Terra Sigillata

Just a quick post on an article that caught my eye: Jazz Pharmaceuticals of Palo Alto, CA, has announced that the US FDA has accepted their new drug application (NDA) filing for JZP-6, or sodium oxybate, for the treatment of pain and fatigue associated with fibromyalgia.

The NDA was based on positive outcomes of two, Phase III clinical trials – those randomized, placebo-controlled double-blind trials that serve as the gold standard for drug efficacy. The company expects an approval decision from FDA by October 2010.

Jazz has already garnered approval for sodium oxybate under the brand name Xyrem® for the treatment of daytime sleepiness in patients with narcolepsy. The company stresses, however, that the drug has not yet been approved for symptoms associated with fibromyalgia.

i-65da522f4aef10161a631fa119fd7edd-200px-4-hydroxybutanoic-acid-thumb-175x70-41338.pngThe item of note here is that sodium oxybate is another name for the sodium salt of gamma-hydroxybutyrate or GHB, a sedative that resembles the inhibitory neurotransmitter GABA but also has its own receptors in the central nervous system. GHB was implicated as far back as the early 1990s on college campuses where young men who lacked any other redeeming qualities to attract women used it to dope the drinks of their dates.

But here we see the study of a drug of abuse giving rise to a useful pharmaceutical, first in narcolepsy and, soon perhaps, for fibromyalgia.

It is a paradox of pharmacology that a sedative like GHB would prevent excessive sleepiness or fatigue. But a similar paradox exists with the use of the stimulant methyphenidate in hyperactivity conditions.

Now that I’ve seen the business reports, I’ll turn to some of my CNS pharmacology colleagues to help explain the neurobiology.

However, this compound demonstrates to me the unanticipated benefits of funding research that aims to investigate drugs of abuse.

Beneficial therapeutic agents come when and where you may least expect them.

Comments

  1. #1 LC
    February 19, 2010

    A few points of clarification.

    1. The prevalence of actual use of GHB for date-rape is unclear and controversial. It is difficult to detect, often untested for, and leaves the body quickly; however, it’s reputation for date-rape likely exceeds it’s actual use for date-rape.

    2. It’s not a paradox that GHB would prevent daytime sleepiness and it’s not similar to methylphenidate and ADHD in this regard. GHB is taken at night and not surprisingly better sleep leads to less daytime sleepiness. The appropriate methylphenidate analogy would be if kids took a stimulant to get all the hyperactivity out before settling down for class.

    3. As much I would like to believe it, the therapeutic value of GHB was not realized as a result of research into it’s effects as a drug of abuse. Folks were studying the therapeutic effects of GHB at least 20 years before it became popularized as a club drug and date-rape drug.

  2. #2 Arlenna
    February 20, 2010

    This is my own unsubstantiated quackery talking, but I think fibromyalgia is mainly vitamin D deficiency combined with lack of exercise. The only basis I have for this was being very nearly diagnosed with fibromyalgia/chronic fatigue and then finally having an endocrinologist test me for vit. d, find VERY low levels, and put me on a vit D supplement level that changed my life. No more fibromyalgia/CFS symptoms since then.

  3. #3 daedalus2u
    February 20, 2010

    I think that fibromyalgia is due to low NO, and that anything that increases NO levels will help it.

    I would look at valproate (used for seizures), acetate and butyrate (used to stimulate fetal hemoglobin in SSA) for insight into the pharmacology.

  4. #4 lucy
    February 21, 2010

    This is very exciting and interesting. But also sad that the abuse of the low cost rather common substance has put such a stigma on Xyrem as a legitimate drug. The abuse of this before it became a controlled prescription has set the stage for lots of hassles to come for people who may benefit from it but will be thwarted by inflated costs and insurance jumping through hoops to get it.

    People abuse other drugs all the time that have serious clinical uses (Klonopin?), but that should not be used as a platform to make it difficult for people who can benefit from it.

    I for one am encouraged that Xyrem could be a potentially effective treatment for people who have fibromyalgia symptoms that are perhaps the caused by a lack of the proper type of restorative sleep.

    @Arlena: re: Vitamin D, it is clear that you had a Vitamin D deficiency causing your symptoms, but perhaps you did not have fibromyalgia. I also was tested for Vit D levels, was found to be somewhat low, and put on supplements, but the result was not a reversal of my symptoms like you experienced. Clearly, I have other issues that were not caused solely by low vitamin D. I am truly so happy for you that you found the cause of your problem and a simple fix.

    I am encouraged by the preliminary studies that suggest that a treatment like Xyrem that could restore my sleep patterns and this could possibly reduce symptoms of pain and all the rest that come with the fibromyalgia syndrome.

  5. #5 Vicki
    February 22, 2010

    As LW says, the use for narcolepsy predates the abuse as a date-rape drug. I first read about GHB in an essay by a woman with narcolepsy, in the 1980s, and when the date-rape stuff hit the press, my first thought was to wonder whether this would make it harder for Teresa to get her needed medication.

  6. #6 Yorkies
    February 23, 2010

    Methyfenidate has both effects on me……taken as directed during the day (10 mg. a.m. and 10 mg. early afternoon allow me the ability to organize my day and accomplish more. I have had diagnosed FM and CFS for 10 years. Then very, very seldom when I am having insomnia problems not rectified by sleep medication, 10 mg. methylfenidate allows me to unwind and fall asleep. But the drug I take for managing anxiety is the true miracle….10 mg. Buspar twice daily. I started taking Buspar when my husband was diagnosed with stage 4 lung cancer. After the first week on Buspar I thought of how differently my life may have turned out had I not been wracked with anxiety for the first 54 years. I can recall anxiety/panic attacks back as far as far as age 6. When the anxiety dissipated I felt like I had taken a warm soothing shower that washed fear and the accompanying emotional pain down the drain. I thank God the last part of my life will be the happiest and most content.

