New approaches are in the pipeline including a 'buprenorphine implant' that will last 6 months.

WHAT IS DRUG ADDICTION AND WHAT CAUSES IT TO HAPPEN?

Addiction is a chronic, often relapsing brain disease that causes compulsive drug seeking and use. Although the initial decision to take drugs is voluntary for most people, the brain changes that occur over time challenge a person’s self control and ability to resist intense impulses urging them to take drugs.

Addiction affects the brain circuits involved in reward, motivation, memory, and inhibitory control. When these circuits are disrupted, so is a person’s capacity to freely choose not to use drugs. In fact, the inability to stop is the essence of addiction, like riding in a car with no brakes.

Addiction is similar to other chronic diseases. PET scans showing healthy versus diseased brain of a cocaine user and health versus diseased heart. Using imaging technology to measure metabolism (in this case, glucose uptake) in the brain and heart, one can see that both addiction and heart disease produce observable changes in organ function. In each pair of images shown to the left, the healthy organ shows greater activity (reds and yellows) than the diseased organ. In drug addiction, the frontal cortex, which is a part of the brain associated with judgment and decision-making, is significantly affected. Like heart disease, drug addiction can be prevented and treated successfully. If left untreated, however, its effects can last a lifetime. Image from NIDA

When drugs enter the brain, they can interrupt the work and actually change how the brain performs its jobs. These changes are what lead to compulsive drug use, the hallmark of addiction.

WHAT REGIONS OF THE BRAIN DOES DRUG ABUSE AFFECT?

Drugs of abuse affect three primary areas of the brain: the brain stem, the limbic system and the cerebral cortex.

The brain stem is in charge of all of the functions our body needs to stay alive—breathing, circulating blood, and digesting food. It also links the brain with the spinal cord, which runs down the back and is responsible for moving muscles and limbs as well as letting the brain know what’s happening to the body. The limbic system links together a bunch of brain structures that control our emotional responses, such as feeling pleasure when we eat chocolate. The good feelings motivate us to repeat the behavior, which is good because eating is critical to our lives. The cerebral cortex is the mushroom-like outer part of the brain (the gray matter). Some areas process information from our senses, enabling us to see, feel, hear, and taste. The front part of the cortex, known as the frontal cortex or forebrain, is the thinking center. It powers our ability to think, plan, solve problems, and make decisions. --Image source from NIDA

WHAT HAPPENS IN THE BRAIN?

Normally, the reward circuit responds to pleasurable experiences by releasing the neurotransmitter dopamine, which creates feelings of pleasure, and tells the brain that this is something important—pay attention and remember it. Drugs hijack this system, causing unusually large amounts of dopamine to flood the system. This flood of dopamine is what causes the “high” or euphoria associated with drug abuse. The brain adapts in response to the overwhelming surges in dopamine. The brain adjusts by decreasing the number of dopamine receptors available– thus diminishing the function of the reward circuit. Drug addicts are compelled to abuse drugs to bring their dopamine function back up to normal, requiring ever larger amounts to achieve the initial dopamine high– an effect known as tolerance. Image and source from NIDA

WHY IS IT SO DIFFICULT TO HAVE A PERMANENT RECOVERY?

What makes permanent recovery difficult is that the drug-induced changes create lasting memories that link the drug to a pleasurable reward. Since many of the brain circuits that govern learning and memory are affected by addiction,. long-term memories are formed by the activity of brain substances (called transcription factors). So repeatedly taking drugs can change the brain cells and make the memory of the pleasurable effects very strong. When a person is addicted, they get conditioned just like Pavlovian dogs. Even after transcription factor levels return to normal, addicts may remain hypersensitive and the risk of relapse in addicts can persist long after they stop taking the drug.

CURRENT TREATMENTS

Methadone

Methadone is a synthetic opiate was developed in Germany during WWII because of a dwindling supply of morphine. Because of its slow metabolic breakdown, it was later used to block or decrease the cravings and withdrawal symptoms from persons that were addicted to opiates such as heroin. Methadone, as an opiate, is a central nervous system depressant and is not a cure for opiate addiction. Methadone lessens the cravings for opiates and coupled with counseling, facilitates recovery. Methadone has a 40-year history of demonstrated success in the treatment of opiate addiction. When used in proper doses in maintenance treatment, methadone does not create euphoria, sedation or an analgesic effect.

Pros and Cons Weblinks

Methadone Pros and Cons. Is MMT Right for You?
What are the pros and cons of treatment with Methadone?

