Naltrexone

Naltrexone Science Based Treatment for Alcoholism

From a Snake Pit to Science

About 14 million American adults meet diagnostic criteria for alcohol abuse or alcohol dependence (alcoholism).  Approximately 1.5 million seek treatment for their alcohol-related problems.  Throughout history, attempts to treat alcoholics have been ill conceived and gave disappointing results. An early treatment for alcoholism may have been devised by ancient Romans, who lowered alcoholics into snake-filled pits, thinking the terror would shock them into abandoning their desire to drink.  (17)

By the close of the 19th Century, Merck’s “Manual of the Materia Medica” (1899) was recommending such nostrums for alcoholism as arsenic, bromides, cocaine, chloral hydrate, opium, and strychnine. Fifty years later, in 1948, disulfiram became the first U.S.  approved drug for alcoholism treatment (Kurtzweil 1996). It induces nausea, vomiting and other aversive reactions in those who drink alcohol while taking the medication.

Forty-six years later, science made available an amazing anti-alcohol medication, Naltrexone HCL.  On December 30, 1994, the United States Food & Drug Administration approved ReVia, which is the brand name for naltrexone.

The deciding factor by the FDA in approving naltrexone were the results from two pivotal studies demonstrating naltrexone’s usefulness as part of a clinical program for treating alcoholism.  In its approval, the FDA strongly recommended that naltrexone be used with adjunctive psychosocial therapies for alcoholism.

Naltrexone’s pharmacologic actions are straight forward. Alcohol is a complex substance, affecting a number of chemical systems in the brain. Among other effects, it is suspected that, when an alcohol dependent person drinks, the brain’s opioid system releases endorphins triggering reinforcement that entices the person to drink more (16)

Unlike earlier drugs used to treat alcoholism, naltrexone is not addictive and does not react adversely with alcohol. It blocks opioid receptors in the brain (it is an antagonist), and this has been proposed as stemming the endorphin-mediated reinforcing effects of drinking alcohol. The validity of this concept has been supported by observations that alcoholics experience increased opioid system activity in response to alcohol (Herz 1997; Miller 1997).

Development

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 Pharmaceuticals purchased Endo Labs.  DuPont had been struggling to develop its drug business since the late 1950’s, 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 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 of 1971, President Richard 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. It is interesting to note that the Nixon Administration placed a priority on research and treatment rather than incarceration (1).   On March 21, 1972 President Richard Nixon followed up his earlier Executive Order by signing the Drug Abuse Office and Treatment Act of 1972. At the time he issued the following statement:

“TODAY I am pleased to sign into law the Drug Abuse office and Treatment Act of 1972, a bipartisan bill designed to mount a frontal assault on our number one public enemy.  The support which this legislation received in the Congress it passed unanimously in both Houses–not only reflects the wisdom of this measure but also attests to the determination of all our people to wipe out drug abuse in America.

The critical feature of this legislation is the statutory authority which it gives to the Special Action office for Drug Abuse Prevention. This office was charged with the responsibility for coordinating all Federal activities concerned with drug abuse prevention, education, treatment, rehabilitation, training, and research. Thus it will be at the cutting edge of our attack” (2).

SAODAP recognized that the development of naltrexone was of no interest to the private pharmaceutical industry, and that governmental funding would be necessary to bring it to market.  The Drug Abuse Office and Treatment Act, called for the development of “long-lasting, non-addictive, blocking and antagonist drugs or other pharmacological substances for the treatment of heroin and opiate addiction.”  Very importantly, this act provided substantial financial support for research.

By mid-1974, as SAODAP began to phase out of existence, the narcotic antagonist development project went 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 intervention, and asked for DuPont’s assistance in facilitating the transit of naltrexone 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.

DuPont’s position was that its 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 (3).  The clinical trials for naltrexone as a treatment for heroin addiction began in 1973

Difficulties in Clinical Trials for Heroin Treatment

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.  Naltrexone was not addicting in any way, either psychologically or physically.  It was not substituting one drug for another, as is the case with methadone treatment.   Dr. Arnold Schecter, who conducted many of the early studies, reported that many opiate-dependent 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 (4).

Patients had to remain opiate-free for a minimum of 5 to 10 days prior to treatment because naltrexone causes immediate and severe withdrawal symptoms in patients with opiates in their system (5).  Many were unable to comply because of the psychological effects of withdrawal, including anxiety and depression.

