tired but do not relieve his pain. He wonders if there is anything else to try for his pain.

Discussion: Tri-cyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and anti-epileptic drugs (AEDs) are the mainstays of adjuvant therapy for neuropathic pain. This Case of the Month will focus on oral anti-epileptic neuropathic pain analgesics. Due to lack of head-to-head data, evidence is presented as numbers needed to treat (NNT) and numbers needed to harm (NNH). For instance, an NNT of 5 for 50% pain reduction means for every 5 patients treated with a drug, only 1 of them would achieve a 50% reduction in pain. Gabapentin (Neurontin) and pregabalin (Lyrica) are considered first-line anti-epileptics for the treatment of neuropathic pain.

Gabapentin is effective in treating central and peripheral neuropathic pain. According to a 2011 Cochrane review of the effect of gabapentin on chronic neuropathic conditions (including post-herpetic neuralgia, painful diabetic neuropathy, mixed neuropathic pain), the NNT is 5.8 (4.8-7.2) to achieve at least moderate benefit. This NNT is more conservative than those previously published due to better definitions of efficacy outcomes and an increased number of participants and studies evaluated.

Adverse effects are frequent and include drowsiness, dizziness and edema. Typically, if the dose is increased slowly these side effects are tolerable (1). Gabapentin should be dose adjusted for renal dysfunction. It should be withdrawn gradually to avoid precipitating seizures (2).

Pregabalin is effective in treating peripheral and central neuropathic pain. Since both gabapentin and pregabalin are chemical analogs of GABA, they are not used simultaneously in clinical practice. There are no comparison studies of gabapentin versus pregabalin. Pregabalin’s effectiveness increases as the dose approaches 600 mg/day. Based on a recent meta-analysis, at a dose of 600 mg/day the NNT to decrease pain by 50% for the following conditions is: 3.9 (range 3.1-5.1) for post-herpetic neuralgia; 5.0 (range 4.0-6.6) for diabetic neuropathy; and 5.6 (range 3.5-14) for central neuropathic pain. There was no difference in incidence of side effects among participants taking pregabalin vs. placebo and no indication of a dose response to side effects (3 - Open Access (OA)).

Carbamazepine is effective in treating neuropathic pain, specifically trigeminal neuralgia, but is not considered first-line therapy due to its adverse effects. A 2011 meta-analysis focused on the use of carbamazepine for chronic neuropathic pain reported carbamazepine reduced pain compared to placebo (NNT of 1.7, range 1.5-2.0). However, adverse events occur frequently: NNH = 2.6, range 2.1-3.5 (4). Common side effects include leukocytosis, thrombocytopenia, dizziness, drowsiness, ataxia, nausea/vomiting and blurred vision. Additionally, there is a risk of agranulocytosis, aplastic anemia, and Stevens Johnson syndrome. Laboratory tests (BUN, complete blood count, sodium, liver function tests, urinalysis) and serum drug levels should be checked at baseline and during treatment. Oxcarbazepine is an analogue of carbemazepine which is equally effective at treating trigeminal neuralgia as carbemazepine (5) but with fewer side effects (6 - OA).

Valproic acid was evaluated in a 2011 meta-analysis for the treatment of neuropathic pain. There were insufficient data for reliable pooled analysis, and the authors recommend against its use as first-line therapy (7).

Several small studies (n less than 60) showed benefit of the use of valproic acid (maximum of 1200 mg/day in divided doses) over placebo in the treatment of diabetic neuropathy (8 - OA). However, this data is not convincing. Other studies of valproic acid have failed to find an effect (9). Adverse effects include liver function test abnormalities, dizziness, drowsiness and nausea (2).

Topiramate was evaluated in a 2010 systematic review for the treatment of neuropathic pain. Of four randomized placebo-controlled trials, three were negative and one positive for the treatment of painful polyneuropathy. No studies were found to evaluate its efficacy in the treatment of post-herpetic neuralgia, peripheral nerve injury or central pain (9). Serious adverse events thought to be related to topiramate included convulsion and bradycardia plus syncope. Additional adverse effects include sedation, nausea, diarrhea and metabolic acidosis (2).

Summary: Neuropathic pain remains best treated with TCAs, SNRIs, and the AEDs gabapentin and pregabalin. For patients who are intolerant to or who experience pain unresponsive to those medications, one can consider therapy with other anti-epileptics. However, these agents are associated with more side effects and lower rates of efficacy.

Resolution of the case: LF was started on gabapentin and titrated up to a dose of 900mg three times a day with moderate pain relief. His opioids were tapered and discontinued.

References:
Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews. 2011, Issue3, Art No.: CD007938. DOI: 10.1002/14651858.CD007938.pub2
Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews. 2009, Issue 3. Art. No.: CD007076. DOI: 10.1002/14651858.CD007076.pub2. Open Access PDF
Wiffen PJ, Derry S, Moore RA, McQuay HJ. Carbamazepine for acute and chronic pain in adults. Cochrane Database of Systematic Reviews. 2011, Issue 1. Art. No.: CD005451. DOI: 10.1002/14651858.CD005451.pub2.
Zakrzewska J, Linskey M. Trigeminal Neuralgia. Clinical Evidence. 2009; 3(1207). Retrieved Nov 15, 2011 from http://clinicalevidence.bmj.com/ceweb/conditions/nud/1207/1207.jsp
Finnerup NB, et al. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain. 12005; 18:289-305.PMID: 16213659. Open Access PDF
Gill D, Derry S, Wiffen PJ, Moore RA. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults.Cochrane Database of Systematic Reviews. 2011, Issue 10. Art. No.: CD009183. DOI: 10.1002/14651858.CD009183.pub2.
Kochar DK, et al. Sodium valproate for painful diabetic neuropathy: A randomized double-blind placebo-controlled study. Quarterly J Med. 2004; 97:33-8. PMID: 14702509 Open Access PDF
Finnerup NB, et al. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010; 150: 573-581. PMID: 20705215

Original Case by Rene Claxton, MD, Edited by Christian Sinclair, MD
Originally posted at the Institute to Enhance Palliative Care,
University of Pittsburgh Medical Center
Original PDF

Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in health care.

http://www.pallimed.org/2013/08/cases-anti-epileptic-medicines-for-pain.html

How Good Is Methadone For Neuropathic Pain

Today's post from mypcnow.org (see link below) takes a look at methadone as an alternative to other opioids for controlling neuropathic pain. Methadone has had an extremely bad rap over the years, mainly because of its association with withdrawal from drug addiction programmes. However, it is an extremely cheap and effective drug for nerve pain and because only low doses are needed, the risks of side effects and addiction are much less than for instance morphine or oxycodone. That said, it is a powerful drug and once you begin, you need to be very careful when and if you want to taper off. Never go cold turkey with methadone - it will react almost instantly. Many doctors are reluctant to issue methadone prescriptions but that's often based on lack of experience rather than factual dangers. If a patient discovers over time that nothing else works, then methadone can be very effective in controlling nerve pain. Remember, all drugs for neuropathy have side effects, so don't be put off by what you may have heard - it all boils down to careful monitoring by your doctor. Discuss it with him or her if you find that almost nothing works for you in reducing the pain of neuropathy.

METHADONE FOR NEUROPATHIC PAIN
David E Weissman MD FAST FACTS AND CONCEPTS #171

Background Prescriptions for methadone have greatly increased in the past decade (1). The reason for this increase is likely related to two factors: reduced cost relative to other potent opioids and basic science data suggesting that methadone may be particularly useful in treating neuropathic pain. Two previous Fast Facts (#75, 86) reviewed methadone’s pharmacological properties. This Fast Fact examines the research base regarding methadone and neuropathic pain and reviews the rise in methadone-related deaths.

Historical Context

Prior to 1985, when long-acting morphine preparations were introduced, methadone was commonly prescribed for cancer-related pain as it had a longer duration of action than morphine. However, it was well appreciated that methadone had a higher risk of respiratory depression due to drug accumulation with chronic dosing – an effect not associated with other opioids, for which there is no drug accumulation in the setting of normal renal function.

Prior to 1990 there was a widespread belief that opioids were relatively ineffective in treating neuropathic pain. Since then, there been a much greater understanding that opioids are an effective part of neuropathic pain treatment.

