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It’s in the Genes Researchers Probe Alcohol’s Effect on Epigenetics

As scientists gain a better understanding of the human genome, one rapidly emerging area of research is the effect of alcohol on epigenetics – external modifications to DNA that turn genes “on” or “off.” Epigenetic changes alter the physical structure of DNA. One example of an epigenetic change is DNA methylation — the addition of a methyl group, or a “chemical cap,” to part of the DNA molecule, which prevents certain genes from being expressed. A recent article in the National Institute on Alcohol Abuse and Alcoholism’s Alcohol Alert reports on a growing body of research showing how alcohol’s influence on epigenetics may be associated with an array of illnesses and disorders. These include fetal alcohol spectrum disorders (FASD), cancer, liver disease and other gastrointestinal disorders, brain development, the body’s internal clock, and immune function. Researchers and clinicians are beginning to explore therapies that might be developed to target the changes occurring through epigenetics. How alcohol affects epigenetics Alcohol consumption leads to

oxygen species (ROS), which are chemically reactive molecules that at high levels can damage cells. Fetal alcohol spectrum disorders Women who drink during pregnancy put their developing fetuses at serious risk for a range of conditions collectively known as FASD. In exploring how epigenetics contributes to FASD, researchers have also begun to investigate two complex enzymes that play a crucial role in cell differentiation during fetal development. One, called polycomb protein, remodels chromatin to turn genes off; the other, called trithorax protein, remodels chromatin to turn genes on. Research suggests that exposure to alcohol may

chemical changes within the body that can affect all the epigenetic mechanisms. For one, excessive alcohol consumption interferes with the body’s ability to process and access a chemical called folate. Folate is critical for methylation, a biochemical process that attaches a methyl group to a specific spot on DNA. DNA methylation acts to lock genes in the “off ” position. Chronic alcohol consumption leads to lower-than-normal methylation, or “hypomethylation.” Research also finds that alcohol metabolism leads to an increase in a substance called NADH, which is a byproduct of alcohol metabolism, and through production of reactive

Researchers and clinicians are beginning to explore therapies that might be developed to target the changes occurring through epigenetics due to alcohol use.

alcohol abuse and alcohol dependence, and may contribute to alcohol relapse and craving. Hope for the future As researchers begin to untangle the exact nature of alcohol’s interactions with epigenetics, they will be able to design better medications to treat or alleviate a wide range of alcohol-related disorders, including FASD, alcohol addiction, cancer and organ damage. In addition, researchers can now analyze DNA methylation patterns for the entire human genome. This work could yield comprehensive maps of DNA methylation changes in alcohol-associated cancers. Those maps then could potentially be used to develop pharmacological treatments that target epigenetic markers and develop new markers for cancer detection and prognosis. 

disrupt these two enzyme complexes, altering how cells differentiate during fetal development.

Liver disease and the gastrointestinal tract

Alcohol affects epigenetics on many levels within the GI tract and liver, where the majority of consumed alcohol is metabolized and cleared from the body. As alcohol enters the liver, it sets off what could be described as a cascade of epigenetic changes that increase the risk of liver disease, liver cancer and immunological problems. In addition, alcohol-associated epigenetic changes may play a role in what researchers call organ “cross- talk” between the GI tract, the liver and other organs. For one, epigenetic changes to genes involved in joining the cells lining the intestines may be partially responsible for “leaky gut,” which allows endotoxins to enter circulation and initiate liver damage. Alcohol-associated cancers As suggested above, alcohol-related changes involved in epigenetics can be linked to the development of liver cancer. In particular, research suggests that some epigenetic changes can transform normal liver cells back into stem cells, which then can develop into liver cancer. In addition, alcohol acts indirectly on a receptor that, when disrupted, is involved in the development of liver cancer. Alcohol’s role in changing DNA methylation patterns, leading to hypomethylation, may be one of the main routes between alcohol consumption and liver cancer as well as other types of alcohol-associated cancers. Changes in brain functioning Alcohol’s epigenetic effects within the brain are complex and intertwined. But increasing evidence suggests that they result in adaptations within the brain that ultimately influence addictive behaviors, including tolerance and alcohol dependence. As seen in other disorders, changes in DNA methylation are one of the epigenetic changes in the brain caused by chronic alcohol consumption. Although researchers still are piecing together the details, findings to date suggest that epigenetic changes in gene expression induced by alcohol consumption may underlie the brain pathology and adaptations in brain functioning associated with

As researchers begin to untangle the exact nature of alcohol’s interactions with epigenetics, they will be able to design better medications to treat or alleviate a wide range of alcohol-related disorders.

