WHEN I FIRST met him, it was hard to imagine that for almost a decade, Peter had been chief of police in one of Sweden’s major cities. After two weeks of having been listed as a missing person, he was found, disheveled and disoriented, in the rough streets behind the main train station in Denmark’s capital, Copenhagen. When he was first picked up, I read in the Danish transfer notes, his clothes were dirty and torn, his body was bruised, and he was unable to identify himself. He was finally able to produce a name, a telephone number, and an address after a couple of nights at Copenhagen’s large university hospital. By then he had been given IV fluids, had his wounds stitched and dressed, and been treated for severe alcohol withdrawal. His address, it turned out, was in a Swedish town just across the narrow strait that separates Denmark from Sweden. That town had an excellent hospital, so the plan was initially to transfer him there for whatever additional treatment that was needed. But the patient was not yet ready for anyone at home to find out about his predicament. He asked to be sent to any other hospital on the Swedish side that would take him. That was how he ended up on a gurney in front of me, in an exam room at St. Lars Psychiatric Hospital, a short drive south of his hometown.
It was my job as a resident to obtain the admission history. Early in my training, I had learned to follow a rigid routine when doing these interviews. Maybe it took a little longer to do it that way, but the reward was that in the end, I usually had a good picture, not only of the medical issues but also of the person. This time, however, as I was interviewing Peter for the intake chart, I could not figure out what kind of police officer this was. Then as now, I knew little about police work. But through a friend who was in law school, I knew that there were two very different career paths in the force. One was through the police academy, patrolling the streets, and perhaps making sergeant with time. The other was through law school, followed by a highly competitive police chief program that included basic police training and patrolling, all eight months of it, but recruited a very different type of person, with very different career prospects. The thing was, Peter didn’t fit any of those categories. Over the next several days and a series of conversations that followed, it became clear why. My patient really was an unusual person. After a couple of years in the merchant marine following high school, he had first attended the police academy and started out as a regular cop on the beat. Along the way he had decided to obtain a law degree through night school, the first person ever to attend university in his family. He had graduated with top grades, despite working and attending school while also raising two sons together with his wife, an equally hardworking ambulance nurse. After that he became chief in record time.
Before he was discharged from the hospital, I had a chance to meet Peter’s family, his deputy, the chair of the police board, and a few of his trusted colleagues. It was clear from talking to them that my patient was indeed an unusually capable person. Yet it was also clear that this was a person with rather severe alcohol addiction, so there were a few issues to sort through. Some were routine. Both the boys were still minors. Could we be sure that this was not a negligent or perhaps even abusive parent? As we all know, being a respected citizen is no guarantee against that. Was there a need to get child protection services involved? What about driving? Other questions, although less frequently encountered, were still standard. Sweden has highly restrictive gun laws, and with that, one of the lowest rates in the world of injuries caused by firearms. We would like to keep it that way. So a permit to own and carry a gun certainly had to be reevaluated in a person with an out-of-control addiction. But in the end, the job situation was the most unique and challenging issue. Could Peter really be trusted with commanding a sizable police force?
As we tried to gather information that would help with all these assessments, none of it really made sense. It was as if we were talking about two different people: the patient found behind the train station and the police chief. Everyone I met, superiors, colleagues, and subordinates alike, spoke of Peter as a hardworking, reliable, unusually conscientious person, equipped with excellent judgment. He never missed a day’s work and was seen as a role model by his colleagues. Words that kept coming up were “unassuming,” “caring,” “a natural leader.” In a job that frequently required difficult decisions, he seemed to have a rare gift for bringing people together, making sure everyone was heard, and then doing what needed to be done. And it seemed he somehow was able to do all that in a way that won respect even from those who disagreed. When I talked to his wife, she cried and spoke of him with unqualified love and trust. She seemed genuinely shocked by what had happened. His sons seemed to adore him and kept asking me if dad would get well soon.
What on earth was wrong?