Basic science data Methadone inhibits reuptake of norepinephrine and serotonin in a similar manner to newer anti-depressants, some of which are effective against neuropathic pain (e.g. duloxetine, venlafaxine). Also, methadone binds to the NMDA receptor, a known modulator of neuropathic pain. Finally, methadone has demonstrated efficacy in animal models of neuropathic pain (2).

Patient data Small non-controlled case series and two small randomized study (methadone vs. placebo) have demonstrated that methadone can reduce neuropathic pain in both cancer and non-cancer patients (3-6). There is no data, for or against the proposition, that methadone is superior to other opioids for neuropathic pain. A 2007 Cochrane Collaborative review found, “there is no trial evidence to support the proposal that methadone has a particular role in neuropathic pain of malignant origin” (7). Furthermore, the review cautioned clinicians about the danger of methadone-induced respiratory depression due to its long terminal half-life.

Methadone deaths There is a growing awareness that the increased prescription of methadone is being paralleled by a similar increase in methadone-related deaths. Methadone has been implicated in 30% to 40% of opioid related deaths in the US, even though methadone remains a small minority of opioids prescribed (8). The US Department of Health and Human Services convened an expert panel in 2003 to investigate the rise in methadone deaths and concluded that the rise was largely due to the increasing use of methadone as an analgesic (9). The Center for Disease Control published a report detailing data from Utah in 2005, suggesting that part of the problem was due to increased prescribing (10). The current data seem to suggest that the general increased supply of methadone, via legitimate prescribing, is leading to deaths due to accidental overdose through improper prescribing or illicit diversion/recreational use. In addition to concern about respiratory depression, there has been an observation that methadone, unlike morphine or hydromorphone, can prolong the QTc interval and lead to serious cardiac conduction abnormalities especially when coadministered with antiretrovirals in HIV patients (11). Note: the overall number of opioid-related deaths has increased, not just from methadone. Note: there are no data on untimely deaths related to methadone prescribing in hospice/palliative care patients.

Summary The renewed interest in an old drug holds exciting promise of benefit for the many patients with neuropathic pain. However, clinical research has yet to confirm or deny a unique clinical role for methadone compared to other opioids. The risk of respiratory depression should give clinicians pause before prescribing methadone based solely on the theory that it is a superior opioid in neuropathic pain. Coadministration of methadone with antiretrovirals may pose a particular risk for cardiac arrhythmias and therefore should be avoided if at all possible., Given that diversion of legitimate opioid prescriptions to the illicit market can occur, even in the practice of hospice and palliative care, physicians and hospice agencies need to recognize they also have a larger social responsibility to the public welfare, and prescribe methadone with care and caution.

References

Warner M, Chen LH, et al. Drug poisoning deaths in the United States, 1980–2008. NCHS Data Brief. 2011; 1-8.

Foley KM. Opioids and chronic neuropathic pain. NEJM 2003; 348:1279-1281.

Morley JS, et al. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Pall Med. 2003; 17:576-587.

Altier N, et al. Management of chronic neuropathic pain with methadone: a review of 13 cases. Clin J Pain. 2005; 21:364-369.

Gagnon B, et al. Methadone in the treatment of neuropathic pain. Pain Res Manage. 2003; 8:149-154.

Moulin DE, et al. Methadone in the management of intractable neuropathic non cancer pain. Can J Neuro Sci. 2005; 32:340-343.

Nicholson, AB. Methadone for cancer pain. Cochrane Database Syst Rev 2007; 4.4.

Centers for Disease Control and Prevention (CDC). Vital signs: risk for overdose from methadone used for pain relief – United States, 1999-2010, Morb Mortal Wkly Rep 2012; 61:493-497.

Increase in poisoning deaths caused by non-illicit drugs--Utah, 1991-2003. MMWR Weekly. 2005; 54:33-36.

US Department of Health and Human Services – Division on Pharmacologic Therapies. Report on Methadone Mortality (http://dpt.samhsa.gov/reports/methodone_mortality-05.htm - no longer publicly available). Updated Report available at: http://www.dpt.samhsa.gov/pdf/MethadoneBackgroundPaper_72007_2_.pdf.

Kao D, Bartelson BB, et al. Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011. Ann of Int Med 2013;158: 735-740.

Version History: This Fast Fact was originally edited by David E Weissman MD and published in December 2006. Version copy-edited in April 2009: web-links updated. Revised again in July 2015 by Sean Marks MD: references and epidemiological data updated.

Fast Facts and Concepts are edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin (PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’s content. The full set of Fast Facts are available at Palliative Care Network of Wisconsin with contact information, and how to reference Fast Facts.

Copyright: All Fast Facts and Concepts are published under a Creative Commons Attribution-NonCommercial 4.0 International Copyright (http://creativecommons.org/licenses/by-nc/4.0/). Fast Facts can only be copied and distributed for non-commercial, educational purposes. If you adapt or distribute a Fast Fact, let us know!

Disclaimer: Fast Facts and Concepts provide educational information for health care professionals. This information is not medical advice. Fast Facts are not continually updated, and new safety information may emerge after a Fast Fact is published. Health care providers should always exercise their own independent clinical judgment and consult other relevant and up-to-date experts and resources. Some Fast Facts cite the use of a product in a dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.

http://www.mypcnow.org/blank-ari0c

Is Methadone An Option For Neuropathic Pain

Today's post from eperc.mcw.edu/ (see link below) was last revised in 2009 but nevertheless sums up current thinking regarding the use of methadone to control neuropathic symptoms. If you Google the subject you will come up with many other articles, including studies, about using methadone as a specific opioid to control nerve pain but this one is relatively easy to understand and sums up the dilemmas that doctors and specialists face in the current climate, where opioid prescription is coming under both social and legal scrutiny, especially in North America. Methadone's efficiency as an analgesic is somewhat clouded by its reputation, as a substitute for morphine, heroine and other opiate-acting drugs but that may be unfair. It seems however, that more and more people are finding that relatively low-dose methadone use can bring relief from their neuropathic pain and it may be worth discussing the possibility with your specialist or doctor, especially if all else seems to have failed. Methadone may well be a good alternative to Tramadol and Oxycodone but it is essential that the decision to take it is taken in complete agreement with your doctor. Just as with all other opioids and strong painkillers, ensuring that your progress will be monitored is also essential to avoid overdose and addiction potential. This article is not the full story but provides useful background information to help with your decision making.
Never attempt to self-medicate with Methadone or other opioids.

Methadone for Neuropathic Pain
Author(s): David E Weissman MD FAST FACTS AND CONCEPTS #171 PDF

Background Prescriptions for methadone have greatly increased in the past six years (1). The reason for this increase is likely related to two factors: reduced cost relative to other potent opioids and basic science data suggesting that methadone may be particularly useful in treating neuropathic pain. Two previous Fast Facts #75, 86) reviewed methadone’s pharmacological properties. This Fast Fact examines the research base regarding methadone and neuropathic pain and reviews the rise in methadone-related deaths.

Historical Context
 
Prior to 1985, when long-acting morphine preparations were introduced, methadone was commonly prescribed for cancer-related pain as it had a longer duration of action than morphine. However, it was well appreciated that methadone had a higher risk of respiratory depression due to drug accumulation with chronic dosing – an effect not associated with other opioids, for which there is no drug accumulation in the setting of normal renal function.

Prior to 1990 there was a widespread belief that opioids were relatively ineffective in treating neuropathic pain. Since then, there been a much greater understanding that opioids are an effective part of neuropathic pain treatment.

Basic science data Methadone inhibits reuptake of norepinephrine and serotonin in a similar manner to newer anti-depressants, some of which are effective against neuropathic pain (e.g. venlafaxine). Also, methadone binds to the NMDA receptor, a known modulator of neuropathic pain. Finally, methadone has demonstrated efficacy in animal models of neuropathic pain (1).

Patient data Small non-controlled case series and at least one small randomized study (methadone vs. placebo) have demonstrated that methadone can reduce neuropathic pain in both cancer and non-cancer patients (2-5). There is no data, for or against the proposition, that methadone is superior to other opioids for neuropathic pain. A 2004 Cochrane Collaborative review found, “there is no trial evidence to support the proposal that methadone has a particular role in neuropathic pain of malignant origin” (6). Furthermore, the review cautioned clinicians about the danger of methadone-induced respiratory depression due to its long terminal half-life.