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Current Clinical Trials using Methadone

Buprenorphine

Buprenorphine is an opioid partial agonist . This means that, although buprenorphine is an opioid, and thus can produce typical opioid agonist effects and side effects such as euphoria and respiratory depression, its maximal effects are less than those of full agonists like heroin and methadone. At low doses buprenorphine produces sufficient agonist effect to enable opioid-addicted individuals to discontinue the misuse of opioids without experiencing withdrawal symptoms. The agonist effects of buprenorphine increase linearly with increasing doses of the drug until at moderate doses they reach a plateau and no longer continue to increase with further increases in dose—the “ceiling effect.” Thus, buprenorphine carries a lower risk of abuse, addiction, and side effects compared to full opioid agonists. In fact, in high doses and under certain circumstances, buprenorphine can actually block the effects of full opioid agonists and can precipitate withdrawal symptoms if administered to an opioid-addicted individual while a full agonist is in the bloodstream. (source)

Buprenorphine itself binds more strongly to receptors in the brain than do other opioids, making it more difficult, regardless of the presence of the naloxone, to become intoxicated via other opioids when buprenorphine is in the system. If enough buprenorphine is in the system, however, it has the same type of effect as naloxone; i.e., it completely or nearly completely blocks or reverses opiate effects from other opioids. 0.3 mg of buprenorphine parenterally is equivalent in antagonistic effect to between 0.4 and 2.0 mg of naloxone parenterally, but with a much longer half-life (WIKI)

According to Walter Ling, M.D., Professor of Psychiatry and Director of the Integrated Substance Abuse Programs (ISAP) at UCLA ..."Buprenorphine is probably the most important advance in treating opiate addiction since the introduction of methadone,""The reason is that buprenorphine, because of its unique pharmacological property, allows the doctors to be more flexible in its use." "The introduction of buprenorphine is giving back the treatment of heroin addiction, or all opiate addiction, to the hands of the physicians.

Buprenorphine (Suboxone and Subutex) are currently available in pill form or film form. The pill or film is taken orally to be absorbed beneath the tongue. Most people take buprenorphine in daily doses. Many people in early recovery have a hard time holding and managing their own buprenorphine. Medication is often lost, stolen or sold.

VIVITROL

Vivitrol is long-acting form of the opioid antagonist naltrexone. Naltrexone is used along with counseling and social support to help people who 'have stopped drinking alcohol and using street drugs' continue to avoid drinking or using drugs.

The Food and Drug Administration recently approved Vivitrol for treating opiate addiction, based on positive research findings in heroin-addicted patients in Russia. The study was done with 250 heroin addicts in Russia. It showed that relapse was reduced (compared to a placebo injection) and allays narcotic cravings. At the end of six months, 86 percent of patients taking Vivitrol were drug-free, going to counseling sessions and functioning in a job or at school, compared to 57 percent of those who got a placebo. (Some experts say that placebo success rate is higher than they'd expect in this country.)

Naltrexone should not be started prior to several (typically 7-10) days of abstinence from opioids. This is due to the risk of acute opioid withdrawal if naltrexone is taken, as naltrexone will displace most opioids from their receptors. Naltrexone is only helpful when it is used as part of an addiction treatment program.

RB'S Suboxone film

RB’s Suboxone combines buprenorphine with naloxone, another drug that deters opioid drug abuse. Suboxone was first developed as a tablet placed under the tongue. RB later developed a dissolvable film version, also placed under the tongue. The product’s sale grew as buprenorphine continues to grow as an opioid dependence treatment option. The Suboxone film is the only transmucosal product available. But Suboxone’s drawback has been an unpleasant taste. Sullivan said nearly all of his patients complain about the taste, but they have had no alternative.

IN THE PIPELINE TREATMENTS

BEMA Buprenorphine

Like Suboxone, BEMA Buprenorphine combines buprenorphine and naloxone in a single transmucosal product. BDSI is developing BEMA Buprenorphine through the U.S. Food and Drug Administration’s 505(b)(2) pathway, which allows the company to seek approval by showing its product is bioequivalent to the already-approved Suboxone. A series of studies requested by the FDA are ongoing or on track to start in 2012. The last study, a safety study in opioid dependent patients, is expected to produce data in the first quarter of 2013. BDSI expects it will be in position to file a new drug application shortly after.

The BEMA drug delivery technology consists of a small, bioerodible polymer film for application to the mucosal membranes (inner lining of cheek). BEMA films are designed to: Adhere to oral mucosa in less than 5 seconds, optimize delivery across the oral mucosa and completely dissolve within 15 to 30 minutes. Daily use is required as with Suboxone.

PROBUPHINE 6 MONTH IMPLANT

Probuphine is buprenorphine in the form of an implant. The probuphine implant delivers a constant dose of the drug for six months, eliminating the need for a daily pill and big obstacle in preventing relapse. The probuphine implant is a small, solid rod. The implant is placed under the skin, usually in the upper arm, by a doctor in a simple office procedure. Probuphine patients get 6 months of continuous buprenorphine dosing from a single implant. One of the problems with buprenorphine in pill form is abuse. Doctors have no way of knowing if their patients are taking the medication as prescribed or selling the pills to others.

Original Contribution Buprenorphine Implants for Treatment of Opioid Dependence: A Randomized Controlled Trial Walter Ling, Paul Casadonte, George Bigelow, Kyle M. Kampman, Ashwin Patkar, Genie L. Bailey, Richard N. Rosenthal, Katherine L. Beebe JAMA. 2010;304(14):1576-1583. read abstract

In an editorial accompanying the study, Dr. Patrick O'Connor of the Yale University School of Medicine, says the study findings represent a potentially important step forward in treating opiate dependence. "If further research suggests that this buprenorphine implant is as good as or better than current treatment approaches," O'Connor writes, "then the study … would represent a major advance in the substantial and continued progress that has occurred in the treatment of opioid dependence since methadone maintenance began in the 1960s."