Naltrexone does not provide any reinforcement or the euphoric effect (the high) associated with using opiates.  Unlike methadone, which helps suppress cravings, naltrexone only prevents an individual from using an opiate. Naltrexone blocks the ability of any opiate to produce either a high or pain relief.  Many of the potential study participant’s feared naltrexone would make them more vulnerable to cravings, and 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.

Since naltrexone is non-addictive and lacks the reinforcing effect of methadone, and it requires more extensive psychosocial support services than methadone. Support services are expensive.  Estimates show 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 psycho/social support services.  Very early, it was clear that naltrexone should be administered concurrently with therapy or counseling (6).

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.”  Experience has shown that although naltrexone is an effective opiate block, clinical success (a reduction in opiate or heroin use) was limited to fully compliant patients.  As a result, 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”. In other words, it was not the “magic bullet” and that for it to be effective an individual had to make the rational decision to take the naltrexone.  Clinical trials concluded that naltrexone was modestly successful in the reduction of opiate use.

On December 30, 1984, the FDA approved naltrexone in a 50 mg dose as a treatment for heroin and opiate dependence.  DuPont named the new anti-opiate medication Trexan.  At the same time DuPont’s naltrexone patent expired.  On March 11, 1985, the FDA designated naltrexone as an orphan drug which provided DuPont with seven additional years of market exclusivity for naltrexone.  Congress passed the Orphan Drug Act of 1983 to stimulate the development of medications that otherwise would not be considered profitable under normal conditions.

Marketing Strategy for Trexan

The DuPont sales force had trouble explaining the mechanism of naltrexone and its benefits not only to a lay audience, but to the medical community. The consumer marketplace had many misunderstandings and negative perceptions about naltrexone.   DuPont also had a very 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 (7).

Pro-methadone treatment providers argued that because methadone was dependence-producing, it was easier to maintain a patient on methadone.  As a result, 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 opiate dependent individuals (8).

Naltrexone as a Treatment for Alcoholism

Dr. Joseph Volpicelli, MD, PhD of the University of Pennsylvania School of Medicine first recognized the potential of naltrexone to treat alcoholism while experimenting and doing opiate research as a graduate student at UPenn. As Volpicelli researched opiate dependence he wondered what would be the result of giving naltrexone to alcohol dependent rats.  Volpicelli had naltrexone available, and there were available alcohol dependent rats that were not part of a study.

Volpicelli wanted to see what kind of reaction the alcohol dependent rats would have while on naltrexone.  Because alcohol and opiates are very different chemically, he had no idea of what to expect.  The result of the experiment was that the rats became sober.  This intrigued him and he continued with the research.  In 1981, he began to publish his findings.

In 1985, Volpicelli and Dr. Charles O’Brien, a professor at UPenn 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.  This is still the case in 2017

.
Dr. Volpicelli and Dr. O’Brien tracked 70 men for 12 weeks in an outpatient detox program. Half of the men received naltrexone, and half a placebo. In the study 54% of the volunteers who received a placebo reverted to drinking, while only 23% of those who took naltrexone experienced a relapse.

In 1991, researchers at the 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 (NIAAA).  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.

The Phase IV trial is also known as a Post Marketing Surveillance Trial. Phase IV trials involve the safety surveillance and ongoing technical support of a drug after it receives permission to be sold. The FDA may or may not Phase IV.  The safety surveillance is designed to detect any rare or long-term adverse effects over a larger patient population and longer time frame than was possible during the Phase I-III clinical trials.  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 Trial’s  

Clinical trials for alcohol dependence faced common challenges,  such as difficulties with patient recruitment and compliance, high cost of clinical support services, and low funding.  Naltrexone researchers had difficulty in recruiting patients, so they accepted all patients who agreed to participate, not rejecting any. 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 (9).

The research confirmed that naltrexone alone as a treatment for alcohol dependence did not perform significantly better than a placebo.  When combined with a comprehensive, multidisciplinary treatment program, naltrexone produced amazing results. (10).   Naltrexone is a very effective tool, not a cure.  Naltrexone clearly works best when used in conjunction with therapy.

Although the government funded and supported the clinical trials, the funding fell short of the amount necessary to provide the necessary intensive psycho-social 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.

On December 30, 1994 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.  With the approval by the FDA, DuPont/Merck changed the brand name from Trexan to ReVia.