Methadone deaths There is a growing awareness that the increased prescription of methadone is being paralleled by a similar increase in methadone-related deaths. Florida, Utah, North Carolina, Oregon, Indiana, Maryland, Alabama and West Virginia have all reported a spike in deaths related to methadone since 2000 (7,8). The US Department of Health and Human Services convened an expert panel in 2003 to investigate the rise in methadone deaths and concluded that the rise was largely due to the increasing use of methadone as an analgesic (9). The Center for Disease Control published a report detailing data from Utah in 2005, suggesting that part of the problem was due to increased prescribing (10). The current data seem to suggest that the general increased supply of methadone, via legitimate prescribing, is leading to deaths due to accidental overdose through improper prescribing or illicit diversion/recreational use. In addition to concern about respiratory depression, there has been a relatively recent observation that methadone, unlike morphine or hydromorphone, can prolong the QTc interval and lead to serious cardiac conduction abnormalities. Note: the overall number of opioid-related deaths has increased, not just from methadone. Note: there are no data on untimely deaths related to methadone prescribing in hospice/palliative care patients.

Summary The renewed interest in an old drug based on new science holds exciting promise of benefit for the many patients with neuropathic pain. However, clinical research has yet to confirm or deny a unique clinical role for methadone compared to other opioids. The risk of respiratory depression should give clinicians pause before prescribing methadone based solely on the theory that it is a superior opioid in neuropathic pain. Furthermore, given that diversion of legitimate opioid prescriptions to the illicit market can occur, even in the practice of hospice and palliative care, physicians and hospice agencies need to recognize they also have a larger social responsibility to the public welfare, and prescribe methadone with care and caution.

References
Foley KM. Opioids and chronic neuropathic pain. NEJM. 2003; 348:1279-1281.
Morley JS, et al. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Pall Med. 2003; 17:576-587.
Altier N, et al. Management of chronic neuropathic pain with methadone: a review of 13 cases. Clin J Pain. 2005; 21:364-369.
Gagnon B, et al. Methadone in the treatment of neuropathic pain. Pain Res Manage. 2003; 8:149-154.
Moulin DE, et al. Methadone in the management of intractable neuropathic non cancer pain. Can J Neuro Sci. 2005; 32:340-343.
Nichloson AB. Methadone for cancer pain: Review. Cochrane Database of systematic reviews. 2004;2:CD003971.
Google Search: ‘Methadone deaths.’ December 2007.
Finn S, Tuckwiller S. Feds act on methadone deaths. West Virginia Gazette. July 23 2006.
Increase in poisoning deaths caused by non-illicit drugs--Utah, 1991-2003. MMWR Weekly. 2005; 54:33-36.
US Department of Health and Human Services – Division on Pharmacologic Therapies. Report on Methadone Mortality (http://dpt.samhsa.gov/reports/methodone_mortality-05.htm - no longer publicly available). Updated Report available at: http://www.dpt.samhsa.gov/pdf/MethadoneBackgroundPaper_72007_2_.pdf.
Fast Facts and Concepts are edited by Drew A Rosielle MD, Palliative Care Center, Medical College of Wisconsin. For more information write to: drosiell@mcw.edu. More information, as well as the complete set of Fast Facts, are available at EPERC: www.eperc.mcw.edu.

Version History: This Fast Fact was originally edited by David E Weissman MD and published in December 2006. Current version re-copy-edited in April 2009; web-links updated.

Copyright/Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Weissman DE. Methadone for Neuropathic Pain. Fast Facts and Concepts. December 2006; 171. Available at: http://www.eperc.mcw.edu/FastFactsIndex/ff_171.htm.

Disclaimer: Fast Facts and Concepts provide educational information. This information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Facts cite the use of a product in a dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.

http://www.eperc.mcw.edu/EPERC/FastFactsIndex/ff_171.htm

Neuropathic Symptoms And The Cold Vid

Today's short video from beatingneuropathy.tv (see link below) is the latest from Dr. Hayes giving advice on how best to deal with extreme cold weather when you have nerve damage and chronic pain. Always worth a few minutes of your time.

Episode 41: Cold and Neuropathy Pain? YES! Here is What to Do! 
Posted by John Hayes Jr Thursday, January 9th, 2014

If you suffer from neuropathy, fibromyalgia, or really any form of chronic pain you already understand how the cold-weather can aggravate. In this brief video Dr. Hayes discusses practical steps you can take today to help you feel better almost immediately!



http://beatingneuropathy.tv/2014/01/episode-41-cold-and-neuropathy-pain-yes-here-is-what-to-do/

HIV And Neuropathic Pain Vid

Today's video is the second this week discussing neuropathy as a result of HIV or its treatment and as this is the core subject of this blog, it is worth viewing for those who find themselves in that position (from between 33% and 50% of all sufferers). Although neuropathy is much the same problem, with many of the same symptoms, irrespective of the cause, there are reasons why people with other conditions such as diabetes, cancer and HIV, are more prone to suffering nerve damage. This may help people living with HIV better understand why they seem to have been landed with yet another serious problem.

Neuropathic Pain in HIV Disease
PAINClinician Uploaded on 23 Feb 2012

David M. Simpson, MD
Professor of Neurology
Mount Sinai School of Medicine





https://www.youtube.com/watch?v=FDzbkYx_LKU

d Methadone For Neuropathic Pain

Today's post from dddmag.com (see link below) looks at d-methadone, a relative of methadone, which is being developed to treat neuropathic pain without the potential side effects associated with methadone and other opioids. Methadone has a bad rap! It's associated with drug addicts weaning off yet stronger drugs, yet is used very successfully with many people with neuropathic pain that doesn't respond to other drugs. Those people may get relief from their pain but have to suffer the unjustified stigma that methadone brings with it. Still in the development phase, d-methadone will achieve the same results without the side effects and that has to be very good news indeed. Unfortunately, parts of this report/article may well appear to be double-dutch to many readers due to the complexity of the science but you will get the gist. d-methadone may end up being a huge breakthrough in efficient treatment of nerve pain.
 

d-Methadone: A Novel Approach for Neuropathic Pain
 Eliseo Salinas, MD, MSc, President and Chief Scientific Officer, Relmada Therapeutics Thu, 03/12/2015
 
At a time when opioid abuse and addiction are making headlines, a new molecule is being studied to treat neuropathic pain without such negative effects. A relative of methadone, a widely known synthetic opioid medication, d-Methadone represents half of methadone’s chemical structure with profoundly different activity on the mu opioid receptor, considered a “gateway for addiction.”

A Gold Standard Treatment

Methadone is a widely known synthetic opioid medication that has been used for decades. It is used to reduce withdrawal symptoms in people addicted to heroin or other narcotic drugs without causing the "high" associated with the drug addiction. Methadone is also used as a pain reliever.

Like many narcotics, methadone suffers from poor safety and tolerability. Some of the adverse effects of methadone include sedation, constipation, dizziness, sleepiness, respiratory depression, and nausea/vomiting. Two enantiomers of a generic amino acid that is chiral Methadone is a chiral compound, meaning that it is comprised of two molecules (optical isomers) with identical composition, but which are arranged in a non-superposable mirror image (see image).

Usually one of the optical isomers of synthetic opioids accounts for most of the pharmacologic activity and the addictiveness of the racemic compound. The other isomer generally exhibits less activity and less addictiveness.

Methadone is an outstanding example of a compound in which greatly different activity and addictiveness occur in the optical isomers. Both the l-optical and d-optical isomers of racemic methadone are noncompetitive inhibitors of N-methyl-D-aspartate (NMDA), a glutamate receptor and ion channel protein found in nerve cells. In view of the fact that upregulation of NMDA plays an important role in neuropathic pain, inhibition of the receptor may provide strong pain relief in neuropathic pain states.

Where the l-optical and d-optical isomers of racemic methadone differ is their effect on the mu opioid receptor. While the l-optical isomer is a potent analgesic with addictiveness greater than or equal to morphine, the d-optical isomer is a weak opioid with potentially low addictiveness. This means d-methadone could be an effective agent to treat neuropathic pain through inhibition of NMDA without the poor safety and tolerability associated with activating the mu opioid receptor.

Early Studies

Leveraging research from Cornell University, d-Methadone is being developed as a novel drug with the potential to treat neuropathic pain. The first Phase 1 study in healthy subjects was initiated in late 2014 to evaluate single ascending doses of d-methadone. The goal of this study is to determine the maximum single dose of d-methadone that can be taken without evidence of the typical opioid effects. The second planned Phase 1 study will evaluate multiple ascending doses. Results from both studies will guide a planned Phase 2 study to assess the effect of d-methadone in patients with neuropathic pain.

