Alcohol and drug abuse is the number one healthcare problem in the United States, representing approximately 3.7% of the Gross National Product. According to the National Institute on Alcohol Abuse and Alcoholism, as much as $185 billion each year is spent directly and indirectly related to alcoholism. We estimate that in the United States and Europe, there are in excess of 22 million alcoholics and 2.0 million heroin addicts. According to the Office of National Drug Control Policy, in the United States, there are an estimated 5 to 6 million cocaine addicts. Substance abuse can have severe social and medical consequences, including imprisonment, car accidents, overdose, liver failure, infections such as HIV and viral hepatitis, and death. In addition, the National Institute of Health estimated that $246 billion dollars is lost each year in the United States due to absenteeism and lost productivity at work related to alcohol and drug abuse.
We estimate that less than 10% of alcholics and drug addicts, approximately 1.2 million patients in the United States, receive treatment for their addiction. According to the Substance Abuse and Mental Health Services Administration, the majority of alcohol and drug abuse patients that receive treatment are treated in the limited number of specialized addiction care centers.Alcohol treatment centers are increasingly playing an important role in curing substance dependency.
Current treatments consist primarily of psychosocial therapy and drug-substitution therapy and are generally not effective in curing alcohol and drug addiction. According to the National Drug and Alcohol Treatment Unit Survey, in 1992, nearly $7.1 billion was spent in the United States to treat alcohol and drug abuse.An estimated $11.00 of social and medical costs are saved for every dollar spent on substance abuse treatment according to the New York State Office of Alcoholism and Substance Abuse Services. Despite the potential medical benefits and cost-savings of treating addictions, we believe the market for addiction care is poorly served by the pharmaceutical industry and that the medical community needs new products to effectively treat alcohol abuse and drug addictions.
Addiction is a chronic disease of the brain triggering the compulsive use of substances like alcohol, heroin, cocaine and methamphetamine at increasing and more frequent doses, despite severe social and medical consequences. Scientists have only recently started to uncover the biology of addiction at the molecular level.
Alcohol and all drugs of abuse interfere with normal neurological pathways that are responsible for transmitting signals in the brain, particularly the pathway that involves the neurotransmitter dopamine. This dopamine pathway in the brain controls euphoria and pain.
All addictive substances impact dopamine directly or indirectly. Alcohol and heroin stimulate a receptor in the brain called the opiate receptor. Heroin binds directly to the opiate receptor, while alcohol triggers the release of naturally occurring endorphins, which then bind to the opiate receptor. Stimulation of the opiate receptor by heroin or alcohol-induced endorphins causes cells to release dopamine. Unlike alcohol and heroin, methamphetamine triggers a direct release of dopamine, while cocaine prevents the normal reabsorption of dopamine following its release. Excess levels of dopamine overstimulate the dopamine receptors of nearby cells, triggering feelings of euphoria.
The scientific community increasingly understands the molecular biology of opiate and dopamine receptors, potentially enabling the rational design of novel medications targeting these receptors. Opiate receptors include several subtypes, mu, delta, and kappa, which are located on the outside of a neuron membrane in several regions of the brain. The opiate receptors are made of proteins that contain six helices. Molecules such as endorphins, morphine, heroin and methadone bind specifically to the helices located in the outer region of the receptor, modify their shape, and trigger transmission of an intracellular signal by the inner region of the receptor.
The molecules that stimulate the opiate receptor are called receptor agonists. Stimulation of the receptors can induce euphoria and resistance to pain. Other molecules, such as naltrexone, can bind to the receptor without triggering its stimulation and can prevent the binding of agonists. They are called antagonists. Dopamine receptors belong to a family of protein receptors expressed on the membrane of neurons in various areas of the brain. Dopamine binds to and stimulates three categories of dopamine receptors called D1, D2 and D3, which mediate different neurochemical signals.
Seven protein helices linked by protein loops make these receptors. Their shape changes when dopamine occupies the receptor, triggering a signal transmission to the neuron. Control of movement, cognitive functions, cardiovascular functions, behavior and emotions involve D1, D2 and D3 receptors.
