Category: Opium

New findings may significantly improve the safety of methadone, a drug widely used to treat cancer pain and addiction to heroin and other opioid drugs, according to researchers at Washington University School of Medicine in St. Louis and the University of Washington in Seattle.

The researchers discovered that the body processes methadone differently than previously believed. Those incorrect assumptions about methadone have been making it difficult for physicians to understand how and when the drug is cleared from the body and may be responsible for unintentional under- or overdosing, inadequate pain relief, side effects and even death.

For many years, methadone has been a mainstay in the treatment of opioid addiction. Taken orally, it suppresses withdrawal and reduces cravings. In recent years, doctors have prescribed methadone more frequently as an effective treatment for acute, chronic and cancer pain. Use of the drug for pain treatment rose 1,300 percent between 1997 and 2006. As more methadone was prescribed, however, adverse events increased by approximately 1,800 percent, and fatalities were up more than 400 percent (from 786 to 3,849) between the years 1999 and 2004.

"Unfortunately, increased methadone use for pain has coincided with a significant increase in adverse events and fatalities related to methadone," says principal investigator Evan D. Kharasch, M.D., Ph.D., an anesthesiologist and clinical pharmacologist at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis. "The important message is that guidelines used by clinicians to direct methadone therapy may be incorrect."

Kharasch, the Russell D. and Mary B. Shelden Professor and director of the Division of Clinical and Translational Research in Anesthesiology at the School of Medicine, and his colleagues report the findings in the March issue of the journal Anesthesiology and online in the journal Drug and Alcohol Dependence.

The investigators wanted to understand how protease inhibitors, drugs that keep the immune system functioning in patients with HIV, interact with methadone. For years, the enzyme P4503A was believed to be responsible for clearing methadone from the body. But when healthy volunteers were given a low dose of methadone together with protease inhibitors that caused profound decreases in the activity of P4503A, there was no reduction in the clearance of methadone.

There were two reasons to study what happened to methadone when taken together with those drugs: First, HIV-AIDS patients may receive methadone for pain and, in some cases, for accompanying substance abuse problems, along with one or more protease inhibitors. In addition, many protease inhibitors interact with the P4503A enzyme that traditionally was thought to be important to methadone clearance. In these studies, Kharasch and his team looked at interactions among methadone, the P4503A enzyme in the intestine and liver and the protease inhibitors nelfinavir, indinavir and ritonavir.

They gave study volunteers a combination of the protease inhibitors ritonavir and indinavir. Both drugs profoundly inhibited the actions of the enzyme. If that enzyme were responsible for methadone clearance, then inhibiting it should have caused methadone to build up in the body. But the researchers found that it had no effect on methadone levels.

Volunteers in the second study received the protease inhibitor nelfinavir. Again, the drug inhibited the action of the P4503A enzyme. That should have meant methadone concentrations would rise, but they actually decreased by half.

"For more than a decade, practitioners have been warned about drug interactions involving the enzyme P4503A that might alter methadone metabolism," Kharasch says. "The package insert says inhibiting the enzyme may cause decreased clearance of methadone, but our research demonstrates that P4503A has no effect on clearing methadone from the body. So the package insert appears to be incorrect, or certainly needs to be reevaluated, as do guidelines that explain methadone dosing and potential drug interactions."

That can be dangerous, Kharasch explains, because a clinician may prescribe too much or too little methadone for patients taking drugs that interact with P4503A, having been informed that they also would influence methadone clearance. Too little methadone will not relieve pain. Too much can contribute to the unintentional build-up of methadone in the system, which can cause slow or shallow breathing and dangerous changes in heartbeat. Physicians could be unintentionally prescribing methadone incorrectly.

"The highest risk period for inadequate pain therapy or adverse side effects is during the first two weeks a patient takes methadone," Kharasch says. "If we can provide clinicians with better dosing guidelines, then I believe we will be able to better treat pain and limit deaths and other adverse events."

About a dozen related liver enzymes are part of the P450 family, and Kharasch believes another enzyme from that family may be the one actually involved in methadone metabolism and clearance. His laboratory is determined to identify the correct enzyme to limit over-and under-dosing of patients taking methadone to improve addiction and pain treatment as well as patient safety. Currently, he's testing the related enzyme P4502B. Laboratory studies and preliminary clinical results indicate that P4502B may be involved, but he says more clinical research is needed.