While early in clinical development, published clinical studies with low doses of another NMDA inhibitor called ketamine (a psychoactive ‘party drug’ better known as Special K) have produced strong pain relief in neuropathic pain states and serve as proof of concept for d-methadone. Severe side effects limit the use of ketamine, such as hallucinations, memory defects, panic attacks, and nausea/vomiting. In contrast, d-methadone appears to be well tolerated.

Neuropathic pain is defined as a disorder of the sensorimotor system and is distinctly different from nociceptive pain, which is a consequence of trauma, injury, or inflammation. The term neuropathic pain is used to describe a wide range of pain syndromes, including painful diabetic neuropathy, postherpetic neuralgia, and trigeminal neuralgia. According to the Neuropathy Association, neuropathic pain is estimated to affect more than 20 million people in the United States alone.

The main classes of drugs used to treat these neuropathic pain conditions are anticonvulsants, antidepressants, opioids, and topical treatments. However, despite the availability of multiple pain medications only about 50 percent of patients respond to treatment with currently available therapy options, and they present the risk of numerous side effects that reduce their tolerability. Accordingly, the treatment of neuropathic pain represents a large unmet medical need.

Eliseo Salinas, MD, MSc joined Relmada Therapeutics in February 2014. Dr. Salinas has more than 20 years of experience developing therapeutic products for CNS disorders in many key jurisdictions worldwide, including the United States, Canada, the European Union, and Japan. Under Dr. Salinas’ leadership, 15 programs obtained regulatory approval in the United States and other major international markets. Prior to joining Relmada, Dr. Salinas was Executive Vice President and Head of Research and Development at StemCells, Inc. Dr. Salinas has also held high-level positions at Elan Pharmaceuticals, Adolor Corporation, and Shire plc. Dr. Salinas earned his medical degree from the University of Buenos Aires, Argentina, performed a residency in psychiatry in Paris at the Clinique des Maladies Mentales et de l'Encéphale, and obtained a master's degree in pharmacology from the Université Pierre et Marie Curie, Académie de Paris, France.

http://www.dddmag.com/articles/2015/03/d-methadone-novel-approach-neuropathic-pain

Neuropathic Pain And Brain Inflammation

Today's post from medicaldaily.com (see link below) is an important one for neuropathy patients, who have trouble explaining the parameters of their pain to doctors, who then have to prescribe the appropriate pain medication. It's not their fault: neuropathic pain is notoriously difficult to quantify and the clichéd scales of 1 to 10, rarely reflect the true nature of nerve pain. This article talks about a breakthrough which in the future will be able to much more accurately match the medication to the extent of the pain. It will be measured by means of brain scans which will measure the neural inflammation in the area of the brain responsible for pain signals. Medicine prescription will become less a question of 'suck it and see' and more based on accurate levels of pain, which can only be a good thing for neuropathy patients who often end up as guinea pigs in the search for pain relief.

Chronic Pain Patients Show Patterns Of Brain Inflammation, Setting Stage For Objective Pain Scale
Jan 12, 2015 02:59 PM By Chris Weller


One day scientists may be able to figure out which pain pills you should take based on nothing but a brain scan. Intel Free Press, CC BY-SA 2.0

“On a scale of 1 to 10, how bad is the pain?”

That question has been asked in a variety of settings for an equally colorful range of afflictions. That’s because doctors, despite 76 million Americans having had suffered from chronic pain at one point or another, don’t yet have a standardized scale for measuring pain — after all, what registers as a 6 for you may be a 9 for someone with a lower threshold. Now, a new study finds that a standardized scale may be within reach, and neuroinflammation, of all things, is here to help.

Researchers from Massachusetts General Hospital collected data on 44 subjects, 19 with chronic lower back pain and 25 who were pain-free. Specifically, they performed scans on the brain’s thalamus, a region that, among other things, is responsible for signaling pain. Using a drug that shows up in contrast on the scan when it binds with a particular protein — known as a translocator protein (TSPO) — they could see how chronic pain correlates to inflammation in the brain, which the protein illuminates in the thalamus.

The findings are significant because they offer a future of health care that doesn’t have to rely on questionable data. Unlike physicians, who can look at high blood pressure and cholesterol levels to assess a patient’s risk for disease, people who study pain have had to trust murky self-reports to go in one direction or another. Now, the findings suggest a new approach, in which doctors can enjoy a solid footing for making complex decisions about pain — all from a helpful batch of brain cells.

“Demonstrating glial activation in chronic pain suggests that these cells may be a therapeutic target, and the consistency with which we found glial activation in chronic pain patients suggests that our results may be an important step toward developing biomarkers for pain conditions,” said Marco Loggia, of the MGH-based Martinos Center for Biomedical Imaging, in a statement. The inflammation was so starkly evident in the scans that Loggia could pick apart the control group from the pain group just by looking at them, he added.

Images created by averaging PET scan data from chronic pain patients (left) and healthy controls (right) reveal higher levels of inflammation-associated translocator protein (orange/red) in the thalamus and other brain regions of chronic pain patients. Marco Loggia, PhD, Martinos Center for Biomedical Imaging, Massachusetts General Hospital

What really interested the investigators was the relationship between TSPO and pain levels. It wasn’t the case that higher pain showed more protein activation. In fact, it was just the opposite.

“While upregulation of TSPO is a marker of glial activation, which is an inflammatory state,” Loggia said, “animal studies have suggested that the protein actually limits the magnitude of glial response after its initiation and promotes the return to a pain-free, pre-injury status.”

This means that people with more pain may actually be expressing less TSPO, sort of as a way to "calm down" the inflammation site, as Loggia explains. "While larger studies would be needed to further support this interpretation, this evidence suggests that drugs called TSPO agonists, which intensify the action of TSPO, may benefit pain patients by helping to limit glial activation."

Up next for the research team is narrowing the focus of glial activation studies. They want to understand how certain forms of pain, like fibromyalgia and rheumatoid arthritis, produce a similar response in the brain. It may be the case, for instance, that each type of pain generates a "glial signature." One day, patients may be able to take different drugs according to the inflammation seen solely in their brain scans.

Source: Loggia M, Chonde D, Akeju O, et al. Evidence for brain glial activation in chronic pain patients. Brain. 2015.

http://www.medicaldaily.com/chronic-pain-patients-show-patterns-brain-inflammation-setting-stage-objective-pain-317374

Do People Really Understand Their Neuropathic Pain

Today's post from healthskills.wordpress.com (see link below) asks the question as to whether people really understand the nature of their neuropathic pain. It's a very interesting study which concludes that people do much better with their problem if they receive a cogent explanation of what's happening to them. Unfortunately, with neuropathy that's rarely the case, as doctors assume that the medical science is often too complex for their patients to understand. It is pretty much a given that patients can cope much better with symptoms if they know why they are happening and what's going on inside their bodies. After that, an explanation of any treatment is also useful.

How well do people understand their neuropathic pain? 
 Martin, S., Daniel, C. Williams,  (2014)

When coming to terms with a chronic pain problem, one of the important steps involves obtaining a diagnosis that fits with both the individual’s personal experience of their pain, and also their knowledge (drawn from what is available in the general population). If the label doesn’t square with their experience, people continue searching until they find something that does.

There has been an enormous wave of excitement about giving people good “pain education”. I’ve always been a bit anxious about the term “education”, because it can so often mean giving an information dump, leaving the person being “educated” with little or no relevant knowledge about their personal concerns – and it’s the individual and unique concerns that influence how a person interprets what is happening, and how they respond. As a result, I prefer “helping people to develop a personal pain formulation” or “reconceptualising” their pain. Putting the pedantics aside, it seems really important for health professionals to not only understand what people with pain already know about their health condition, but also to understand how people interpret what they’re told – if they’re told anything.

In this study, 75 people with neuropathic pain were asked to sort a series of statements about neuropathic pain according to their level of agreement with them. This is known as Q-methodology. The sorted statements are then analysed to identify common features amongst them.

 Four factors were identified:
Neuropathic pain is a nervous system problem, psychology influences the pain experience and acceptance, and being open to psychological interventions – this group of respondents had tried psychological treatments, their pain was on average about 6 – 7 years.

Neuropathic pain is nerve damage, psychology is irrelevant in pain experience, neutral about psychological treatments – this group of people had not tried psychological treatments, but had tried surgery and medications.

