Sex and Gender Differences in Alcohol Use Disorder

Sex and Gender Differences in Alcohol Use Disorder

At the end of the lecture, you will be able to: • Discuss recommended levels of drinking for men and women. • Define Alcohol Use Disorder (AUD). • Discuss sex differences in pathology seen with alcohol consumption. • Screen for AUD using validated screening tools. • Describe effective treatments for AUD. Objectives

What is Normal Drinking?

One Drink is… 1 • 12 fl oz of regular beer (5% alcohol) • 8 -9 fl oz of malt liquor (7% alcohol) • 5 fl oz of table wine (12% alcohol) • 1. 5 fl oz shot of 80 -proof spirits: i. e. hard liquor, whiskey, gin, rum, vodka, tequila, etc. . . (40% alcohol) What counts as a drink?

NIAAA (National Institute of Alcohol Abuse and Alcoholism) Recommendations Differ for Women & Men: *keep in mind that “low risk”, which varies between individuals, is not “NO risk”. Drinking Recommendations

Alcohol Metabolism

“Alcohol” as consumed in the diet is in the form of ethanol. In the body, ethanol is absorbed from upper GI tract where it enters the hepatic portal system and is taken to the liver for hepatic metabolism. 1 Alcohol Metabolism

Metabolism: 1 • Ethanol to Acetaldehyde via alcohol dehydrogenase (ADH). • Aldehyde to Acetate via aldehyde dehydrogenase (ALDH). • Acetate used as energy for the body. Alcohol Metabolism

First Pass Metabolism • The liver contains an ADH isoform that is active at low ethanol concentrations and is therefore responsible for metabolizing the majority of ethanol in the body. 1 • Higher first pass metabolism in males contributes to lower blood alcohol concentrations (BACs) compared to females. 1 Alcohol Metabolism

Women have faster rates of alcohol elimination when corrected for lean body mass. 1 Alcohol Dehydrogenase (ADH) levels: • Females between the ages of 25 -55 have less stomach ADH compared to age-matched males. 2 • ADH levels for older males (>50 years old) and females are the same. 2 • Thus, a 30 year old female consuming the same amount of alcohol as a 30 year old male will have more alcohol entering her system. Sex Differences in Alcohol Metabolism

Epidemiology of Alcohol Abuse

Average of first drink in surveyed college students: 1 16. 5 years old Drinking among minors: • 41% of 9 th grade girls (aged 14) report drinking in the past month. 2 • This rate is roughly the same for boys of the same age. 2 • More than 20% of these girls report 5+ drinks on a single occasion in the past month. 2 Early Drinking

Early drinking has been tied to a greater risk of abusive consumption and development of Alcohol Use Disorder (AUD). 1 • Drinking at the ages of 11 -14 tied to highest risk of progression to harmful drinking. 1 Early Drinking

1980’s • Alcohol Use Disorders were 5 x more common in men than women. 1 2008 • Alcohol Use Disorders were only 2 x more common in men than women. 2 Sex Differences

Women: • Report a later age of onset of alcohol dependence by approximately 3 years. 1 • Are significantly less likely to have had previous alcohol treatment. 1 • Drink fewer drinks per drinking day. 1 • Go to primary health care more frequently than to specialty substance abuse programs for treatment. 1 • Have greater difficulty admitting that drinking harms their health and are less likely to admit their health problems are related to drinking. 2 Sex Differences

Women: Heavy/problematic drinking is more common among women who: 1 • Have never married • Live unmarried with a partner • Are divorced or separated Sex Differences

Women: Factors increasing the likelihood women will drink excessively: 1 • Blood relatives with alcohol problems • A partner who drinks heavily • The ability to “hold her liquor” more than others • History of depression • History of childhood physical or sexual abuse Sex Differences

Relapse rates are similar between men and women. 1 Men • More likely to relapse when unmarried or single 2, 3 • Less likely to be married to problem drinker 1 • Marriage protective against relapse 2 Relapse

Women • More likely to relapse in the company of friends or romantic partners 1 • More likely to be married to a problem drinker 1 • Married women are more likely to relapse 2, 3 • Interpersonal conflict reported as a precipitating event for relapse more often 4 Relapse