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Boom, Bust, and Drugs Study says economic downturn leads to increase in substance use disorders When the economy tanks, drug abuse goes up.That’s the finding of a new study which shows the state of the economy is closely linked with substance abuse disorder rates for a variety of substances. The study, conducted by researchers from Vanderbilt University, the University of Colorado and the Substance Abuse and Mental Health Services Administration (SAMHSA), found the use of substances like ecstasy becomes more prevalent during economic downturns. Researchers also found that other drugs like LSD and PCP see increased use only when the economy is strong. But for overall substance use disorders, the findings were clear.

“Problematic use (i.e., substance use disorder) goes up significantly when the economy weakens,” says Christopher Carpenter, one of the lead researchers. “Our results are more limited in telling us why this happens.” Researchers say it’s possible that people turn to substance use as a means of coping with a job loss or other major life changes caused by economic pressures, but their particular study did not pinpoint an exact cause and effect. Not all drugs are equal The study showed that a downward shift in the economy has the biggest impact on painkillers and hallucinogens. Rates of substance abuse disorders were significantly higher for those two categories than any other class of drug.

Researchers also found the change in disorder rates was highest for white adult males, a group which was one of the hardest hit during the Great Recession.They say more research is needed to determine exactly how the economy and drug use are related, but they say the study highlighted some key groups for prevention and treatment workers to target during future economic downturns.

“Problematic use (i.e., substance use disorder) goes up significantly when the economy weakens.” - Christopher Carpenter, Vanderbilt University

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Slippery slope Despite some lingering questions, researchers were able to show the significance of the economy’s role in problematic substance use.The study showed that even a small change in the unemployment rate can have a tremendous impact on the risks for substance abuse disorders. “For each percentage point increase in the state unemployment rate, these estimates represent about a 6 percent increase in the likelihood of having a disorder involving analgesics and an 11 percent increase in the likelihood of having a disorder involving hallucinogens,” the authors write. Previous studies have focused on the economy’s link to marijuana and alcohol, with many looking at young people in particular.This study is one of the first to highlight illicit drugs, which given the current opioid epidemic, holds important lessons for those working to curb problematic drug use.

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When it’s needed most The study bears significant weight for treatment facilities and public policy makers in particular. During economic downturns, government agencies typically look to cut spending on treatment programs as a way to save money, something researchers say may be more costly in the end. “Our results suggest that this is unwise,” Carpenter says. “Such spending would likely be particularly effective during downturns since rates of substance use disorders are increasing when unemployment rates rise, at least for disorders involving prescription painkillers and hallucinogens.”

“Spending would likely be particularly effective during downturns since rates of substance use disorders are increasing when unemployment rates rise.” - Christopher Carpenter, Vanderbilt University

“We were surprised that morphine was able to induce these really long-lasting changes,” says Dr. Peter Grace, the study’s lead author. Dr. Grace says the cause of the chronic pain increase has to do with cells that form part of the immune system. He says if those areas could be isolated or their eects reduced, the resulting pain may not be as great. “If it does turn out to be a relevant issue to patients, then what our study suggests is that targeting the immune system may be the key to avoiding these kinds of eects,” Dr. Grace says. “Opioids could essentially work better if we could shut down the immune system in the spinal cord.” e team’s research only looked at spinal cord injuries and morphine, and did not study other opioids that are commonly prescribed to patients experiencing pain. But he said it’s likely drugs like Vicodin or OxyContin could aect other parts of the body in a similar way. “While we haven't actually tested other opioids in this particular paradigm, we predict that we would see similar eects,” Dr. Grace says.

ain relievers are supposed to relieve pain. It sounds simple enough, but new research suggests a common pain medication may actually be prolonging chronic pain. Morphine is an opioid painkiller commonly prescribed in hospitals and clinics, and while it is eective in the short term, doctors don’t always consider the potential consequences for pain down the road.at’s why a team of researchers based out of the University of Colorado - Boulder set out to study how morphine treatment aects chronic pain, and found some troubling results. e team, which used mice with spinal cord injuries, found that in mice not given morphine, their pain thresholds went back to normal about four to ve weeks after the injury. But mice who were given morphine didn’t see their pain levels return to normal until around 10 to 11 weeks, meaning the use of morphine eectively doubled the length of their chronic pain. P

