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

Can We Learn About Medication Via Internet Chatrooms

Today's video from www.live.wsj.com (see link below) is an interesting one for people with neuropathy and other illnesses (including HIV) because it highlights something many people already know. There is much more information available on the internet about drug interactions and reactions than your doctors may themselves be aware of. Visiting a trustworthy forum and seeing how other people have reacted to certain drugs, can help build up your knowledge base before discussing it with your doctor. That's not to say that you should believe everything you read on internet forums; far from it but if you notice that a significant number of people have had the same experience, it may be worth taking that information with you to your appointment. For people with neuropathy and HIV for instance, the number of different drugs being taken can be alarmingly high. Knowing what they can potentially do to you may be very useful - knowledge is always power in this respect.





Can Web Chatter Make Medication Safer?
From live.wsj.com - October 10, 2012

Is it possible to make medication safer by analyzing information publicly available on the internet, such as patient complaints on web chats? The medical community is starting to think so, reports Shirley Wang on Lunch Break.

http://live.wsj.com/video/can-web-chatter-make-medication-safer/46F629BD-8D3A-4BF2-8917-F6201DB60C9E.html#!46F629BD-8D3A-4BF2-8917-F6201DB60C9E

HOMOEOPATHIC REMEDIES FOR AILMENTS DUE TO SUPPRESSION

One of the most important contributions of homeopathy to the theory of health and disease is the concept of suppression of symptoms.

Both in conventional and in some alternative forms of medicine reduction of symptoms and alleviation of suffering are viewed as the towering goals of treatment.

The clinical philosophy shared by naturopathic and homeopathic medicine holds, in contrast, that a symptom is an expression of inner disharmonyrather than a problematic thing in itself, and that the disappearance of a symptom may or may not be an indication of cure when health is considered holistically.

In homeopathy it is very important to distinguish between a curative and a suppressive effect because the goal of treatment is healing of the entire person at the deepest possible level. To achieve this the homeopath first needs to know the patient’s medical history in order to determine whether any past treatments have been suppressive; second, the homeopath needs to evaluate the response of the patient to homeopathic treatment, in order to determine whether or not the patient is progressing in the desired direction toward greater health.

Some common treatments that unnecessarily lead to suppression of symptoms include:-Antibiotics,Anti-inflammatory medications (especially corticosteroids), Surgeries (tonsillectomies, nasal polypectomies, removal of benign skin lesions, and more),Anti-fever medications,High doses of certain supplements,Homeopathic remedies used symptomatically (these include remedies prescribed with the help of machines, muscle testing, and complex formulations (mixtures), Improper long-term administration of single homeopathic remedies

HOMOEOPATHIC REMEDIES

ABROTANUM 30-Rheumatism after suppression of diarrhea

AMMONIUM MUR. 30- Hemorrhoids due to suppression of leucorrhea

CAUSTICUM 200- Diseases like asthma , arising on account of suppression of skin diseases like itching of skin or eczema

MEDORRHINUM 1000- Bad effects following suppression of gonorrhea

OLEUM ANI 200- Asthma due to wetting of feet or chilling them, when perspiring

PLATINUM MET. 200- Mental problems due to suppression of menses. Physical symptoms disappear as mental problems develop

SARACA INDICA Q- Headache due to suppression of menses, better as the flow starts

SILICEA 200-Convulsions due to suppression of menses, better as the flow starts

SULPHUR 200- Skin problems when suppressed with ointments cause some other problems , especially respiratory. In such cases a dose of Sulphur 200 every day in the morning for four days will bring out the original diseases, which can then be cured by the indicated remedies. Insanity due to suppression is also cured by this remedy

THLASPI BURSA Q- After effects suppressed uterine diseases

ZINCUM METATALLICUM 200- Mania due to suppression of eruptions 

Leg Pain not always Neuropathy

This blog almost always relates HIV-related, foot and leg pain to Neuropathy but that's not always the case and it's always worth bearing in mind that there are other possible causes, before jumping to conclusions. When you're HIV positive, it's easy to pin a label on a problem at the first sign of trouble, after all, when it comes to secondary infections, virus, or drug related conditions, we're prone to almost everything (and they wonder why some people become hypochondriacs!) This article from Pain.com (see link below) outlines the commonest causes of leg pain. The true cause will eventually be discovered by your doctors but keeping an open mind before you get the diagnosis weeks or months later, is always advisable.