Neuropathic pain is irreparable nerve damage, symptom management is needed, psychological factors play a part in pain perception but psychological treatment is not OK – this group of individuals had pain for an average of 10 years, and they had used breathing, positive thoughts, medications and physical treatments.

Neuropathic pain cause should be identified, psychological influences may play a part, and treatment can include both medical and psychological – this group had pain for an average of 1 -2 years, and they had tried a range of medications, physical methods, yoga, meditation and complementary therapies.

The authors point out several limitations of this study – people were not recruited on the basis of an particular characteristics, there could be a number of recruitment biases, and they were all identified via online recruitment processes, therefore it’s hard to generalise. What it does indicate is that there is no coherent biopsychosocial explanation put forward by participants, they appeared to have received very little explanation about their problem, and this affected their readiness for psychological or self management interventions.

Another interesting point is how many of these participants, across all the four factor groups, described experiencing being given psychosomatic explanations of their pain. The authors write :”Across all accounts, participants’ comments indicated that they had received psychosomatic explanations of their pain and had been distressed and offended, consistent with other studies which use open-ended methods to sample patients’ experiences. (p. 353).” The influence of psychological factors was found to be associated more with adjusting to chronic pain, rather than to developing an integrated model of pain. Factor 1 were the only group to endorse the notion of acceptance, or learning to live with pain – and the groups in Factors 3 and 4 were strongly against the idea that pain could be lived with.

I find this study interesting, not so much in what it has discovered, but rather more in terms of the discussion about psychological factors and medical factors – but nothing on social factors. I find myself wondering again whether we have a biopsychological model of pain, rather than a more complex biopsychosocial model.

That being said, I agree with a point made in the conclusion: people with chronic pain value a coherent explanation for their pain, it helps resolve their worry and enables them to approach their pain differently. The problem facing people with chronic pain is how to access evidence-based and accessible information about neuropathic (or indeed any type of) pain. Often people find out about neuropathic via biomedical models, and they rarely get exposed to the complexity of a biopsychological model, let alone a biopsychosocial one.

We desperately need to understand the best ways to personalise an explanation for an individual with chronic pain. I think a case formulation approach is the most useful, but I’ve found that many clinicians think this takes “too long” and is “too complex”. I wonder about this. A formulation might take a couple of sessions, but it’s a lot less expensive and has lower risk than surgery.

In light of the very limited range of interventions for people with neuropathic pain, perhaps taking the time to respond to the person’s unique questions about their pain would be time and money well spent.

People who have chronic pain are often very reluctant to consider the influence of psychological factors on their pain, reflecting their fear that by accepting this, their pain is being dismissed as “not real”, or not legitimate. This means people may not accept (or indeed be referred for) psychological interventions. Treatment approaches based on a cognitive behavioural approach have good evidence to support them, but they don’t do much good if people are not ready for them, or even referred for them.

Martin, S., Daniel, C., & Williams, A. (2014). How do people understand their neuropathic pain? A Q-study PAIN®, 155 (2), 349-355 DOI: 10.1016/j.pain.2013.10.021

http://healthskills.wordpress.com/2014/03/11/how-well-do-people-understand-their-neuropathic-pain/

Neuropathic Men And Erection Problems

Today's post from sexhealthmatters.org (see link below) revisits the subject of erectile dysfunction as a result of neuropathy. Women readers may complain that this ignores their own particular problems with neuropathy and sexuality (which are just as serious and do exist) but the article talks in this case I'm afraid, just about men. Women with male neuropathy patient partners may well be interested. Unfortunately, males give their penises the highest priority and normal function is 'everything'! There are enough reasons for erectile dysfunction without neuropathy being added to them but unfortunately many men with nerve damage and especially autonomic neuropathy, may face this problem sooner or later. This article tends to aim at diabetic patients but as we all know, they are just one of the groups who are affected by neuropathy and the information applies to all. It may be worth following some of the links and resources to get a fuller picture of what's going on with ED and nerve damage. One tip is certain: if you benefit from little blue pills and the like, the possibility is that you may need a stronger dose to achieve full and satisfying erections if the cause of your ED is neuropathy. Best discuss it with your doctor or at least a medical professional specialising in sexual health.

Neuropathy a Common Cause of ED
Jul 29, 2015
 
An erection is a complex process. It may not seem that complicated – a man can be sexually turned on by his partner’s smile, an erotic fantasy, or a beautiful person who passes him on the street. An erection might even seem automatic.

But inside his brain and body, connections must be in tip-top shape for an erection to occur. The sexual stimulus – that smile or a sexy voice – gets processed by his brain, which sends signals to his genitals to trigger an erection. Smooth muscle tissue needs to relax, arteries need to widen, blood needs to flow into the penis, and veins need to constrict to keep the blood in place until he ejaculates or the stimulation stops.

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Neuropathy is a common cause of erectile dysfunction. More here.... (Click to tweet)

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Today, we’re going to focus on the signaling that takes place in the central nervous system – the network that connects the brain and the genitals. For some men, nerve damage interferes with the pathway, making it more difficult – or impossible – for sexual signals to get through. A man may experience something that makes him excited, but the erection just doesn’t happen.

What is neuropathy?

The medical term for this nerve damage is neuropathy. The type of neuropathy associated with erectile dysfunction (ED) is called peripheral neuropathy. This term is used because the nerve damage affects other parts of the body, like the hands, feet, and penis.

This type of neuropathy is also classified as autonomic. It affects processes that happen without our thinking much about them, like breathing, digestion, and erections.

What causes neuropathy?

Neuropathy that leads to ED can have a number of causes. Here are some examples:

· Injury to the genitals

· Endocrine disorders, especially diabetes

· Blood vessel diseases

· Cancer and cancer treatments, particularly chemotherapy

· Infections

· Excessive alcohol consumption

Diabetic neuropathy

The National Institute of Neurological Disorders and Stroke estimates that 60% to 70% of people with diabetes have some degree of neuropathy. And diabetes is an important risk factor for ED. Diabetic men are almost four times more likely to develop ED than non-diabetic men. And they tend to develop ED ten to fifteen years earlier, too.

High blood sugar can disrupt the signals between the brain and genitals. It can also damage blood vessels, reducing blood flow to the penis. (To learn more about diabetes and erectile dysfunction, click here.)

Treating neuropathy

Sometimes, nerves can heal when the cause of the damage is addressed. For example, drinking less alcohol or treating an infection may be enough for the nerves to repair themselves.

Diabetic men are encouraged to keep their blood sugar under control. Managing diabetes may involve medication, special diets, and exercise programs. Your doctor can tell you more about the best approaches for you. And be sure to check your blood sugar levels regularly.

Reducing the risk

As with many health issues, maintaining healthy habits plays a key role in preventing neuropathy. If you drink too much, try to cut down (and don’t hesitate to ask for professional help if you need it). If you smoke, ask your doctor about a smoking cessation program. If you have diabetes, follow your doctor’s instructions to the letter. Make healthy food choices and keep to a healthy weight. Try joining a gym or getting together with friends to exercise.

The benefits of good habits are enormous. You’ll maintain your health, reduce the risk of neuropathy, and might enhance your sex life, too!

Print this article or view it as a PDF file here: Neuropathy a Common Cause of ED

Resources

Medscape Medical News
Newman, Laura
“Neuropathy an Underappreciated Cause of Erectile Dysfunction”
(November 16, 2011)
http://www.medscape.com/viewarticle/753728

National Institute of Neurological Disorders and Stroke
“Peripheral Neuropathy Fact Sheet”
(December 2014)
http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm

Sexual Medicine Society of North America
“Understanding Diabetic Neuropathy and Erectile Dysfunction”
http://www.sexhealthmatters.org/for-healthcare-providers/understanding-diabetic-neuropathy-and-erectile-dysfunction/

http://www.sexhealthmatters.org/sex-health-blog/neuropathy-a-common-cause-of-ed

NeP Neuropathic Pain

 Today's post from neurocentre.com (see link below) is another general post about neuropathic pain and another good one for people looking for general information. Many people arrive at the blog, newly affected by neuropathy and may be put off by some of the more specific and scientifically complex posts. All they really want to do is find out what's going on. Every 'general information' post here is different and they all bring a slightly different angle to the subject. For that reason, this article is also useful for seasoned neuropathy sufferers.

What Is Nep?