Marketing Strategy for ReVia

In 1991 DuPont in  an effort to improve marketing and sales, joined with Merck Pharmaceuticals to create DuPont/Merck.  The alcohol treatment system is less regulated than the opiate treatment system, giving DuPont/Merck more flexibility in marketing ReVia directly to clinics and treatment providers. Despite ReVia’s clinical efficacy and less restrictive distribution channels DuPont/Merck’s sales force encountered enormous marketing problems.  Like Trexan, it was thought that ReVia would be most successful in highly motivated patients, for example a medical doctor whose license is at risk, and who had access to strong psycho-social support and counseling services.

One of the numerous impediments to successfully marketing ReVia was the lack of training and experience by medical doctors as regard to treating alcohol dependence.  It has been estimated that the average physician gets less than two hours of formal training regarding addiction.  Most doctors were trained to refer their patients to AA.  In July 2011 the American medical establishment took the first step to rectify this problem.  Ten major medical schools for the first time created Residency Programs for Addiction Science.

DuPont/Merck was not successful in selling ReVia, except to comprehensive alcohol treatment programs such as Assisted Recovery Centers of America (ARCA), located In Phoenix, Arizona.  The difficult task of creating acceptance of the new medication is illustrated by the experience of Lloyd Vacovsky, Director of ARCA who in 1995 was a social worker at Central Arizona Shelter Services (CASS).   CASS is the largest provider of services to the homeless in Arizona.  Alcohol directly impacted many if not most of the clients at CASS.  Traditional 12 Step Treatment was all that was available and it just was not working for the vast majority of his clients.  Vacovsky became very frustrated with the fact that despite a lot of work, people were not getting sober.

Vacovsky contacted DuPont/Merck in January 1995 after reading an article in the ARIZONA REPUBLIC announcing the approval of ReVia by the FDA.  DuPont/Merck sent product information to Vacovsky.  Lloyd remembers thinking at the time, after reviewing the DuPont/Merck materials that naltrexone should be “put in the water, like fluoride”

Armed with information on naltrexone Vacovsky went to the Director of CASS Mary Orton, wanting to start a naltrexone based program for shelter clients.  He was told that CASS provided housing and was not an alcohol treatment agency.  He was told however that if he could get another outside agency to run the program, CASS would provide the meeting space.

Vacovsky approached several outside agencies expecting them to be excited at the prospect of a new and hopefully effective alcohol treatment option.  “I was confronted with a stone wall.  I was told that naltrexone was voodoo medicine and that the only effective treatment was 12 Step based.”  Vacovsky was shocked at the resistance to even hear information about naltrexone.  What bothered him was the fact that it was crystal clear that traditional treatment methods simply were simply not effective for a majority of people, yet there was no desire to improve treatment methods and outcomes.

Instead of giving up, Vacovsky went back to CASS Director Orton and asked if he could start a group on his own time.  It was agreed that he could start a naltrexone based group on his own time.  He would face numerous hurdles including who would write the prescriptions for the naltrexone and how to pay for it.

Vacovsky went to the Maricopa County Homeless Clinic, which provided medical services to CASS clients.   It was quickly agreed that the clinic psychiatrist would write the prescriptions but they had no funding to purchase the naltrexone.  While Vacovsky was trying to find a funding source for the naltrexone, in February 1995 the first client, Kurt was put on naltrexone.  He was 30 years old and had tried on numerous occasions to stop drinking.  He had several treatment experiences ranging from expensive 30-day residential to simply attending 12 Step meetings.  Armed with a prescription from the Homeless Clinic, Vacovsky and Kurt went to Walgreen’s.  Since it was a new medication, they were told that it would take Walgreen’s two days to get the naltrexone.

After only one day the pharmacist called and said the naltrexone had arrived and they could come and pick it up.  The night before, Kurt had gone on a mini-binge; he drank everything he could get his hands on including mouthwash.  Arriving at Walgreen’s they proceeded through the store having to pass the fully stocked liquor department.  Lloyd could sense Kurt wanting to linger in the liquor aisle surrounded by his old friends, having doubts about this medication which he hoped would completely change his life.  Finally, they got to the pharmacist window and Vacovsky paid for the naltrexone.  Kurt swallowed the 50mg tablet and said “now what.”  Vacovsky said let’s wait and see.

