Posts Tagged ‘opioid’

Scientists at The Scripps Research Institute (TSRI) have achieved a major milestone toward designing a safe and effective vaccine to both treat heroin addiction and block lethal overdose of the drug. Their research, published today in the journal Molecular Pharmaceutics, shows how a new anti-heroin formulation that is safe in animal models remains stable at room temperature for at least 30 days. As a result, the vaccine is close to being ready for human testing.

“The heroin vaccine is one step closer to clinical evaluation,” says Candy S. Hwang, PhD, first author of the study and a research associate at TSRI.

According to the National Institute on Drug Abuse, 15,446 Americans died from heroin overdose between 2000 and 2016, and the mortality rates are increasing. Heroin abuse has been further fueled by a rise in prescription opioid abuse—studies show that opioid pain reliever users are 40 times more likely to abuse heroin.

The first formulation of the heroin vaccine was developed in 2013 by a team led by Kim D. Janda, PhD, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI. It has been shown to be effective—and safe—in both mouse and non-human primate models.

The vaccine works by training the immune system antibodies to recognize and bind to heroin molecules, blocking the drug from reaching the brain to cause a “high.” Researchers believe that blocking the high of heroin will help eliminate the motivation for many recovering addicts to relapse into drug use.

The heroin molecule does not naturally prompt an antibody response, so researchers attach it to a carrier protein that alerts the immune system to start making antibodies. Scientists also add an ingredient called an adjuvant to the vaccine, which boosts the immune response and makes the vaccine more effective.

Hwang says, “Our goal was to prepare a vaccine that could be advanced to clinical trials. As such, we were looking for the best combination of ‘hapten’ (the heroin molecule), carrier protein and adjuvant to keep the vaccine both stable for transport and storage but still efficacious.”

For the new study, the researchers investigated how 20 different carrier protein/adjuvant combinations worked, including shelf stability based on temperature and storage time and whether the formulation was a liquid or powder.

Their experiments in rodent models showed that the best vaccine formulation contained a carrier protein called tetanus toxoid (TT) and adjuvants called alum and CpG ODN. The discovery that alum worked best as an adjuvant was especially significant since alum is one of the few adjuvants used in vaccines already approved by the U.S. Food and Drug Administration. The researchers also found that there was no difference in how well it worked between the liquid and powder versions of this formulation.

Hwang notes that the best vaccine formulation showed protection against lethal doses of heroin. This is particularly important as many heroin addicts have succumb to overdose and death during their attempts to quit the drug.

With this new study, the researchers have shown that the vaccine is safe and effective in animal models, stable under clinical conditions and reliant on an already-approved adjuvant. The next step is to find a producer to make the vaccine on a large scale.

“We believe that a heroin vaccine would be tremendously beneficial for people who have a heroin substance use disorder but have found difficulty in trying to quit,” says Hwang.

In addition to Hwang and Janda, authors of the study, “Enhancing Efficacy and Stability of an Anti-Heroin Vaccine: Examination of Antinociception, Opioid Binding Profile, and Lethality,” were Paul T. Bremer, Cody J. Wenthur, Beverly Ellis and Bin Zhou of The Scripps Research Institute; and Sam On Ho, SuMing Chiang and Gary Fujii of Molecular Express, Inc.

The study was supported by the National Institutes of Health (grants UH3DA041146, F32AI126628, F32DA043323, R42DA040422 and R44AI094770).

https://www.scripps.edu/news/press/2018/20180213janda.html

Kratom

Posted: February 9, 2018 in Uncategorized
Tags: , , ,

by MARY JO DILONARDO

Fans of the herb kratom say it offers pain relief, calms anxiety, and can help ease opioid withdrawal symptoms. However, a new report from the Food and Drug Administration says the popular herbal substance acts like a prescription-strength opioid and is associated with several dozen deaths.

What exactly is this polarizing botanical drug?