"The research also is important for the treatment of HIV-AIDS," Kharasch says. "Protease inhibitors can interfere with the activity of P4503A but increase the activity of P4502B. This paradox is highly unusual, and because these two enzymes metabolize so many prescription drugs, there are many potential drug interactions that we'll be able to understand better if we can get a better handle on how these pathways absorb drugs into the system and clear them from the body."

This research was supported by grants from the National Institute on Drug Abuse of the National Institute of Health and by an NIH grant to the University of Washington General Clinical Research Center.

Journal References:

1. Kharasch et al. Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity. Drug and Alcohol Dependence, 2009; DOI: 10.1016/j.drugalcdep.2008.12.009
2. Kharasch et al. Methadone Pharmacokinetics Are Independent of Cytochrome P4503A (CYP3A) Activity and Gastrointestinal Drug Transport. Anesthesiology, 2009; 110 (3): 660 DOI: 10.1097/ALN.0b013e3181986a9a

NewsPsychology (Mar. 3, 2009) — Research lead by the University of Otago, Christchurch provides useful new information on the extent of drug use in New Zealand, and when people first begin using drugs for non-medical purposes.

The data comes from an analysis of over 12,000 interviews of people aged 16 or over carried out by the New Zealand Mental Health Survey (2003/2004), in conjunction with the World Health Organization (WHO).

The aim of the research is to determine the age when drugs are first used and the percentage of the population who have ever used drugs for non-medical purposes. This is shown for the total population, by age and by ethnicity.

Overall key findings show:

• alcohol is the most commonly used drug, with 94% of the population having ever used it
• tobacco has been used by nearly 51% of people,
• cannabis is the next most common drug with 41% of people having ever used it,
• cocaine is much less commonly used (4.2%) while opioid use (heroin and morphine) is uncommon (2.9%)
• prescription drugs have been used for non-medical purposes by 6% of those surveyed
• nearly 10% have used other drugs such as LSD or glue

These results are similar to those for Australia and the US for all drugs except for cocaine which is four times as likely to have ever been used in the US (16.2%). In contrast the percentage who have ever used cocaine in Colombia and Mexico is similar to that in New Zealand (4.0% for both countries).

In developed countries the use of alcohol is nearly universal, but there are marked variations in cannabis use with New Zealand, Australia and the US all being high use countries. Europe has lower use of cannabis than New Zealand (6.6-19.9% have ever used) and lower use of cocaine (1.0-1.9%) except for Spain (4.1%). The US has a high use of cocaine.

The study also produced some interesting results in relation to the use of drugs by different age groups in NZ. The percentage who had ever smoked tobacco was lowest in younger age groups in 2003-2004, while the percentage of those who had ever used a drug rose slightly between 24-30 years, but then decreased rapidly across the two older age groups.

It is a consistent finding that the percentage of drug users across all drugs is higher for the 25-44 age group than the 16-24 cohort. However analysis of the age of onset showed that this was because many in the youngest age group had not yet started using.

Most people who have tried or used drugs did so for the first time between 16 and 30 years, with few new users at older ages. Alcohol is the drug used first (half had used by around 15 years), followed by cannabis, then opioids and lastly cocaine (in the late 20s).

Ethnic comparisons of onset of drug use were carried out only for those born in New Zealand and aged under 45. Pacific people had delayed onset of alcohol use compared with Māori and the composite ‘Other’ ethnic group, although almost all did use alcohol at least once by the age of 25. For other drugs it appeared that Pacific people were less likely to ever use than ‘Others’, who in turn were less likely to use than Māori.

The researchers say that these results indicate that a range of strategies to combat drug use and abuse should start in adolescence, not only through schools, but also through interventions at national and local levels.

A disadvantage in understanding recent drug trends is that questions specifically on methamphetamine and ‘party pill’ use were not included in the New Zealand Mental Health Survey. An international interview was used in which these drugs were included within drug groups, but not asked about on their own.

The ‘Onset and lifetime use of drugs in New Zealand’ study has been published in the Drug and Alcohol Review and was funded by the New Zealand Lotteries Grants Board. The survey was funded by the Ministry of Health, the Health Research Council of New Zealand and the Alcohol Advisory Council.

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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.

 A national panel of pain management experts representing the American Pain Society (APS) and the American Academy of Pain Medicine (AAPM) has published the first comprehensive, evidence-based clinical practice guideline to assist clinicians in prescribing potent opioid pain medications for patients with chronic non-cancer pain.