Fifteen minutes after taking the naltrexone, Vacovsky asked, “do you want a drink?” Previously Kurt had been anxious and stressed.  Vacovsky noticed a calmness that had not been present just moments before.  Kurt then stated that he didn’t understand why, but that he did not want a drink.   It was at that moment that Vacovsky realized that science had finally provided an effective tool to help people who previously had little or no hope for a happy life without alcohol.

One of the first contacts that Vacovsky made was with Dr. Volpicelli in Philadelphia.  He had read that Volpicelli had played a pivotal role in the development of naltrexone, especially for his research on its effect on alcohol. Dr. Volpicelli was especially gracious and immediately offered to help Vacovsky put together a program at the shelter that would include naltrexone and psychotherapy.  He explained to Vacovsky that treatment could be compared to a three-legged stool.  With all three legs, you have a working piece of furniture.  You take away one of the legs and your furniture is incomplete and not as functional.  He went on to say that treatment for alcohol dependence was similar to the stool.  The Biological, the Psychological and the Social components of the recovery process all had to be addressed in order to have an effective treatment protocol. Dr. Volpicelli helped Vacovsky create one of the first Bio-Psycho-Social treatment programs in the country utilizing naltrexone.

Vacovsky again contacted DuPont/Merck and was referred to Percy Menzies, who was a DuPont/Merck product representative based in Denver, Colorado.  Vacovsky detailed to Menzies his frustration in helping his clients and how traditional treatment just did not seem to work. He told Menzies about Kurt, who by that time had been sober for several weeks.  Menzies agreed to fly to Phoenix and meet with Lloyd at CASS.  Previously it was thought that naltrexone would be only effective for highly motivated professional people who had a lot to lose; airline pilots, doctors and lawyers.  If a naltrexone based pharmacotherapy program could work at a homeless shelter, it would work anywhere.

Menzies recognized the passion and the desire by Vacovsky to find an effective state of the art treatment protocol for his clients.  Menzies agreed to help and asked DuPont/Merck to provide the naltrexone to enable Vacovsky to start a pilot program at CASS.  DuPont/Merck agreed to provide ReVia to the Maricopa County Homeless Clinic and one of the first pharmacotherapy programs utilizing naltrexone (ReVia) was born.

Vacovsky recruited David Heward, a close friend and himself a recovering alcoholic to help with his project.  Together they created a Bio-Psycho-Social treatment protocol.  Heward had come across a new, non 12 Step alternative called SMART Recovery.  SMART, which stands for Self Management and Recovery Training has become the leading secular alternative to the traditional 12 Step approach.  The psycho-social support was delivered via SMART meetings facilitated by Heward and Vacovsky, while the bio component was delivered by the ReVia (naltrexone).  The success of the program at Central Arizona Shelter Services led to the creation of Assisted Recovery Centers of America in April 1997.

The Bio-Psycho-Social treatment protocol that was created was named The Pennsylvania Model of Recovery in honor of the research in the field by the University of Pennsylvania and particularly, Dr. Volpicelli and Dr. O’Brien.  The protocol developed combines safe, effective and approved medications with cognitive behavioral therapy.  This approach is supported by the U.S. Department of Health Services, in its publication HELPING PATIENTS WHO DRINK TOO MUCH, A Clinician’s Guide, Updated 2005 Edition.

An early major roadblock to naltrexone’s wider acceptance was insurance coverage.  “Insurance companies often didn’t allow naltrexone to be prescribed by a primary care physician,” said Tania Graves, spokeswoman for the Arizona Medical Association. “Their point of view was that drug or addiction problems should be sent to a specialist.”  The only problem with that is again, until just recently, American medical schools were not training doctors to be “addiction specialists”. By 2017 naltrexone is covered by virtually all commercial and government insurance by any licensed physician and without prior authorization.

Some insurance companies did 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 (11).

Some physicians were reluctant to prescribe naltrexone due to the “black box” warning of liver toxicity in the package insert. Researchers conducting the naltrexone clinical trials had noticed that many individuals taking naltrexone had lost weight.  This created a stir among the research team in that perhaps they had a medication that not only combated alcohol and drug abuse, but also obesity. DuPont backed a study that would document this effect.  It was a very small study, with a total of 12 participants.  Six were given naltrexone and six were given a placebo.  None of the participants had a history of alcohol abuse and were not drinking alcohol at the time of the study.  The study participants were given up to 300 mg of naltrexone per day.