Subcutaneous buprenorphine implants (Probuphine™) deliver constant, low levels of buprenorphine for up to six months with minimal fluctuations in steady-state plasma concentration, and offer potential treatment advantages over sublingual buprenorphine by ensuring patient compliance and limiting diversion. In previous studies, treatment with buprenorphine implants has been shown to be well-tolerated and efficacious in significantly reducing illicit opioid use, retaining patients in treatment, controlling withdrawal symptoms and opioid cravings, and improving global disease severity.

In recently released results of a six month, randomized, controlled, phase 3 trial comparing buprenorphine implants to placebo implants and sublingual buprenorphine/naloxone it was shown that the implants was non-inferior and comparable to sublingual buprenorphine.

In addition ..."Patients treated with sublingual buprenorphine during the initial 24 week period and then switched to the probuphine implants during the 24 week re-treatment phase reported high levels of satisfaction with the implants in comparison to sublingual buprenorphine...." see abstract of data.

Note: The Probuphine implant is a product of Titan Pharmaceuticals and is expected to be available in 2013.

Vaccines against narcotics

The scientists who are working to create vaccines against narcotics include Thomas Kosten at the Baylor College of Medicine and S. Michael Owens at the University of Arkansas and Kim Janda from Scripps Research Institute. Dr. Kosten has had limited success with a cocaine vaccine, while Dr. Owens is focused on vaccines for methamphetamines.

The initial problem confronting Janda in producing a vaccine was that these drugs, make terrible targets because they are way too small for the immune system to even detect them. To overcome that, Dr. Janda attaches a hapten — which is either a bit of the drug itself, or a synthetic version of it — to a larger protein that acts as a platform. The last part of the vaccine is an adjuvant, a chemical cocktail that attracts the immune system’s notice, effectively tricking it into making antibodies against a substance it usually wouldn’t see.

In July 2011 , Janda made news when he announced that an anti-heroin vax seemed to work in rat experiments (see article in Medical News Today) meaning it could move into safety trials for humans. However considering the recent setback with a nicotine vaccine using a similar approach it appears that vaccines of this type are still many years away.

Drug Name	Molecular Structure	Mechanism of Action	Use
Buprenorphine (see 3-D structure of molecule and information)		Buprenorphine is a partial opioid agonist. It binds to the µ-opioid receptors in the brain that are responsible for opioid intoxication.. Buprenorphine has very high affinity for µ-opioid receptors receptors and therefore is not displaced by other opioids. Since it is a partial agonist, it does not produce as much euphoria but does suppress withdrawal and cravings.	Buprenorphine is a semi-synthetic opioid that is used to treat opioid addiction
Naltrexone (see 3-D structure of molecule and information)		Naltrexone and its active metabolite 6-ß-naltrexol are competitive antagonists at µ- and k-opioid receptors, and to a lesser extent at d-opioid receptors	The main use of naltrexone is for the treatment of alcohol dependence
Naloxone (see 3-D structure of molecule and information)		Naloxone appears to antagonize the opioid effects by competing for the same receptor sites, especially the opioid mu receptor. Recently, naloxone has been shown to bind all three opioid receptors (mu, kappa and gamma) but the strongest binding is to the mu receptor.	Naloxone is a drug used to counter the effects of opiate overdose.
Methadone (see 3-D structure of molecule and information)		Methadone is a full µ-opioid agonist. Methadone also binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate.	Methadone is used for treatment of moderate-to-severe pain and maintenance treatment of addiction to heroin.
Morphine (see 3-D structure of molecule and information)		Morphine first acts on the mu-opioid receptors. It has also been shown that morphine binds to and inhibits GABA inhibitory interneurons. These interneurons normally inhibit the descending pain inhibition pathway. So, without the inhibitory signals, pain modulation can proceed downstream.	Morphine is mainly used for treating short-term and long-term pain in adults
Hydrocodone(Vicodin) (see 3-D structure of molecule and information)		Acts at µ-opioid receptors	Vicodin is used to relieve moderate to severe pain
Oxycodone --(Ocycontin) (see 3-D structure of moleculeand information)		The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.	OxyContin is used to treat moderate to severe pain

References

Addiction Science: From Molecules to Managed Care
Brain and Addiction
Drug Implant for Opioid Addiction Looks Effective
Hooked: Why it's not so easy to "just say no"
Important Treatment Advances for Addiction to Heroin and other Opiates --Nora D. Volkow
Drug Abuse.gov
Dopamine in drug abuse and addiction: results of imaging studies and treatment implications.
Why bad habits are hard to break
The Changing Landscape of Vaccine Development: Vaccines for Chronic Diseases
An Addiction Vaccine, Tantalizingly Close
Researcher Makes a Career Developing Cocaine Vaccine, But Pharmaceutical Companies Won’t Produce It
Drug Implant for Opioid Addiction Looks Effective