Why aren’t people using the drug for alcohol dependence developed with the help of rats?
Medications for alcohol dependence were developed in Finland using rats. Very few people are prescribed them, however.
American psychologist David Sinclair first arrived in Finland on a snowy day in May 1972. He had recently received his PhD and had read in the journal Science that a research facility in Helsinki was using rats to study alcohol.
So advanced was the research at the laboratory, which was owned and funded by Alko, a government-owned alcohol distribution company, that Sinclair was willing to join the team there, even without the certainty of a salary.
In particular, Sinclair wanted to work with the alcoholic rats, which had been bred for many generations. Research by Kalervo Eriksson, published in 1968 in Science, showed that the offspring of rats that were fond of drinking liquor were also inclined to prefer liquor. The offspring of abstinent rats, however, did not prefer alcohol.
This discovery led Sinclair to question whether the premise for treating alcohol addiction using the popular “one day at a time” mantra was wrong. His research indicated a person with an addiction to alcohol would find it increasingly difficult over time to abstain from liquor.
Finland and the United States were similar in several ways. Post-Prohibition Finland held a moralistic view of alcohol. ‘Good’ people worked hard, practiced frugality and remained sober. For about three decades, those wishing to purchase alcohol had a personal card on which alcohol purchases were recorded. Alko’s representatives acted as detectives, searching for home drunkenness. Where there were no Alko stores, illicit alcohol production flourished.
People in Finland consumed less alcohol than the average European, but those who drank too much were considered troublemakers and were dealt with by the law. Those who abused alcohol were sent to labor in detox camps for weeks at a time.
Until something changed in America that was, at the time, miraculous.
Wilson, a stockbroker, had been drinking a couple of bottles of whiskey each day. At the time, there were no known treatments for addiction. His attempts to wean himself off the liquor included experimental medicine - an extract of henbane and deadly nightshade. The drugs caused strong hallucinations, but led Wilson to the conclusion that individuals are incapable of curing alcoholism on their own and need the help of a greater force.
Wilson was proof of his conclusion, and after leaving the hospital he never drank again. Instead, he began his own treatment program.
At the heart of the program was a 12-step staircase and teachings taken directly from an evangelical religious denomination. Prior to his hospitalization, he had taken part in the meetings of this sect.
The first step was: "We admitted we were powerless over alcohol – that our lives had become unmanageable."
Wilson wrote what later became known as “The Big Book.” The book lays out the tenets of Alcoholics Anonymous.
Once a person has recognized himself as a spiritually and mentally weak alcoholic, the path to a higher power and sobriety becomes possible.
The final step directed the newly sober to evangelize and share knowledge of the program: "Having had a spiritual awakening as a result of these steps, we tried to carry this message to alcoholics, and to practice these principles in all our affairs."
By 1948, Alcoholics Anonymous was being spread through Finland.
Alcohol itself, however, is a small molecule. Its simplicity allows it to adhere to almost any part of the body, making its study difficult. It was already known at the time that endorphins are released when drinking, attaching to the same synapses that convey the effects of heroin - the opioid receptors.
When drinking occurs, the opioid receptors trigger nerve impulses. These impulses race through nerve filaments, accelerating brain activity. The pleasure hormone dopamine and the neurological moderator gamma-aminobutyric acid are released. Secretion of glutamate, a neurostimulator, decreases.
The final result is a feeling of reduced inhibitions and progressive relaxation. This is the euphoric ascent of intoxication.
An addict can be likened to Pavlov’s dog. The dog salivates at the sound of a bell, and an addict produces more and more endorphins when they ingest alcohol.
The synapses affected by alcohol retain memories of the pleasant feeling and learn through reinforcement to react to progressively smaller stimuli. At the same time, excessive amounts of endorphins, dopamine, and gamma-aminobutyric acid are secreted by the brain. This creates a craving for alcohol that can lead to almost anything becoming a trigger for continued drinking.
Sinclair gave naltrexone, nalmefene and naloxone, three supposed opiate blockers previously used in the rehabilitation of heroin addicts, to the rats. The drugs bound to the receptors where the released endorphins were supposed to attach, preventing the euphoric feelings.
