SEPT/OCT 2008
Volume 14 - No. 3
SRNT Newsletter
SEPTEMBER/OCTOBER 2008, Volume 14, Number 3
In Memoriam Ove Fernö - The Inventor of NRT and The Past, Present, and Future of NRT
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Ove Fernö, the inventor of nicotine replacement (NR), died at the age of 91 years in October 2007 in Helsingborg, Sweden. He was born in Gothenburg 1916 and was trained as an organic chemist at the University of Lund, Lund, Sweden. During the late 1960s and 70s he was responsible for the development of the first NR product _ a chewing gum. Tens of millions of smokers have used nicotine gum to aid their cessation attempts.
Conceptualization
In 1967, two researchers- Drs Stefan Lichtneckert and Claes Lundgren from the University of
Lund, in Lund, Sweden were interested in studying the effects of different atmospheric pressure on
human physiology. Therefore, they began studying submarine crews and made an observation that some
of the crew members used a smoke-free tobacco product called snus. At that time the use of snus
was relatively rare in young males. Snus use was largely confined to the elderly, working class men
living in the countryside. When asked why they used snus, the crew members referred to the
complete smoking ban in submarines and that said that snus helped them to abstain from cigarettes.
Upon hearing this story, Drs Lichtneckert and Lundgren wrote a letter to a nearby pharmaceutical
company, AB Leo, in December 1967 and suggested that pure nicotine could be used to aid in
smoking cessation. The letter appeared on the desk of Dr Ove Fernö, the director of research, who
himself was a heavy smoker and whose wife disapproved of his smoking. He immediately saw the
beauty and the potential of using a "clean nicotine" administration form as a means to aid quitting
smoking. This thinking took place at a time when there was very little understanding about the role of
nicotine in tobacco use. The difficulties in giving up smoking were recognized but they were ascribed to
the very strong habit formation. The work of Drs Murry Jarvik and Michael Russell had not had
an impact at the time. The critical question for Drs Lichtneckert and Lundgren was how
smokefree tobacco could make it easier to forego the dependence associated with cigarette smoking.
Eventually, they realized that the common denominator could be nicotine.
Perhaps the doctors also had some knowledge from Dr. Börje Ejerup´s insights from Stockholm. Dr. Ejerup was using nicotine to diagnose heart failure by closely monitoring the time it took from a nicotine injection to a cough response. He found that many patients lost interest in smoking for some time. (A long time to the cough reflex was an indicator of heart failure). As a consequence Dr, Ejrup started to help smokers quit with the help of injected nicotine but later he turned to the presumably safer lobeline.
Dr Fernö did not have an easy task promoting the idea within the company. He was approaching a sophisticated pharmaceutical company- one that was developing anti-cancer drugs, among other things-to embark on a project with a new drug. This new drug was nicotine, which was regarded as a dangerous toxin and a pesticide, and he was proposing a new indication _ an aid to smoking cessation, and a new form of administration- a chewing gum, both of which were unheard of in the pharmaceutical industry at the time.
It is probably fair to say that without Dr Fernö's determination and dedication, possibly aided by his own need to stop smoking, and the possibility to use some of the company's resources at his discretion, nicotine replacement (NR) would not have been developed in Helsingborg, Sweden in the late sixties and early seventies. Furthermore, the project was also evaluated and disapproved of by external experts forming AB LEO´s scientific advisory board. One of them chaired a Nobel Prize committee, so the opposition was formidable.
Early development
After trying several administration forms (e.g., aerosol) the gum was chosen, mainly for
safety reasons. Chewing was required to release nicotine from the gum base and thus a self-control
element was added to minimize risk of intoxication. In addition, it was eventually discovered that when
large doses of nicotine in the form of gum (10 pieces -4mg) were swallowed, only a few milligrams
ended up in the blood circulation. At that time physicians knew little about nicotine except that it had
the potential to kill animals when they experimented with it in medical school.
