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March 2007 Issue
Crystal’s Multiple Sclerosis, Transverse Myelitis and LDN (Low Dose Naltrexone) Monthly Newsletter
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“Happy Birthday” to all the March Babies having a Birthday this month!!!!




Crystal’s MS, TM and LDN Website
Lots of Information about MS, TM and LDN

Plus Lots More…

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~LDN as Treatment for Multiple Sclerosis~
http://www.mult-sclerosis.org/news/Jun2004/MSSonLowDoseNaltrexone.html
~The History of Naltrexone~
Naltrexone, short for Naltrexone Hydrochloride (C20H23NO4-HCl), is an opiate antagonist.  At a therapeutic dose of 50mg per day, Naltrexone blocks the parts of the brain that “feel” pleasure when a person uses alcohol or narcotics.  When these areas of the brain are blocked, a person feels less need for “one more drink” or “one more hit.”  

FDA-approved for the treatment of alcohol and opiate abuse, Naltrexone has recently shown great promise in the treatment of other medical conditions.


The Beginnings

Naltrexone was originally synthesized in 1963 and patented in 1967 as “Endo 1639A” (US patent no. 3332950) by Endo Laboratories, a small pharmaceutical company in Long Island, NY, a company with extensive experience in narcotics.

In 1969, DuPont purchased Endo Labs.  DuPont had been struggling to develop its drug business since the late 1950s, and the acquisition of Endo provided DuPont with valuable expertise in drug manufacturing and marketing.  

In the purchase, DuPont acquired the rights to several successful Endo drugs, including: Coumadin (warfarin), an anticoagulant; Percodan, a prescription narcotic; and Naloxone, a drug used for narcotic overdose.  

Naltrexone, still in its early development phase, came to DuPont as part of the overall purchase of Endo.  

At the time it seemed unlikely that DuPont would develop Naltrexone, because at the time, Naltrexone seemed to have relatively low market potential, and its patent would probably expire before the completion of any clinical trials.


The Federal Government Steps In

In June 1971; President Nixon created the Special Action Office for Drug Abuse Prevention (SAODAP).  The first director of SAODAP, Dr. Jerome Taffe, was determined to improve access to drug abuse treatment by shifting services from prisons and hospitals to community-based services.  “I regarded the development of Naltrexone as one of my high priorities,” said Dr. Taffe.

SAODAP recognized that the development of Naltrexone was of no burning interest to the private pharmaceutical industry, and that governmental funding would be necessary to bring it to market.  

In March 1972, Congress passed the Drug Abuse Office and Treatment Act, calling for development of "long-lasting, non-addictive, blocking and antagonist drugs or other pharmacological substances for the treatment of heroin addiction."  This Act provided substantial financial support for research.

By mid-1974, as SAODAP began to phase out of existence, the narcotic antagonist development project fell to the newly formed National Institute on Drug Abuse (NIDA).That same year, NIDA approached DuPont with the idea of developing Naltrexone as a drug addiction therapy, and asked for DuPont's assistance in facilitating Naltrexone's
transit through the FDA approval process. DuPont agreed to assist NIDA with the development of Naltrexone.  In return, NIDA agreed to pay for the bulk of clinical development costs.

When asked later, DuPont representatives said that the primary reason for helping the government was DuPont’s "public spirit", and that Naltrexone would probably not have been developed without the government's clinical and financial support.

The clinical trials for Naltrexone as a treatment for heroin addiction began in 1973 (Schecter 1974, O'Brien 1978).   


Difficulties in Clinical Trials

Early trials of Naltrexone in rats, rabbits, dogs and monkeys had determined that the drug was nontoxic at therapeutic levels, with very few side effects. The subsequent human trials confirmed that the drug was safe for humans, but the efficacy trials ran into some unexpected problems.  

Dr. Arnold Schecter, who conducted many of the early studies, reported that many opiate-addicted patients feared a new drug, lacked a desire to become drug free, were unwilling to possibly receive a placebo, and disliked the rigid protocols associated with the clinical trials (Schecter 1980).

Patients had to remain opiate-free for a minimum of 5 to 10 days prior to treatment because Naltrexone causes severe withdrawal symptoms in patients with opioids in their system (Schecter 1974).  Many addicts were unable to comply, due to the physiological effects of withdrawal.

Taking Naltrexone does not provide any drug reinforcement (“high”), and produces no negative consequences (withdrawal) when discontinued. Unlike methadone, which helps suppress cravings, Naltrexone has no effect until the addict attempts to use heroin. Some patients feared Naltrexone would make them more vulnerable to these cravings, and felt that methadone was more effective in controlling them.