Alcohol use increases the risk for several cancers including: 1 • Mouth • Esophagus • Pharynx • Liver • Breast • Colon (5 or more drinks/day) • Rectal (5 or more drinks/day) Cancer

Females • More sensitive than males to all alcohol-related cancers. 1 • With as little as one drink per day, women greatly increase their risk for breast cancer. 1 • 11% of breast cancers are attributed to alcohol use. 1 Cancer

Males • Men who abuse alcohol frequently present with co-morbid antisocial personality disorder and dependency on other drugs. 1 Psychiatric

Females • Psychiatric disorders linked with alcohol abuse are more frequent in women. 1 • Alcohol use disorders & co-morbid mood disorders are more prevalent in women. 2 • Depressed women may experience stronger cravings to drink than depressed men. 3, 4 • The desire to drink alcohol when an individual is living with a depressed mood manifests more intensely in women than men. 3, 4 Psychiatric

Fetal Alcohol Spectrum Disorders • Full range of physical, learning, and behavioral problems that result from prenatal alcohol exposure. 1 • Fetal Alcohol Syndrome (FAS) is the most serious of these defects. • Leading preventable birth defect in the United States. 1 • According to the CDC, prevalence ranges from 0. 1 to 1. 5 cases per 1, 000 live births. 2 Birth Defects

Fetal Alcohol Syndrome • Characterized by facial dysmorphology, CNS abnormalities, and growth deficiency. 1 • Brains are smaller than normal and contain fewer cells. 2 • Average annual medical expenses for a child with FAS is nine times greater than those for children without FAS. 1 Birth Defects

Alcohol Withdrawal Syndrome (AWS) • Chronic alcohol use removes the neural “brakes” and sudden abstinence can cause the brain to be hyperexcitable. • Symptoms may appear within hours of stopping or even lowering alcohol intake. 1 • AWS can present during hospital stays and confound the presentation of other medical conditions. • Be aware of alcohol abuse to recognize AWS, initiate prophylaxis promptly, and maximize treatment. Alcohol Withdrawal

Alcohol Withdrawal Symptoms: 1 • Tremor • Craving for alcohol • Loss of appetite • Insomnia • Nausea/vomiting • Vivid dreams • Headache • Anxiety • Sweating • Hypervigilance • Delirium tremens (DTs), 5% mortality • Agitation/irritability Alcohol Withdrawal

Alcohol Withdrawal Management: 1 • Step 1: Monitor patient symptoms. • Step 2: Assess with Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) scale. • Quantifies symptoms consistent with DT. • Patient’s score determines appropriate treatment. CIWA-Ar Scale: Mild Withdrawal: Score < 8 Severe Withdrawal: Score ≥ 8 No pharmacotherapy recommended. Pharmacotherapy recommended. Withdrawal Management

Alcohol Withdrawal Pharmacotherapy: 1 • Benzodiazepines are the pharmacotherapy of choice for alcohol withdrawal: • Diazepam (long-acting) • Chlordiazepoxide (long-acting) • Lorazepam (short-acting) • Requires concurrent inpatient monitoring. • In the E. R. or inpatient setting, patients supplemented with normal saline (I. V. ), thiamine, glucose, multivitamin with folate, and electrolyte replacement. Withdrawal Pharmacotherapies

Alcohol-Related Pathology

Males • Males have a higher prevalence for alcohol dependence than females. 1 General

Females • Females are more susceptible to the toxic effects of alcohol than males. 1 • Develop alcohol problems later in life than males. 2 • Female alcoholics have death rates 50 -100% higher than those of male alcoholics. 2 • Deaths include those from alcohol-related accidents, heart disease, stroke, liver cirrhosis, and suicide. General

Moderate consumption of alcohol may confer cardiovascular protection in men and women. 1 • Studies have reported a 30% to 50% coronary risk reduction among moderate drinkers as compared to nondrinkers. 1 • 50% of coronary heart disease risk reduction is attributed to alcohol-related increases in HDL cholesterol. 1 • Heavy alcohol use, however, increases risk for negative complications. 1 Cardiovascular- Benefits