At the end of two years there was no significant weight loss. The naltrexone group gained more weight than the placebo group. The warning was included based on elevated liver enzymes in one of the six of the naltrexone group. One in six is statistically significant.   The results were reported to the FDA, which then issued the warning.   A review of literature and the adverse effect reports from DuPont/Merck demonstrated that a 50 mg/day dose posed no risk for liver damage, but the warning remains.  It should be noted that the injectable form of naltrexone, Vivitrol has the warning removed as it bypasses the liver.

People lost weight because they had altered their life style.  They were not drinking alcohol and otherwise took better care of themselves, for example improving nutrition and exercising. This alone has probably prevented thousands of people not being prescribed naltrexone due to largely unfounded fear created by the warning.  While naltrexone may slightly elevate the enzyme level, the reality is that drinking alcohol is far more damaging to the lover.  The trade off in terms of enzyme levels between taking naltrexone and NOT drinking alcohol is crystal clear.

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 (12).”

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 (13).

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 (14).

On December 30, 1997, DuPont/Merck’s ReVia market exclusivity agreement expired. 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.

In 2001, Bristol Myers Squibb acquired DuPont/Merck 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 50 mg 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 100 mg naltrexone pills in the U.S. under the trade name Depade.
Other 50 mg 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: Vivitrol

Researchers continued to explore the potential of naltrexone as a drug and alcohol therapy.   Attempts to address compliance issues resulted in the introduction of a naltrexone implant in 2003.  This was a very controversial use of naltrexone which never received FDA approval.

A milestone in the history and development of naltrexone came when Alkermes, Inc. a pharmaceutical company then based in Cambridge, Massachusetts became interested in naltrexone.  Alkermes developed products based on sophisticated drug delivery technologies which enhanced therapeutic outcomes and compliance. Alkermes wanted to develop a long lasting form of naltrexone.  The Company’s primary medical product, Risperdal Consta ((risperidone) is a long-acting injection, and was the first long-acting atypical anti-psychotic medication approved for use in schizophrenia.

On April 1,2005 Alkermes announced that it has submitted a New Drug Application (NDA) to the FDA.  Initially the medication was named Vivitrex and it would be naltrexone in a long-acting injection. Vivitrex was developed as a once-monthly injection for the treatment of alcohol dependence.

The Company had a pipeline of extended-release injectable products and pulmonary drug products based on its proprietary technology and expertise. Alkermes’ product development strategy had it partner its proprietary technology systems and drug delivery expertise with several of the world’s finest pharmaceutical companies.  It also develops novel, proprietary drug candidates for its own account for example naltrexone.   If approved, Vivitrex would be the first medication available for the treatment of alcohol dependence in a formulation that is administered once-monthly by injection.  This NDA submission was a major milestone in the Vivitrex development program, which included a comprehensive U.S .clinical trials program, manufacturing infrastructure and extensive regulatory and research expertise.

Vivitrex, an injectable, long-acting formulation of the already approved drug naltrexone, was designed utilizing Alkermes’ proprietary Medisorb (r) drug-delivery technology. Using the Medisorb technology, naltrexone is encapsulated in micro-spheres made of a biodegradable polymer that dissolve slowly and release drug at a controlled rate following intramuscular injection.  On December 28, 2005 – Alkermes, Inc. announced that the U.S. Food and Drug Administration (FDA) issued an approval letter for Vivitrol(TM) (naltrexone for extended-release injectable suspension), which is under review for the treatment of alcohol dependence in combination with a treatment program that includes psycho-social support. Alkermes changed the name of its injectable naltrexone from Vivitrex to Vivitrol in response to issues raised by the FDA.

On April 13, 2006, Vivitrol was formally approved by the FDA for use in the treatment of alcohol dependence.  This was a major new weapon in the fight against alcohol and opiate dependence.  While fully approved as an anti-alcohol medication, Vivitrol was utilized “off label by opiate treatment providers until October 13, 2010, when it was further formally approved for opiate treatment.

On going research documents the effectiveness of combining medications such as Vivitrol with psycho-social support like cognitive behavioral therapy.  Alcohol dependent individuals suffered fewer drinking days and fewer heavy drinking days according to Steven Lamm, M.D. who is an internist and clinical assistant professor of medicine at the New York University School of Medicine, and is a nationally recognized expert on alcohol and opiate dependence and their treatment options. He says, “Advances in research have furthered the understanding of addiction as a serious brain disease with both physical and psychological components.”