The alcoholic rats were given the drugs and drank the liquor they were served until they suddenly lost the taste for the alcohol.
Based on his research, Sinclair developed a new treatment regimen. The idea was that the drugs naltrexone and nalmefene work on the same principle - ingestion before the first drink so that the brain associates it with alcohol. As a result, patients need not exercise abstinence, and instead, lose the craving for alcohol.
Wilson’s Alcoholics Anonymous filled a void and groups spread rapidly. Public relations experts and public figures who were focused on temperance, such as John D. Rockefeller and Elizabeth Taylor, lobbied the public with the good news.
It did not matter that there was no scientific evidence on the efficacy of the AA. When Wilson first presented his ideas to the American Medical Association, the scientists laughed at them. After all, the idea is not much more than a peer chat. But the clinics seemed to help thousands of people.
AA commissioned scientific research to prove its effectiveness. But there were difficulties, since there were no written records of participants at the meetings.
Psychologist E. M. Jellinek sent surveys to 1,600 AA visitors in 1946 and received over 100 answers. But since women’s answers varied so greatly from men’s, the answers from women were excluded from the study.
Jellinek eventually concluded, based on the answers of 98 men, that alcoholism is analogous to a horseshoe: a disease beyond man’s control that progressively worsens until he finds himself at the bottom. When he understands he needs to sober up, he can begin an upward trajectory.
For AA, the study served as adequate evidence in spite of the lack of scientific value, and the 1955 edition of the Big Book contained a promise that 75 percent of those who participated in AA meetings would sober up. If one were to “try very hard” it would be enough.
The 12-step regimen was well established by the time the American Medical Association classified alcoholism as a disease in 1956.
Fifteen years later Harold Hughes, a former AA participant and Senator from Iowa, helped push through a law in Congress that would intensify the reduction of alcohol-related harm. Health insurance companies began covering the 12-step treatment and Congress heard testimony of the efficacy of AA from central organization figures including Wilson.
Soon, about 80 percent of alcohol treatment in the US was based on the 12-step model of treatment or one of its variations.
Some of AA’s variations made their way to Finland. The so-called mill treatment centers that were based on the Minnesota model began in Finland in the early 1980s.
The method, developed in 1949 at the Hazelden sanatorium in Minnesota, aims for complete abstinence like AA clubs, but is administered by medical professionals, former alcoholics and peer supporters.
The Minnesota model is popular in Sweden, but Sweden lacks a quasi-public system like the Finnish A-Clinic Foundation.
In Finland, those seeking the Minnesota model will only find it in private treatment facilities. Juha Kankkunen, Samuli Edelmann and Mikko Kuustonen have all given testimonials of how they left alcohol in their past with the help of periods of treatments there costing EUR 6,000.
Many of these clinics are staffed by “substance therapists” who are either recovered alcoholics or related to one, according to model guidelines. In Finland, there is no certified training for substance therapists and use of the title is not protected by Valvira. Only the Kalliola Settlement reports that every employee holds a diploma in social care or health education.
The efficacy of the mill treatment has not been studied extensively in Finland, but some clinics market themselves with claims of great success rates.
PhD research conducted at the at Kalliola clinic in Nurmijärvi estimates 14 percent of participants stayed sober for a full year after treatment.
The 2006 report was based on multiple studies by the Cochrane network made up of top international researchers. It failed to find any evidence that the 12-step model was effective, in spite of 70 years of the treatment’s existence to study.
Decades later, the commonly accepted model for alcohol dependence treatment options offers two choices: abstinence or out-of-control drinking.
Since doctors in Finland were once a part of the temperance movement, 28 percent of Finnish physicians continue to believe moderation is counterproductive to controlling alcohol addiction.
Science has been able to prove since the 1960s, however, that this is not the case. Without medication, only 20 percent of alcohol addicts achieve moderation. Nonetheless, it is possible.
It is estimated that there are about 200,000 people addicted to alcohol in Finland. Dependence is diagnosed by evaluating an individual’s control of his or her consumption and the importance of alcohol in their lives.