When the gum was first tried the nicotine was released too fast. In order to slow down the release, Dr Fernö discovered that an ion exchanger could be incorporated in the gum to bind and stabilize nicotine. When chewing this complex the cations in the saliva would enter the chewing gum base and exchange with nicotine so that it came out in the oral cavity as nicotinium ions. Later, when a method was developed to determine levels of nicotine in the blood, Dr. Fernö discovered that little nicotine was being absorbed from the gum. He soon realized that a buffer had to be added to the gum to improve absorption.
Around 1973 Professor Michael Russell got interested in the idea of using nicotine in smoking cessation after having tried behavioral methods without much success. Professor Russell did numerous studies with the nicotine gum and he and Dr Fernö came to be personal friends. The impact of the interest and support that Professor Russell gave to the early development of the project can hardly be overestimated. In 1976, Russell wrote to Dr. Fernö: " I believe that your chewing gum represents a major breakthrough for the treatment of heavy smokers".
In the United States, Dr. Murray Jarvik and Dr. Nina Schneider were the first to experiment with the gum; they became great ambassadors and conducted many important studies. The nicotine gum was first presented at the world conference on Smoking and Health in New York in 1975.
The First Clinical Trials
At the nearby Medical School at the University of Lund there was a Smoking Cessation
Clinic headed by Professor Westling, who began to liberally use gum for the Clinic's patients in 1970.
The experience from this uncontrolled clinical use became important for various reformulations of the
gum and gave support to later discussions on licensing with various medical authorities. Westling´s
group also carried out a short term placebo controlled study where smokers rated active gum as more
helpful than the placebo. The randomized placebo controlled trials in smoking cessation came later. The
most important may have been the studies conducted by Puska in 1979 with the 4mg strength, and
later Fagerström, Jarvis et al, and Christen et al, which tested the 2mg strength. Tonnesen also
documented the superior efficacy of the 4mg strength vs. the 2mg strength in two trials among high dependent
smokers.
The First Marketing Authorizations
In the home market of Sweden there was a discussion as to whether the Food or the
Medicine´s Agency should regulate the marketing of nicotine gum. Gum was considered food, but nicotine was
not an approved food additive. After several years, during which the Swedish Tobacco Monopoly
showed an interest, the government finally decided that the gum should be regulated as a medicine. This
discussion between the two authorities postponed the marketing approval until 1981. Meanwhile it was
first approved in Switzerland in 1978, Canada followed in 1979, and the UK in 1980. It was by no
means easy and straight forward to obtain marketing approval for the nicotine gum. For example, it was
not understood by regulators and many scientists that one cigarette contained 3-4 times more nicotine
than a 4 mg piece of gum. With the exception of a small pack size in Switzerland, it was never
seriously discussed that the nicotine gum could be sold without a physician's prescription. Use under a
physician's control was considered necessary because the physician could give the counseling needed for the
gum to be effective. The anxiety surrounding the nicotine gum was particularly strong in the USA and
Germany, and later in Japan. Is it a coincidence that these countries have also opposed the WHO´s
World Convention for Tobacco Control that has been negotiated during the last 2 years? In the U.S. a
subsidiary of Dow Chemical, Merrell Dow, had been appointed distributor of the nicotine gum in the
early eighties. During the pre-filing negotiations with the FDA it was understood that the chance to get
approval for the 4 mg strength was small.
In an FDA advisory committee meeting hearing in 1983, at which the authors were present, there was a lot of controversy surrounding the gum´s possible approval. It is our understanding that a deal was negotiated between the sponsor-Merrell Dow- and the FDA such that rather than risking a total rejection the sponsor agreed to withdraw the 4 mg strength from the application to ease the way for the 2 mg formulation to be approved. Unofficially, a responsible officer at FDA stated that "an approval of the 4 mg will be over my dead body". The same resistance seemed to have occurred later in France when an OTC license was discussed. Some of the behavioural scientists and clinicians present at the FDA advisory committee meeting were not very supportive due to the fact that they thought nicotine played a much smaller role than behavioral dependence.In the US the 2 mg strength was finally receiving marketing approval in 1984 and the 4 mg received approval after additional clinical studies in 1991.