Females In a Nurse’s Health Study, female subjects who consumed one drink of alcohol per day experienced a 40% reduction in Coronary Heart Disease risk as compared with nondrinkers over a 4 year period!1 Cardiovascular- Benefits

Chronic and binge alcohol use can lead to: • Hypertension. 1 • Arrhythmias including atrial fibrillation and ventricular tachycardia. 1 • Stroke, even with no preexisting coronary heart disease. 1 • Cardiovascular disease. 1 • Alcohol use linked to decreased fibrinogen and tissue-type plasminogen activator. 2 • Levels of HDL cholesterol, fibrinogen, and hemoglobin A 1 C accounted for 75% observed correlation between drinking frequency and myocardial infarction in females and 100% in males. 2 Cardiovascular- Risks

Long-term drinking can lead to alcoholic cardiomyopathy. 1, 2 • Females more susceptible to this condition than males. Cardiovascular- Risks

Heavy drinking can lead to fat deposition in the liver (steatosis), hepatitis, fibrosis, and even cirrhosis. 1 Males A majority of patients who suffer from alcoholic liver disease are male. 2 Liver

Females • Significantly higher risk of developing cirrhosis at any level of alcohol intake. 1 Liver • In a study where subjects consumed 28 -41 drinks/week, males were found to have one-third the risk of developing cirrhosis when compared to females. 1 • Females only require 20 -60 g/day of alcohol to increase risk of developing cirrhosis, while males require 40 -80 g/day. 1

Heavy drinking can trigger acute pancreatitis. 1 • Over 200, 000 people in the United States suffer from acute pancreatitis each year and a large percentage of these cases are due to heavy alcohol consumption. 1 Repeated attacks of acute pancreatitis can lead to chronic pancreatitis. 1 • Complications include reduced pancreatic function, reduced digestion, and inability to regulate the blood sugar (diabetes). 1 • Death has also been reported. 1 Pancreas

Chronic alcohol use tied to global cerebral atrophy and neurodegeneration in males and females. 1 Males More susceptible to white matter losses in corpus callosum. 2 Brain

Females • More sensitive to degenerative effects of prolonged alcohol dependence and binge alcohol intake. 1 • Alcohol-dependent females show greater loss of brain matter, greater loss of brain volume, and increased sulcal and ventricular CSF than alcohol-dependent males. 2 • More susceptible to white matter losses in frontal and temporal lobes. 1 • White matter recovers more quickly with abstinence. 1 Brain

Males • Alcohol consumption tied to impotence, infertility, and reduced male secondary sex characteristics. 1 • Alcohol inhibits Sertoli and Leydig cell function in testes. 1 • High alcohol consumption tied to reduced Testosterone levels in the blood. 1 • Alcohol decreases production of LH and FSH from the pituitary gland in males. 1 • May also impair hormone secretion from the hypothalamus, which regulates the male sex hormones. 1 Reproductive

Females • Alcoholism linked to amenorrhea, irregular menorrhea, infertility, and spontaneous abortions in reproductive aged females. 1 • Animal models have shown that high levels of alcohol intake alone can be associated with these gynecological changes. 2 • Evidence indicates people who are heavy drinkers have decreased luteinizing hormone (LH) levels. 1, 2 • Pathologically, the ovaries of animals with amenorrhea resemble those of a menopausal animal suggesting that alcoholinduced amenorrhea could be misinterpreted by a physician or patient as menopause without further information. 3 Reproductive

Alcohol Use Disorder

Alcohol Use Disorder (AUD) is indicated by the presence of at least 2 of the following symptoms: 1 • Alcohol is often taken in larger amounts or over a longer period than was intended. • There is a persistent desire or unsuccessful efforts to cut down or control alcohol use. • A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects. • Craving, or a strong desire or urge to use alcohol. • Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home. Alcohol Use Disorder (DSM V)

Alcohol Use Disorder Criteria Continued: 1 • Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol. • Important social, occupational, or recreational activities are given up or reduced because of alcohol use. • Recurrent alcohol use in situations in which it is physically hazardous. • Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol. Alcohol Use Disorder (DSM V)

