Category: Opium

 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.

New research demonstrates that blocking the delta opioid receptor in mice created resistance to weight gain and stimulated gene expression promoting non-shivering thermogenesis.

— In a major breakthrough, an international team of scientists has proven that addiction to morphine and heroin can be blocked, while at the same time increasing pain relief.

A change in the formula of the frequently abused prescription painkiller OxyContin has many abusers switching to a drug that is potentially more dangerous, according to researchers at Washington University School of Medicine in St. Louis.

The formula change makes inhaling or injecting the opioid drug more difficult, so many users are switching to heroin, the scientists report in the July 12 issue of the New England Journal of Medicine.

For nearly three years, the investigators have been collecting information from patients entering treatment for drug abuse. More than 2,500 patients from 150 treatment centers in 39 states have answered survey questions about their drug use with a particular focus on the reformulation of OxyContin.

The widely prescribed pain-killing drug originally was thought to be part of the solution to the abuse of opioid drugs because OxyContin was designed to be released into the system slowly, thus not contributing to an immediate "high." But drug abusers could evade the slow-release mechanism by crushing the pills and inhaling the powder, or by dissolving the pills in water and injecting the solution, getting an immediate rush as large amounts of oxycodone entered the system all at once.

In addition, because OxyContin was designed to be a slow-release form of the generic oxycodone, the pills contained large amounts of the drug, making it even more attractive to abusers. Standard oxycodone tablets contained smaller amounts of the drug and did not produce as big a rush when inhaled or injected.

Then in 2010, a new formulation of the drug was introduced. The new pills were much more difficult to crush and dissolved more slowly. The idea, according to principal investigator Theodore J. Cicero, PhD, was to make the drug less attractive to illicit users who wanted to experience an immediate high.

"Our data show that OxyContin use by inhalation or intravenous administration has dropped significantly since that abuse-deterrent formulation came onto the market," says Cicero, a professor of neuropharmacology in psychiatry. "In that sense, the new formulation was very successful."

The researchers still are analyzing data, but Cicero says they wanted to make their findings public as quickly as possible. The new report appears as a letter to the editor in the journal. Although he found that many users stopped using OxyContin, they didn't stop using drugs.

"The most unexpected, and probably detrimental, effect of the abuse-deterrent formulation was that it contributed to a huge surge in the use of heroin, which is like OxyContin in that it also is inhaled or injected," he says. "We're now seeing reports from across the country of large quantities of heroin appearing in suburbs and rural areas. Unable to use OxyContin easily, which was a very popular drug in suburban and rural areas, drug abusers who prefer snorting or IV drug administration now have shifted either to more potent opioids, if they can find them, or to heroin."

Since the researchers started gathering data from patients admitted to drug treatment centers, the number of users who selected OxyContin as their primary drug of abuse has decreased from 35.6 percent of respondents before the release of the abuse-deterrent formulation to 12.8 percent now.

When users answered a question about which opioid they used to get high "in the past 30 days at least once," OxyContin fell from 47.4 percent of respondents to 30 percent. During the same time period, reported use of heroin nearly doubled.

In addition to answering a confidential questionnaire when admitted to a drug treatment program, more than 125 of the study subjects also agreed to longer phone interviews during which they discussed their drug use and the impact of the new OxyContin formulation on their individual choices.

"When we asked if they had stopped using OxyContin, the normal response was 'yes,'" Cicero says. "And then when we asked about what drug they were using now, most said something like: 'Because of the decreased availability of OxyContin, I switched to heroin.'"

These findings may explain why so many law enforcement officials around the country are reporting increases in heroin use, Cicero says. He compares attempts to limit illicit drug use to a levee holding back floodwaters. Where the new formulation of OxyContin may have made it harder for abusers to use that particular drug, the "water" of illicit drug use simply has sought out other weak spots in the "levee" of drug policy.

"This trend toward increases in heroin use is important enough that we want to get the word out to physicians, regulatory officials and the public, so they can be aware of what's happening," he says. "Heroin is a very dangerous drug, and dealers always 'cut' the drug with something, with the result that some users will overdose. As users switch to heroin, overdoses may become more common."

Funding for this research comes from the Denver Health and Hospital Authority, which provided an unrestricted research grant to fund the Survey of Key Informants' Patients (SKIP) Program, a component of the RADARS (Researched Abuse, Diversion and Addition-Related Surveillance) System.

NewsPsychology (June 20, 2012) — Genetics play a significant role in determining which patients will suffer the most from the disturbing side effects of opiates, commonly prescribed painkillers for severe to moderate pain, according to a new Stanford University School of Medicine study, which pinpoints nausea, slowed breathing and potential for addiction as heritable traits.

“One of the most hated side effects of these opiates, nausea, is strongly inherited,” said Martin Angst, MD, professor of anesthesia and one of two principal investigators for the new study, which explores individual variations in the response to opiate use. The study was published June 20 in Anesthesiology. Genetics also play a likely role in determining which patients will suffer from itchiness and sedation associated with the use of these powerful medications, which include morphine, methadone and oxycodone.

