Category: Illegal Drugs

 A study by a team of University of Kentucky researchers has shed new light on the potential habit-forming properties of the popular pain medication tramadol, in research funded by the National Institute on Drug Abuse. The paper is slated to appear in an upcoming edition of the academic journal Psychopharmacology.

Prescription pain killer abuse is a major public health problem in the U.S. In 2010, more individuals over the age of 12 reported nonmedical use of prescription pain relievers in the past month than use of cocaine, methamphetamine or heroin.

"Prescription pain pill abuse is a real problem in Kentucky. We have lots of overdoses. We held a summit here in February specifically about partnering law enforcement and medicine to tackle this problem," said lead study author William W. Stoops of the UK College of Medicine Department of Behavioral Science, the UK Center on Drug and Alcohol Research (CDAR) and the UK College of Arts and Sciences Department of Psychology.

Other UK authors include: Michelle R. Lofwall, Paul A. Nuzzo, Lori B. Craig, Anthony J. Siegel and Sharon L. Walsh.

The study utilized a double-blind, placebo-controlled design. Participants were given one of 12 possible dose combinations of placebo, tramadol, naltrexone and hydromorphone. Naltrexone is an opioid receptor blocker, used to attenuate the effects of opioid medications. Following drug administration, participants were evaluated based on self-reported measures, observer-reported measures, ocular measurements (such as pupil dilation) and performance tasks. Ten participants completed the study.

It was expected that if both tramadol and hydromorphone (Dilaudid®), a common opioid analgesic, acted similarly upon the nervous system, administering naltrexone would mitigate the effects of both drugs in a similar fashion. What was found was that while participants given both hydromorphone and naltrexone reported a lack of influence by the drug, patients taking tramadol and naltrexone reported still feeling "high." Participants who received hydropmorphone or tramadol with placebo also reported feeling affected.

"When we've given them placebo and the opioid receptors are not blocked, tramadol and hydromorphone produce fairly similar effects," said Stoops. "They make subjects say that they're high, they make subjects say that they like the drug, those kind of things. Tramadol does produce some bad effects; folks are saying that it makes them a little nauseous so it is a little distinct from hydromorphone in that manner, which is important. When we gave folks naltrexone, when we blocked those opioid receptors, hydromorphone didn't produce any effects, it was like we'd given them placebo. It completely blocked the effects of hydromorphone because the primary way hydromorphone works is on the opioid receptors in the brain; they're blocked so of course hydoromorphone isn't going to produce an effect. With tramadol, we did not see anywhere near the blockaded effect that we saw with hydromorphone. We need to test a higher naltrexone dose to confirm that this is the case."

The overall results of the study indicated that on measures such as "liking" and "street value," participants rated tramadol highly, suggesting an increased potential for abuse. However, in order to reach these favorable ratings, participants had to take doses well above the normal therapeutic range, and into a range which also produced several negative side effects such as gastrointestinal illness, vomiting and feeling unwell.

"The important thing about this is I think we all assumed that any abuse of tramadol or any abuse potential tramadol had was because of the way it activated the opioid receptors in the brain and that may not be the case," said Stoops "It's pretty well accepted that with opioid drugs like oxycodone, hydromorphone and hydrocodone, when you block the opioid receptors in the brain, folks aren't going to abuse the drug. That is not the case for tramadol. Opioid receptors are important in tramadol use and abuse, but they appear to not be the entire story."

— Resveratrol — the same natural polyphenol found in red wine — preserves the potent pain-relieving effect of morphine in rats that have developed morphine tolerance, suggests a study in the October issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).

If the findings are confirmed in humans, resveratrol might become a useful addition to clinical pain management approaches — especially in patients with chronic, severe pain who have become tolerant to the effects of morphine. The study was performed by Dr Chih-Shung Wong and colleagues of Cathay General Hospital, Taipei, Taiwan.

Resveratrol's Effects in Spinal Cord Affects Morphine Responses

The researchers designed experiments to evaluate whether and how resveratrol affects behavioral pain responses to morphine in morphine-tolerant rats. Morphine and related opioid drugs play an important role in the treatment of severe pain, including cancer pain and other chronic pain conditions. However, the development of tolerance — requiring much higher doses for effective pain control — is an important limiting factor on their use.

Resveratrol is a polyphenol compound found in many plant-based foods; its presence in the skins of grapes may contribute to the health benefits of red wine. Previous studies have shown several biological effects of resveratrol, including antioxidant and anti-inflammatory effects as well as protective effects on the nervous system.

After inducing morphine tolerance in rats, the researchers tested the animals' spinal cord responses to morphine, with or without resveratrol. The results showed significant enhancement of morphine's effects in animals receiving resveratrol. In morphine-tolerant rats, the pain-relieving response to morphine was about 20 percent of normal. In rats receiving resveratrol, morphine responses were restored to about 60 percent of normal.

In preserving the pain-relieving effects of morphine, resveratrol appeared to work in two ways. It reversed the increase in expression of a type of neurotransmitter (N-methyl D-aspartate, or NMDA) receptors associated with morphine tolerance. Resveratrol also blocked the increase of inflammation-promoting substances, called cytokines, in rats with morphine tolerance.

The results add to other recent experimental evidence suggesting that resveratrol can maintain the pain-relieving effect of morphine. It also adds new information on how that effect may occur — specifically through resveratrol's effects on the NMDA receptors and neuroinflammatory responses.

More research will be needed to determine whether some form of resveratrol treatment could be useful in clinical pain management — "particularly for patients who need long-term morphine administration and for morphine-tolerant patients who require better pain relief," the researchers conclude.

