Saturday, 28 February 2009

The Search for Non Addictive Morphine

Commonly Available Drug Found To Treat Opioid Addiction
Feb 2009

Scientists at Stanford University School of Medicine have discovered that a commonly available non-addictive drug can prevent symptoms of withdrawal from opioids with little likelihood of serious side effects. The drug, ondansetron, which is already approved to treat nausea and vomiting, appears to avoid some of the problems that accompany existing treatments for addiction to these powerful painkillers, the scientists said.

Opioids encompass a diverse array of prescription and illegal drugs, including codeine, morphine and heroin. In 2007, about 12.5 million Americans aged 12 and older used prescription pain medications for non-medical purposes, according to the National Survey on Drug Use and Health, administered by the federal government's Substance Abuse and Mental Health Services Administration.

"Opioid abuse is rising at a faster rate than any other type of illicit drug use, yet only about a quarter of those dependent on opioids seek treatment," said Larry F. Chu, MD, assistant professor of anesthesia at the School of Medicine and lead author of the study that will be published online Feb. 17 in the Journal of Pharmacogenetics and Genomics. "One barrier to treatment is that when you abruptly stop taking the drugs, there is a constellation of symptoms associated with withdrawal." Chu described opioid withdrawal as a "bad flu," characterized by agitation, insomnia, diarrhea, nausea and vomiting.

Current methods of treatment are not completely effective, according to Chu. One drug used for withdrawal, clonidine, requires close medical supervision as it can cause severe side effects, while two others, methadone and buprenorphine, don't provide a satisfactory solution because they act through the same mechanism as the abused drugs. "It's like replacing one drug with another," said co-investigator Gary Peltz, MD, PhD, professor of anesthesia.

"What we need is a magic bullet," said Chu. "Something that treats the symptoms of withdrawal, does not lead to addiction and can be taken at home."

The researchers' investigation led them to the drug ondansetron, after they determined that it would block certain receptors involved in withdrawal symptoms.

The scientists were able to make this connection thanks to their having a good animal model for opioid dependence. Mice given morphine for several days develop the mouse equivalent of addiction. Researchers then stop providing morphine to trigger withdrawal symptoms. Strikingly, these mice, when placed into a plastic cylinder, will start to jump into the air. One can measure how dependent these mice are by counting how many times they jump. Like humans, dependent mice also become very sensitive to pain when they stop receiving morphine.

But the responses vary among the laboratory animals. There are "different flavors of mice," explained Peltz. "Some strains of mice are more likely to become dependent on opioids." By comparing the withdrawal symptoms and genomes of these different strains, it's possible to figure out which genes play a major role in addiction.

To accomplish this feat, Peltz and his colleagues used a powerful computational "haplotype-based" genetic mapping method that he had recently developed, which can sample a large portion of the genome within just a few hours. This method pinpoints genes responsible for the variation in withdrawal symptoms across these strains of mice.

The analysis revealed an unambiguous result: One particular gene determined the severity of withdrawal. That gene codes for the 5-HT3 receptor, a protein that responds to the brain-signaling chemical serotonin.
To confirm these results, the researchers injected the dependent mice with ondansetron, a drug that specifically blocks 5-HT3 receptors. The drug significantly reduced the jumping behavior of mice as well as pain sensitivity — two signs of addiction.

The scientists were able to jump from "from mouse to man" by sheer luck: It turns out that ondansetron is already on the market for the treatment of pain and nausea. As a result, they were able to immediately use this drug, approved by the Food and Drug Administration, in eight healthy, non-opioid-dependent humans. In one session, they received only a single large dose of morphine, and in another session that was separated by at least week, they took ondansetron in combination with morphine. They were then given questionnaires to assess their withdrawal symptoms.

Similar to mice, humans treated with ondansetron before or while receiving morphine showed a significant reduction in withdrawal signs compared with when they received morphine but not ondansetron. "A major accomplishment of this study was to take lab findings and translate them to humans," said principal investigator J. David Clark, MD, PhD, professor of anesthesia at Stanford University School of Medicine and the Palo Alto Veterans Affairs Health Care System.