May 12, 2009 by Neuropathy Trust
 

We all know what toothache or a bad-headache feels like and how glad we are when these painful conditions subside. It’s almost beyond our capability to imagine pain which doesn’t always go away and which might even last for years. Picture someone very close to you, in desperation because of neuropathic pain in the feet, going outside at four o’clock on a winter’s morning and standing on a frozen lawn to lessen the pain and burning sensations. This is a real-life example, by no means extreme, of how this type of pain may affect a person.

In the UK alone such significant suffering is believed to affect at least half a million people today.
Neuropathic pain may be defined as pain arising from a disturbance of function or pathological change in a nerve. The multiple kinds of abnormal pain sensations may suggest that several different changes from the normal healthy state of the nerves has taken place. Some people, for example, may experience severe pain as a result of just light pressure from clothing, air movement, or changes in temperature. Others may even experience spontaneous pain for which no obvious cause can be determined. Such pain may be continuous or may even occur in intermittent bursts.
When tests and examinations are performed on people affected in this way, it is common to also discover different areas of numbness, due to the damaged nerves. There is a growing awareness amongst doctors that our perception of pain is complex and that many different factors are involved. Ideally, how pain is defined and how it is treated should take account of these factors.

Causes of Neuropathic Pain
The term ‘neuropathic pain’ covers a number of different causes and types of pain, examples are:

• Diabetes:
‘Diabetic neuropathy’, at it’s simplest, is most often experienced as pain and/or numbness in the feet and is one of the complications of having diabetes.

• Shingles:
After someone has had chicken pox, the virus (varicella zoster) becomes permanently resident in nerve cells, although this in itself does not cause symptoms. However, in some patients, the virus can become reactivated to cause the acutely painful condition of shingles or herpes zoster. In a small number of patients with shingles the affected nerve can become permanently damaged to give neuropathic pain long after the shingles has resolved. This is known as post herpetic neuralgia.

• Amputation of a limb:
When people have a limb amputated some people may experience ‘phantom limb pain’. They feel pain in the amputated limb, even though the limb is no longer there.
• Cancer:
Neuropathic pain is experienced by some people with cancer as a result of either the tumour or the treatment given.

 • Trigeminal neuralgia:
This is a type of neuropathic pain that occurs in the face. It is due to problems with one of the facial nerves.

• HIV infection:
Having the HIV virus can result in HIV related painful peripheral neuropathy. Some treatments for HIV may also cause the condition.

• Multiple Sclerosis:
Pain can be a symptom of multiple sclerosis because the layer of insulation around the nerve becomes damaged (demyelination).

• Stroke:
Some people who have a stroke develop neuropathic pain.
• Surgery and trauma:
Pain can follow surgery or trauma due to accidental damage to a nerve.

• Drugs:
Some drugs can cause a peripheral neuropathy.

• Back problems:
Some people who have back pain also experience sciatica. Sciatica is the term given to a neuropathic pain down the leg. This is caused by irritation of the sciatic nerve which is the main nerve into the leg.
In some instances is it not always possible to discover the underlying cause and these cases are described as ‘idiopathic’ or ‘cryptogenic’.

http://neurocentre.com/community/?p=21

Depression Caused by Neuropathic Pain

Today's post is the second in a week-long series from 4therapy.com (see link below). It talks about how chronic pain (pain lasting longer than a few weeks)conditions can cause depression and therefore affect all areas of your life. It's advisable to seek help if this happens and not attempt to bottle it up inside, because the spiral of pain and depression can be helped by the right doctors and sensible advice.

Unemployment, Chronic Pain and Depression Can Be Inextricably Connected

A high percentage of individuals develop a depressive illness within six months of becoming unemployed. In fact, after relationship difficulties, unemployment is the most likely thing to push someone into a bad depression. This isn’t surprising, since work is often a significant source of an individual’s sense of worth and self-esteem. When you lose your job you risk going from a position of feeling in control to facing an uncertain future and suffering from an eroded sense of self-confidence--especially if it takes a long time to find another job.

Frequently, depression first shows up in physical symptoms, such as headaches, gastrointestinal distress, and sexual dysfunction. When you're suffering from depression, you and others close to you may notice some of the following changes in your overall affect:

You’re more irritable than usual and may lash out at those who try to offer help;

You’re worrying--even obsessing--about things more than usual;

You're unusually quiet and seem unable to share what's bothering you;

You're sluggish, fatigued, and lack your usual interest in things you usually enjoy.

When you’re in the throes of depression, the shift from your usual way of acting and feeling can make it harder to get another job, putting into play a cycle of defeat and despair that makes your depression deepen. Instead of getting help for their symptoms of depression, too many too frequently try to make themselves feel better by "self medicating" with alcohol or drugs. This clearly makes things worse.

Depression is a serious medical condition that affects your body, mood, and thoughts. Like any illness, depression requires treatment—the sooner the better. While it may take courage to reach out and ask for help, seeking professional treatment will bring the relief you deserve and that you need to get your life headed in a positive direction.

http://www.4therapy.com/life-topics/chronic-pain/unemployment-chronic-pain-and-depression-can-be-inextricably-connected-2853

Is Zonisamide A Good Idea For Neuropathic Pain

Today's post from onlinelibrary.wiley.com (see link below) looks at Zonisamide as a possibly effective drug for reducing neuropathic pain. Zonisamide is one of the anti-epileptic/ anti-convulsant drugs that are designed to treat epilepsy. Like some other anti-convulsants, it's now being prescribed to treat neuropathic pain and discomfort. However, this study shows that there is very little evidence to support its effectiveness in suppressing nerve pain and that other anti-epileptics are far more effective - for instance, Gabapentin and pregabalin (Lyrica). However, there are also questions surrounding the effectiveness of pregabalin especially for neuropathy caused by diabetes and HIV (see other articles on this blog), not least from the manufacturers themselves! Gabapentin has a far better reputation but as this article shows, Zonisamide hasn't proved to be effective at all. Worth discussing with your doctor or neurologist, if anti-convulsants are being prescribed for you.
 

Zonisamide for neuropathic pain in adults
R Andrew Moore1,*, Philip J Wiffen1, Sheena Derry1, Michael PT Lunn2 
Editorial Group: Cochrane Pain, Palliative and Supportive Care Group
Published Online: 22 JAN 2015

Abstract

Background

Antiepileptic drugs have been used in pain management since the 1960s; some have shown efficacy in treating different neuropathic pain conditions. The efficacy of zonisamide for the relief of neuropathic pain has not previously been reviewed.

Objectives

To assess the analgesic efficacy and associated adverse events of zonisamide for chronic neuropathic pain in adults.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (via CRSO), MEDLINE, EMBASE, and two clinical trials databases (ClinicalTrials.gov. and the World Health Organisation Clinical Trials Registry Platform) to 1 August 2014, together with reference lists of retrieved papers and reviews.

Selection criteria

We included randomised, double-blind studies of at least two weeks' duration comparing zonisamide with placebo or another active treatment in chronic neuropathic pain. Participants were adults aged 18 and over. We included only full journal publication articles and clinical trial summaries.

Data collection and analysis

Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We considered the evidence using three tiers. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design); second tier evidence derived from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison; and third tier evidence derived from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.

We planned to calculate risk ratio (RR) and numbers needed to treat (NNT) and harm (NNH) for one additional event using standard methods expected by The Cochrane Collaboration.

Main results

We included a single study treating 25 participants (13 zonisamide, 12 placebo) with painful diabetic neuropathy over 12 weeks. No first or second tier evidence was available for any outcome. The small size of the study and potential major bias due to a high proportion of early study withdrawals with zonisamide precluded any conclusions being drawn. There were two serious adverse events (one death) in zonisamide-treated participants, which were apparently not related to treatment.

Authors' conclusions

The review found a lack of evidence suggesting that zonisamide provides pain relief in any neuropathic pain condition. Effective medicines with much greater supportive evidence are available.

Plain language summary

Zonisamide for neuropathic pain in adults

Neuropathic pain can arise from damage to nerves and injury to the central nervous system. It is different from pain messages carried along healthy nerves from damaged tissue (a fall, or cut, or arthritic knee). Neuropathic pain is treated by different medicines than those used for pain from damaged tissue. Medicines like paracetamol or ibuprofen are not usually effective in neuropathic pain, while medicines that are sometimes used to treat depression or epilepsy can be very effective in some people with neuropathic pain.