The long-awaited guideline appears in the current issue of The Journal of Pain.

To create this guideline, researchers in the Oregon Evidence-based Practice Center (EPC) at Oregon Health & Science University collaborated with the APS and AAPM for two years, reviewing more than 8,000 published abstracts and nonpublished studies to assess clinical evidence on which the new recommendations are based.

"This guideline was a true multidisciplinary effort that sought to address in a balanced manner the many challenging issues that clinicians face with regard to when and how to prescribe opioids for chronic noncancer pain," said Roger Chou, M.D., principal investigator; director of the American Pain Society Clinical Practice Guidelines Program; scientific director of the Oregon Evidence-Based Practice Center at OHSU; and associate professor of medical informatics and clinical epidemiology, and medicine (general internal medicine and geriatrics) in the OHSU School of Medicine.

"A key part of this process was performing a comprehensive literature review to inform the recommendations — though an important take-home message is that even though the recommendations represent the best judgment of the panel based on the currently available literature, there is still a lot of research that needs to be done."

The expert panel concluded that opioid pain medications are safe and effective for carefully selected, well-monitored patients with chronic non-cancer pain. They made 25 specific recommendations and achieved unanimous consensus on nearly all.

Opioid prescribing has increased significantly due to growing professional acceptance that the drugs can relieve chronic non-cancer pain, and the guideline acknowledges there are widespread concerns about increases in prescription opioid abuse, addiction and diversion.

Opioids, such as morphine, oxycodone, oxymorphone and fentanyl are potent analgesics. They traditionally have been used to relieve pain following surgery, from cancer and at the end of life. Today opioids are used widely to relieve severe pain caused by chronic low-back injury, accident trauma, crippling arthritis, sickle cell, fibromyalgia, and other painful conditions.

Prior to initiating chronic opioid therapy, the guideline advises clinicians to determine if the pain can be treated with other medications. If opioids are appropriate, the clinician should conduct a thorough medical history and examination and assess potential risk for substance abuse, misuse or addiction.

Diligent Patient Monitoring Is Essential

A key recommendation urges clinicians to continuously assess patients on chronic opioid therapy by monitoring pain intensity, level of functioning and adherence to prescribed treatments. Periodic drug screens should be ordered for patients at risk for aberrant drug behavior.

Other recommendations in the APS/AAPM clinical practice guideline include:

• Methadone: Use of methadone for pain management has increased dramatically but few trials have evaluated its benefits and harms for treatment of chronic non-cancer pain. Methadone, therefore, should be started at low doses and titrated slowly. Because of its long half-life and variable pharmacokinetics, the panel recommends methadone not be used to treat breakthrough pain or as an as-needed medication.
• Abusers: Chronic opioid therapy must be discontinued in patients known to be diverting their medication or in those engaging in serious aberrant behaviors.
• Breakthrough Pain: As-needed opioids can be prescribed based on initial and ongoing analysis of therapeutic benefit versus risk.
• High Doses: Patients who need high doses of opioids (200 mg daily of morphine or equivalent) should be evaluated for adverse events on an ongoing basis, and clinicians should consider rotating pain medications when patients experience intolerable side effects or inadequate benefit despite appropriate dose increases.
• Driving and Work Safety: Patients should be educated about the greater risk for impairment when starting chronic opioid therapy and counseled not to drive or engage in potentially dangerous work if impaired.
• Pregnancy: Clinicians should counsel women about risks of opioids in pregnancy and encourage minimal or no use of chronic opioid therapy unless potential benefits outweigh risks.

The guideline on opioid therapy for chronic non-cancer pain is the first such collaboration between APS and AAPM. It is the sixth evidenced-based, pain management clinical practice guideline published by APS. Others have covered sickle-cell disease, arthritis, cancer, fibromyalgia, and low back pain.

Though treatment of pain and attention to end-of-life care for pediatric cancer patients has improved over the last few decades, there is still work to be done. Additionally, opioid prescriptions for pediatric cancer patients while hospitalized during the last week of life vary greatly among hospitals. These were the findings of a study and editorial published in Pediatric Blood & Cancer.

Cancer is the leading cause of death by disease in children between the ages of 1 and 19. Children with terminal cancer commonly receive pain medication. The chances that a child with cancer who dies in a hospital will receive this medication, commonly an opioid drug, may depend on which hospital is treating the child.