In a way, it was actually quite simple. But let’s start from the beginning. Peter grew up as the oldest son in a reasonably thriving blue-collar family, unremarkable except perhaps for their Pentecostal denomination. Because of his parents’ religious affiliation, he did not encounter alcohol in the first eighteen years of his life. As far as he knew, no particular diseases ran in the family, and his two little brothers had done well in life. An average student and a better athlete, he went to sea, he said, because he had always wanted to experience the world beyond his small village on the plains of southern Sweden. Onboard it did not take long before he experienced alcohol for the first time. To his surprise, he found that it gave him an intense pleasure. He also discovered that he tolerated it better than most of his shipmates did. After a couple of years, however, he also noticed that the quantities he ended up drinking kept increasing, and he became concerned. He did not have any withdrawal symptoms, mind you. But even though he felt physically fine and ready for the next day’s work, a lot of times he was unable to remember what had happened the night before.
An ugly street fight during which knives were flashed became a turning point. After that scare Peter went ashore, vowed never to drink again, and applied to the police academy. In secret he read every book on alcoholism and its management he could get his hands on. He learned the crucial habit of saying “no, thanks” when drinks were offered. In the end he decided to come out of the closet and joined a local Alcoholics Anonymous (AA) group. It was a step considered a bit unusual given his by then close to eight years of sobriety. It served him well, though. After a few years most of his friends and colleagues had forgotten his openly disclosed alcoholism or had come to regard it as something of the past. But along the way they also learned not to question his soft drinks at parties. And if they ever forgot, his quiet “no, thanks” did not require an explanation. “Ah, that’s right. You are in AA.”
And then there was an intense two-week course for police officials from all over the country. To celebrate its completion, the whole group took a short dinner cruise to Denmark. Onboard the ferry, good Danish food was served, together with cheap, tax-exempt alcohol. This was a group of people Peter did not know well, and they did not know him. When he was offered a drink, he told me, he could not in the moment find in his arsenal a response that would allow him to decline. After that first drink there was no going back and saying that, in fact, he did not drink. Of course, when we revisited this chain of events a couple of conversations later,
1 an additional reason emerged. That first drink had felt amazingly good. Over the years he had forgotten just
how good. At the same time, it seemed entirely innocent. He was in control, among people he could trust. He took another one.
After that he did not stop for the better part of the two weeks it took before a Danish police patrol found him behind the railway station, beaten bloody.
Peter’s story illustrates a fundamental tenet of addiction medicine. Remember, addiction is a chronic, relapsing illness. Anyone can stop taking drugs with relative ease. In fact, people with addiction do it all the time. In contrast, staying sober and eliminating or at least minimizing relapse in the long run is a tremendous challenge. To successfully treat addiction, we need to understand what triggers relapse, what mechanisms are involved when it happens, and how we can intervene in those mechanisms to prevent relapse. So here comes critical lesson number one: reexposing the brain of an addicted person to a small amount of drug is one of the most powerful triggers for relapse. The phenomenon, called priming, is simply striking in countless clinical histories. As the Big Book of Alcoholics Anonymous wisely teaches, “the real alcoholic does not have a defense against the first drink.”
The priming phenomenon has in recent years been possible to replicate in the laboratory. Doing so has allowed scientists to map out brain circuitry and molecular signals that are involved when a priming dose of drug leads someone to resume drug seeking and taking. This is a good place to introduce what has almost become a standard model of relapse in basic science laboratories around the world. Introducing this model will nicely show how basic and clinical science are coming together in the field of addiction research.
