What biology tells us about addiction

Second of a series on opioids

To understand how opioids take hold of humans and create addicts out of us, it’s important to see how they interact with our bodies and the cells that construct them. Most of the work needed to keep cells and bodies alive is done by proteins: the enzymes that drive chemical reactions, the collagen in bone and tendons, and the hemoglobin to transport oxygen are all proteins, which are chains of smaller subunits called amino acids. A particular protein, called the Mu opioid receptor, crosses the membrane of neurons and exists partly inside neurons and partly outside the cell. The outside part folds into a pocket that fits the shape of morphine and other opioids.  Its function is to detect opioids and signal neurons in the reward centers of our brains that they should respond to them. 

Without the Mu receptor, nerve cells throughout the brain and spinal cord would not bind opioids, and morphine would not help pain, cause euphoria or stop breathing. The fragment of Mu that pokes out of the cell also binds naloxone, which blocks the action of other opioids, whether morphine, heroin or OxyContin. Called an opioid antagonist, naloxone (one of its brand names is probably familiar: Narcan) interrupts the euphoric high of a user and plunges him or her into withdrawal, so most users do not like it at all. However, since breathing depends on the activity of neurons that are silenced by opioids, naloxone is also a lifesaver.  

Two other molecules, methadone and buprenorphine, do not cause euphoria or relieve pain, but they do prevent the symptoms of withdrawal by partially activating the Mu receptor. They are therefore used in medically assisted maintenance therapy for addicts to prevent relapse. 

The Grail of pain research is to find an opioid or other drug that relieves chronic pain but does not cause euphoria or addiction.  So far, no such compound has been found, but several candidates are beginning clinical trials. The Mu receptor changes shape when it binds an opioid and then engages other proteins.  This binding kicks off a cascade of biochemical activities in neurons that are understood in detail — information that may yet provide targets for new therapeutic drugs.  

Illicit drugs are often laced with fentanyl, so it is all too easy to overdose. That is because opioids bind to the Mu receptor with different affinities: heroin binds tighter than morphine, while fentanyl binds about 50 times tighter than heroin, which means that less fentanyl than heroin is needed to elicit euphoria, or to stop breathing.  

Constant exposure to opioids numbs an addict’s reaction to them. The biological reason for that is exposure causes neurons to inactivate their Mu receptors and to withdraw them from surface membranes. The result is the Mu receptors that remain on the cell surface or are dulled by chemical modification need more opioid or a second drug for a user to match that first well-remembered feeling of euphoria.  

So imagine an opioid user who has just been to rehab or prison and is not taking opioids. During the period of abstinence, downregulated opioid receptors will have been restored, making the neurons that control breathing more sensitive to heroin.  If and when there is a relapse, the patient may inject too much heroin, or perhaps fentanyl. In the United States in 2017, breathing stopped in about 72,000 lethal cases, up about 20 percent from the 2016.  According to an excellent report from the Aspen Institute Health Strategy Group, people recently out of rehab have a much greater chance of dying of an overdose than general users. 

Therapy is not simple. Post-detox medical and psychological support is crucial.  Simple detox is not sufficient.  Many drug users are mobile, live in dysfunctional groups and do not want to give up their drugs.  There are also laws regulating who can distribute methadone and buprenorphine, which complicates treatment. 

Despite these problems, there are heroes in the field. Dr. Herbert Kleber was a pioneer of medically assisted therapy, starting in the 1960s. For a time he was also a leader at the National Institute of Drug Abuse, a position that required Senate confirmation. Sen. Edward Kennedy, no stranger to substance abuse, asked, “Well, Dr. Kleber, you’ve been in the field for many years. How have you managed to keep up your optimism and energy and enthusiasm?” 

“No one had ever asked me that”, Dr. Kleber told the researcher William L. White, who interviewed him in 2013. “So I thought for a moment and out of the blue came a Talmud quote that I had read many years before: “The day is short. The task is difficult. It is not our duty to finish it. But we are forbidden not to try.”  That remains the case.

Richard Kessin of Norfolk, Conn., Professor Emeritus of Pathology and Cell Biology at the Columbia University Medical Center. Contact him at: Richard.Kessin@gmail.com for sources, especially The Aspen Institute report and more on Dr. Herbert Kleber, who recently died.