Alcohol Use Disorder Criteria Continued: 1 • Tolerance, as defined by either of the following: • A need for markedly increased amounts of alcohol to achieve intoxication or desired effect. • A markedly diminished effect with continued use of the same amount of alcohol. • Withdrawal, as manifested by either of the following: • The characteristic withdrawal syndrome for alcohol as defined by DSM 5. • Alcohol (or a closely related substance, such as benzodiazepine) is taken to relieve or avoid withdrawal symptoms. Alcohol Use Disorder (DSM V)

The severity of the Alcohol Use Disorder is defined as: 1 • Mild: the presence of 2 to 3 symptoms. • Moderate: the presence of 4 to 5 symptoms. • Severe: the presence of 6 or more symptoms. Alcohol Use Disorder (DSM V)

Screening Tools

CAGE - Four-question screening tool commonly used by physicians in primary care to screen for Alcohol Use Disorder. 1 • Yes to two or more of these questions is considered a positive test for alcohol abuse. 1 CAGE Questionnaire

CAGE Questions: 1 1. Have you ever felt that you need to Cut down on your drinking? 2. Have you been Annoyed when people criticize your drinking? 3. Do you ever feel Guilt about your drinking? 4. Do you ever need an Eye-opener (a drink first thing in the morning)? CAGE Questionnaire

Pros: 1 • Simple to use. • Fast. Cons: 2 • Insensitive in detecting heavy drinking. • Does not distinguish between a current or past drinking problem. CAGE Questionnaire

Gender Differences: 3 • Men are consistently more likely to answer “yes” to each CAGE question after adjustments are made for ethnicity, income, and alcohol use indicators. • Given these findings, it is expected that many men who do not meet the full criteria for AUD would answer “yes” to each question. CAGE Questionnaire

World Health Organization- The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) • Eight-item questionnaire designed to assess current and lifetime substance abuse. 1 • A score of 5 or more has been shown to identify alcohol abuse with a sensitivity of 66% and specificity of 66%. 2 WHO-ASSIST

Pros: 1 • High reliability. Cons: • Long administration time (average of 16 minutes). 1 • Lower sensitivity and specificity than other screening measures. 2 WHO-ASSIST

Alcohol Use Disorder Identification Test (AUDIT) • Ten-question screening tool used to detect excessive drinking and alcohol dependence. 1 AUDIT Instrument

Pros: • Comprehensive. • Identifies recent heavy drinking and alcohol dependence more effectively than CAGE. 1 • Higher ROC value, sensitivity, and specificity than WHO-ASSIST. 2 Cons: • Significant length makes it difficult to implement in primary care setting. 1 AUDIT Instrument

Gender Differences: • Ability to detect current dependence and high risk alcohol use was good in men and excellent in women. 1 • Alcohol Use Disorder specificity of 80% attained at different scores on the AUDIT scale for men and women: 1 • Score of 5 or greater in females. • Score of 8 or greater in males. AUDIT Instrument

Alcohol Use Disorder Identification Test for Clinicians (AUDIT-C) • Shortened form of the AUDIT Instrument (three questions) that is catered for use in a primary care setting. 1 • AUDIT-C does not perform as well overall as the traditional AUDIT analysis, but has acceptable sensitivity and excellent specificity for the identification of heavy drinking. 1 AUDIT-C Instrument

AUDIT-C Questions: 1 1. How often did you have a drink containing alcohol in the past year? 2. How many drinks did you have on a typical day when you were drinking in the past year? 3. How often did you have 6 or more drinks on one occasion in the past year? AUDIT-C Instrument

Treatment

Cognitive Behavioral Coping Skills Therapy (CBST)1 • Drinking viewed as being related to major problems in person’s life. • Skills-training to: • Overcome deficits and increase one’s ability to cope with high risk relapse precipitants. • Develop adaptive strategies for coping with life stressors rather than alcohol use. Behavioral Treatment

Motivational Enhancement Therapy (MET)1 • Based on motivational psychology, a way of approaching problem drinkers that helps to evoke change. • