Promising New Pain Killer Not Addictive Like Opioids



Scientists have developed a new drug that promises the pain-numbing effects of opioids without their addictive characteristics. An article last week in MIT Technology Review said this “promising new pain-killer… appears to separate the powerful pain dulling effects of synthetic opioids from side effects that include physical dependence, constipation, and potentially fatal respiratory depression.”

To find the new drug–named PZM21 and detailed in a paper published August 17 in Nature–a research team at UCSF’s School of Pharmacy simulated some four trillion different chemical interactions between the brain’s “morphine receptors,” and a virtual library of close to 4 million commercially available drug compounds. Choosing the best candidates, they then worked in collaboration with researchers from three other institutions to develop a compound that functioned in the way they hoped, after testing it in mice.

“Opioids can cause respiratory depression–that’s why people die, because they stop breathing,” says Brian Shoichet, a professor of pharmaceutical chemistry at UCSF’s School of Pharmacy and co-senior author on the paper. “Our hope was to come up a molecule that doesn’t have those effects.”

Chart shows the rise in heroin addiction and opioid use. Credit: Associated Press

The scientists have raised venture capital funds from Kleiner, Perkins, Caufield and Byers to start a new company called Epiodyne, that will seek to develop the painkillers.

The finding is just the latest promising development in the ongoing effort to separate the pain numbing effects of opioids from their potentially deadly and addictive side effects—an effort that has taken on new urgency as opioid-related deaths and addiction in the United States reach epidemic proportions. (See “The Painkillers that Could End the Opioid Crisis”). A number of efforts are underway to develop a new painkiller without side effects, including a similar compound that’s currently being tested in humans.

An estimated 100 million Americans are afflicted with chronic pain. Up to 8 percent of patients prescribed narcotic painkillers for chronic pain will become addicted, according to the National Institute of Drug Abuse. In 2014, the number of deaths from opioid overdoses in the United States topped 18,000, about 50 a day—more than three times the number in 2001. And that doesn’t even take into account painkiller addicts who have turned to heroin to soothe their cravings. Officials at the Centers for Disease Control and Prevention recently compared the scale of the problem to the HIV epidemic of the 1980s.

The Nature paper, produced by scientists at UC San Francisco, Stanford University, the University of North Carolina, and the Friedrich-Alexander University Erlangen-Nürnberg in Germany, grew out of a years-long collaboration between Shoichet and Brian Kobilka, a Stanford University Nobel Laureate, Bryan Roth, a leading expert in opioid pharmacology, and Peter Gmeiner, a leading medicinal chemist.


Brian Kobilka, a Stanford University Nobel Laureate, is among the researchers behind the drug discovery.

The findings showcase the power of two key innovations that make it easier to develop new drugs. In 2007, Kobilka developed a new method that for the first time allowed scientists to map the precise atomic structure of a class of proteins in the brain known as G protein-coupled receptors (GPCRs). (In 2012, Kobilka’s innovations won him the Nobel Prize). GPCRs straddle the inside and outside of the cells and play a key role in the ability of brain cells to respond to biochemical signals emanating from elsewhere in the body—including the nerve impulses that make us feel pain.

Shoichet, meanwhile, has been working for almost three decades to build a computer program capable of simulating the way that different kinds of drugs interact on the molecular level with the brain. At the time of the analysis for the Nature paper, Shoichet’s computer program included a database with the chemical structures of between three and four million commercially available drugs.

Shoichet and Kobilka have been collaborating since 2007, when the Stanford researcher first developed his new techniques for mapping GPCRs. So when one of Kobilka’s graduate students, Aashish Manglik, used his methods to, for the first time, map the atomic structure of the receptors activated by opioids, it seemed an ideal opportunity.

Opioids, from OxyContin to heroin and morphine, work their magic by binding to what are known as MU receptors at the junctions where nerve cells meet. The binding reduces the ability of these cells to fire. So when nerve fibers at the periphery of the body send pain signals up to the brain for processing, the neurons that would normally make us feel this pain don’t respond.

But MU receptors aren’t located simply in the centers of the brain that detect pain. They are also found at other junctions all around the body in areas that have nothing to do with registering pain. Thus opioids can cause a wide number of side effects by exerting their influence in other parts of the body.

The challenge has been to find novel drug compounds that activate the proteins that numb pain without activating proteins that lead to the side effects. Working with another graduate student in Shoichet’s lab, Manglik programmed the database to simulate the way different drugs might interact with the receptor, in the hopes of finding one that did not produce unwanted side effects, which is what PZM21 appears to do.

“The virtual screening technology really pulled this out of a 4 million compound haystack,” says Stanford’s Kobilka, a co-author on the paper.