Because of these recruiting difficulties, researchers made no effort to screen out patients who might be difficult to manage in clinical trials -- e.g., patients who were poorly compliant -- and this may have compromised the results of the trials (Schecter 1980).

Since Naltrexone is non-addictive and lacks the reinforcing effect of methadone, it requires more extensive psychosocial support services than methadone. Support services are expensive.  Schecter estimated that total clinical treatment with Naltrexone was almost twice as expensive as methadone  -- not because of the medication itself, but because of the more intensive support services.

Early trial results showed that, compared with the methadone patients, the patients who were attracted to Naltrexone therapy were relatively "more motivated and emotionally stable."  Other studies showed that although Naltrexone was an effective opiate block, clinical success (a reduction in heroin use), was limited to fully compliant patients.
As a result of these findings, the product labeling for Naltrexone reads, "[Naltrexone]… does not reinforce medication compliance and is expected to have a therapeutic effect only when given under external conditions that support continued use of the medication".

The final results of the clinical trials showed that Naltrexone was modestly successful in the reduction of heroin use.  

In 1984, the FDA approved Naltrexone in a 50mg dose as a treatment for heroin addiction. DuPont brand-named the drug Trexan.

The same year, DuPont’s Naltrexone patent expired.

On March 11, 1985, the FDA designated Naltrexone as an orphan drug,** which provided seven additional years of market exclusivity for Naltrexone for DuPont.


Marketing Strategy for Trexan

The DuPont sales force had trouble explaining the mechanism of Naltrexone and its benefits to a lay audience. The consumer marketplace had many misunderstandings and negative perceptions about Naltrexone.  One former member of the DuPont sales force
said these misunderstandings were a great barrier to the use of Trexan.

DuPont also had an extremely difficult time trying to convince methadone clinic personnel to use Trexan.  Most facilities could not afford to implement Naltrexone therapy due to the combined price of the drug, the drug treatment program, and the additional time and staff necessary for psychosocial counseling.

Methadone clinics were also reluctant to refer patients for Trexan because of their need to keep their own censuses high enough to receive funding (Schecter 1980).

Pro-methadone treatment providers argued that because methadone was dependence-producing, it was easier to maintain a patient on methadone, and thus more likely that treatment would be successful.

As a result of these problems, Trexan failed to penetrate the highly regulated federal treatment market for opioid addiction.

By 1995, Trexan sales were approximately $5-8 million annually, which represented approximately 15-25,000 patients per year, or less than 5% of the estimated number of heroin addicts (Scrip 1993).


Naltrexone as a Treatment for Alcoholism

Dr. Joseph Volpicelli first recognized Naltrexone's potential to treat alcoholism while experimenting with rats as a graduate student in University of Pennsylvania.   In 1981, he began to publish his findings.

In 1985, Volpicelli and Dr. Charles O'Brien, a professor at Penn and chief of psychiatry at Philadelphia's Veterans Administration Center, began a Naltrexone study using volunteers at the Veterans Administration Hospital.

"We did it without any outside funding," says O'Brien. "We got it started against pretty great odds." According to O'Brien, the researchers had difficulty recruiting subjects because the idea of treating alcoholism with medication was not commonly accepted in the 1980’s.

They tracked 70 men for 12 weeks in an outpatient detox program. Half received Naltrexone, half a placebo.  While 54% of the volunteers who received a placebo reverted to drinking, only 23% of those who took Naltrexone experienced a relapse.

In 1991, researchers at Yale University School of Medicine tested the effects of Naltrexone in conjunction with psychological therapy in 104 alcohol-dependent men and women.  Patients who took Naltrexone were nearly twice as successful in their clinical outcomes as those who took a placebo.

After the Penn and Yale studies were published in the Archives of General Psychiatry in November 1992, DuPont showed interest in marketing Naltrexone specifically as an alcoholism treatment.  

Governmental funding for the development of Naltrexone as a therapy for alcoholism was provided by the National Institute on Alcohol Abuse and Alcoholism.  The FDA modified existing regulatory requirements to encourage DuPont to develop Naltrexone as an alcoholism therapy. They offered DuPont three additional years of post-approval market exclusivity for Naltrexone as an alcohol therapy.

Marketing exclusivity allows a pharmaceutical company to sell its drug for a certain length of time free of competition from generic versions of the drug. This type of marketing exclusivity is often granted to encourage pharmaceutical companies to develop a use for a drug whose patent has expired or to encourage a company to
develop an already approved drug for a new use. With market exclusivity, the expected returns are higher, thus improving the profitability of the drug.

The FDA also linked phase IV clinical trial requirements to annual sales.  No phase IV trials would be required if Naltrexone as an alcoholism therapy did not meet certain sales thresholds.  If the drug did well in the alcohol-abuse market, DuPont would have to conduct phase IV trials based on the level of sales.

By allowing for flexible phase IV studies, the federal government lowered post-marketing costs, improved profitability projections, and made investment in Naltrexone as an alcoholism therapy more attractive to DuPont.


Clinical Trials


Clinical trials for Naltrexone as an alcoholism therapy encountered familiar problems -- difficulties with patient recruitment and compliance, high cost of clinical support services, and low funding of treatment centers.

Because researchers had difficulty recruiting patients, they accepted all patients who agreed to participate, and didn’t reject any unsuitable patients. This may have negatively affected the results of the clinical trials by including a high proportion of high-risk patients, who may have been motivated more by payment for participating in the trial
than a desire for treatment, which led to poorer compliance and higher drop-out rates (Schecter 1980).

The study found that Naltrexone as an alcoholism therapy did not perform significantly better than a placebo unless it was administered as part of a comprehensive, multidisciplinary treatment program (O'Malley 1995).

Although the government funded and supported the clinical trials, the funding fell short of the amount necessary to provide the necessary intensive psychosocial support. As a result, the labeling for ReVia (the brand-name eventually chosen by DuPont) includes the following stipulation, "ReVia should be considered as only one of many
factors determining the success of treatment of alcoholism." Understandably, this labeling had a profoundly negative effect on marketing strategy and sales.

In 1995, the FDA approved Naltrexone in a 50mg dose as a treatment for alcohol abuse.  

The FDA surprised the researchers by authorizing Naltrexone's use in alcoholism treatment in just six months. According to Volpicelli, the FDA was "pretty confident" that the drug was safe: It had been researched for 20 years and was on the market for 10 as a treatment for heroin addiction.

At this point, DuPont changed the brand name from Trexan to ReVia (pronounced "REV-ya"..   


Marketing Strategy for ReVia


Because the alcohol treatment system is less regulated than the heroin treatment system, DuPont had more flexibility in marketing ReVia directly to clinics and treatment providers. Despite ReVia's clinical effectiveness and less restrictive distribution channels, however, DuPont's sales force encountered marketing problems.

Like Trexan, ReVia is most successful in highly motivated patients who have a strong psychosocial support and access to counseling services.  

DuPont was not successful in selling ReVia, except in comprehensive alcohol treatment programs such as VA hospitals and "white collar" treatment centers.  These patients tended to be more highly motivated and have a stronger support network. ReVia became the treatment of choice for more upscale patients, such as physicians, nurses,
pharmacists and attorneys (O'Brien).

Another roadblock to Naltrexone’s wider acceptance was insurance regulations. "Insurance companies often don't allow Naltrexone to be prescribed by a primary care physician," said Tania Graves, spokeswoman for the Arizona Medical Association. "Their point of view is that drug or addiction problems should be sent to a specialist."

Some insurance companies do not accept Naltrexone at all.  For example, a chain of California treatment centers using Naltrexone as the primary treatment had to suspend operations after only six months, citing managed care companies' unwillingness to cover the treatment (Behavioral Health Treatment 1996).

Some physicians were reluctant to prescribe Naltrexone due to the "black box" warning of liver toxicity in the package insert. The warning was included based on liver enzyme elevations reported with the100-300mg/day dose (the recommended dose is 50mg) that
was given during a study of Naltrexone treatment for obesity. A review of literature and adverse effect reports from DuPont demonstrates that a 50 mg/day dose poses no risk for liver damage, but the warning remains (Galloway).