Chronic morphine exposure has the opposite effect on the brain compared to cocaine in mice, providing new insight into the basis of opiate addiction, according to Mount Sinai School of Medicine researchers. They found that a protein called brain-derived neurotrophic factor (BDNF), which is increased in cocaine addiction, is inhibited in opioid addiction.

The research is published in the October 5 issue of Science.

"Our study shows that BDNF responds completely differently with opioid administration compared to cocaine," said Ja Wook Koo, PhD, Postdoctoral Fellow in the Department of Neuroscience at Mount Sinai School of Medicine. "Morphine creates reward by inhibiting BDNF, whereas cocaine acts by enhancing BDNF activity."

BDNF is key to several functions in the brain and peripheral nervous system, notably for making new nerve cells and helping the survival of existing ones. It is also known to activate reward centers in the brain. Cocaine causes an increase in the presence of BDNF in a reward center of the brain called the nucleus accumbens, which results in activation of the reward center.

In the current study, the research team found that morphine suppresses BDNF in a different reward center of the brain known as the ventral tegmental area (VTA), in order to achieve reward and chronic addiction. The morphine caused a depletion of BDNF in the VTA of mice, which activated the reward centers. However, when BDNF was administered to the VTA of mice, it inhibited that reward. When BDNF was administered to the nucleus accumbens, there was no reward.

When researchers analyzed morphine-induced changes in gene expression in the nucleus accumbens, the area of the brain in which morphine caused no reward or response they found that two genes, sox11 and gadd45g, mediated the brain's response to morphine, preventing any reward and addiction.

"This study provides important insight into the molecular basis for morphine addiction, and is the first to show that BDNF is a negative modulator in brain, especially in opioid addiction, unlike stimulant addiction," said Dr. Koo. "While further research is needed, the genes we identified may be useful targets in preventing addiction. Also, our data show that administering BDNF to the VTA may be a viable treatment in counteracting opioid addiction." Continuing to study the counteractive response of BDNF in morphine as compared to cocaine may also help researchers determine how poly-drug use may impact the brain.

Dr. Koo is part of the Eric Nestler, MD,PhD laboratory at Mount Sinai School of Medicine. Dr. Nestler is the Nash Family Professor and Chair of Neuroscience and Director of the Friedman Brain Institute at Mount Sinai. Students in the Mount Sinai Graduate School of Biological Sciences also participated in the research, including Haosheng Sun and Diane Damez-Werno.

This study was supported by grants from the National Institute on Drug Abuse and a Rubicon Grant from the Dutch Scientific Organization.

A new study by the University of Colorado Denver reveals that today's adolescents are abusing prescription pain medications like vicodin, valium and oxycontin at a rate 40 percent higher than previous generations.

That makes it the second most common form of illegal drug use in the U.S. after marijuana, according to Richard Miech, Ph.D., lead author of the study and professor of sociology at CU Denver.

"Prescription drug use is the next big epidemic," Miech said. "Everyone in this field has recognized that there is a big increase in the abuse of nonmedical analgesics but our study shows that it is accelerating among today's generation of adolescents."

The study was published Tuesday in the Journal of Adolescent Health.

It drew on data from the National Survey on Drug Use and Health, a series of annual, nationally representative, cross-sectional surveys of U.S. drug use. The analysis used data from 1985 through 2009.

According to Miech, the prevalence of prescription pain medication abuse among the current generation of youth is "higher than any generation ever measured." This finding was present among subgroups of men, women, non-Hispanic whites, non-Hispanic blacks and Hispanics.

Miech and his co-authors said a number of factors were driving this trend.

"The increasing availability of analgesics in the general population is well documented, as the total number of hydrocodone and oxycodone products prescribed legally in the U.S. increased more than fourfold from about 40 million in 1991 to nearly 180 million in 2007," the study said. "Higher prevalence of analgesics makes first-time NAU among contemporary youth easier than in the past because more homes have prescription analgesics in their medicine cabinets."

Miech said parents often model drug use behavior for their children.

"Youth who observe their parents taking analgesics as prescribed may come to the conclusion that any use of these drugs is OK and safe," he said.

Yet the consequences are often severe.

Miech said there are now more deaths due to accidental overdoses of these drugs than deaths due to overdoses of cocaine and heroin combined.

Most people who abuse prescription pain relievers report that they obtained them from family or friends.

"While most people recognize the dangers of leaving a loaded gun lying around the house," said Miech, "what few people realize is that far more people die as a result of unsecured prescription medications."

According to the study:

• Nonmedical analgesic use accounted for an increase in emergency room visits of 129 percent between 2004 and 2009.
• Between 1997 and 2007, NAU accounted for more than a 500 percent increase in the number of Americans seeking treatment for prescription opioid dependency.
• Prescription drug abuse led to a threefold increase in unintentional overdose mortality from the 1990s to 2007.

Miech, who studies drug abuse issues, published a paper last year in the American Sociological Review showing that of the 100 top causes of death, the biggest increase has been prescription drug overdose.

He concludes his more recent study by saying that there seems to be little social cost in abusing nonmedical analgesics.

"These results suggest that current policies and interventions are not yet effective enough to counter the factors that have increased nonmedical analgesic use among U.S. youth and the general population," he said. "But it is critical that we devise a strategy to deal with an epidemic that shows little sign of ebbing."

The study's other researchers include Kennon Heard, MD, of the University of Colorado School of Medicine; Jason Boardman, Ph.D., of the University of Colorado Boulder and Amy Bohnert, Ph.D., of the Department of Veterans Affairs, HSR&D Center of Excellence and the Serious Mental Illness Treatment Resource and Evaluation Center, Ann Arbor, MI.