The nasal spray and other administration forms.
Along with the possibility to determine low levels of nicotine in the blood plasma, which
Professor Russell was able to do with the help of Colin Feyerabent in 1972, it became evident that a gum
could not deliver nicotine to the same extent that a cigarette could do in terms of speed (T max) and dose
(C max and AUC). Simultaneously, Rolf Lundgren and Sven-Erik Falkman at LEO developed a method
to determine nicotine in plasma. As a way to remedy the relatively slow absorption of nicotine from
the gum, Professor Russell and Dr. Fernö agreed to investigate the absorption of nicotine through the
nasal mucosa in 1979. There were some rumours that this new form of absorption was investigated
because Mrs. Fernö now disapproved of Ove´s continued chewing. Initially a 2mg dose was tested (1mg in
each nostril) but because of local side effects it was reduced to 1 mg/dose with some but not a
considerable reduction in side effects. Russell's group made most of the clinical development with the
spray and advocated that in a smoker's clinic with heavy dependent smokers it was the most effective
tool. The nasal spray was first approved in Iceland in 1994 followed by Sweden, Denmark, UK,
New Zealand, Belgium and Ireland in the same year.
In the U.S., the FDA was very ambivalent about an approval. Abuse liability and long term use were causes of concern. Finally, after having considered classifying it as a controlled substance, the FDA approved the nicotine nasal spray as a regular prescription medicine in 1996. These deliberations clearly showed the inequalities between the regulatory issues facing tobacco dependence treatment products and the almost total freedom to market the tobacco products causing the disease _ the cigarette. Thereafter, a number of "me-too" products in terms of nicotine delivery were developed by different pharmaceutical companies. In order to give options to those not keen to chew and otherwise meet the preferences among the smokers, Pharmacia developed a buccal/oral inhaler and a sublingual tablet. These two preparations deliver nicotine roughly with the same characteristics as the 2 mg gum and the efficacy is also the same.
Use of Nicotine Replacement
Today, NR is marketed in some 70 countries and it sells for well over a billion U.S. dollars and
the market is increasing. The largest market by far is the U.S., followed by the UK, and the per
capita use is highest in Sweden, where an average smoker spends $23 per year on NR. The NR
product with the highest sales is the gum, followed by patch. Major countries with very low penetration
are Germany, Japan and Italy.
Deregulation of NR Products
During the last 15 years or so we have seen the medicine regulatory authorities relaxing their
attitude towards nicotine and the expressed safety concerns. When NR products were first approved
for marketing, the authorities requested many restrictions that became obstacles to an effective
treatment of smokers. Examples of such restrictions are
- not allowing high strengths
- requiring prescriptions and counseling from physicians (this rarely happened and was practically unfeasible)
- only allowing short term use
- forbidding combined use of NR products despite evidence of increased efficacy and adequate safety,
- contraindicating products to individuals with high risk medical problems (e.g. recent sufferers of myocardial infarction) despite most of such patients go back to smoking and
- not allowing smokers who could not quit abruptly to use NR to quit gradually.