The National Institute on Drug Abuse defines ‘opioids’ thusly:

Opioids are medications that relieve pain. They reduce the intensity of pain signals reaching the brain and affect those brain areas controlling emotion, which diminishes the effects of a painful stimulus. Medications that fall within this class include hydrocodone (e.g., Vicodin), oxycodone (e.g., OxyContin, Percocet), morphine (e.g., Kadian, Avinza), codeine, and related drugs. Hydrocodone products are the most commonly prescribed for a variety of painful conditions, including dental and injury-related pain. Morphine is often used before and after surgical procedures to alleviate severe pain. Codeine, on the other hand, is often prescribed for mild pain. In addition to their pain relieving properties, some of these drugs—codeine and diphenoxylate (Lomotil) for example—can be used to relieve coughs and severe diarrhea.

Opioids act by attaching to specific proteins called opioid receptors, which are found in the brain, spinal cord, gastrointestinal tract, and other organs in the body. When these drugs attach to their receptors, they reduce the perception of pain. Opioids can also produce drowsiness, mental confusion, nausea, constipation, and, depending upon the amount of drug taken, can depress respiration. Some people experience a euphoric response to opioid medications, since these drugs also affect the brain regions involved in reward. Those who abuse opioids may seek to intensify their experience by taking the drug in ways other than those prescribed. For example, OxyContin is an oral medication used to treat moderate to severe pain through a slow, steady release of the opioid. People who abuse OxyContin may snort or inject it, thereby increasing their risk for serious medical complications, including overdose.

Fewer HIV Sufferers Need Hospital Care: New Study


Hospital admissions to treat HIV fell by one-third between 2000 and 2013, even though the number of people living with HIV increased by more than 50 percent during that time, according to a new study from AHRQ – the Agency for Healthcare Research and Quality, a part of the U.S. Department of Health and Human Services.

The analysis is the first to show that a downward trend in the number of hospital admissions per person living with HIV continued after 2010. Based on HIV patient data in five states – California, Florida, New Jersey, New York, South Carolina – the study found that people with HIV were 64 percent less likely to be hospitalized in 2013 than they were in 2000.

The study attributed the reduction to highly active antiretroviral therapy to treat HIV that was introduced between 1995 and 2000 as well as clinicians’ enhanced ability to treat HIV.

An abstract of the study, “Hospital Use by Persons With HIV in the 21st Century: a 5-State Study,” which was published in Medical Care, is available here.

GMO Bill Heads To White House – Why?



With both the Senate and the House of Representatives signed off on it, a much-discussed, somewhat controversial bill concerning the labeling of genetically modified foods is on its way to the White House for signing by President Obama.

The bill has been hailed by some in the food industry and soundly decried by others. And an

‘interactive feature’ in The New York Times last week gave consumers pause to consider how much better off, or wiser, they’ll be (or not) with this or any other GMO-oriented legislation.

The July 11 New York Times piece (cited above) pretty much sums up what consumers need to know, right now, or in the foreseeable future, on the GMO issue. (Spoiler: The issue isn’t as big a deal many would have you believe.)

The problem comes with the concept of genetic manipulation of food, and where it happens in the food chain. At first glance, if you were unfortunate enough to see a ‘modern’ bred-for-cooking chicken in the flesh, as it were, your first reaction no doubt would be, ‘nature would never make something that looks, and is, by design, as physically challenged as this poor creature is’. And you’d be right.

An unfortunately large number of the chickens bred these days for eating – so called ‘food chickens – are a far cry, physically, from their ancestors of half a century ago. They’ve been dramatically ‘modified’ by selective breeding – not by having their genes manipulated. The objective has been to satisfy the public’s desire for white, as opposed to dark, chicken meat, and the best white meat – in terms of quantity and solid volume, is found in the breast. So, chickens have been selectively bred to have enormous breasts – to a point, as The Times interactive feature notes, its “legs can barely support.”

An article linked-to at that point in the ‘interactive’ article goes so far as to describe the selective breeding of chickens – “modern chicken genetics” – as “a form of abuse”: Chickens today, the linked-to piece says, “stagger about, sometimes on splayed legs, or mostly just sit down.”

A good share of the corn grown in the U.S. today is genetically modified so it resistant to the chemical glyphosate, the active ingredient in the Monsanto herbicide Roundup. This gene modification was necessary because Roundup is designed to travel down through a broad spectrum of plants, killing them all the way down to their root system. So, it can  keep corn fields pretty clear of weeds that grab moisture the corn needs, etc. Some think the chemical (glyphosate) is toxic, possibly contributing to the development of cancer, in humans.