The basic principle of the relapse model is first to train an animal so that it learns to self-administer an addictive drug. This, as already discussed, is typically done by allowing it to press a lever that delivers the drug. But in the relapse model, once the animal has learned to lever press at stable rates, drug delivery stops. Pressing the lever no longer has any foreseeable consequences. If daily sessions are run under these new conditions, animals will press the lever less and less, until the behavior is almost entirely “extinguished.” Extinction usually takes a week or two, but in the end, the rates of lever pressing decline to what they were before the drug was offered. One might be tempted to think that this is a boring, passive process of forgetting. Maybe the memory of self-administration has just faded away? It hasn’t. Under the surface, the old memory trace is still there, dormant, but ready to kick in on a moment’s notice. One powerful way to reveal it is to give the animal a small, priming dose of drug. The animal will then run back to the lever that used to deliver the drug and resume pressing, at rates similar to those that were observed when drug was still available. This model is commonly called reinstatement of drug seeking. Originally developed in the late 1980s by Jane Stewart of Concordia University in Montreal and her student at the time, Harriet de Wit,
2 it has perhaps most successfully been used to understand relapse by the research group of another Stewart trainee. In 2006 Yavin Shaham of the National Institute on Drug Abuse received the Jacob P. Waletzky Memorial Award from the Society for Neuroscience for these contributions.
3Reinstatement occurs in response to priming doses of drug, and also, as I will discuss in coming chapters, in response to other stimuli known to trigger relapse in addicted patients.
4 It seems that once drug seeking and self-administration have become established, the brain processes that underlie them never fully go away. In that sense there may be a degree of truth to the statement “once an addict, always an addict.” This is a disturbing contention, but it does seem to be supported by the laboratory data. For instance, initial training to establish self-administration takes a while and requires in the case of alcohol at least some clever manipulations before stable rates of lever pressing are achieved. Yet after extinction, stimuli that trigger relapse in patients make experimental animals resume pressing the lever that used to deliver the drug with no delay. A memory trace of the behavior seems to be stored somewhere, ready to be reactivated. In fact, we can reveal that stored trace. If we inactivate a particular part of the frontal lobe, lever pressing in pursuit of drug will reemerge in the absence of any meaningful trigger.
5 Whatever memory trace or behavioral program that was established for self-administration to occur must have remained in place, albeit suppressed and therefore inactive. Rather than representing a passive fading away and reverting to the original, drug-naïve state, extinction seems to have been an active process that superimposed new learning onto previously learned behavior of self-administration and suppressed it.
6Ability to block relapse induced by priming is of critical clinical importance. I will discuss addiction medications in considerable detail in coming chapters. But I have already mentioned Chuck O’Brien, who together with his team discovered naltrexone as a treatment for alcoholism in the early 1990s, a discovery for which he received the Jellinek Memorial Award in 2012. The now classical study from 1992 that first established the efficacy of naltrexone
7 might never have become the groundbreaking discovery it turned into had Chuck not as a clinician understood the relationship between priming and relapse. To appreciate this, one has to know some things about choices facing an investigator when designing a study to evaluate a new alcoholism treatment. One of the most important choices is what outcome to use in determining whether the medication works. Although this may sound trivial, it isn’t. A typical research study goes on for three or perhaps six months. In contrast, most of the important things we would like to improve in the lives of people with addictive disorders, such as medical complications and disruption of family life, happen on a time scale of years to decades. So in designing a study, we have to pick something that we can measure in the limited timeframe available to us, but that at the same time can tell us something about the longer-term outcomes in real life. With alcohol, then as now, total abstinence was the only treatment outcome thought to be relevant. Importantly, that was for a long time also the position of the U.S. Food and Drug Administration. Yet it is clear that relapse to heavy drinking is what causes harm, not consuming the occasional drink or two.
Now, under most clinical conditions, that distinction does not make a whole lot of a difference in a patient with alcoholism, simply because the latter most of the time will lead to the former. So I hasten to say that I do not advise anyone who has developed alcoholism to attempt to achieve controlled drinking on his or her own.
8 But what if there were a medication that prevented the progression from a priming dose of alcohol, or a “slip,” to relapse to heavy drinking? Initial clinical observations seemed to indicate that naltrexone might do just that. So that was what the University of Pennsylvania team decided to test in a controlled study. But the effect of naltrexone would have escaped discovery had the study team chosen the more conventional outcome measure—ability to produce abstinence.