Allowing NR to be sold over the counter without a prescription (OTC) was the first area in which de-regulation started. Among the first countries to switch from prescription only availability to OTC was Finland 1988, Denmark 1989 and UK 1991. In making the gum more available to smokers FDA actually showed great courage as OTC status also means sales outside the pharmacies. Whether the organization or individual assessors such as Dr Spyker should be credited we do not know. We do remember a pre-filing meeting that the sponsor had with the FDA represented by, among others, Dr. Spyker. The sponsor asked for a switch to the 2mg strength. In the meeting Dr. Spyker directly asks first author (KF) "What do you think, Dr. Fagerström, should not also the 4mg be available since it is the more effective strength"? Being in the meeting on behalf of the sponsor that had only asked for a 2mg switch, I felt, for a tenth of a second, caught in ambivalence, but fortunately KF said without hesitation: "Yes definitively". This resulted in a request from Dr. Spyker to the sponsor to test both strengths in OTC simulating studies. We think these tests both resulted in both strengths becoming OTC in the US at the same time. However, there were times when the regulatory authorities seemed to be ahead of the manufacturing company. The UK authority asked Pharmacia in the mid 1980 ties if the company would consider a prescription free status for the nicotine gum. Pharmacia´s response was that it was too early to consider such an option.
In some countries it took a long time to achieve OTC status. For example in Japan in took until 2001. In Germany the authority was even trying to bring OTC gum back on prescription in 1996 after having approved it for OTC sales. A more recent development in terms of availability is the move from a pharmacy only license to even greater availability (general sales). This started in Denmark 2000 and has since happened in United Kingdom, Canada and Norway.
An additional kind of deregulation has taken place on the indicated use of NR products. Up to 1997 the only approved indication was as an aid to smoking cessation. However, after substantial research on smoking reduction in smokers unwilling to quit, largely sponsored by Pharmacia Inc., reduced smoking as an additional indication was granted in Denmark 1997 and later in Iceland, Brazil, Austria, Belgium, New Zealand and Malaysia..
Another closely related indication is concurrent use of NR with smoking (e.g. Temporary Abstinence), when smokers can not smoke due to restrictions. This was first approved in Norway and thereafter such use has been licensed in Austria, Brazil, Portugal, Colombia, Venezuela, New Zealand and France. More recently NR has also been indicated for smokers attempting to Reduce to Quit. Ove Fernö foresaw the development towards increased availability. He realized that in order to fully exploit the utility of NR it should not be less freely available than cigarettes. Unfortunately, we are not to that point yet.
The future of NR.
We would like to think that the following thoughts and remarks on the future development of NR in
the society were very much shared by Mr Fernö; he served as a teacher for us. There are few if
any examples of cultures entirely free of recreational drugs. Aldous Huxley wrote "That humanity at
large will ever be able to dispense with Artificial Paradises seems very unlikely. Most men and women
lead lives at the worst so painful, at the best so monotonous, poor and limited that the urge to escape,
the longing to transcend themselves if only for a few moments, is and has always been one of the
principal appetites of the soul"(9).
However, drugs can be more or less accepted by societies. It seems that the attitudes towards drugs have to do with their psychotoxicity. The more it alters the conscience and normal behavior of the user, the more condemned the drug seems to be. For example, drugs that make their consumers hallucinate, become violent or become so euphoric that its users lose interest in normal duties and responsibilities are a threat to others and the whole society. Caffeine and nicotine seem not to have been condemned, although there are some exceptions, probably because of their mild psychotoxicity. I assume that there are many people that do not even regard coffee, tea or tobacco as containing drugs. Today, tobacco smoking is very much condemned in many countries but that is, I suppose, because of the hazardous health effects it has on the smoker and those smoking passively. Any abnormal behavior in a smoker is hard if not impossible to observe. Therefore it seems to me that if the "enjoyment" of nicotine could be made safe there is no more reason to restrict nicotine than caffeine. In comparison with alcohol, it seems that nicotine has a much more benign psychotoxicity although possibly a stronger dependence potential, at least when the vehicle is tobacco. But what if the vehicle is something else that delivers clean nicotine? Clean nicotine is available today outside the pharmacy with no signs of primary addiction. Our wish is that the NR products should be on the very same shelf as the cigarettes. After some time I hope the world is ready to move the cigarettes away and let only the NR be visible. In this way the smokers are exposed to the products which we think will increase their curiosity and lower the barriers for trying them. For NR products to be available on the same shelf as cigarettes in a free market, some form of licence to sell cigarettes may be needed where availability of NR can be mandated.