Lamm continues, “Research shows that the combination of medication, such as Vivitrol, and psychosocial support, such as counseling, is a safe and effective approach and has helped many who struggle with alcoholism to stop drinking, stay sober and rebuild their lives.” (14)

“I have witnessed every complication from alcoholism – from suicide to cirrhosis to dementia.  Many of my patients have been able to remain sober with medication and counseling; these people had tried other options in the past, but it wasn’t until they used Vivitrol that they were able to remain sober or dramatically reduce their number of drinking days per month. With Vivitrol patients don’t have to remember to take a pill. Especially when first starting treatment, patients lack clarity that they achieve later on in the process. It’s during these first few days when it can be hard for them to think of taking a daily pill. They might miss it the first day, miss it the second day, and then be paying the consequences on the third day. “

According to the American Council on Alcoholism, “Vivitrol will play a major and eve expanding role in the fight against alcoholism and opiate abuse. It is the goal and mission of the American Council on Alcoholism to educate not only the general public but also medical and alcohol/drug treatment providers about the value of science based pharmacotherapy.”  (12)

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.  Through bred horses often experience what is known as “crib” or “stall” rage.  Naltrexone calms them down.  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. (13)

 

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.

Summary

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) states that medication(naltrexone) is best used in combination with long term therapeutic help, for example cognitive behavioral therapy.  Therapy should include pharmaceutical intervention by a licensed provider. Ideally, there should be firm commitment to staying compliant to the medications and psycho-social support.  This psycho-social support includes such well proven groups SMART Recovery as well as the many state financed, or state supervised, alcoholic recovery programs.

What makes doctors optimistic about Vivitrol is this: it offers “people struggling with alcohol dependence a new alternative…and shown to be both effective and well tolerated” by the people using the medication. This information from the Vivitrol website is supplemented by a relatively short, and relatively mild, set of “complications” foreseen in some uses of the drug. Some forms of drug addiction, for example, and some liver diseases are contraindicated, meaning that use of Vivitrol by persons having these problems is risky business.

 

References

(1)  PBS/FRONTLINE, Does Treatment Work,http://www.pbs.org/wgbh/pages/frontline/shows/drugs/buyers/doitwork.html

(2)   The American Presidency Project, Richard Nixon:http://www.presidency.ucsb.edu/ws/index.php?pid=3782

(3)   Market Barriers to the Development of Naltrexone: Case studhttp://aspe.hhs.gov/health/reports/cocaine/4cases.htm

(4)   Schecter, A.J. 1980. The role of narcotic antagonists in the rehabilitation of opiate addicts: a review of naltrexone. American Journal of Drug and Alcohol Abuse, 7(1): 1-18.

(5)   Schecter, A.J., Friedman, J. and Grossman, D. 1974.  Clinical use of naltrexone (EN-1639A).

(6)  National Institute on Drug Abuse; Research Monograph Series, Integrating Behavioral Therapies With Medications in the Treatment of Drug Dependence, page 56

(7)  Schecter, A.J. 1980. The role of narcotic antagonists in the rehabilitation of opiate addicts: a review of naltrexone. American Journal of Drug and Alcohol Abuse, 7(1): 1-18.

(8)  Script’s 1993 EC pharmaceutical report: classify.oclc.org/classify

(9)  Schecter, A.J. 1980. The role of narcotic antagonists in the rehabilitation of opiate addicts: a review of naltrexone. American Journal of Drug and Alcohol Abuse, 7(1): 1-18.

(10)               O’Malley and colleagues (2) randomly assigned male and female alcoholics, who ….. Am J Psychiatry 1995; 152:613—615 

(11)                The Robert Wood Johnson Foundation: Cost, Lack of Insurance Coverage, Anti-Medication Bias Limit Scripts of Naltrexone for Alcoholism, 1996

(12)                The American Council on Alcoholism website;http://www.aca-usa.org/pharm2.htm

(13)                Script’s 1993 EC pharmaceutical report: classify.oclc.org/classify

(14)                The Pink Sheet: 1996

(15)                HUFFPost Healthy Living; Vivitrol: A Cure for Alcoholism?,Jan 25, 2008

(16)                (Goldstein 1997; Naltrexone…1997; O’Brien 1997; O’Malley 1998, Swift 1995).

(17)                 Sournia (1990) A history of alcoholism

.