Using detailed data from the Pediatric Health Information System, the investigators examined the cases of 1,466 subjects 24 years of age and under who were treated at 33 hospitals at time of death between 2001 and 2005. They found that only 56 percent received opioids every day during the hospitalized portion of their last week of life. Substantial variation was found across children’s hospitals, ranging from 0 to 90.5 percent of eligible patients at a given hospital receiving daily opioid therapy.

Patients with private insurance received daily opioids 63.4 percent of the time, compared to 52 percent for those with Medicaid or other government coverage. Age and diagnosis also played a role: patients aged 10-19 years were more likely to receive daily opioids (61 percent) than those who were younger or older; and patients with brain tumors were less likely than those with other forms of cancer, such as leukemia/lymphoma, to receive daily therapy.

Multiple factors may contribute to the manner in which opioids are used within a particular hospital, including: the prevailing medical culture, attitudes towards death and the care of dying patients, the lingering stigma associated with opioids, the potential influence of clinicians with special interests in end-of-life care and the availability of hospice and other community resources.

The number of children with cancer who die in pain is unknown, though parent interview studies have revealed that pain management skills by pediatric oncologists may need further improvement.

Many parents report that the suffering of children dying from cancer was not adequately relieved and identify pain as a prominent concern, Additionally, a number of attending physicians, residents and nurses have reported that they feel inexperienced in pain management.

Regardless of the precise reasons, the existence of substantial variation among hospitals in pediatric EOL care practices strongly suggests that interventions to alter these practices will be most effective if they are adapted to the specific social, cultural, technical and institutional configuration of each hospital.

“The findings demonstrate how useful it would be to have indicators to measure the quality of pediatric end-of-life care and enable comparisons across hospitals. Interventions to improve practices in pediatric end-of-life care may be most effective if adapted individually to each hospital,” says Andrea D. Orsey, M.D., M.S.C.E., co-author of the study.

According to Sarah Friebert, M.D., author of a related editorial on the subject, “As the field of pediatric palliative care expands, future studies should focus on monitoring quality indicators across time and diverse settings.”

Many barriers to adequate pain management exist. In resource-rich countries where opioid availability is not a factor, a few of the reasons for inadequate pain management in the pediatric oncology population include: difficulties in assessing young children, poor training in pain management, fear of opiod addiction and the unwillingness of children or parents to acknowledge pain for fear of what it signifies (recurrent/relapsed disease, necessary hospital visits and death).

“Despite these and other obstacles, good pain management seems to be the least we can do for our pediatric patients with cancer,” says Friebert. “In addition to comprising good, holistic pediatric care, adequate pain management improves ability to cope with therapy (both physically and psychologically), improves nutrition and sleep and facilitates healing.”

“Importantly, for those for whom the journey of cancer will not end in cure, relief of distress from pain at the end of life carries long-lasting implications for bereaved parents, who cope much better when their dying children’s pain is well controlled,” says Friebert.

Journal Reference:

1. Orsey et al. Variation in receipt of opioids by pediatric oncology patients who died in children's hospitals. Pediatric Blood & Cancer, 2008; DOI: 10.1002/pbc.21824

— Investigators at Georgia State University's Neuroscience Institute and Center for Behavioral Neuroscience are the first to identify the most likely reason analgesic drug treatment is usually less potent in females than males. This discovery is a major step toward finding more effective treatments for females suffering from persistent pain.

"Opioid-based narcotics (such as morphine) are the most widely prescribed therapeutic agents for the alleviation of persistent pain; however, it is becoming increasingly clear that morphine is significantly less potent in women compared with men. Until now, the mechanism driving the phenomenon was unknown," said Anne Murphy, Ph.D., a Georgia State Professor of Neuroscience and member of the Center for Behavioral Neuroscience, who conducted the research with Dayna Loyd, Ph.D.

Murphy recently solved the mystery with findings printed in the December issue of The Journal of Neuroscience that show that previously reported differences in morphine's ability to block pain in male versus female rats are most likely due to sex differences in mu-opioid receptor expression in a region of the brain called the periaqueductal gray area (PAG).