From the American Council on Alcoholism website, 2005:  

Many physicians and non-physicians in treatment programs are unaware of the usefulness of Naltrexone or how to use it. In other areas of medicine, it is highly probable that the development of such an efficacious medication would prompt physicians to use it readily. The biggest obstacle to using Naltrexone for the treatment of alcoholism is the 'pharmacophobia' of many alcoholism-treatment professionals. This near-hysterical resistance to medication for
treating alcoholism (or other substance-abuse disorders) has deep and tangled roots. Many recovering professionals learned in their recoveries that MDs and their prescription pads were evil purveyors of pharmacological lies and temptations. This attitude is often accompanied by a deeply rooted and strongly held belief that recovery has only one successful formula (usually the 12-step program) and that any modification to that approach is unethical. Scientific evidence is irrelevant to these individuals. They believe they have the 'truth' about recovery and don't want to be bothered with other points of view.

http://www.aca-usa.org/pharm2.htm



Poor Sales

DuPont never expected either Trexan or ReVia to become major revenue generators, but sales fell far short of even DuPont's modest expectations.  In 1994, just prior to the launch of ReVia, Trexan sales were approximately $5-8 million annually, which
represented approximately 15-25,000 patients per year, or less than 5% of the estimated number of heroin addicts in the US (Scrip 1993).

When ReVia was launched in January 1995, DuPont expected US sales of ReVia to rise to $15-25 million annually.  As of October 1996, however, ReVia had not even reached the FDA's threshold of the 200,000 prescriptions required to trigger phase IV clinical
trials (Pink Sheet 1996).

In 1997, ReVia’s market exclusivity agreement lapsed.  Other companies were now free to manufacture and market generic Naltrexone. In May 1998, the first generic version of ReVia was produced by Barr Laboratories in Pomona NY.   At this time,
ReVia had annual sales of approximately $20 million.

In 2001, Bristol Myers Squibb acquired DuPont Pharmaceuticals. In April 2002, Bristol Myers Squibb sold the ReVia brand-name rights in the U.S. and Canada to Barr Laboratories.  

As of February 2005, Barr manufactures ReVia in 50mg pills in the U.S and Canada. Bristol Myers Squibb continues to market ReVia in countries outside of the U.S. and Canada.   

Other versions of Naltrexone are currently manufactured in the U.S. by Eon Labs and Amide Pharmaceutical; Mallinckrodt Pharmaceuticals manufactures 50mg and 100mg Naltrexone pills in the U.S. under the trade name Depade.  

Other 50mg versions of Naltrexone are named Nalorex (manufactured by Bristol-Myers Squibb in the UK); Nodict (manufactured by Sun Pharma in India); Naltima
(manufactured by INTAS in India), Narpan (by Duopharma in Malaysia), Antaxone (by Pharmazam in Spain), Celupan (by Lacer in Spain), Narcoral (by Siton in Italy), Nemexin (Bristol Myers Squibb in Germany), as well as  Revez, Naltrexona, and
Naltrexonum.

The Future of Naltrexone

Researchers continue to explore the potential of Naltrexone as a drug and alcohol therapy. Attempts to address compliance issues have resulted in the introduction of a ReVia implant (2003).  In addition, Alkermes, Inc. recently developed Vivitrex, a Naltrexone injection which lasts a month.  (Phase III clinical studies are set to begin in 2005.)

Over the years, researchers have tested Naltrexone for a wide variety of medical conditions, including obesity, schizophrenia, and chronic obstructive pulmonary disease. In March 2005, Yale researchers began investigating the use of the Naltrexone to help men and women quit smoking without gaining weight.

The FDA has awarded orphan drug** status to Naltrexone to treat symptoms of childhood autism.  Another orphan grant has been issued to Naltrexone as a therapy for self-injurious behaviors. (Naltrexone therapy for self-injurious behavior is already used
extensively in veterinary medicine.)

In addition, researchers have used derivatives of naltrexone to treat other conditions. For example, the FDA granted orphan drug status to methyl-naltrexone as a drug that blocks the side effects of morphine without interfering with pain relief in cancer
treatment. (Oncology 1996)

Low Dose Naltrexone

Naltrexone in substantially lower doses (Low Dose Naltrexone) is showing great promise as a treatment for multiple sclerosis, Crohn’s disease, AIDS, rheumatoid arthritis, celiac disease, CFIDS, lupus, and certain forms of cancer.

Unfortunately, obtaining FDA approval for LDN will not be a straightforward process. Since naltrexone is now a generic drug, no pharmaceutical company currently holds exclusive manufacturing rights.  No company is eager to fund an expensive clinical trial for a drug that will make them so little profit.

However, even without governmental approval or corporate support, LDN is gaining significant grass-roots attention among patients and doctors. The exchange of research information over the internet has greatly accelerated the recognition of the off-label use of LDN.  

In the past, the federal government and the pharmaceutical corporations cooperated to create an environment where naltrexone was tested, approved and made available to
patients who needed it.  Perhaps someday soon they will find a way to do the same for Low Dose Naltrexone.  


