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).
Naltexone 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.