A much greater number of people drink at close to risk levels. One out of five Finns is estimated to drink risky levels of alcohol, based on the consumption limits of 24 servings or 7 servings in a session for men and 16 weekly or 5 servings in a session for women.
Addiction does not have to mean that a person stands in line for vodka early in the morning. About 70 percent of alcohol addicts hold regular jobs. For these people, the problem is only alcohol because their health, work and social life are still functioning adequately.
But few people seek treatment. In Finland, only about 10 percent of alcohol addicts receive any treatment. So public health care and the A-clinics see patients in the extreme stages of alcohol addiction, resulting in poor treatment results.
It is likely that the notion of complete abstinence to control drinking further raises the threshold for seeking treatment at the early stages of harmful drinking. At this point, one’s life is still under control and addiction is not highly advanced.
"It is not considered acceptable that someone does not want to give up alcohol completely. That someone says, ‘I need help, but I am not yet ripe for total abstinence,’" says Antti Holopainen, the Medical Director Emeritus of Järvenpää social hospital. Dr. Holopainen, who is now retired, prescribed naltrexone to his patients as soon as it was first available.
Treatment of alcohol addiction should be compared with obesity. If you are morbidly overweight, attaining a normal weight is not the primary objective. Instead, the focus is on mitigating the health risks. Some people will continue dieting until a normal weight is reached. Similarly, about a third of people using naltrexone or nalmefene eventually stop drinking alcohol completely.
Naltrexone was launched in the Finnish market in 1996, two years after the FDA approved the drug for the treatment of alcohol dependence in the United States.
In the US, naltrexone was prescribed primarily at a handful of clinics that catered to wealthier populations who would travel across the country in search of treatment. But suddenly in Finland, tens of thousands of prescriptions were issued.
Many hoped naltrexone would be a miracle drug.
When one takes the medication, one is able to drink, but the alcohol does not reinforce the addiction and cause the insatiable cravings. The side effects aren’t severe. Alcohol still enters the bloodstream, but the euphoria is gone, like loading up on a sugary drink.
One user of naltrexone reported after taking the medication at a party for the first time:
After two pints of beer, nothing. No sensation from the naltrexone, but the effect was noticeable. Instead of a mellow, talkative high there was restrained nodding and wandering about. The desire to drink more was gone, as was the craving. Instead of partying wildly into the morning hours, the user was among the first to go home before midnight.
Best of all, the user had no need to explain away a lack of drinking to other guests or reveal a drinking problem. It helped with recovery.
The surge in prescriptions led to disappointment.
Naltrexone has been proven to be undeniably effective, but not for everyone. It was not a flash of light or even a miracle.
"If your doctor gives a prescription and says, “Why don’t you try to reduce your drinking with this and come back in six months?” it is not likely to work. The effect of the drug would have to be really strong, and if it were, it would've already got the Nobel Prize," says the University of Helsinki professor of addiction medicine Hannu Alho, who is also a physician at a private clinic treating patients according to the Sinclair model. "But it is has a pretty good effect when it is prescribed properly and used properly."
For example, during a peer-reviewed clinical study in the mid-1990s at the hospital run by Holopainen, 78 percent of patients surveyed were able to reduce their weekly alcohol consumption to just over nine servings when using Sinclair’s method.
Similar results with naltrexone and nalmefene have been observed with Sinclair’s method. When the drugs were used with abstinence, however, no effect was discovered.
It is difficult to estimate how many people have benefited from naltrexone and nalmefene.
For example, in Finland there were 4,000 naltrexone packages sold in 2010. The drug is usually prescribed one package at a time, so the number of users can be estimated as the population of a small, rural community.
That same year Kela, the Finnish social security institution, only reimbursed 92 people for naltrexone. However, it is important to note that people must qualify for a special certificate in order to be reimbursed.
Further, reimbursement results in a permanent record of a person’s addiction to alcohol. This leads to fewer people seeking compensation for fear of being labelled an addict. Kela only reimburses 35 percent of the total cost to certificate holders.
Although Kela has slowly relaxed the policy and lengthened the certificate intervals from three to 12 months, Medical Director Emeritus Antti Holopainen considers the practice to be punitive.