Leg Pain
May 21, 2011

In addition to injuries and muscle cramps, various medical conditions can cause leg pain. This article covers some of the medical conditions that can cause leg pain. Medical conditions involving the cardiovascular system will be discussed in a separate article in this series about leg pain.

Peripheral neuropathy is not a disease in itself, but a symptom of nerve damage in the limbs that is caused by other medical conditions. Peripheral neuropathy is common in patients with diabetes, HIV/AIDS, vitamin B12 deficiency, cancer, lupus, syphilis, lyme disease, rheumatoid arthritis, sarcoidosis, hypothyroidism, toxic exposure, certain genetic diseases and so on. Peripheral neuropathy is a common symptom and it can be inherited, caused by an infection, caused by exposure to certain chemicals, experienced as a side effect of some medications, caused by metabolic disorders or nutritional deficiencies, caused by inflammatory diseases, caused by oxygen starvation or caused by trauma to a peripheral nerve.

Peripheral neuropathy commonly affects the feet and legs. If a nerve that carries sensation from the body to the central nervous system is damaged, a person may experience pain, burning, numbness or tingling in the leg or foot. Proprioception, or the ability to sense where a body part is without looking, can also be affected and a person can become more uncoordinated. If a motor nerve that supplies a muscle is damaged, a muscle becomes weak because it can not contract as well. It is possible for some muscles to become paralyzed, depending on the extent of the nerve damage. In some cases, muscles may cramp up instead of becoming flaccid and weak. Treatment of peripheral neuropathy involves treating the underlying cause of the problem, along with symptomatic care for pain and physical or occupational therapy if necessary.

Another possible medical cause of leg pain is a bone infection, called osteomyelitis. Osteomyelitis is a bacterial infection that can be caused by several different types of bacteria. People can contract a bone infection via a wound, such as when an open fracture occurs or when a person has surgery, or an infection can spread to the bone from a different part of the body. A type of skin infection called cellulitis can spread to underlying tissues and bones in the leg, or an internal infection like a bladder infection can spread to other parts of the body through the bloodstream.

Any patient with a suppressed immune system due to aggressive immunosuppressive therapy or an immune deficiency like HIV/AIDS is more likely to develop infections, including osteomyelitis. Treatment for osteomyelitis includes antibiotic medications to get rid of the infection and medications to control pain. If the infection is not treated early, it is possible for the infection to spread to other tissues in the leg, making amputation of the leg necessary. It is also possible for a person with an untreated infection to go into septic shock when the bacteria infect the bloodstream.

If your leg pain is in your joints, you may have arthritis, or joint inflammation. There are many different types of arthritis, including osteoarthritis, gout and rheumatoid arthritis. More information about the various types of arthritis can be found at http://pain.com/library/2011/05/01-arthritis-awareness-month/. Infections in the joint capsule itself can also cause joint pain. Osteoarthritis, the most common type of arthritis, is caused by “wear and tear” on the cartilage of the joint. Rheumatoid arthritis is an autoimmune disease. Gout is caused by having too much of a substance called uric acid in your body, which builds up in the joints and causes pain and inflammation. Common symptoms of many different types of arthritis include joint pain, joint stiffness or decreased joint mobility and joint swelling. Treatment for arthritis varies depending on the type of arthritis. Talk to your doctor if you think you may have arthritis pain.

Fibromyalgia is a medical condition that can cause muscle pain in the legs and in other parts of the body. In addition to muscle pain, people with fibromyalgia may also have chronic fatigue, sleep disorders, tension headaches and mood disorders. The cause of fibromyalgia is unknown, but researchers think that people with fibromyalgia have a lowered tolerance to pain because of abnormalities in the way that their brains process pain signals. Treatment for fibromyalgia is symptomatic and aims to control pain, improve sleep and treat mood disorders. Not all aspects of fibromyalgia can be treated medically; for example, the frustration that a patient with fibromyalgia may feel in not knowing how to deal with chronic pain and fatigue may benefit from counseling.

Peripheral neuropathy, infections, arthritis and fibromyalgia are just a sampling of the medical conditions that may cause leg pain. These conditions are not as common as muscle cramps and injuries, but a good proportion of older people develop some degree of osteoarthritis and peripheral neuropathy can be caused by a variety of medical conditions. Always talk to your doctor if you have persistent leg pain and you do not know what is causing it.

http://pain.com/library/2011/05/21-leg-pain-3/

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

TUMORS MIGHT GROW FASTER AT NIGHT

They emerge at night, while we sleep unaware, growing and spreading out as quickly as they can. And they are deadly. In a surprise finding that was recently published in Nature Communications, Weizmann Institute of Science researchers showed that nighttime is the right time for cancer to grow and spread in the body. Their findings suggest that administering certain treatments in time with the body's day-night cycle could boost their efficiency.

