1. Description of the Related Art
Problem Drinking
Consumption of alcohol is an accepted part of modern life in most societies, and for most individuals, self-moderation of alcohol intake ensures that alcohol consumption is non-problematic with respect to posing adverse health or social consequence(s). For some individuals, alcohol consumption does not remain with safe limits within single sessions or over longer time periods and, for those individuals, problem drinking may develop.
As used herein, the term “problem drinking” means an acute or chronic alcohol consumption associated with the development of one or more life problems or adverse health effects, including actual adverse consequence(s) and an elevated risk thereof. Commonly, problem drinking is harmful and/or hazardous to any person, and/or likely to lead to alcohol dependency or constitute alcohol dependency in the consumer. Alcohol misuse is similar to hazardous drinking in so far as it refers to any alcohol consumption that is associated with risk, ranging from hazardous drinking to alcohol dependence.
Problem drinking imposes a significant burden to the individual in terms of reduced physical and/or mental and/or social health and well-being, as well as possible adverse economic effects. For example, problem drinkers suffer from or have increased risk relative to moderate drinkers of contracting any one or more of a number of diseases or conditions indicative of poor health e.g., fatty liver disease; hypermegaly of the liver; alcoholic hepatitis; cirrhosis of the liver; renal hypermegaly, renal failure; cancer, such as oesophageal cancer, lip cancer, oral cancer, pharyngeal cancer, laryngeal cancer or breast cancer; cardiovascular disease; coronary heart disease; hyperglycemia; hypoglycemia e.g., in diabetic subjects; hypertensive disease; ischemic heart disease; ischemic stroke; hemorrhagic stroke; gout; arthritis; protein-energy malnutrition e.g., as determined by deficiency in one or more of protein, calcium, iron, vitamin A, vitamin C, thiamine, vitamin B6 and riboflavin, and/or impaired absorption of one or more of calcium, phosphorus, vitamin D and zinc; neuropathy; dementia; impaired balance; impaired memory; depression; anxiety; or insomnia. Risk factors for cardiovascular disease e.g., elevated blood pressure and/or elevated high density lipoprotein (HDL) content, are well-documented side-effects of problem drinking. Impaired neuropsychological functioning may also promote risk-taking behavior e.g., unprotected sex, aggression, other substance misuse, as well as contribute to short-term memory dysfunction and/or long-term memory dysfunction in the problem drinker.
In addition to adverse effects and disease implications for problem drinkers, problem drinking in pregnant females may produce adverse consequences for their unborn fetus leading to one or more neonatal and/or childhood problems e.g., reduced birth weight, reduced active sleep period, growth deficit, central nervous system (CNS) dysfunction including impaired brain function, learning difficulty, mental retardation, craniofacial abnormality, poor host defense, elevated incidence and severity of infection, or long-lasting deficiency in humoral and/or cell-mediated immunity including B cell deficiency. Fetal alcohol syndrome (FAS) may develop in offspring exposed in utero to alcohol.
Alternatively, or in addition, there are obvious adverse social effects of problem drinking e.g., third party personal injury arising from machine use by problem drinkers when intoxicated or suffering from other problems of alcohol abuse, injury to property by problem drinkers, and abusive behavior. Problem drinking also carries significant social costs resulting e.g., from premature mortality, reduced health and income. For example, acute and chronic problem drinking leads to increased health care costs associated with treatment of injured or unwell individuals, and education programs to increase awareness of the problem or prevent problem drinking, as well as increased social security costs in supplementing lost income. The costs of social, health and welfare programs vary between countries, however it is not unusual for approximately 1-2% of GDP to be spent on the prevention or treatment of problem drinking in the OECD countries. For example, AUD 3.83 billion was spent in Australia in 1992 on treatment and/or prevention of problem drinking, accounting for 1.0% of that country's GDP.
Problem drinking is characterized by high frequency of alcohol intake and/or high level of alcohol consumption. Problem drinking includes any pattern of high alcohol consumption e.g., in single weekly sessions or during multiple days in one or more weeks, or over an extended period of time e.g., one or more months or over several years.
For example, problem drinking may be any acute or chronic excessive alcohol consumption that is sufficient to reduce the health of the consumer. For example, harmful drinking is an acute or chronic excessive alcohol consumption that has caused damage to health e.g., physical damage such as liver damage from chronic drinking or mental damage such as episodic depression secondary to drinking. Chronic alcohol abusers or misusers who consume excessive amounts of alcohol on a regular basis e.g., harmful or hazardous drinkers, may not demonstrate marked impairment at high blood alcohol levels however are more likely to suffer from long-term health defects.