When brain cells are repeatedly exposed to addictive substances, levels of dopamine and other neurotransmitters, such as serotonin and GABA, and their corresponding neuroreceptors are chronically modified, creating a chemical imbalance. As a result of this chemical-imbalance, an abuser's neurological pathways demand the presence of the addictive substance and the abuser has become addicted. Once addicted, the substance abuser will use the substance more frequently to induce euphoria at the expense of normal activities. The substance abuser will also increase the amount of the substance taken, because an increased concentration of alcohol or drug becomes necessary to obtain the same level of euphoria. As dopamine and the other affected neurotransmitters play a key role in multiple brain functions, this chemical imbalance often leads to other neurological manifestations such as impaired judgement and perceptions, memory loss, depression, irritability, aggressive behavior, seizures and thoughts of suicide.
- acute effects of a drug overdose or binge drinking
- chronic toxicity of repeated use on various biological systems and brain functions
- acute withdrawal syndrome
- lifelong risk of relapse Acute effects
Drug overdose and binge drinking affect multiple organs and biological systems. Acute intoxication often results in psychotic episodes, respiratory or cardiovascular distress, accidental injury or death. For example, a 1992 study, The Economic Costs of Alcohol and Drug Abuse in the U.S., has shown that approximately 40% of fatal car accidents in the United States are alcohol-related. The Drug Abuse Warning Network estimated 250,000 emergency room visits per year are the result of drug overdose.
As brain chemistry is modified on a chronic basis, substance abusers may suffer multiple psychiatric and neurological disorders such as depression, suicidal thoughts and psychotic behavior. Permanent neurological damage may occur.
Withdrawal is a condition resulting from sudden discontinuation of a substance to which a person is addicted. Withdrawal from alcohol can result in rapid heart rate, difficulty sleeping and life threatening delirium tremens. Heroin withdrawal can result in irritability, pain, nausea, vomiting, cramps and muscle aches. Withdrawal from cocaine or methamphetamine can result in irritability, sleeplessness, and depression.
The ultimate goal of medical treatment for addicts is to achieve an alcohol- and drug-free state called abstinence. However, several studies found that for patients who have achieved abstinence, the rate of relapse is high within the first months of therapy, and remains a significant risk over the patient's lifetime. Relapse can be very severe, and many patients experience multiple cycles of detoxification, abstinence, relapse and overdose. Due to the long-term risk of relapse, alcohol abusers and drug addicts are life-long patients.
Care for addiction includes chronic therapy and emergency therapy. Chronic therapy promotes and attempts to maintain long-term abstinence following detoxification. Emergency therapy attempts to reverse the effects of overdose. Few medications are available to promote abstinence in alcohol and heroin abusers. No medication is available to treat cocaine and methamphetamine addiction or overdose. Studies have shown that as many as eighty percent of patients are not compliant with their therapeutic regimen, typically resulting in treatment failure.
Chronic therapy relies heavily on psychosocial therapy because few medications are available. Psychosocial therapy, which consists of regular counseling sessions, is the cornerstone of addiction care but has limited success because it does not address the biological basis of addiction.
There are two types of medications available for long-term therapy of addicts. Substitution therapy is the use of a pharmaceutical product that mimics the abused substance. Abstinence therapy is the use of a medication to help the addict abstain from substance use and cure addiction.
Substitution therapy is used for heroin addicts whose dependence is too severe to permit abstinence therapy. It consists of medications which are chemically related to heroin and which bind to and stimulate the opiate receptor. These medications prevent withdrawal symptoms and maintain the state of addiction, but in a medically-controlled environment. Substitution therapy is not a cure for addiction. However, there are significant medical and social benefits, such as reducing the risk of contracting infections and decreasing propensity to commit crime.Substitution therapy can be used as a temporary therapy for patients who can then be detoxified and become abstinent, or as a long-term therapy for severe addicts who are unresponsive to abstinence therapies.
Abstinence therapy is medically more desirable than substitution therapy, as it can effectively reduce dependence and may restore normal brain functions. However, there are few medications available to promote abstinence, and medication non-compliance is a major limitation. An estimated 80% of patients fail to take their medication on a daily basis as prescribed and typically relapse into severe alcohol and heroin abuse. A minority of alcoholics and heroin addicts receiving abstinence treatment typically remain abstinent after one year.