This finding arose out of an investigation into the relationships between different receptors in the cell -- a complex network that we still do not completely understand. The receptors -- protein molecules on the cell's surface or within cells -- take in biochemical messages secreted by other cells and pass them on into the cell's interior. The scientists, led by Dr. Mattia Lauriola, a postdoctoral fellow in the research group of Prof. Yosef Yarden of the Weizmann Institute's Biological Regulation Department, working together with Prof. Eytan Domany of the Physics of Complex Systems Department, focused on two particular receptors. The first, the epidermal growth factor receptor, EGFR, promotes the growth and migration of cells, including cancer cells. The second binds to a steroid hormone called a glucocorticoid (GC). Glucocorticoids play a role in maintaining the body's energy levels during the day, as well as the metabolic exchange of materials. It is often called the stress hormone because its levels rise in stressful situations, rapidly bringing the body to a state of full alert.

With multiple receptors, the cell receives all sorts of messages at once, and some of these messages can take precedence over others. In the experiment, Lauriola and Yarden found that cell migration -- the activity promoted by the EGF receptor -- is suppressed when the GC receptor is bound to its steroid messenger.

Since the steroid levels peak during waking hours and drop off during sleep, the scientists asked how this might affect the second receptor -- EGFR. Checking the levels of this activity in mice, they found that there was a significant difference: This receptor is much more active during sleep and quiescent during waking hours.

How relevant are these findings for cancers, particularly those which use the EGF receptors to grow and spread? To find out, the scientists gave Lapatinib -- one of the new generation of cancer drugs -- to mouse models of cancer. This drug, used to treat breast cancer, is designed to inhibit EGFR, and thus to prevent the growth and migration of the cancer cells. In the experiment, they gave the mice the drug at different times of day. The results revealed significant differences between the sizes of tumors in the different groups of mice, depending on whether they had been given the drug during sleep or waking hours. The experimental findings suggest that it is indeed the rise and fall in the levels of the GC steroids over the course of 24 hours that hinder or enable the growth of the cancer.

The conclusion, say the scientists, is that it could be more efficient to administer certain anticancer drugs at night.

"It seems to be an issue of timing," says Yarden. "Cancer treatments are often administered in the daytime, just when the patient's body is suppressing the spread of the cancer on its own. What we propose is not a new treatment, but rather a new treatment schedule for some of the current drugs."

Molecule PSR 1 Can Repair Damaged Nerve Cells

Today's post from sciencedaily.com (see link below) looks at the discovery of a unique 'wonder' molecule that can eliminate diseased cells but also apparently regenerate damaged nerve cells. The fact that it can re-join and fuse together broken axons in the central nervous system (frequent causes of neuropathic symptoms) is astonishing and has many implications for the future of neuropathy treatment. That said, as with so many of these findings, we're a long way from translating the theory into effective treatment models but take comfort from the fact that new discoveries are being made and will lead to improvements for future generations

Research findings have implications for regenerating damaged nerve cells 
Date:January 7, 2015 Source:University of Colorado at Boulder
 
Summary:

Two new studies have identified a unique molecule that not only gobbles up bad cells, but also has the ability to repair damaged nerve cells. Known as the phosphatidylserine receptor, or PSR-1, the molecule can locate and clear out apoptotic cells that are pre-programmed to die as well as necrotic cells that have been injured and are causing inflammation. Programmed cell death, or apoptosis, is a natural process that kills billions of cells in a typical human body each day.
 
Two new studies involving the University of Colorado Boulder and the University of Queensland (UQ) in Brisbane, Australia have identified a unique molecule that not only gobbles up bad cells, but also has the ability to repair damaged nerve cells.

Known as the phosphatidylserine receptor, or PSR-1, the molecule can locate and clear out apoptotic cells that are pre-programmed to die as well as necrotic cells that have been injured and are causing inflammation, said CU-Boulder Professor Ding Xue, who led one study and co-authored the other. Programmed cell death, or apoptosis, is a natural process that kills billions of cells in a typical human body each day.