Alternatively, or in addition, problem drinking is a pattern and/or level of alcohol consumption that is sufficient to increase a risk of disease in a subject. For example, hazardous drinking is any acute or chronic excessive alcohol consumption carrying with it a risk of harmful consequences to the drinker e.g., damage to physical or mental health, or social consequence to the drinker or others. Individuals who consume large quantities of alcohol on particular occasions, however otherwise consume moderate amounts of alcohol on a regular e.g., weekly basis, including binge drinkers and heavy drinkers, generally present an acute risk of injury, and/or violence and/or loss of control affecting others as well as themselves.
Exemplary chronic and acute drinking behaviors that are considered to be either harmful drinking or hazardous drinking are provided in Table 1. Equivalent alcohol intake frequencies and levels to those listed in Table 1 are obtained for any one-month period or any annual period by standard procedures and, for example, a male consuming about 1000 g or more alcohol per calendar month, or a female consuming about 800 g or more alcohol per calendar month, is a heavy drinker.
Because the alcohol contents of different types of alcoholic beverages e.g., wine, spirit, beer and ale, often vary considerably, the term “standard drink” was introduced in an attempt to standardize safe and non-safe drinking behaviors e.g., Table 2. This merely provides consumers with a conversion factor for determining a number of alcoholic beverages of a particular kind that may be consumed in a specified period of time without becoming harmful/hazardous behavior e.g., based on weight of alcohol consumption in a defined period as provided in Table 1 hereof.
The demographics of problem drinkers also suggest heterogenic groupings of individuals based on patterns of drinking, wherein the bulk of problem drinkers engage in acute harmful or hazardous drinking as opposed to having an established pattern over a longer period of time i.e., chronic problem drinking. However, all categories of problem drinker pose health and social problems. For example, a smaller section e.g., 5-10% of problem drinkers suffer multiple negative consequences of chronic harmful drinking or chronic hazardous drinking behavior, whilst a larger section e.g., 10-20% of problem drinkers suffer from a single adverse consequence such as memory loss of chronic harmful drinking or chronic hazardous drinking behavior, and an even larger proportion e.g., up to about 70-85%, of problem drinkers engage in acute problem drinking behavior with injurious results. All such classes are likely to have attempted suicide at some stage, however those suffering multiple negative consequences are more likely to suffer from a generalized anxiety disorder or mixed anxiety or depressive disorder. Excess consumption increases the risk of injury or disease almost exponentially in proportion to the frequency and/or level of alcohol consumption.
TABLE 1Behavioral alcohol consumption index for problem drinking behaviorsHarmful/hazardousDrinking BehaviorAlcohol intake (males)Alcohol intake (females)Chronic drinkingEquivalent of 250 grams or moreEquivalent of 160 grams or morealcohol consumed per day for 7 days inalcohol consumed per day for 4 days orany one-week periodmore in any one-week periodororEquivalent of 490 grams or moreEquivalent of 250 grams or morealcohol consumed per day for 4-6 daysalcohol consumed per day for 2-3 daysin any one-week periodin any one-week periodororEquivalent of 240 grams or moreEquivalent of 360 grams or morealcohol consumed per day for 2-3 daysalcohol consumed per day for 2 or morein any one-week perioddays in any one-week periodororTwo or more bouts of binge drinking orTwo or more bouts of binge drinking orheavy drinking in any two-week periodheavy drinking in any two-week periodororLess than two alcohol-free days in anyLess than two alcohol-free days in anyone-week periodone-week periodororAlcohol intake sufficient to reach aAlcohol intake sufficient to reach ablood alcohol level of 0.05% on two orblood alcohol level of 0.05% on two ormore consecutive days in any one-weekmore consecutive days in any one-weekperiodperiodorAny regular alcohol consumption overtwo or more consecutive days whenpregnant or breast-feedingBinge DrinkingAlcohol intake sufficient to reach aAlcohol intake sufficient to reach ablood alcohol level of 0.08% on at leastblood alcohol level of 0.08% on at leastone day in a one-week periodone day in a one-week periodHeavy DrinkingEquivalent of 250 grams of alcohol onEquivalent of 90 grams of alcohol onone day in a one-week periodone day in a one-week periodOther Acute ProblemAlcohol intake sufficient to reach aAlcohol intake sufficient to reach aDrinkingblood alcohol level of 0.05% on one dayblood alcohol level of 0.05% on one dayin a one-week periodin a one-week periodorAny alcohol consumption on one daywhen pregnant or breast-feeding
TABLE 2Exemplary alcohol contents of standard drinksMass Alcohol inCountryStd. Drink (g)Australia10Austria6Canada13.5Denmark12Finland11France12Hungary17Iceland9.5Ireland10Italy10Japan19.75Netherlands9.9New Zealand10Poland10Portugal14Spain10UK7.9USA14
Chronic harmful or chronic hazardous drinking behavior clearly increases the risk of developing alcohol dependence syndrome, which may also be considered a form of problem drinking. Alcohol dependence syndrome is a cluster of cognitive, behavioral, and physiological symptoms characterized by three or more of the following symptoms in a twelve-month period:    1. a strong desire or sense of compulsion to drink; and/or    2. difficulties in controlling drinking in terms of onset, termination, or levels of use; and/or    3. a physiological withdrawal state when alcohol use has ceased or been reduced, or use of alcohol to relieve or avoid withdrawal symptoms; and/or    4. evidence of tolerance, such that increased doses of alcohol are required to achieve effects originally produced by lower doses; and/or    5. progressive neglect of alternative pleasures or interests because of alcohol use; and/or    6. continued use despite clear evidence of harmful consequences.Predictors of Problem Drinking
Widespread risk factors in early life are associated with problem drinking, and both genetic and environmental factors have been associated with the development of problem drinking.