What is kratom?
Kratom is a tropical tree (Mitragyna speciosa) related to coffee that is native to Southeast Asia. Leaves from the tree have been used for centuries as a traditional remedy for pain.

The leaves can be eaten raw, but are usually crushed and made into a powder. The powder is then consumed in capsules, smoked or brewed in teas.

According to the U.S. Drug Enforcement Administration, consumption of kratom in low doses produces simulating effects. However, in large amounts it acts as a sedative, and can lead to psychotic symptoms, as well as psychological and physiological dependence.

Why there is concern
The DEA includes kratom on its Drugs of Concern list (substances that aren’t regulated by the Controlled Substances Act, but that could pose risks to people who abuse them), and the National Institute of Drug Abuse has identified kratom as an emerging drug of abuse.

Between 2010 and 2015, the Centers for Disease Control and Prevention noted a tenfold increase in calls about kratom to poison control centers across the U.S., from 26 to 263. About 42 percent of those cases involved non-life-threatening symptoms that required some treatment. About 7 percent were classified as major and life-threatening.

In the February 2018 report, FDA Commissioner Scott Gottlieb, M.D. said, “There is no evidence to indicate that kratom is safe or effective for any medical use. And claiming that kratom is benign because it’s ‘just a plant’ is shortsighted and dangerous. After all, heroin is an illegal, dangerous, and highly-addictive substance containing the opioid morphine, derived from the seed pod of the various opium poppy plants.”

Gottleib warned of potential side effects including changes in neurologic and cardiovascular function. He also cited 44 reported deaths “associated with the use of kratom.”

Consumer Reports points out other possible dangers associated with kratom:

Kratom has been found to be laced with opioids, including tramadol and hydrocodone.
There’s little research about drug interactions, and users are mixing kratom with legal and illegal drugs, which can be dangerous.
Some users who have turned to kratom to kick an opioid addiction have become hooked on kratom instead.
It kratom legal?
In 2016, the DEA announced plans to list kratom as a Schedule 1 substance, which would add it to the ranks of LSD, heroin, marijuana and ecstasy. The plan would have essentially banned kratom, but the DEA changed course and instead gave the public a chance to comment.

Now, the substance is mostly legal in the U.S., depending on where you live. According to the American Kratom Association, several cities, counties and seven states (Alabama, Arkansas, Indiana, Rhode Island, Tennessee, Vermont and Wisconsin) and the District of Columbia have banned or seriously restricted the use of kratom.

While supporters are working hard to keep kratom legal, the DEA and detractors argue that the substance is not safe.

“We’ve learned a tragic lesson from the opioid crisis,” Gottleib said. “That we must pay early attention to the potential for new products to cause addiction and we must take strong, decisive measures to intervene.”

https://www.mnn.com/health/fitness-well-being/stories/what-kratom-and-it-dangerous

By Christopher Ingraham

There’s a body of research showing that painkiller abuse and overdose are lower in states with medical marijuana laws. These studies have generally assumed that when medical marijuana is available, pain patients are increasingly choosing pot over powerful and deadly prescription narcotics. But that’s always been just an assumption.

Now a new study, released in the journal Health Affairs, validates these findings by providing clear evidence of a missing link in the causal chain running from medical marijuana to falling overdoses. Ashley and W. David Bradford, a daughter-father pair of researchers at the University of Georgia, scoured the database of all prescription drugs paid for under Medicare Part D from 2010 to 2013.

They found that, in the 17 states with a medical-marijuana law in place by 2013, prescriptions for painkillers and other classes of drugs fell sharply compared with states that did not have a medical-marijuana law. The drops were quite significant: In medical-marijuana states, the average doctor prescribed 265 fewer doses of antidepressants each year, 486 fewer doses of seizure medication, 541 fewer anti-nausea doses and 562 fewer doses of anti-anxiety medication.

But most strikingly, the typical physician in a medical-marijuana state prescribed 1,826 fewer doses of painkillers in a given year.