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Chronic problem Chronic pain can be debilitating for many people facing serious health problems, and it can also be a key factor in substance abuse. Many people report developing a dependence on opioids after having them prescribed for an injury. But new research suggests the number of people who develop dependency issues because of chronic pain may be far higher than people realize. A study from researchers at Boston University looked at a group of nearly 600 people who had either used illicit substances or misused prescription drugs.

ey found that 87 percent reported suering from chronic

pain, with 50 percent of those people rating their pain as severe.ey also found that 51 percent of people who had used illicit drugs like marijuana, cocaine and heroin had done so to treat their pain. While many prevention eorts focus on recreational users, the numbers suggest that chronic pain plays just as prominent a role in substance abuse. “Many patients using illicit drugs, misusing prescription drugs and using alcohol reported doing so in order to self-medicate their pain,” the authors of the study wrote. “Pain needs to be addressed when patients are counseled about their substance use.”

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Talkin’ ‘Bout My Generation

NIDA Researchers Develop Screening Tool for Teen Substance Use This article is a condensed version of a piece that originally appeared on the National Institute on Drug Abuse (NIDA) website.

Teens’ use of addictive substances often goes undetected by health care providers. But NIDA-supported researchers have developed a Brief Screener for Tobacco, Alcohol and other Drugs (BSTAD), to help spot teens’ problematic habits. In a recent study, BSTAD developers Dr. Sharon Kelly and colleagues at the Friends Research Institute in Baltimore examined the frequencies of use likely to qualify a teen for a diagnosis of an alcohol use disorder (AUD), nicotine use disorder (NUD), or cannabis use disorder (CUD). The frequencies proved to be surprisingly low, according to the researchers.

Teen drug substance use revealed For the study, the BSTAD survey employed a few, simple questions about teens’ use of alcohol, tobacco or drugs within the past year.The teens’ BSTAD responses revealed that 22 percent had used alcohol in the past year, 16 percent had used marijuana, 10 percent had used tobacco, and 3 percent had used at least one illicit substance other

than marijuana. (Original article by Eric Sarlin, M.Ed., M.A., NIDA Notes Contributing Writer) 28

“ Health care providers should have a one-on-one discussion with teens who indicate any substance use to assess level of risk, provide brief advice, and, if necessary, recommend further assessment for a treatment intervention. “

-Dr. Sharon Kelly, Friends Research Institute

Analysis of the data showed that almost all teens who reported on the BSTAD that they had consumed an alcoholic beverage on two or more days during the past year had an AUD. Conversely, teens who reported drinking on fewer than two days were unlikely to have this disorder.The corresponding BSTAD cut point for an NUD was nicotine use on two or more days during the past year and for a CUD was marijuana use on two or more days. BSTAD enables early detection Using these cut points, the researchers found that the BSTAD was highly sensitive. Ninety-six percent of teens with an AUD, 95 percent with an NUD, and 80 percent with a CUD would be flagged as likely in need of further assessment for a brief intervention or referral to treatment. BSTAD’s specificity was also high: 85 percent of teens without an AUD, 97 percent without an NUD, and 93 percent without a CUD reported use below the cut points, and so would be correctly classified. “Very low substance use frequencies were found to be optimal in identifying these disorders,” Dr. Kelly comments. The BSTAD does not distinguish

Researchers encourage regular screening Both the World Health Organization and the American Academy of Pediatrics recommend screening all adolescent patients for substance use since problems later in life often originate in adolescence. Still, many providers do not regularly screen their patients for substance abuse. “Providers are extremely busy and need a quick and valid screening measure for identifying teens who use substances,” says Dr. Kelly. She and colleagues developed the BSTAD in response to a NIDA call for new tools to fill this need. To create the BSTAD, Dr. Kelly and colleagues added the questions about tobacco and marijuana to the widely disseminated National Institute on Alcohol Abuse and Alcoholism screen for youth alcohol use. In the validation study, the FRI research team administered the BSTAD in person to half of the participants, and the rest of the participants self-administered the instrument on an iPad. The teens reported a strong preference for the iPad. The iPad version offers the potential extra convenience that results can be automatically transferred into a teen’s electronic medical record. 