The existing medications are summarized in the following table.
| Product/First US Approval Date | Technology | Usage | Substance of Abuse | Dosage Regimen / Limitation | |
| Methadone (1975) | Binds to and stimulates opiate receptor | Substitution therapy | Heroin and other opiates | Requires daily therapy at a licensed clinic | |
| Buprenorphine* | Binds to and stimulates opiate receptor | Substitution therapy | Heroin and other opiates | Requires daily therapy | |
| LAAM (1993) | Binds to and stimulates opiate receptor | Substitution therapy | Heroin and other opiates | Requires therapy 2 times per week at clinic | |
| Naltrexone (1984, heroin; 1994, alcohol) | Blocks opiate receptor | Abstinence maintenance | Alcohol and heroin | Daily/non-compliance | |
| Acamprosate** | GABA antagonist | Abstinence maintenance | Alcohol | Daily/non-compliance | |
| Disulfiram (1951) | Induces nausea and vomiting upon alcohol absorption | Relapse prevention | Alcohol | Toxicity/non-compliance | |
| *Approved in France in 1995. **Approved in France in 1987 and subsequently in other European countries. |
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The opiate agonists, methadone, LAAM and buprenorphine, are the three substitution medications. According to the Substance Abuse and Mental Health Services Administration, an estimated 180,000 patients in the United States use methadone. Sales of this off-patent generic product are subject to low pricing, with approximately $20.0 million in sales in 1999 in the United States. Methadone binds to the opiate receptor, triggering a stimulation of the dopamine pathway. It decreases the use of heroin but maintains dependence. Licensed methadone clinics dispense methadone and typically require the patient to visit several times per week. LAAM is structurally related to methadone, has similar effects, and is administered three times a week at the clinic. Buprenorphine, currently marketed only in France, is a compound structurally related to methadone, but which stimulates the opiate receptor to a lesser extent. An estimated 62,000 patients in France, approximately 37% of the heroin addict population, use buprenorphine on a daily basis. In 1999, sales in France reached approximately $80 million. Buprenorphine therapy may result in significant diversion of use and potential lethal overdoses, as the patient is responsible for administration.
The two main products available to promote and maintain abstinence are naltrexone, for alcoholics and heroin addicts, and acamprosate (available only in the EU) for alcoholics. Both naltrexone and acamprosate are available as oral daily tablets. Naltrexone is an opiate antagonist that blocks the opiate receptor, thereby decreasing the effects of and desire to use both alcohol and heroin, and promoting an alcohol and heroin-free state when used on a chronic basis. Acamprosate only affects alcohol dependence. Worldwide sales of branded and generic naltrexone were an estimated $34 million in 1999. Sales of acamprosate were an estimated $20 million in 1999. Naltrexone and acamprosate have a similar efficacy and safety profile in alcoholics and are both limited by severe patient non-compliance. To avoid prescribing therapies which will not be used, physicians typically prescribe these medications only to the small subset of their patients who are highly motivated to comply. We believe that we can develop a sustained-release formulation of naltrexone to address the issue of non-compliance, but that acamprosate is not conducive to sustained-release formulation development because of the high dose required to obtain a therapeutic effect. The other medication to treat alcoholism is disulfiram. Disulfiram induces nausea and vomiting when the patient drinks alcohol because it increases the concentration of toxic alcohol byproducts. Few patients are willing to use disulfiram long term.
For cocaine and methamphetamine dependence, no medication is currently available.
Emergency therapy focuses on reversing the life-threatening effects of alcohol and drug overdose. The goal is to use an antidote to block the effect of or rapidly remove the toxic substance from the patient's blood stream and tissue, reduce the complications of the overdose and lower the overall cost of emergency care. Heroin is the only drug of abuse for which there is an antidote, called naloxone. Naloxone binds to the opiate receptor, displaces molecules of heroin already bound to the receptor, and prevents further binding of heroin to the receptor. For cocaine and methamphetamine overdose, there is no antidote available.
Other medications commonly used in alcoholics and drug addicts are products to treat medical conditions resulting from substance abuse such as depression, infectious diseases or liver dysfunction.
We believe that due to the seriousness of addiction and the low compliance with current medications, there is a substantial need for medications that treat the biological basis of addiction, facilitate medication compliance through less frequent dosing schedules and promote alcohol and drug abstinence.