These conditions are among those for which medical marijuana is most often approved under state laws. So as a sanity check, the Bradfords ran a similar analysis on drug categories that pot typically is not recommended for — blood thinners, anti-viral drugs and antibiotics. And on those drugs, they found no changes in prescribing patterns after the passage of marijuana laws.

“This provides strong evidence that the observed shifts in prescribing patterns were in fact due to the passage of the medical marijuana laws,” they write.

In a news release, lead author Ashley Bradford wrote, “The results suggest people are really using marijuana as medicine and not just using it for recreational purposes.”

One interesting wrinkle in the data is glaucoma, for which there was a small increase in demand for traditional drugs in medical-marijuana states. It’s routinely listed as an approved condition under medical-marijuana laws, and studies have shown that marijuana provides some degree of temporary relief for its symptoms.

The Bradfords hypothesize that the short duration of the glaucoma relief provided by marijuana — roughly an hour or so — may actually stimulate more demand in traditional glaucoma medications. Glaucoma patients may experience some short-term relief from marijuana, which may prompt them to seek other, robust treatment options from their doctors.

The tanking numbers for painkiller prescriptions in medical marijuana states are likely to cause some concern among pharmaceutical companies. These companies have long been at the forefront of opposition to marijuana reform, funding research by anti-pot academics and funneling dollars to groups, such as the Community Anti-Drug Coalitions of America, that oppose marijuana legalization.

Pharmaceutical companies have also lobbied federal agencies directly to prevent the liberalization of marijuana laws. In one case, recently uncovered by the office of Sen. Kirsten Gillibrand (D-N.Y.), the Department of Health and Human Services recommended that naturally derived THC, the main psychoactive component of marijuana, be moved from Schedule 1 to Schedule 3 of the Controlled Substances Act — a less restrictive category that would acknowledge the drug’s medical use and make it easier to research and prescribe. Several months after HHS submitted its recommendation, at least one drug company that manufactures a synthetic version of THC — which would presumably have to compete with any natural derivatives — wrote to the Drug Enforcement Administration to express opposition to rescheduling natural THC, citing “the abuse potential in terms of the need to grow and cultivate substantial crops of marijuana in the United States.”

The DEA ultimately rejected the HHS recommendation without explanation.

In what may be the most concerning finding for the pharmaceutical industry, the Bradfords took their analysis a step further by estimating the cost savings to Medicare from the decreased prescribing. They found that about $165 million was saved in the 17 medical marijuana states in 2013. In a back-of-the-envelope calculation, the estimated annual Medicare prescription savings would be nearly half a billion dollars if all 50 states were to implement similar programs.

“That amount would have represented just under 0.5 percent of all Medicare Part D spending in 2013,” they calculate.

Cost-savings alone are not a sufficient justification for implementing a medical-marijuana program. The bottom line is better health, and the Bradfords’ research shows promising evidence that medical-marijuana users are finding plant-based relief for conditions that otherwise would have required a pill to treat.

“Our findings and existing clinical literature imply that patients respond to medical marijuana legislation as if there are clinical benefits to the drug, which adds to the growing body of evidence suggesting that the Schedule 1 status of marijuana is outdated,” the study concludes.

One limitation of the study is that it only looks at Medicare Part D spending, which applies only to seniors. Previous studies have shown that seniors are among the most reluctant medical-marijuana users, so the net effect of medical marijuana for all prescription patients may be even greater.

The Bradfords will next look at whether similar patterns hold for Medicaid.

https://www.washingtonpost.com/news/wonk/wp/2016/07/13/one-striking-chart-shows-why-pharma-companies-are-fighting-legal-marijuana/

Thanks to Kebmodee for bringing this to the It’s Interesting community.