Chu plans on conducting a clinical study to confirm the effectiveness of another ondansetron-like drug in treating opioid withdrawal symptoms in a larger group of healthy humans. And the research team will continue to test the effectiveness of ondansetron in treating opioid addiction.

The scientists warned that ondansetron will not by itself resolve the problems that arise with continued use of these painkillers. Addiction is a long-term, complex process, involving both physical and psychological factors that lead to compulsive drug use. "This is not a cure for addiction," said Clark. "It's naïve to think that any one receptor is a panacea for treatment. Treating the withdrawal component is only one way of alleviating the suffering. With luck and determination, we can identify additional targets and put together a comprehensive treatment program."

Collaborators on this study included De-Yong Liang, PhD, the study's co-lead author, previously a research associate in the Department of Anesthesia and currently a research associate at the Palo Alto Institute for Research and Education; Xiangqi Li, MD, a life science research assistant in the department; Nicole D'Arcy, a medical student: Peyman Sahbaie, MD, a research associate at the institute; and Guochun Liao, PhD, of the pharmaceutical company Hoffman-La Roche. This work was supported by grants to Clark from the National Institutes of Health and the National Institute on Drug Abuse, and grants to Chu from the NIH and the National Institute of General Medical Sciences.

The researchers are working with the Stanford University Office of Technology Licensing to seek a patent for the use of ondansetron and related medicines in the treatment of drug addiction.

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Stanford University Medical Center.

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Anonymous said...

Interesting what the article says about different people (or mice) having a different tolerance to addiction.

I used for a couple of years, probably 4 days a week, generally twice a day, without developing a physical dependance. The people i lived and used with were all hooked in no time.

I also took tramadol (about 10 years after i quit H) every day for two months after a car crash and never suffered withdrawal.

However, i do have a well entrenched weed habit, and suffer physical symptoms of sweating, nausea and agitation when i dont smoke.

Funny how drugs effect people differently, isnt it?

I also found that heroin gave me insomnia, has anyone else experienced this?

Terry Wright said...

Thanks Anon.

You lucky bastard!!! Opiates without addiction would change the whole world ... literally.

I get insomnia from heroin as well. I think it's fairly common that the "morphine dreams" keep waking users up. For me, the feeling of being overtired resembles a heroin buzz in a way. If I use at night, I wake up 4-5 times and will even get up at about 4am-5am. I then nod off for the rest of the day.

It's strange about the weed. I understand the irritation but not the nausea.

Anonymous said...

"It's strange about the weed. I understand the irritation but not the nausea."

I know THC is used for cancer and HIV patients to reduce nausea, and to improve appetite.

I have wondered if the nausea i experience when i don't smoke is to do with the weeds anti-emetic qualities.

Sort of like how heroin replaces your own endorphins, and withdrawal makes you more sensitive to pain. Maybe if you are a heavy smoker, your body comes to rely on the weed's anti nausea effect, and can't cope without it.

Either way, it sucks!

What really shits me is that law abiding guys like you and me are forced, on occasion, to deal with the criminal element.

All i want is to be able to get on with my life and my job with the minimum of stress, and preferably with no involvment with crims or dealers.

If i never had to visit a dealer again, and could buy my poison at at a tobacconist, id die a happy man!

(BTW, just think of all those wasted tax dollars that, as we speak, are lining the pockets of organised criminals)

Anon, aka DBD

Terry Wright said...

Howdy anon.

Interesting theory about the cannabis and nausea.

The legalisation movement in the US is kicking some major arse at the moment. Where are you from?

Have you thought of growing your own? If it's just for yourself/partner, $500-$1000 should get you going. You only need 2 plants and then you would have your supply provided free all year round.

Thanks for your input.

Anonymous said...

Im from south Oz terry.

I didnt know there was much happening re: legalisation in the US at the moment. Ill have to take a look.

As far as growing my own, we live in a smallish country town so im nervous about possible ramifications. Its easy to get a bad rep in the country, not so easy to get rid of it. Im probably being overly cautious, but better safe than sorry, eh?

Also my partner doesnt smoke, so i would probably meet some resistance if i tried to set up a grow room!

Cheers, DBD.

BTW, really enjoy the site, its important that someone tries to counter all the misinformation that gets thrown around in the drug debate.