For example, children of alcoholics are significantly more likely than children of non-alcoholics to initiate drinking during adolescence and to develop alcohol dependency, and early initiation of drinking is an important risk factor for later alcohol-related problems. Lack of parental support, monitoring, and communication have been significantly related to frequency of drinking, heavy drinking, and drunkenness among adolescents. Harsh, inconsistent discipline and hostility or rejection are also predictive of adolescent drinking and alcohol-related problems.
Child abuse and other trauma have been proposed as risk factors for subsequent alcohol problems. Adolescents in treatment for alcohol abuse or dependence reported higher rates of physical abuse, sexual abuse, violent victimization, witnessing violence, and other traumas compared with controls such that adolescents in treatment are about 6 times more likely than controls to have ever been abused physically and at least 18 times more likely to have ever been abused sexually. At least about 10% of problem drinking adolescents have experienced posttraumatic stress disorder.
Of the numerous markers associated with problem drinking in men at age 30, low birth weight, number of life crises in childhood, ratings of childhood unhappiness and antisocial personality disorder have been shown to be independent risk factors.
Peer drinking and peer acceptance of drinking are also important factors associated with problem drinking in adolescents.
Accordingly, acute hazardous drinking behavior in a subject having one or more of the foregoing risk factors may be indicative of the subject being at risk of developing problem drinking.
Current Therapies
Current therapies for harmful and/or hazardous drinking are limited to brief interventions by families, friends and health care professionals. Such brief interventions generally involve counseling to reduce alcohol consumption. Currently, there are no therapeutics having proven efficacy in preventing or treating non-dependent problem drinking, especially acute problem drinking.
Pharmaceutical therapeutics for treatment of alcohol dependence syndrome generally address alcohol withdrawal or relapse, but have no proven effect in prolonging abstinence beyond the short-medium term e.g., up to about 6 months.
For example, during detoxification, patients in primary care may be administered one or more benzodiazepines to manage withdrawal symptoms including delirium tremens, albeit for a maximum period of seven days. For patients managed in the community, chlordiazepoxide or valium is a preferred benzodiazepine for managing withdrawal symptoms. Patients suffering from Wemicke-Korsakov syndrome are administered Pabrinex over several days, ideally in an inpatient setting having adequate resuscitation facilities.
To assist in preventing relapse or prolong abstinence in subjects suffering from alcohol dependence syndrome, acamprosate may be administered to newly-detoxified dependent patients as an adjunct to psycho-social intervention. Acamprosate acts on the GABA and glutamate neurotransmitter systems and is thought to reduce symptoms of protracted abstinence such as insomnia, anxiety, restlessness, and dysphoria. Acamprosate may increase the proportion of dependent drinkers who maintain abstinence for several weeks to months, wherein about 36% of patients taking acamprosate were continuously abstinent after 6 months, compared with 23% of subjects taking a placebo.
Topiramate, a putative GABA agonist and glutamate antagonist, has been shown to increased the proportion of subjects with 28 consecutive days of abstinence or non-hazardous/harmful drinking i.e., short-term abstinence.
Naltrexone may also reduce alcohol cravings in dependent subjects, by blocking opioid receptors that are involved in the rewarding effects of drinking alcohol and the craving for alcohol. Oral naltrexone also reduces relapse during the first 3 months by about 36%, however it less effective in maintaining abstinence over the medium to long term.
Disulfuram may be administered orally, however it requires abstinence to avoid disulfuram—alcohol reaction resulting flushing, nausea, and palpitations.
Acamprosate, naltrexone, topiramate and disulfuram each have serious contraindications associated with their use, including common side effects of nausea, vomiting, decreased appetite, headache, dizziness, fatigue, anxiety, reactions at injection sites, joint pain, muscle aches or cramps, diarrhea, somnolence, dermatitis, taste perversion, anorexia and weight loss, and cognitive dysfunction. Hepatitis, liver failure and renal impairment may arise from use of naltrexone or acamprosate.
It is clear that there is a need for new drugs for the treatment and/or prevention of problem drinking, especially in non-dependent problem drinkers and for prolonging abstinence in dependent problem drinkers beyond a short term.