But it is the finding that the PSR-1 molecule also can help reconnect and knit together broken nerve fibers, called axons, that has caught the attention of both science teams.

"I would call this an unexpected and somewhat stunning finding," said Xue of CU-Boulder's Department of Molecular, Cellular and Developmental Biology. "This is the first time a molecule involved in apoptosis has been found to have the ability to repair severed axons, and we believe it has great therapeutic potential."

Xue is the lead author on a paper being published Jan. 7 in Nature Communications that details how PSR-1 recognizes and removes cells that are pre-programmed to die or damaged. He also is co-author of the companion paper being published in Jan. 7 in Nature led by Associate Professor Massimo Hilliard of the UQ's Queensland Brain Institute that shows the major role played by PSR-1 in the regeneration of nerve axons, a holy grail of sorts for neurologists involved with patients who have suffered central nervous system damage from accidents or diseases.

Both studies relied on a popular lab organism known as C. elegans, a nearly microscopic nematode that is fast growing, translucent and has a sequenced genome showing that nearly half its genes are closely related to corresponding human genes.

"This will open new avenues to try and exploit this knowledge in other systems closer to human physiology and hopefully move toward solving injuries," said Hilliard. In the future, neurosurgery may be combined with molecular biology to deliver positive clinical outcomes and perhaps treat conditions like spinal cord or nerve injuries, he said.

During programmed cell death, apoptotic cells flag themselves for elimination by moving a specific cell membrane component known as phosphatidylserine (PS) from the inner membrane to the cell surface, setting them up to be engulfed. "These are what we call 'eat me' signals," said Xue.

In contrast, broken axons in nerve cells send PSR-1 molecules an SOS alert. "The moment there is a cut to the nerve cell we see a change in the cell membrane PS composition, which acts as a signal to PSR-1 molecules in the other part of the nerve that essentially says "I am in danger, come and save me," said Xue.

One of the most encouraging finding is that PSR-1 plays an early role in the axonal fusion process required for neuroregeneration, said Xue. "Whether human PSR has the capacity to repair injured axons is still unknown," he said. "But I think our new research findings will spur a number of research groups to chase this question."

While biomedical researchers have had some successes in repairing peripheral nerves and nerve clusters outside the brain and spinal cord in humans, there currently is no effective way to regenerate broken nerve cells in the central nervous system, said Xue. Such nerve damage can cause partial or total paralysis.

Xue, who first identified the PSR-1 receptor in 2003, said the collaboration between CU-Boulder and UQ has pushed scientific discovery forward. "We are trying to understand how PSR-1 removes cells through apoptosis and necrosis, and they are trying to understand if molecules involved in apoptosis also play a role in the neuroregeneration process," said Xue.

CU-Boulder postdoctoral researcher Yu-Zen Chen, a Nature Communications paper co-author, said the team currently is trying to find ways to raise the level of the PSR-1 in nematode cells, which likely would promote faster healing in nerve axons. "We think the higher the PSR-1 level, the higher the repair capacity of the molecule," said Chen.

Xue said C. elegans is an ideal organism to use in the hunt for new therapeutics to treat nerve damage because of its relatively small, well-known genome and short life span -- just a few days. "This makes drug screening much easier, faster and less expensive than using a mouse model, for instance," said Xue.

"The big finding is that we have a single receptor that does two different jobs," Xue said. "We don't have a solution yet for treating people with nerve damage, but we feel these findings offer promise in seeking new and effective therapeutics."

Story Source:

The above story is based on materials provided by University of Colorado at Boulder. Note: Materials may be edited for content and length.

Journal References:
Hengwen Yang, Yu-Zen Chen, Yi Zhang, Xiaohui Wang, Xiang Zhao, James I. Godfroy, Qian Liang, Man Zhang, Tianying Zhang, Quan Yuan, Mary Ann Royal, Monica Driscoll, Ning-Shao Xia, Hang Yin, Ding Xue. A lysine-rich motif in the phosphatidylserine receptor PSR-1 mediates recognition and removal of apoptotic cells. Nature Communications, 2015; 6: 5717 DOI: 10.1038/ncomms6717
Brent Neumann, Sean Coakley, Rosina Giordano-Santini, Casey Linton, Eui Seung Lee, Akihisa Nakagawa, Ding Xue, Massimo A. Hilliard. EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature, 2015; 517 (7533): 219 DOI: 10.1038/nature14102

http://www.sciencedaily.com/releases/2015/01/150107122912.htm