Located in the midbrain area, the PAG plays a major role in the modulation of pain by housing a large population of mu-opioid receptor expressing neurons. Morphine and similar drugs bind to these mu-opioid receptors analogous to a 'lock and key' and, ultimately, tell the brain to stop responding to pain signals to the nerve cells resulting in the reduced sensation of pain.

Using a series of anatomical and behavioral tests, Murphy and Loyd were able to determine that male rats have a significantly higher level of mu-opioid receptors in the PAG region of the brain compared with females. This higher level of receptors is what makes morphine more potent in males because less drug is required to activate enough receptors to reduce the experience of pain. Interestingly, when they used a plant-derived toxin to remove the mu-opioid receptor from the PAG, morphine no longer worked, suggesting that this brain region is required for opiate-mediated pain relief.

Additional tests also found females reacted differently to morphine depending on the stage of their estrous cycle. These findings indicate that steroid hormones may affect mu-opioid receptor levels in the region of the PAG that are essential for analgesia and also suggest that the actions of morphine are estrous stage-dependent.

"Interestingly, sex is not the only factor that has been shown to affect the potency of various pharmacological agents. Recent studies have reported an influence of age and ethnicity, and further argue for the inclusion of a wide range of study subjects in pain management research," Murphy said. "In addition, despite the rapidly mounting evidence regarding the limitations of opiates in treating persistent pain, opioid-based drugs remain the primary pharmacological tool for pain management. Clearly additional research with the inclusion of female subjects needs to be devoted to determining a more potent treatment for persistent pain in women."

Murphy's work was supported by grants from the National Institutes of Health.

A Princeton University scientist will present new evidence today demonstrating that sugar can be an addictive substance, wielding its power over the brains of lab animals in a manner similar to many drugs of abuse.

Professor Bart Hoebel and his team in the Department of Psychology and the Princeton Neuroscience Institute have been studying signs of sugar addiction in rats for years. Until now, the rats under study have met two of the three elements of addiction. They have demonstrated a behavioral pattern of increased intake and then showed signs of withdrawal. His current experiments captured craving and relapse to complete the picture.

"If bingeing on sugar is really a form of addiction, there should be long-lasting effects in the brains of sugar addicts," Hoebel said. "Craving and relapse are critical components of addiction, and we have been able to demonstrate these behaviors in sugar-bingeing rats in a number of ways."

At the annual meeting of the American College of Neuropsychopharmacology in Scottsdale, Ariz., Hoebel will report on profound behavioral changes in rats that, through experimental conditions, have been trained to become dependent on high doses of sugar.

"We have the first set of comprehensive studies showing the strong suggestion of sugar addiction in rats and a mechanism that might underlie it," Hoebel said. The findings eventually could have implications for the treatment of humans with eating disorders, he said.

Lab animals, in Hoebel's experiments, that were denied sugar for a prolonged period after learning to binge worked harder to get it when it was reintroduced to them. They consumed more sugar than they ever had before, suggesting craving and relapse behavior. Their motivation for sugar had grown. "In this case, abstinence makes the heart grow fonder," Hoebel said.

The rats drank more alcohol than normal after their sugar supply was cut off, showing that the bingeing behavior had forged changes in brain function. These functions served as "gateways" to other paths of destructive behavior, such as increased alcohol intake. And, after receiving a dose of amphetamine normally so minimal it has no effect, they became significantly hyperactive. The increased sensitivity to the psychostimulant is a long-lasting brain effect that can be a component of addiction, Hoebel said.

The data to be presented by Hoebel is contained in a research paper that has been submitted to The Journal of Nutrition. Visiting researchers Nicole Avena, who earned her Ph.D. from Princeton in 2006, and Pedro Rada from the University of Los Andes in Venezuela wrote the paper with Hoebel.

Hoebel has been interested in the brain mechanisms that control appetite and body weight since he was an undergraduate at Harvard University studying with the renowned behaviorist B.F. Skinner. On the Princeton faculty since 1963, he has pioneered studies into the mental rewards of eating. Over the past decade, Hoebel has led work that has now completed an animal model of sugar addiction.

Hoebel has shown that rats eating large amounts of sugar when hungry, a phenomenon he describes as sugar-bingeing, undergo neurochemical changes in the brain that appear to mimic those produced by substances of abuse, including cocaine, morphine and nicotine. Sugar induces behavioral changes, too. "In certain models, sugar-bingeing causes long-lasting effects in the brain and increases the inclination to take other drugs of abuse, such as alcohol," Hoebel said.