Zonisamide is one of a type of medicine normally used to treat epilepsy. Some of these medicines are also useful for treating neuropathic pain. We looked for clinical trials that used zonisamide to treat neuropathic pain. We found a single study with 25 participants treated either with zonisamide or placebo. Study reporting may have led to major over-estimation of any treatment effects because most (8/13) participants treated with zonisamide withdrew before the end of 12 weeks of treatment for a variety of reasons, mostly adverse events (side effects).

There was too little information, which was of inadequate quality, to give any guidance as to whether zonisamide works as a pain medicine in any neuropathic pain condition. Other medicines have been shown to be effective in some types of neuropathic pain.

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011241.pub2/abstract

Why Neuropathic Pain Hurts Vid

Today's YouTube video is a Ted Talk video about why pain hurts and this applies to neuropathic pain too. In fact, you'll learn more about how your nervous system responds to and delivers pain signals than from a host of text-only articles. There's a good chance you'll have a giggle too (something never to be turned down) because this guy is funny and knows how to engage an audience. If he can engage an audience of neuropathic patients (that's you, the readers), he's a freaking genius! he may use the word 'groovy' a bit too much but you'll forgive him. Give it a try, you're going to learn something about your brain and the nervous system for sure. Definitely worth 15 minutes of your time.

TEDxAdelaide - Lorimer Moseley - Why Things Hurt

Uploaded on 21 Nov 2011 Why do we hurt?

Do we actually experience pain, or is it merely illusion?

In this video, Lorimer Moseley explores these questions, and position the pain that we feel as our bodies' way of protecting us from damaging tissues further. He also looks at what this might mean for those who suffer from chronic pain.




https://www.youtube.com/watch?v=gwd-wLdIHjs#t=8s

The Nature Of Neuropathic Pain

Today's post from nature.com (see link below) is an interesting and informative article looking at what neuropathic pain is and ways to treat it more effectively but more important than that, is the call for better diagnostic tests to establish what sort of neuropathic pain it is. If the testing is improved, then using what is already known about how pain signals in nerves and sodium channels can be blocked, certain current drugs can be re-purposed to better effect. Worth a read and you'll probably learn more than you thought you knew about your condition.

Neuropathy: A name for their pain
Michael Eisenstein Nature (14 July 2016) doi:10.1038/535S10a Published online

  People with neuropathic pain have struggled to find relief with conventional drugs. Researchers are investigating whether more meaningful pain classifications could help.

Two years ago, with little fanfare, neurologist Søren Sindrup reported the results of a successful clinical trial1. On the face of it, it was a modest success story. Instead of coming up with a wonder drug, Sindrup and his team repurposed an existing medication. Nevertheless, some pain researchers consider the trial a potential game-changer — one that marked a turning point in how researchers think about neuropathic pain.

This type of chronic pain arises from damage to the nerves that sense, transmit or process information about environmental stimuli. It can result from numerous initial insults, including spinal cord injury, diabetes and chemotherapy. Patients have generally been grouped on the basis of this initial trauma. But Sindrup, who is at Odense University Hospital in Denmark, and his colleagues took a different approach. They used diagnostic work-ups to cluster patients by their symptoms. This allowed the researchers to home in on a cohort that was more likely to respond to treatment. This is a huge step forward in an area where clinicians have struggled to help their patients. “The drugs we have relieve 50% of pain in somewhere between 1 in 4 and 1 in 7 of the patients we treat,” says Andrew Rice, a pain researcher at Imperial College London. “That's for the best drugs — and that's not very good.”

A growing number of pain researchers think that improvements can be found by analysing symptoms for clues about the underlying nerve damage. Neurologist Giorgio Cruccu of Sapienza University in Rome draws a comparison with another area of neurology. “There is no universal treatment for epilepsy,” he says. Instead, “it depends on the type of seizures”. Pain is a challenging medical target — doctors gain much of their insight from patients' reports rather than from external observations. But clinicians are attempting to devise more-sophisticated diagnostic tools to give the field a quantitative edge — and perhaps usher this patient population into a new era of evidence-based treatment.

Testing your patients
“There were hints in the literature that there are different mechanisms at work.”

Pain is initially recognized through peripheral sensors in the skin known as nociceptors, which react to potential sources of injury such as heat or mechanical trauma. Nociceptors send signals through specialized nerve fibres to the spinal cord, and from there to the brain (see page S2). Disruption to any part of this process can trigger enduring discomfort, although the severity and sensations experienced — burning or shock-like pain, numbness or tingling — can vary widely depending on the nature of the underlying damage. Not all injuries result in the same pain symptoms. For example, people with post-herpetic neuralgia (which can result after an outbreak of shingles) often have spontaneous pain that resembles an electric shock, but some experience allodynia — pain as a result of benign physical contact, such as clothing rubbing against skin. Over the past two decades, clinical researchers have come to appreciate that this variety of symptoms offers a way to understand how pain works. “There were hints in the literature that there are different mechanisms at work across various neuropathic pain entities, where patients have the same 'origin' of pain, but a different pain mechanism,” says Christoph Maier, a pain specialist at University Hospital Bergmannsheil in Bochum, Germany. “Today, we know this idea is correct.”

If these symptoms do represent different underlying mechanisms, that would help to explain why people in the same patient group respond differently to the same drugs — and that might have implications for treatment. “We have tried to develop a classification that is based on symptoms, which may give some indirect clue about the pain mechanism,” says Nadine Attal, a neurologist at Versailles Saint-Quentin-en-Yvelines University in France. Over the past decade, several questionnaires have been developed, including painDETECT and Douleur Neuropathique 4, which help to distinguish pain associated with nerve injury from that brought on by other causes, and the more detailed Neuropathic Pain Symptom Inventory (NPSI), for further subclassification of patients. These can be completed by patients in minutes, and have proved to be a reliable way to assess the nature and intensity of their pain.

Left to right, a whisker-like fibre, pin prick and thermal stimulus are used to test pain sensitivity as part of the quantitative sensory testing protocol.

But questionnaires do not objectively measure pain, nor can they zero in on the factors that trigger it. To provide such insights, Maier and other researchers affiliated with the German Research Network on Neuropathic Pain (DFNS) have devised a standardized battery of assessments known as quantitative sensory testing (QST). The QST protocol includes components such as hot and cold probes, to determine whether pain is triggered by thermal stimuli, and thin, whisker-like filaments that are applied to the skin to assess sensitivity to touch. “If you have somebody with allodynia, that small filament would feel painful,” says Ian Gilron, an anaesthesiologist at Queen's University in Kingston, Canada. QST can help researchers to measure the response of different types of sensory nerve, including both the small fibres that detect painful stimuli and the large ones that transmit information about movement and vibration. Although QST enables clinicians to measure and monitor pain symptoms, it is a labour-intensive process that requires extensive training. Furthermore, the variability in pain response across or even within individuals means that QST is better suited to identifying subgroups in a population than for diagnosing individuals.

Skin biopsies taken from the area of pain can provide a more detailed picture of what is happening at the tissue level. “You can demonstrate the loss of small fibres by directly counting how many free nerve endings can be found in the epidermis,” says Cruccu. He also advocates the use of tests that directly measure how well individual nerves function. Such techniques, says Cruccu, “provide objective measures unpolluted by cognitive biases”. Although this type of neurophysiological testing can reveal the nature of nerve damage, it requires costly, specialized equipment and expertise — and some of the more cutting-edge tools have yet to be validated for clinical use.
In search of subgroups

Researchers are still deciding how to rewrite the diagnostic rule book, but preliminary studies support the idea that a deeper assessment of pain symptoms can lead to more effective care. For example, in Sindrup's clinical trial1, although the team recruited patients with diverse neuropathic traumas, it used QST to identify common characteristics that might predict drug efficacy. The researchers found that people with nerves that had become hyper-responsive to temperature or physical probing — the 'irritable nociceptor' phenotype — were more than three times as likely to have pain relief from the anticonvulsant drug oxcarbazepine as those who had the non-irritable phenotype. This response also makes mechanistic sense: Sindrup and colleagues noted that oxcarbazepine blocks the sodium channel proteins that are responsible for nerve signalling, which could well be hyperactive in patients with irritable nociceptors.