But the point of the corn gene manipulation was to enable the plant to defeat the chemical’s objective, and it works. As or more important, though, is the fact that in the course of traveling down through a plant to its roots the glyphosate apparently in no modifies the corn in a way that could be harmful to humans.

(Full disclosure: For the better part of a year, in the mid-1970’s, shortly after Roundup was first marketed, I helped promote it by producing, at Monsanto’s expense, ‘user stories’ from wheat farmers, municipal and state roadside maintenance authorities, NASA, the Orange Bowl, cemetery managers, wholesale plant growers, lawn care professionals, and many others from one side of the U.S. to the other. The articles were placed in trade magazine serving specific trades – and they were glad to get them, because Roundup was, and still widely is, considered to be something of a ‘miracle product’ that cuts labor costs by vastly reducing the amount of time it takes to clear away unwanted plants.

(A Monsanto sales rep I traveled with in Texas told me a story of an instance where a woman complained to him that Roundup was “killing my dogs, my chickens and my kids; Notice the priorities, there, he said.” His response: He pulled out a sample size of the product – a couple of ounces – and promptly drank it! “She all but fainted,” he laughed.)

Another issue, also pointed out in The Times’ interactive piece, is the fact that, with GMOs being talked about by some as posing health risks (no proof, so far) et cetera, some manufacturers are sticking ‘GMO free’ and similar labels on products – including ground oats, and water – where GMOs are not an issue!

Sadly, there is no ‘safe source’ of authoritative information on whether or not, ultimately, some GMOs might be found to be less than beneficial, without posing any risk to humans.

Chickens are routinely fed genetically modified grain – modified to help chickens ward off diseases. No one has ever suggested that GMO grain, or the breeding manipulations causing chickens to grown far faster and end up with far great breast weights than nature intended, is causing fried chicken eaters to gain weight or developed clogged arteries. Both have a far more direct relationship to the cooking fat that favorite food is cooked in.

People notoriously try to blame ‘something else’ on such conditions as having high blood pressure (cut your salt intake!) water retention (ditto’) or being too ‘bulky’ (you can see where this is going!).

In the grand scheme of things, as we can see that scheme today, GMOs are the least of the worries of people who consume way too much salt, and sugar (in the form of soft drinks, candy, etc.) and fail to exercise.

For the moment, it would be best to keep the GMO ‘threat’ in perspective: It ain’t one, that anyone’s been able to pin down.

The president can sign the bill, creating a new law, and the food industry can say – or it could, if the language of the bill were clear enough – ‘see, we’re doing what you want! Isn’t that wonderful?’

No, in fact, it isn’t.

I’ve worked (as a writer) on the fringe of the food industry for the better part of forty years. The technological changes in that time – what’s known now that wasn’t even imaged then – is mind boggling. Maybe there’s some reason why, in some instances, genetically modified foods might pose a risk of some sort to people. Maybe there isn’t. But none of what I regularly read about developments in the trade suggest there’s any reason why careful manipulations shouldn’t continue, when risk are clearly evaluated and taken into consideration.

A lot of what Congress does is wheel-spinning, or publicity-oriented. This bill may represent one, the other or both of those. What it doesn’t represent is a viable means of addressing what may, or may not,  be an issue worth getting excited about. Or wasting all the Congressional time and energy this bill has.

While some Congressional bills may require as few as two pages  – the one authorizing President Obama to give gold metals to the Apollo astronauts on the 40th anniversary of the moon landing – many spending bills and some others are notorious for filling 1,000 or more pages, as was the one authorizing The Affordable Care Act.

Multiply than times 500 or so – for 435 members of Congress plus other need-to-see’s. That amounts to 1,000 reams of paper – at 500 pages per ream – per bill. And that’s just the House version.

Every month, I attend meetings of county-level Board of Supervisors in Virginia meetings where the agenda, including multiple pages of explanatory files and charts, etc., is readily available on tablet-sized computers placed conveniently in front of each Supervisor. Small towns, as mine is (at 4,000 or so souls), and right-thinking counties really need to watch their expenditures, and it’s pretty obvious that using even a few reams of paper to duplicate, every month, something stored in an electronic file, is beyond wasteful: It’s an irresponsible use of public money.

Call me stupid, but I have enough faith that those who produce the food we eat, have no interest whatsoever in poisoning us. I can’t imagine any major (or even a minor) food producer introducing GMO ingredients into what they intend to market if they had the least suspicion the GMO aspect could put their customers – members of the shopping and consuming public – at risk.

All else aside, doing so would be illegal under existing law. The about-to-be GMO labeling law is highly unlikely to have any positive effect, but certainly could have some negative ones: Companies charged with mislabeling when the ‘facts’ are, between the complainant  and the accused, are, well, disputable.