                                               Last edited 9/16/05
                                               Copyright 2005 by Gazorpa.com



*Note on brand names and companies:  Naltrexone as used for drug addiction was originally brand-named Trexan.  When it was approved for treatment of alcohol dependence, the name was changed to ReVia.  In 1991, DuPont and Merck & Co. formed a partnership known as DuPont Merck, which owned the rights to Trexan and ReVia. DuPont Merck marketed ReVia under the name DuPont Pharma.  In 2001, Bristol Myers Squibb acquired the rights to ReVia when it acquired DuPont Pharmaceuticals.  In 2002, BMS sold the ReVia rights in the US and Canada to Barr Laboratories. Bristol Myers Squibb continues to market ReVia in countries other than the US and Canada.

** Orphan drug status is granted by the FDA to qualifying products intended for the diagnosis, prevention and treatment of rare diseases, or conditions where no current therapy exists, and which affect fewer than 200,000 patients in the US.

Companies developing products that fit this profile may receive help through the Orphan Drug Program in facilitating the development of the product, may be able to gain marketing approval for the product with a smaller amount of data than would usually be required, and may be entitled to seven years of marketing exclusivity upon final FDA marketing approval. Companies may also be eligible to recoup some of the costs of drug development.

To learn more about the orphan drug program, visit the Office of Orphan Products Development at http://www.fda.gov/orphan/          

A major part of the research used to write this article comes from a 2004 case study on developing and marketing medications for drug abuse and addiction published by the US Department of Health and Human Services:  

http://aspe.hhs.gov/health/reports/cocaine/4cases.htm

Also see National Institute on Drug Abuse Research Monograph 9: Narcotics Antagonists Progress Report: Naltrexone:  http://www.nida.nih.gov/pdf/monographs/09.pdf
A History of Naltrexone” -- http://gazorpa.com/History.html


MS PATIENT ADVOCATES FUND FIRST HUMAN TRIAL OF LDN
The first and much-anticipated human clinical trial of Low Dose Naltrexone (LDN) for MS will begin this March. The double-blind crossover study will involve 80 patients and will be conducted at the University of California, San Francisco MS Research Center.

Over the last decade, anecdotal reports indicated that a very low dose of
naltrexone, an FDA-approved drug, provides effective symptom relief for many individuals with MS. Frustrated by the absence of scientific research, volunteers began raising money to fund a human clinical trial of Low Dose Naltrexone (LDN) for MS. This effort produced a $25,000 gift to the San Francisco MS Research Center.

Twenty years ago, naltrexone was approved for treating addiction, but
researchers at Penn State University discovered its ability, when used in
very low doses, to normalize a dysfunctional immune system. Dr. Bernard Bihari, a Harvard trained neurologist in New York City, observed positive results in his patients using LDN for MS and other immune system disorders. His observations were published at
www.ldninfo.org, which is where SammyJo Wilkinson, who was
diagnosed with MS in 1995 at the age of 30, learned of it.
Despite years of using the FDA-approved disease-modifying drugs for MS, SammyJo's condition worsened. By the end of 2003, she required a motorized wheelchair.

In February of 2004, SammyJo took her first 4.5 mg. capsule and has been
doing well ever since. In 2005 she attended the 1st LDN Conference, and in conjunction with other patient advocates, formed a committee to raise funds toward research for LDN treatment of MS.

Because naltrexone is an inexpensive generic drug, it seemed there would be little commercial interest in research. Consequently, MS advocates felt it was up to them to get LDN into a clinical trial for MS. Besides SammyJo, Robert Lester, volunteer, and Art Mellor, founder of the Accelerated Cure Project, were also on the committee.

They created a website,
www.LDNers.org, and received enthusiastic support from others who had benefited from LDN. The finale of the fundraising effort was a California gala attended by over 250 people. The event organizer, Vicky Finlayson, had experienced positive results after taking LDN, and felt passionately about funding the research so that others with MS could also find relief.

To learn more, visit
www.ldners.org. To learn more about recruitment for the clinical trial, contact Elena Kornyeyeva, M.D., Ph.D., Clinical Research Manager, at 415-514-2467 or Elena.Kornyeyeva@ucsf.edu .

*Please Note: During the 17-week clinical trial, participants will be
required to make three visits to the University of California, San Francisco MS Research Center and must do so at their own expense.



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Pregnancy Hormone May Help Treat MS
Hormone, Called Prolactin, Might Spur Repair of Nerve Damage in Multiple Sclerosis
By Miranda Hitti
WebMD Medical News


Reviewed by Louise Chang, MD
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