The U.S. Food and Drug Administration today approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for six months in patients who are already stable on low-to-moderate doses of other forms of buprenorphine, as part of a complete treatment program.
Until today, buprenorphine for the treatment of opioid dependence was only approved as a pill or a film placed under the tongue or on the inside of a person’s cheek until it dissolved. While effective, a pill or film may be lost, forgotten or stolen. However, as an implant, Probuphine provides a new treatment option for people in recovery who may value the unique benefits of a six-month implant compared to other forms of buprenorphine, such as the possibility of improved patient convenience from not needing to take medication on a daily basis. An independent FDA advisory committee supported the approval of Probuphine in a meeting held earlier this year.

“Opioid abuse and addiction have taken a devastating toll on American families. We must do everything we can to make new, innovative treatment options available that can help patients regain control over their lives,” said FDA Commissioner Robert M. Califf, M.D. “Today’s approval provides the first-ever implantable option to support patients’ efforts to maintain treatment as part of their overall recovery program.”

Expanding the use and availability of medication-assisted treatment (MAT) options like buprenorphine is an important component of the FDA’s opioid action plan and one of three top priorities for the U.S. Department of Health and Human Services’ Opioid Initiative aimed at reducing prescription opioid and heroin related overdose, death and dependence.

Opioid dependence is the diagnostic term used for the more common concept, “addiction,” in the Probuphine clinical trials. Addiction is defined as a cluster of behavioral, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use, persisting in drug use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, as well as the possibility of the development of tolerance or development of physical dependence. Physical dependence is not the same as addiction. Newer diagnostic terminology uses the term “opioid use disorder,” which includes both milder forms of problematic opioid use as well as addiction.

MAT is a comprehensive approach that combines approved medications (currently, methadone, buprenorphine or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder. Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use, without causing the cycle of highs and lows associated with opioid misuse or abuse. At sufficient doses, it also decreases the pleasurable effects of other opioids, making continued opioid abuse less attractive. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for their opioid use disorder cut their risk of death from all causes in half.

“Scientific evidence suggests that maintenance treatment with these medications in the context of behavioral treatment and recovery support are more effective in the treatment of opioid use disorder than short-term detoxification programs aimed at abstinence,” said Nora Volkow, M.D., director of the National Institute on Drug Abuse at the National Institutes of Health. “This product will expand the treatment alternatives available to people suffering from an opioid use disorder.”

Probuphine should be used as part of a complete treatment program that includes counseling and psychosocial support. Probuphine consists of four, one-inch-long rods that are implanted under the skin on the inside of the upper arm and provide treatment for six months. Administering Probuphine requires specific training because it must be surgically inserted and removed. Only a health care provider who has completed the training and become certified through a restricted program called the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program should insert and remove the implants. If further treatment is needed, new implants may be inserted in the opposite arm for one additional course of treatment. The FDA is requiring postmarketing studies to establish the safety and feasibility of placing the Probuphine implants for additional courses of treatment.

The safety and efficacy of Probuphine were demonstrated in a randomized clinical trial of adults who met the clinical criteria for opioid dependence and were considered stable after prior buprenorphine treatment. A response to MAT was measured by urine screening and self-reporting of illicit opioid use during the six month treatment period. Sixty-three percent of Probuphine-treated patients had no evidence of illicit opioid use throughout the six months of treatment – similar to the 64 percent of those who responded to sublingual (under the tongue) buprenorphine alone.

The most common side effects from treatment with Probuphine include implant-site pain, itching, and redness, as well as headache, depression, constipation, nausea, vomiting, back pain, toothache and oropharyngeal pain. The safety and efficacy of Probuphine have not been established in children or adolescents less than 16 years of age. Clinical studies of Probuphine did not include participants over the age of 65.

Probuphine has a boxed warning that provides important safety information for health care professionals, including a warning that insertion and removal of Probuphine are associated with the risk of implant migration, protrusion, expulsion and nerve damage resulting from the procedure. Probuphine must be prescribed and dispensed according to the Probuphine REMS program because of the risks of surgical complications and because of the risks of accidental overdose, misuse and abuse if an implant comes out or protrudes from the skin. As part of this program, Probuphine can only be prescribed and dispensed by health care providers who are certified with the REMS program and have completed live training, among other requirements.