"After all, there are no rational, sensible or scientific knowledge-based criteria for the policy. Neither doctors nor patients are treated this way for any other disease. This is purely an attitude problem within the bureaucracy, and it is offensive to both medical professional ethics and human dignity," Holopainen said.
Kela justifies the certificate requirement because the Pharmaceuticals Pricing Board has determined it to be part of a broader alcohol use disorder treatment therapy. If a regular prescription were enough to obtain naltrexone, there would be no way to enforce the requirement for additional therapy. It would also be costly for Kela if it were unable to associate value with therapeutic results. (Nalmefene costs about five Euro per tablet while naltrexone is a third of this price. However, the effect of naltrexone is said to be a third of the effective time for nalmefene.)
Professor Alho disagrees with this argument claiming the only purpose is an immediate cost saving. He says alcohol is responsible for 20 percent of Finland’s health care costs.
In Finland as a whole, only two percent of alcoholics receive medication therapy. More than two thirds of that number are prescribed disulfiram, better known as Antabuse. Antabuse is used to prevent alcohol use entirely.
"If drugs were fully reimbursed, or even non-prescription drugs, and people were to reduce risky consumption of alcohol by, say, 20 percent, then the savings derived thereby would easily cover the cost of drugs," Alho said.
Kela insists on therapy as a condition for reimbursement, but nalmefene has been shown in studies to work without it. Prescriptions accompanied by health guidance would be sufficient and this guidance could come from public health nurses and pharmacists. This would benefit those who are not currently seeking treatment for alcohol addiction.
Simo Seppelin, a substance abuse therapist and reformed alcoholic, opened a Minnesota-care clinic in Lapua in the early 1990s. He claims that not a single one of the patients in his facility has ever benefitted from naltrexone or nalmefene. He believes it is unrealistic to say that an alcoholic could ever have an occasional drink. He says naltrexone is an enabling drug that suits alcoholics well since they are allowed to drink, but maintains “an alcoholic can never drink.”
At the Kalliola treatment facility in Nurmijärvi, director Jyrki Lausvaara expresses his opinion more diplomatically. He admits some patients may be helped by medication, but the objective of his facility is abstinence. Patients at the facility are not prescribed drugs.
Since 2006, the Hazelden Center in Minnesota - the origin of the treatment used in Lapua and Nurmijärvi - has been prescribing naltrexone.
In the mid-1990s, the position of the Salmisaari biomedical laboratory became precarious.
EU monopoly regulations forced Alko to separate its marketing and manufacturing operations. The sociological research was transferred to the Institute of Social Affairs. Health and the biomedical research, which worked with the rats, was transferred to the National Public Health Institute. The reorganization left the laboratory with a significantly smaller budget.
By the mid-2000s, the government began planning a merger of the research institutes. Kalervo Kiianmaa, Head of the Laboratory, had worked with Sinclair from the beginning, and hoped the social science and biomedical research would be brought back together under the same roof.
Unfortunately, that did not happen. The Institute for Health and Welfare, THL, quickly made it clear that maintaining research laboratories was too expensive.
"The problem is that it takes twenty years from the stage when the study starts, to the point where the results can be put into practice," Kiianmaa said. "Maybe it's too much for decision-makers. They need the information right away. At some point, someone said to me that we have these problems now and they should be addressed now. There is no time here to explore."
Kiianmaa recalls Sinclair as the type of scientist who had radical ideas.
"Rarely in the scientific world, are things in the hands of one man. But that is the spirit of the time. David's fingers really were all over the cutting edge."
When Kiianmaa retired in 2009, the alcoholic rats were given to the University of Helsinki.
David Sinclair passed away in April at the age of 72.
The Big Book says:
"There are such unfortunates. They are not at fault; they seem to have been born that way. They are naturally incapable of grasping and developing a manner of living which demands rigorous honesty."
Interviewees for this article include: Current chief physician Kaarlo Simojoki of the A-Clinic Foundation, his predecessor, specialist in psychiatry Pekka Heinälä and specialist in general medicine Esti Laaksonen, who defended at the beginning of June her doctoral thesis on factors affecting alcohol addiction treatment outcome.