This study is one of the few to select patients up front on the basis of pain characteristics, but others have applied similar techniques retrospectively. By using QST and skin-biopsy data collected during a trial of botulinum toxin A, which inhibits the firing of pain nerves, Attal and her colleagues found that people with both allodynia and a higher density of epidermal pain-sensing fibres were more likely to benefit from this treatment2. And a team led by Didier Bouhassira, a colleague of Attal's at Versailles, is preparing to report a study that re-examined data from 1,200 patients who previously participated in unsuccessful clinical trials for a heavily studied neuropathic pain drug. These findings offer hope for improved patient–drug 'matchmaking', whereby symptom profiles inform smarter trial design and help doctors to prescribe the treatments that are most likely to be effective.

Integrating data sets from multiple diagnostic approaches offers a way to improve this process. One such effort, by neurologist Roy Freeman at the Beth Israel Deaconess Medical Center in Boston, Massachusetts, and colleagues, analysed QST and NPSI data from past clinical trials to identify four distinct patterns of pain symptoms that seem to correlate in different groups of patients3. These profiles could be developed into 'fingerprints' for specific types of neuropathic injury by, for instance, connecting specific pain triggers such as pressure or cold with manifestations of pain such as stabbing or tingling sensations.

Researchers hope that such correlations will reveal information about the roots of pain pathology. A large European patient registry maintained by the DFNS and the public–private organization the Innovative Medicines Initiative (IMI) is enabling a more thorough hunt for such patterns. “It contains about 4,000 patients,” says Maier, who manages the data set as part of the IMI's Europain project. “It includes somatosensory profiles, clinical data, QST data, microscopy and skin-biopsy data and, in some cases, genetic data.”

Despite having only a handful of trials to serve as proof of concept, several consortia — including the US-based Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) — are planning on using these phenotyping tools in clinical trials. For now, most of the enthusiasm is coming from the academic sector; pharmaceutical companies expect much stronger evidence before taking on the additional cost. There is also the likelihood that more refined testing will shrink the patient population that drug companies can target with new analgesic drugs. “Instead of getting an approval for all of post-herpetic neuralgia, for example, they'd get one just for post-herpetic neuralgia with allodynia,” Rice says.

Nevertheless, according to Cruccu, a growing number of trials now use the quick questionnaires as a cost-effective fail-safe. Even if, overall, a trial seems unsuccessful, the availability of these data could enable a later search for specific subgroups in which efficacy can be demonstrated. Maier says that findings such as those from Sindrup's trial suggest that many 'failures' may be masking successes: small numbers of patients whose positive response to a drug is drowned out by the sea of people whose pain is poorly matched to the therapy being tested.

For now, the diagnostic tools available give only basic signposts for clinicians who treat people with neuropathic pain. But, given the dearth of effective treatments, even modest gains could have an outsized impact — especially once a next generation of analgesics enters the pipeline. “If there was a way to know who was most likely to respond to a drug and really focus on that in a clinical trial,” says Rice, “that would be magic.”

References

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Demant, D. T. et al. Pain 155, 2263–2273 (2014).
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Attal, N. et al. Lancet Neurol. 15, 555–565 (2016).
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Freeman, R., Baron, R., Bouhassira, D., Cabrera, J. & Emir, B. Pain 155, 367–376 (2014).
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Michael Eisenstein is a freelance science writer based in Philadelphia, Pennsylvania.

http://www.nature.com/nature/journal/v535/n7611_supp/full/535S10a.html?WT.feed_name=subjects_drug-discovery

Corydalis Yanhusuo Herbal Remedy For Neuropathic Pain

Today's post from news.uci.edu (see link below) talks about a compound derived from the Corydalis plant that is both effective against neuropathic pain and non-addictive. Everybody is looking for alternatives to opioids as nerve pain analgesics and as such, there has been more investigation into Chinese medicine, where herbal drugs such as Corydalis have been used for a great deal of time. As far as the West is concerned, they are accepting the analgesic qualities but looking for a more 'refined' and scientifically acceptable way of presenting the compound. In the meantime, the herb is available in health shops. However, many health shop preparations are not fully tested and the customer takes a risk if they use them. Maybe it's a question of doing as much research as possible and trying it out for yourself, for a reasonable but relatively short period of time but again...let the buyer beware.

Chinese herbal compound relieves inflammatory and neuropathic pain
 Irvine, Calif., Jan. 2, 2014 
 
UCI study also shows novel analgesic to be nonaddictive

— A compound derived from a traditional Chinese herbal medicine has been found effective at alleviating pain, pointing the way to a new nonaddictive analgesic for acute inflammatory and nerve pain, according to UC Irvine pharmacology researchers.

Working with Chinese scientists, Olivier Civelli and his UC Irvine colleagues isolated a compound called dehydrocorybulbine (DHCB) from the roots of the Corydalis yanhusuo plant. In tests on rodents, DHCB proved to diminish both inflammatory pain, which is associated with tissue damage and the infiltration of immune cells, and injury-induced neuropathic pain, which is caused by damage to the nervous system. This is important because there are no current adequate treatments for neuropathic pain.

Moreover, the researchers found that DHCB did not generate the tolerance seen with continued use of most conventional pain relievers, such as morphine.

“Today the pharmaceutical industry struggles to find new drugs. Yet for centuries people have used herbal remedies to address myriad health conditions, including pain. Our objective was to identify compounds in these herbal remedies that may help us discover new ways to treat health problems,” said Civelli, the Eric L. ; Lila D. Nelson Chair in Neuropharmacology. “We’re excited that this one shows promise as an effective pharmaceutical. It also shows a different way to understand the pain mechanism.”

Study results appear in the Jan. 20 issue of Current Biology.

They are the product of a collaboration between two teams separated by the Pacific Ocean. As traditional Chinese medicine gains greater acceptance in Western medical practice, Xinmiao Liang at the Dalian Institute of Chemical Physics in China and his group have been working to create an “herbalome” of all the compounds in plant extracts that display pharmacological properties. The UC Irvine team suggested applying “reverse pharmacology” – a novel drug discovery approach that Civelli devised about 25 years ago – to the herbalome project.

Together they screened 10 traditional Chinese medicines known as analgesics, testing nearly 500 compounds for their pain-relief abilities. Only DHCB in corydalis induced a reproducible effect.

Corydalis is a flowering herbal plant that grows in Siberia, Northern China and Japan. People utilize its root extract to alleviate menstrual cramps, chest pain and abdominal pain. It’s been previously studied for its analgesic properties, but this is the first time DHCB has been identified, extracted and tested.

Chronic neuropathic pain affects more than 50 million Americans, yet management of this pain remains a major clinical challenge due to the poor results and severe side effects of conventional analgesics. Civelli said that drawing upon traditional Chinese medical-herbal products could lead to a breakthrough treatment for these patients.

DHCB needs to be evaluated for any toxicity before it can be developed as a drug. It’s also possible that if the compound is chemically modified, a more potent pharmaceutical may be found. While DHCB is not currently available, it is part of the Corydalis yanhusuo root or extracts that can be purchased in health stores or online.

Yan Zhang, Lien Wang, Gregory Scott Parks, Kang-Wu Li, Mi Kyeong Kim, Benjamin Vo, Emiliana Borrelli, Zhiwei Wang, M. Julia Garcia-Fuster and Z. David Luo of UC Irvine;

Chaoran Wang, Xiuli Zhang, Zhimou Guo, Guangbo Ge and Ling Yang of the Dalian Institute of Chemical Physics in China; and Yanxiong Ke of the East China University of Science & Technology also contributed to the study, which was supported by the National Institutes of Health (grants MH60231 and DA024746), the National Alliance for Research on Schizophrenia & Depression (now the Brain & Behavior Research Foundation), the Tourette Syndrome Association, the National Natural Science Foundation of China, and the National High-Tech Research & Development Program of China.

About the University of California, Irvine: Located in coastal Orange County, near a thriving employment hub in one of the nation’s safest cities, UC Irvine was founded in 1965. One of only 62 members of the Association of American Universities, it’s ranked first among U.S. universities under 50 years old by the London-based Times Higher Education. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Michael Drake since 2005, UC Irvine has more than 28,000 students and offers 192 degree programs. It’s Orange County’s second-largest employer, contributing $4.3 billion annually to the local economy.

Media access: UC Irvine maintains an online directory of faculty available as experts to the media at communications.uci.edu/for-journalists/experts/. Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UC Irvine faculty and experts, subject to availability and university approval. For more UC Irvine news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

http://news.uci.edu/press-releases/chinese-herbal-compound-relieves-inflammatory-and-neuropathic-pain/