“The study is a significant step forward in efforts to understand the basis of individual variability in response to opioids and to eventually personalize opioid treatment plans for patients,” said Angst, director of the Stanford Human Pain Research Laboratory. “Our findings strongly encourage the use of downstream molecular genetics to identify patients who are more likely or less likely to benefit from these drugs — to help make decisions on how aggressive you want to be with treatment, how carefully you monitor patients and whether certain patients are suitable candidates for prolonged treatment.”

Treatment with opiates, also known as narcotics, is tricky because of this variability in drug response. Certain patients may require 10 times the amount of these painkillers to get the same level of pain relief as others. In fact, in some patients the occurrence of side effects may prevent the use of opioids for effectively alleviating pain. Side effects such as nausea or sedation can be debilitating to some, while nonexistent for others. Similarly, some patients can take medications for months with little addiction potential, while others are at risk within weeks.

Millions of U.S. patients are prescribed opiates for pain each year. A better understanding of the potential risk of side effects motivated the researchers to explore individual variation in pairs of identical and fraternal twins, Angst said. The study was prompted by past genetic studies in animals that have shown a strong genetic component in the response to opiates.

“We rely heavily on narcotics as the cornerstone medication for the relief of pain,” said Angst. “Yet we don’t know the answers to fundamental questions, such as why some people ‘like’ narcotics more than others — drug liking and disliking could be key in determining addiction potential.”

Researchers recruited 121 twin pairs for the randomized, double-blinded and placebo-controlled study. Pain sensitivity and analgesic response were measured by applying a heat probe and by immersing a hand in ice-cold water, both before and during an infusion of the opiate alfentanil, a short-acting painkiller prescribed by anesthesiologists. The team also compared individual variations in levels of sedation, mental acuity, respiratory depression, nausea, itch, and drug-liking/disliking — a surrogate measure of addiction potential — between identical twins, non-identical twins and non-related subjects. This provided an estimate of the extent to which variations in responses to opiates are inherited. For example, the finding that identical twins are more similar in their responses to opiates than non-identical twins suggested inheritance plays a significant role.

Heritability was found to account for 30 percent of the variability for respiratory depression, 59 percent of the variability for nausea and 36 percent for drug disliking. Additionally, up to 38 percent for itchiness, 32 percent for dizziness and 26 percent for drug-liking could be due to heritable factors. An earlier study published by the same researchers in the March issue of Pain reported that genetics accounted for 60 percent of the variability in the effectiveness of opiates in relieving pain.

“Since side effects are common among patients who use opioid medications, it will be beneficial to use such research to help at-risk patients avoid serious, life-threatening complications,” said David Clark, MD, PhD, professor of anesthesia and the other principal investigator for the study.

Other Stanford co-authors included Martha Tingle, RN, research nurse; Laura Lazzeroni, PhD, associate professor of psychiatry and behavioral sciences; Nicholas Phillips, MS, research associate; David Drover, MD, associate professor of anesthesiology; and Amrita Ray, PhD, research scientist. The researchers also collaborated with Gary Swan, PhD, director of the Center for Health Sciences at SRI International in Menlo Park, Calif., who is also a co-author of the study.

The study was supported by a grant from the National Institute on Drug Abuse.

Other social bookmarking and sharing tools:

---

Story Source:

The above story is reprinted from materials provided by Stanford University Medical Center. The original article was written by Tracie White.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

---

Journal Reference:

1. Martin S. Angst, Laura C. Lazzeroni, Nicholas G. Phillips, David R. Drover, Martha Tingle, Amrita Ray, Gary E. Swan, J. David Clark. Aversive and Reinforcing Opioid Effects. Anesthesiology, 2012; 117 (1): 22 DOI: 10.1097/ALN.0b013e31825a2a4e

An investigational cannabinoid therapy helped provide effective analgesia when used as an adjuvant medication for cancer patients with pain that responded poorly to opioids, according to results of a multicenter trial reported in The Journal of Pain, published by the American Pain Society.

While opioid therapy is the mainstay treatment for cancer pain in patients with advanced disease, a substantial minority experience pain that cannot be adequately controlled at safe and tolerable doses. The most common treatment approach is co-administration of another analgesic. Cannabinoids are being analyzed as potential adjuvant analgesics. In this randomized multicenter study, nabiximols, a cannabinoid delivered as an oral mucosal spray, was studied to obtain information about the dose response for analgesia and safety in a population with pain not adequately controlled with an opioid.

Patients were eligible to participate in the study if they had active cancer and chronic pain that was moderate to severe despite taking opioids. The study timeline was a five to 14 day baseline period, five weeks titration and treatment, and a post-study visit after two weeks. Every day, patients responded to questions to rate their pain, gauge their sleep quality, and determine how many sprays of the nabiximols they were taking.

Results of the study showed that nabiximols has analgesic efficacy when used as an add-on therapy for cancer patients with pain not controlled by an opioid alone. In the low-dose nabiximols group, there was a 25 percent improvement in pain compared with baseline. However, there was no analgesic effect in the high-dose group and the high dose was not well tolerated. Just 66 percent of subjects in that group finished the study. The authors concluded that nabiximols in a tolerable dose range may offer analgesic benefits to very ill cancer patients with refractory pain.