Hoebel and his team also have found that a chemical known as dopamine is released in a region of the brain known as the nucleus accumbens when hungry rats drink a sugar solution. This chemical signal is thought to trigger motivation and, eventually with repetition, addiction.

The researchers conducted the studies by restricting rats of their food while the rats slept and for four hours after waking. "It's a little bit like missing breakfast," Hoebel said. "As a result, they quickly eat some chow and drink a lot of sugar water." And, he added, "That's what is called binge eating — when you eat a lot all at once — in this case they are bingeing on a 10 percent sucrose solution, which is like a soft drink."

Hungry rats that binge on sugar provoke a surge of dopamine in their brains. After a month, the structure of the brains of these rats adapts to increased dopamine levels, showing fewer of a certain type of dopamine receptor than they used to have and more opioid receptors. These dopamine and opioid systems are involved in motivation and reward, systems that control wanting and liking something. Similar changes also are seen in the brains of rats on cocaine and heroin.

In experiments, the researchers have been able to induce signs of withdrawal in the lab animals by taking away their sugar supply. The rats' brain levels of dopamine dropped and, as a result, they exhibited anxiety as a sign of withdrawal. The rats' teeth chattered, and the creatures were unwilling to venture forth into the open arm of their maze, preferring to stay in a tunnel area. Normally rats like to explore their environment, but the rats in sugar withdrawal were too anxious to explore.

The findings are exciting, Hoebel said, but more research is needed to understand the implications for people. The most obvious application for humans would be in the field of eating disorders.

"It seems possible that the brain adaptations and behavioral signs seen in rats may occur in some individuals with binge-eating disorder or bulimia," Hoebel said. "Our work provides links between the traditionally defined substance-use disorders, such as drug addiction, and the development of abnormal desires for natural substances. This knowledge might help us to devise new ways of diagnosing and treating addictions in people."

— An examination of unintentional overdose deaths in West Virginia, a state that has experienced one of the highest increases in the rate of drug overdose deaths, finds that the majority of these were associated with the nonmedical use and diversion of pharmaceuticals, primarily pain relievers, according to a new study.

In 1997, two expert panels in the United States introduced clinical guidelines for management of chronic pain, including encouraging expanded use of opioid pain medications after careful patient evaluation and counseling when other treatments are inadequate. In the 10 years since the guidelines were first published, per capita retail purchases of the pain relievers methadone, hydrocodone, and oxycodone in the United States increased dramatically, according to background information in the article. Along with the increase in legitimate sales of opioids, rates of emergency department visits and deaths attributable to opioid analgesic overdoses have also increased.

Aron J. Hall, D.V.M., M.S.P.H., of the Centers for Disease Control and Prevention, Atlanta, and colleagues conducted a study to determine the risk characteristics and other factors associated with persons dying of unintentional pharmaceutical overdose in West Virginia in 2006. During 1999-2004, West Virginia experienced the nation's most substantial increase (550 percent) in death from unintentional poisoning. The researchers used data from medical examiner, prescription drug monitoring program, and opiate treatment program records.

Of 295 persons who died (decedents), 198 (67.1 percent) were men and 271 (91.9 percent) were age 18 through 54 years. Among all decedents, 63.1 percent had used pharmaceuticals that contributed to their death without documented prescriptions (i.e., diversion), and 21.4 percent had 5 or more clinicians prescribe them controlled substances in the year prior to death (i.e., doctor shopping). Women were significantly more likely to have evidence of doctor shopping than men (30.9 percent vs. 16.7 percent). Prevalence of diversion was greatest among the group age 18 through 24 years. Relative to all other age groups, the group age 35 through 44 years was associated with a significantly greater rate of doctor shopping (30.7 percent vs. 18.2 percent). Of the 295 persons who died, 94.6 percent had at least 1 indicator of substance abuse.

Compared with deaths involving prescribed pharmaceuticals, deaths involving diversion were associated with history of substance abuse, nonmedical route of pharmaceutical administration, and a contributory illicit drug. In contrast, decedents with evidence of doctor shopping were significantly more likely to have had a previous overdose and significantly less likely to have used contributory alcohol compared with decedents who had fewer than 5 clinicians prescribe them controlled substances in the year prior to death.