Let us make an assumption that coffee was smoked and inhaled in a certain culture. If we further assume that pyrolisis of coffee beans was producing the same and equally harmful products as smoking tobacco does, would we then outlaw coffee use if we knew of no safer alternative. However, if we knew that coffee could be "enjoyed" safely if brewed, I assume we would accept and welcome brewed coffee. With pure nicotine we are in a situation today where many believe it is far from safe and 70 % of EU smokers think it causes lung cancer. However, professionals and laymen are gradually becoming more enlightened and in some future, at least in democracies that care for their citizen's health, it is hard to see that cigarettes will be the acceptable source for nicotine. As Prof. Russell put it 1991 "It is argued that it is not so much the efficacy of a new nicotine delivery systems as temporary aids to cessation, but their potential as long-term alternatives to tobacco, that makes the virtual elimination of tobacco a realistic future target".
We can certainly see that smoking has a lot of inherent appeal with its taste, smell, visual stimuli and fast nicotine delivery- so it will most likely never disappear completely. But if people could use clean nicotine most of the time and smoke a cigarette after the "Sunday dinner", we think we have come a long way in reducing its harm. Instead of being the number one risk factor for death and disease, such a new use pattern would probably be difficult to document as a risk factor at all with a possible exception for the sequels of smoking during pregnancy.
Who is going to provide the new products- the reformed tobacco industry, the pharmaceutical industry or a new type of industry? I would personally like to see the pharmaceutical industry providing the products but realize that it is unlikely; pharmaceutical companies would most likely not want to be associated with providing nicotine as a substitute for tobacco that could also involve primary addiction in adolescents. Will the tobacco industry then, which largely is synonymous with the cigarette industry, risk its cigarette business by providing clean nicotine? This is probable if society makes it clear enough that it is not ready to accept cigarette smoking as a normal behavior. We are already seeing products entering the U.S. market that are at least alternative nicotine systems, if not properly clean nicotine delivery systems. Sweden is the country that has gone the furthest in this direction where almost 50% of all nicotine consumed comes from unburned sources. However, most of it comes from smokefree tobacco and only a small percent comes from clean nicotine.
How nicotine will be consumed in the future also has to do with how it will be regulated. So far, all societies, without exception, have favored the most contaminated and hazardous system. The cigarette has been virtually unregulated while the pure nicotine products to help smokers quit smoking cigarettes were difficult to register at all. This situation is gradually changing but a regulatory framework where one agency has the power to regulate all nicotine containing products would be very instrumental in guaranteeing the best public health impact. This is also something that most scientists and advocates seem to agree on, and large and reputable organizations and bodies like the British Royal College of Physicians and The House of Commons in the UK have recently petitioned its health department to move in that direction.
We believe and hope that nicotine will one day be consumed in its pure form. It would mean that we have largely eliminated a giant risk factor for death and disease. Some nicotine addiction would of course still be prevailing- a price that it seems we must be ready to pay, at least in the short term. Hopefully we could at some later stage also get rid of the addiction, which would need a regulation on the amount of nicotine that the products were allowed to deliver. Such a profound change in behavior could undoubtedly take a long time. The concept of "culture" is key here. We are dealing with something which has deep cultural roots and will require at least one if not several generations to change. Whatever time it takes, we are convinced that something very important for the benefit of mankind happened in southern Sweden in the late 1960 ties.
Ove Fernö´s thinking and foresight , and perhaps personal circumstances, made him a decisive driver in the development of Nicotine Replacement. His work has helped countless smokers to break the dependence. But he was also a great man to spend an evening with, usually over a glass of beer, to speculate about the future of NT and other matters of importance, very often philosophy. His originality and individuality showed up early; after graduation from high school he biked from Sweden to Spain and back in order to learn languages, cultures and countries. He is greatly missed.