  7. #7 Abel Pharmboy
    February 23, 2010

    As I am not a card-carrying neuropharmacologist, I really appreciate all of the feedback and clarification, especially that of LC in comment #1. This post is getting a fair bit of referral traffic from the New York Times Science website so I should be more clear than the post’s title suggests.

    The literature on GHB is actually quite rich and it seems to have been studied extensively as far back as the late 60s. The first case report I can find of using GHB as a treatment for narcolepsy was in 1981:

    http://www.ncbi.nlm.nih.gov/pubmed/7232968

    So I stand corrected – this compound has been the subject of systematic investigation for decades before it was reportedly used in slipping someone a Mickey.

    I also know that some bodybuilders were experimenting with it in the late 80s and early 90s because of its purported effects on the pituitary gland to increase release of endogenous human growth hormone.

    But regardless of its history, I am happy to see that GHB/sodium oxybate is being used for disorders where patients have few options.

  8. #8 Trinka Porrata
    February 26, 2010

    You wouldn’t consider taking GHB for fibro (or anything else) if you knew what I know about this drug. Having researched hundreds of sexual assaults because of it (and yes, Virginia, drug rape DOES exist) and plenty of overdose cases and more than 400 GHB related deaths (yes, including a few from Xyrem) and having worked with more than 3,000 GHB addicts in 20 countries, I wouldn’t consider taking GHB for anything, no matter how desperate I became. This drug IS addictive and involves the single more severe and prolonged drug detox of all drugs of abuse. Unfortunately it is a secret drug issue and trying to get medical help to get off of it is a nightmare as few ERs or treatment facilities have any comprehension about it. Detox is 10-14 days, often intensive care, sedated to the ground in four-point restraints. Opening the door to even more people being given this drug for fibro will also make our work much harder. Project GHB is unfunded because no one cares about the reality of this problem. We donate hours and hours and hours of time and postage and such trying to help people who have been victimized by GHB in one way or another. We are currently overloaded with GHB addiction help requests, especially in the USA and UK. Xyrem should NOT be given to anyone with sleep apnea and yet it IS being prescribed in spite of that diagnosis. It should never be given to anyone with prior addiction or mental health issues, but it IS being done. It should not be taken with a cocktail of other drugs that are CNS depressants, but it is. I know it is supposedly carefully manage to avoid diversion. Baloney is all I can say, especially if the flow increases. And even people on limited supply can and have become addicted. They simply end up using it all quickly and then surviving on antidepressants and booze until the next batch arrives or they start buying street GHB. Most doctors prescribing Xyrem have no comprehension of this drug in reality, only what the drug company has told them.

  9. #9 Mary Elizabeth Nichols
    February 26, 2010

    “Former” [ ???? ]date rape drug ??????

    International Narcotics Control Board
    United Nations

    INCB WARNS ABOUT DRUGS BEING USED TO COMMIT
    SEXUAL CRIMES

    VIENNA, 24 February (United Nations Information Service)—The International Narcotics Control Board is warning of an increase in the use of date-rape drugs by criminals to lure their victims. Despite efforts to curb their misuse, the abuse of these so-called date-rape drugs is on the rise. INCB is raising the alarm about new psychoactive substances that are easier to get hold of and under less stringent international controls.

    The “date-rape drug” phenomenon, although fairly new, is evolving rapidly, as sexual abusers attempt to circumvent stricter drug controls by using substances not restricted by international drug conventions.

    Benzodiazepines, which are controlled under the 1971 Convention, have been frequently used by criminals to weaken the resistance of their victims and to exploit their property or body without their consent. Flunitrazepam, a benzodiazepine sold under the brand name Rohypnol, was once so commonly misused for sexual assault that it was called the “date-rape drug”. However, the adoption of stricter control measures by Governments, in close cooperation with the pharmaceutical industry, has proven effective: nowadays, reports of the misuse of Rohypnol for sexual assault have become rare. At the same time, criminals are turning now to other substances—notably gamma-Hydroxybutyric acid (GHB), a psychotropic substance that was not under international control until recently, as well as substances that remain outside drug conventions such as ketamine and gamma-Butyrolactone (GBL).

    Since in many countries most of those drugs are easily available, they frequently fall into criminal hands.

    What is alarming is the unscrupulous way in which those drugs are used upon unwitting victims—the drugs, which are usually disguised in food or drinks, are introduced in dosages that are significantly higher than the dosages used for therapeutic purposes—a practice which entails serious health risks for the victims. Sexual assault crimes are often committed in public places such as bars, restaurants, nightclubs but also in private surroundings.

    In view of this serious menace, the international community has come together and shown commitment to address the problem. In March 2009, the Commission on Narcotic Drugs urged all countries of the world to adopt measures to combat the misuse of pharmaceutical products for sexual assault and to enhance public awareness about this serious problem (resolution 52/8). The Commission also invited the pharmaceutical industry to develop formulations with safety features, such as dyes and flavourings, to alert possible victims to the contamination of their drinks, without affecting the bioavailability of the active ingredients in legitimate drugs.

    In its Report, INCB calls on all Governments to implement the Commission on Narcotic Drugs resolution 52/8 as soon as possible and to be vigilant about the worrying increase in “date-rape drug” abuse. The report also highlights the importance of cooperation with the pharmaceutical industry and calls on countries to solicit their support.

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