Multiple contributory substances were implicated in 234 deaths (79.3 percent). Opioid analgesics were the most prevalent class of drugs, contributing to 93.2 percent of deaths; of these, only 44.4 percent included evidence of prescription documentation for all of the contributory opioids. The most common drug identified was methadone, which was involved in 40 percent of all deaths. The percentage of decedents with valid prescriptions for methadone was lower than the percentage of those with valid prescriptions for hydrocodone or oxycodone.

"Clinicians have a critical role to play in preventing the diversion of prescription drugs. Clinicians and pharmacists need to counsel patients who are prescribed opioids not only about the risk of overdose to themselves but also about the risk to others with whom they might share their medication. In addition, clinicians should follow recent published guidelines for the management of chronic pain and refer patients as needed to pain management specialists. Clinicians should also make use of state prescription drug monitoring programs to determine whether their patients are getting scheduled drugs from other clinicians. Clinicians can now obtain such information about their patients from prescription drug monitoring programs in most states," the authors write.

Editorial: Prescription Opioids, Overdose Deaths, and Physician Responsibility

In an accompanying editorial, A. Thomas McLellan, Ph.D., of the Treatment Research Institute, and Barbara Turner, M.D., Ms.Ed., of the University of Pennsylvania School of Medicine, Philadelphia, write that there are steps physicians can take to help reduce the likelihood of prescription diversion.

"When deciding whether to prescribe an opioid, physicians should ask patients about their prior and current histories of alcohol and other drug use. Patients with histories of substance use, mental health problems, or both should receive special attention and co-management from pain management specialists when possible. Treatment of mental health disorders should be considered part of successful pain management."

"Physicians also should consider an opioid treatment agreement (contract) with the patient stipulating the frequency of obtaining medications, timely refills but no early replacements for lost prescriptions, safe storage, no sharing, single-source prescribing, monitoring through urine screens, and adherence to monitoring visits. The agreement should be presented as a way of simultaneously protecting the patient from adverse events and promoting a collaborative, responsible relationship."

Adolescents addicted to opioids who received continuing treatment with the combination medication buprenorphine-naloxone had lower rates of testing positive or reporting use of opioids compared to youths who went through a short-term detoxification program using the same medication, according to a study in the November 5 issue of JAMA.

Recent data suggest that abuse of opioids, including heroin and prescription pain-relief drugs, is increasing among adolescents, according to background information in the article. "The usual treatment for opioid-addicted youth is short-term detoxification and individual or group therapy in residential or outpatient settings over weeks or months. Clinicians report that relapse is high, yet many programs remain strongly committed to this approach and, except for treating withdrawal, do not use agonist [a drug that mimics the action of a naturally occurring substance] medication," the authors write.

George Woody, M.D., of the University of Pennsylvania, Philadelphia, and colleagues conducted a study comparing outcomes of treating opioid addiction among adolescents with extended treatment using buprenorphine-naloxone vs. short-term detoxification. Buprenorphine is an oral medication that acts by relieving the symptoms of opiate withdrawal. Naloxone is a drug that prevents or reverses the effects of opioids if it is injected. The study included 152 patients, age 15 to 21 years. Patients in the 12-week buprenorphine-naloxone group were prescribed up to 24 mg. per day for 9 weeks and then tapered to week 12; patients in the detox group were prescribed up to 14 mg. per day and then tapered to day 14. All were offered weekly individual and group counseling.

The researchers found that overall, patients in the detox group had higher proportions of opioid-positive urine test results at weeks 4 and 8 but not at week 12. At week 4, 61 percent of detox patients had positive results vs. 26 percent of the 12-week buprenorphine-naloxone patients. At week 8, 54 percent of detox patients had positive results vs. 23 percent of 12-week buprenorphine-naloxone patients. At week 12, 51 percent of detox patients had positive results vs. 43 percent of buprenorphine-naloxone patients, who by that time had been tapered off their medication.

By week 12, 20.5 percent of detox patients remained in treatment vs. 70 percent of 12-week buprenorphine-naloxone patients. During weeks 1 through 12, patients in the 12-week buprenorphine-naloxone group reported less use of opioids, cocaine and marijuana, less injecting, and less need for additional addiction treatment. High levels of opioid use occurred in both groups at follow-up.

"Taken together, these data show that stopping buprenorphine-naloxone had comparably negative effects in both groups, with effects occurring earlier and with somewhat greater severity in patients in the detox group," the authors write.