As an aside, two decades later, a medication that is a cousin of naltrexone, nalmefene, has just demonstrated its ability to reduce relapse to heavy drinking. Based on these data, the European Medicines Agency has now approved nalmefene for treatment. What is noteworthy is the intended use. The company that markets nalmefene sought approval for “targeted use,” which means specifically to block the progression from light, controlled drinking to relapse and heavy consumption. When patients know that they might soon find themselves in situations of increased risk for priming-induced relapse, such as onboard a ferryboat to Copenhagen, they will soon be able to use nalmefene as a pretreatment. Had Peter had access to this medication, he might have avoided the near-death experience that led him to the streets behind Copenhagen’s station.
Fortunately, Peter seemed to do well even in the absence of this tool. For the close to five years that I continued, on and off, to work at the psychiatric hospital and kept a mailbox there, he sent me Christmas cards. It was in one of those he mentioned a conversation with his aging father. Only in the course of that conversation did he learn that, as a young man, his father had almost gone under from alcoholism. He had turned to the Pentecostal Church and absolutism literally to be saved.
Peter was atypical in many ways. The ability to stay free from relapse for so many years is in itself unusual in more severe cases of alcoholism, those I call “clinical,” or treatment seeking. The resources he had available to him, such as a great job, a wonderful family, character strength, social skills, and everything else that had made Peter so successful for all but two weeks of the time I got a glimpse of his life are, unfortunately, not typical of patients who seek treatment for addictive disorders. Perhaps most important, Peter had an unusual ability for self-reflection. And yet it was a very different patient who brought home to me what this whole thing with priming is about at some fundamental human level.
Lars was homeless, was severely alcohol addicted, and rarely managed to stay sober for more than a week. When I met him, in a visit that created little more than a snapshot along a long, drawn-out process of ever-worsening health, dental status, and social situation, I was still young and naïve. I looked in his chart, saw the lab values that indicated ongoing liver inflammation, and informed him about the dangers to his liver in my most serious doctor voice. He nodded but didn’t show much else of a reaction. It was clear that I was sharing old news. I didn’t get it. He knew his liver was well on its way to cirrhosis. This is a condition that in the absence of a liver transplant invariably leads to a painful death, or rather one that involves literally itching to death, which is worse. And yet he not only drank but drank enormous quantities of moonshine.
I tried to challenge him to explain how this could happen. He shook his head. “You don’t understand, Doc. I just drink a beer. After that, a bright light is on in my head. Once that happens, I am helpless.” It is true, I did not understand. I had never in my life experienced anything that powerful. But his drinking buddies did understand, all right. These were guys among whom money wasn’t exactly plentiful. Buying each other drinks wasn’t common. My patient never had any money at all, so it was first a mystery to me how, time after time, he could find himself at a restaurant table, drinking beer that even in those days didn’t cost less than $10 a pint with all those Swedish taxes. More in-depth questioning revealed the secret. My patient may not have had any money, but he did have a contact where cheap moonshine could be bought. He wouldn’t give up that contact to anyone, for fear of losing it. The bootlegger didn’t care much for visits from people he did not know, who might be plainclothes police officers. But my patient’s drinking buddies had figured out that if they bought him a beer or two, just enough to turn on that bright light inside his head, nothing could stop him from seeking out his supplier and coming back with a large plastic container of booze. The return on investment was clearly worth it. They were happy to pay, every time.
It is clear that these guys knew a lot more about priming-induced reinstatement than I did in those days. They were effectively able to use their empirical knowledge of the phenomenon to achieve their objectives. This was almost thirty years ago, in 1985. Incidentally, it preceded the publication of the seminal animal model papers on priming-induced reinstatement by several years. I have been working hard to catch up ever since, and so has much of the field.