the severities of the disorders, she notes, so when it flags a teen, providers need to follow up with questions to determine appropriate interventions or referrals to treatment. Furthermore, Dr. Kelly says, “Health care providers should have a one-on-one discussion with teens who indicate any substance use to assess level of risk, provide brief advice, and, if necessary, recommend further assessment for a treatment intervention.” Providers also should rescreen teens regularly, because onset of substance use can occur abruptly during adolescence. Pediatrics recommend screening all adolescent patients for substance use since problems later in life often originate in adolescence. Both the World Health Organization and the American Academy of

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Sign of the times Experts say the newly approved implant also provides a big boost to the concept of medication-assisted treatment (MAT) in general. For years, the idea that someone could achieve recovery through the use of drugs like methadone and buprenorphine was rejected by many professionals in the eld who saw complete abstinence as the only true sobriety. Many still hold that belief, but attitudes appear to be changing. Top government oŽcials say they want to increase the amount of MAT taking place at the country’s treatment centers. Several states as well as the federal government have enacted laws making it easier for physicians to prescribe medications like buprenorphine, but they say too few patients receive the medication they need. National Institute on Drug Abuse, in a statement. “is product will expand the treatment alternatives available to people suering from an opioid use disorder.” ] [ "Opioid abuse and addiction have taken a devastating toll on American families.” - Dr. Robert M. Cali, FDA Commissioner “Scientic evidence suggests that maintenance treatment with these medications in the context of behavioral treatment and recovery support are more eective in the treatment of opioid use disorder than short-term detoxication programs aimed at abstinence,” said Dr. Nora Volkow, director of the

M

edication-assisted treatment is growing in popularity and acceptance among addiction recovery professionals. And now it’s taken a revolutionary step forward that could oer renewed hope to thousands of people struggling with an addiction to opioids. is summer, the U.S. Food and Drug Administration approved a new buprenorphine implant to treat opioid dependence. Buprenorphine had previously been available only as a pill or a dissolvable lm placed under the tongue. But the new implant, known as Probuphine, can administer a six-month dose of the drug to keep those dependent on opioids from using by reducing cravings and withdrawal symptoms. "Opioid abuse and addiction have taken a devastating toll on American families,” FDA Commissioner Dr. Robert M. Cali said in a statement. “We must do everything we can to make new, innovative treatment options available that can help patients regain control over their lives.” e implant comes in the form of four one-inch rods that are placed under the skin on the upper arm.e implant must be administered surgically and comes with the possibility of certain side eects, but experts say it could be more convenient and more eective for patients.ey say by eliminating the need to take pills, ll prescriptions and generally manage their medication, it makes it easier for people to focus on the other areas of their recovery while making it less likely someone will lapse in their treatment plan.

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Although the implant is certainly a new alternative, it has yet to show any increased success in keeping people from relapsing compared to the pill or lm tablet. In a study of the implant’s eectiveness, they found that 63 percent of people given the implant were free of illicit drugs at six months, compared to 64 percent of people who took buprenorphine by pill. Still, those rates are much higher than the success rates of people who follow abstinence-only treatment plans. And oŽcials hope the new implant will lead more people to get MAT, increasing the number of successful recoveries across the country.

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Bend But Don’t Break Yoga is being used to help people maintain recovery and avoid relapse

Yoga is no longer exercise your annoying, health-conscious friend won’t stop talking about.The ancient practice is now being used to help people recover from addiction. While scholars estimate yoga was developed sometime around 300 to 400 B.C., the practice hasn’t stopped changing over the last 2,000 years. A new wave of yogis are now helping people in recovery connect their spiritual and physical sides through yoga by combining the practice with more traditional 12-step elements. “It’s just a way of coming back to a sense of wholeness,” says Nikki Myers, a yoga therapist who helped develop the 12-step yoga system. “We use yoga as a process in order to bring that reintegration.”

Myers says she developed the system primarily as a means of relapse prevention. She says a typical 12-step yoga session would begin the same way most 12- step meetings do, with a focus on sharing and discussion of important recovery topics. Once the “meeting” portion of the session is over, the group will then move into a series of yoga poses designed to help participants focus on their physical recovery. “A focus needs to be on the body- based piece as well as the cognitive piece in order for wholeness to really be manifested,”Myers says. “Once you include those things, the whole idea is that these will begin to offer us a set of tools that we can use both on the mat in the yoga practice and off the mat when the triggers of life show up.”