"Because much opioid addiction treatment has shifted from inpatient to outpatient where buprenorphine-naloxone can be administered, having it available in primary care, family practice, and adolescent programs has the potential to expand the treatment options currently available to opioid-addicted youth and significantly improve outcomes. Other effective medications, or longer and more intensive psychosocial treatments, may have similarly positive results. Studies are needed to explore these possibilities and to assess the efficacy and safety of longer-term treatment with buprenorphine for young individuals with opioid dependence."

Editorial: Treatment of Adolescent Opioid Dependence – No Quick Fix

In an accompanying editorial, David A. Fiellin, M.D., of the Yale University School of Medicine, New Haven, Conn., writes that there is a need for more evidence regarding effective opioid-addiction treatments.

"The results of this trial should prompt clinicians to use caution when tapering buprenorphine-naloxone in adolescent patients who receive this medication. Supportive counseling; close monitoring for relapse; and, in some cases, naltrexone should be offered following buprenorphine tapers. From a research perspective, additional efforts are needed to provide a stronger evidence base from which to make recommendations for adolescents who use opioids. There is limited research on prevention of opioid experimentation and effective strategies to identify experimentation and intercede to disrupt the transition from opioid use to abuse and dependence."

Journal References:

1. George E. Woody; Sabrina A. Poole; Geetha Subramaniam; Karen Dugosh; Michael Bogenschutz; Patrick Abbott; Ashwin Patkar; Mark Publicker; Karen McCain; Jennifer Sharpe Potter; Robert Forman; Victoria Vetter; Laura McNicholas; Jack Blaine; Kevin G. Lynch; Paul Fudala. Extended vs Short-term Buprenorphine-Naloxone for Treatment of Opioid-Addicted Youth: A Randomized Trial. JAMA, 2008; 300 (17): 2003-2011 [link]
2. David A. Fiellin. Treatment of Adolescent Opioid Dependence: No Quick Fix. JAMA, 2008; 300 (17): 2057-2059 [link]

 A recent study conducted by researchers at Georgia State University is the first of its kind to demonstrate that administration of preemptive morphine prior to a painful procedure in infancy blocks the long-term negative consequences of pain in adult rodents. These studies have serious implications for the way anesthetics and analgesics are administered to neonates prior to surgery.

Infant rodents that did not receive preemptive pain medication prior to surgery were less sensitive to the effects of morphine in adulthood.

This means that infants undergoing invasive procedures at birth that do not receive any pain medicine will require more morphine in adulthood to modulate their pain.

This study — conducted by Anne Z. Murphy, Ph.D., a GSU Professor of Neuroscience and member of the Center for Behavioral Neuroscience, and graduate student Jamie LaPrairie — has serious clinical implications for the more than 400,000 human infants that are admitted to a newborn intensive care unit (NICU) in the United States each year.

Past studies have shown human infants born between 25-42 weeks gestation experience on average 14 painful procedures per day during the first two weeks of life with fewer than 35 percent receiving appropriate analgesic therapy.

"While such surgical procedures in preterm infants are clearly necessary, the resulting pain and inflammation has been shown to lead to negative behavioral consequences later in life," Murphy said. "Our previous studies have shown that, just as in humans, neonatal inflammation in rodents (that did not receive preemptive pain medication) results in an increase in sensitivity to pain, stress, and decreased reaction to morphine as adults.

While evidence exists that morphine is efficacious in neonatal rodents, this is the first study to confirm the long-term behavioral benefits.

In this study, published online in Pediatric Research, a group of rat pups received an injection of morphine sulfate on the day of birth prior to inducing inflammation; another group received a saline injection instead. The groups were then raised identically and received identical procedures during a 60-day period. Rodents that received preemptive morphine behaved normally while those rats that received saline showed significant increases in pain sensitivity and were resistant to the pain relieving effects of morphine in adulthood.

"This tells us that morphine doesn't work very well in human children and adults that were formally in the NICU and didn't receive preemptive pain treatment, and since morphine is still the primary drug used to treat severe pain, this means that there is an entire subpopulation for which morphine doesn't work efficiently," Murphy said. "These results suggest that there are long-term benefits of providing all newborns with some sort of pain relieving medicine prior to the initiation of an invasive procedure."

Murphy's work was supported by the National Institutes of Health, the Center for Behavioral Neuroscience, and the GSU Brains and Behavior Program.