Probuphine implants contain a significant amount of drug that can potentially be expelled or removed, resulting in the potential for accidental exposure or intentional misuse and abuse if the implant comes out of the skin. Patients should be seen during the first week after insertion and a visit schedule of no less than once-monthly is recommended for continued counseling and psychosocial support.

Probuphine is marketed by San Francisco-based Titan Pharmaceuticals Inc. and Braeburn Pharmaceuticals based in Princeton, New Jersey.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503719.htm

Written by Honor Whiteman

Anew study has questioned the benefits of opioid painkillers, after finding the drugs might worsen chronic pain rather than ease it.

Study co-leader Prof. Peter Grace, of the University of Colorado at Boulder (CU-Boulder), and colleagues recently published their findings in the Proceedings of the National Academy of Sciences.

Opioids are among the most commonly used painkillers in the United States; almost 250 million opioid prescriptions were written in 2013 – the equivalent to one bottle of pills for every American adult.

Previous studies have suggested opioids – such as codeine, oxycodone, morphine, and fentanyl – are effective pain relievers. They bind to proteins in the brain, spinal cord, and gastrointestinal tract called opioid receptors, reducing pain perception.

Increasing use and abuse of opioids, however, has become a major public health concern in the U.S.; opioid overdoses are responsible for 78 deaths in the country every day.

Now, Prof. Grace and colleagues have questioned whether opioids really work for pain relief, after finding the opioid morphine worsened chronic pain in rats.

Just 5 days of morphine treatment increased chronic pain in rats
According to Prof. Grace, previous studies assessing morphine use have focused on how the drug affects pain in the short term.

With this in mind, the researchers set out to investigate the longer-term effects of morphine use for chronic pain.

For their study, the team assessed two groups of rats with chronic nerve pain. One group was treated with morphine, while the other was not.

Compared with the non-treatment group, the team found that the chronic pain of the morphine group worsened with just 5 days of treatment. What is more, this effect persisted for several months.

“We are showing for the first time that even a brief exposure to opioids can have long-term negative effects on pain,” says Prof. Grace. “We found the treatment was contributing to the problem.”

Another ‘ugly side’ to opioids
According to the authors, the combination of morphine and nerve injury triggered a “cascade” of glial cell signaling, which increased chronic pain.

Glial cells are the “immune cells” of the central nervous system, which support and insulate nerve cells and aid nerve injury recovery.

They found that this cascade activated signaling from a protein called interleukin-1beta (IL-1b), which led to overactivity of nerve cells in the brain and spinal cord that respond to pain. This process can increase and prolong pain.

The researchers say their findings have important implications for individuals with chronic pain – a condition that is estimated to affect around 100 million Americans.

“The implications for people taking opioids like morphine, oxycodone and methadone are great, since we show the short-term decision to take such opioids can have devastating consequences of making pain worse and longer lasting. This is a very ugly side to opioids that had not been recognized before.”

Study co-leader Prof. Linda Watkins, CU-Boulder

It is not all bad news, however. The researchers found they were able to reverse morphine’s pain-increasing effect using a technique called “designer receptor exclusively activated by designer drugs” (DREADD), which involves the use of a targeted drug that stops glial cell receptors from recognizing opioids.

“Importantly, we’ve also been able to block the two main receptors involved in this immune response, including Toll-Like receptor 4 (TLR4) and another one called P2X7R, which have both been separately implicated in chronic pain before,” notes Prof. Grace.

“By blocking these receptors, we’re preventing the immune response from kicking in, enabling the painkilling benefits of morphine to be delivered without resulting in further chronic pain.”

He adds that drugs that can block such receptors are currently in development, but it is likely to be at least another 5 years before they are available for clinical use.

http://www.medicalnewstoday.com/articles/310645.php

Thanks to Kebmnodee for bringing this to the attention of the It’s Interesting community.