“It’s just a way of coming back to a sense of wholeness.” - Nikki Myers, yoga therapist

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The right tools Myers says the idea that yoga can provide a set of tools is critical as the practice of yoga is much more than the poses themselves. She says there’s also a focus on breathing techniques, a meditation of sorts, and a connection to one’s physical reactions that can prove vital when faced with difficult circumstances. Myers recalls how one woman who participated in 12-step yoga later found herself in a very stressful situation at home with her kids misbehaving and everything going wrong. She said she could feel the negativity boiling up inside her. It was the kind of stress that had triggered her to drink in the past, but the woman said in that moment she was able to relax and calm herself by focusing on her breathing and remembering the feeling of tranquility she had experienced in class. “It had a way of creating a space, giving her tools to create a space between her reactions and instead take a different neural pathway,”Myers says. “These are the kind of tools that we’re looking to have people use.” “A focus needs to be on the body-based piece as well as the cognitive piece in order for wholeness to really be manifested.” - Nikki Myers

Not a replacement Myers is quick to point out that yoga is not a substitute for traditional 12-step support, but rather an additional measure that some people may find helpful. She says some people have pushed back against the practice, but others have been enthusiastic about its power, with classes spreading across the country and even internationally. Myers says she hopes that one day 12-step yoga will be as common as other treatment programs. But she says as long as people are maintaining sobriety and finding wholeness within themselves, she’ll be proud of the difference her system has made. “We’ll tell people, ‘Notice this in your body, what it really feels like,’” Myers says. “Healing only happens in safe space.”

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INTERVIEW 4

Discrimination, whether based on race, gender, or sexual orientation, has long been thought to be a contributor to substance abuse. Now a new study has confirmed the relationship between discrimination and addiction, but it’s also brought up many more questions that still need to be answered in order to improve treatment outcomes. Researchers at the University of Iowa recently completed a peer review study in which they looked at 97 previous studies on discrimination and alcohol use. Their goal was to summarize the collective knowledge researchers have uncovered throughout the years, and what they found confirmed in more detail what many had previously suspected.

“Generally there is good scientific support, but the evidence is mixed for different groups

and for types of discrimination.” - Dr.Paul Gilbert, University of Iowa

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overtly racist or sexist to another person. But less research has been done on what are known as micro-aggressions, small everyday occurrences that can rub a person the wrong way. That research is improving, but there are other factors that need to be more fully explored. While studies have looked at historical trauma in the African-American population, the concept has not been fully investigated with regards to Hispanic and Asian populations. “This notion of historic trauma could be really relevant to other groups, but it hasn't received much attention at all,” Dr. Gilbert says. “This is something we should pay attention to.” All of this adds up to the fact that treatment providers may be missing a key piece of the substance abuse puzzle.

INTERVIEW 4 The team found that discrimination did indeed lead to an increase in drinking frequency, quantity of alcohol consumed, and in the risk for alcohol use disorders. Researchers say drinking can represent a coping mechanism in response to the stress caused

by discrimination, and several studies showed clients acknowledging this direct link themselves. But when looking at specific populations and types of discrimination, the picture becomes less clear. “The story is that generally there is good scientific support, but the evidence is mixed for different groups and for types of discrimination,” says Dr. Paul Gilbert, the study’s lead author. “We don’t really know comparing one type or one level to another.” For example, much research has been done on interpersonal discrimination where someone is

But just because the intricacies of how discrimination affects drinking aren’t yet fully understood, that doesn’t mean our current knowledge base can’t be helpful. Dr. Gilbert says simply knowing that experiences with discrimination can drive drinking could inform the way treatment providers interact with clients, opening new areas of their lives to explore during treatment. “It can serve as sort of an early warning or indicator,” Dr. Gilbert says. “For treatment providers, it’s worth looking at: is there something that may be keeping folks from accessing services or affecting outcomes?”

Dr. Gilbert says treatment providers should continue to address discrimination as part of a holistic approach to recovery. He says it will be up to researchers to fill

in the gaps to find the precise ways that discrimination affects drinking behavior. “We’ve got good evidence on this level of interpersonal discrimination,” Dr. Gilbert says. “We’ve gotten the low-hanging fruit, now it’s time to start working on the stuff that’s a little further up the tree.”

“It can serve as sort of an early warning or indicator.”

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PAIN IS REAL, BUT SO IS HOPE!

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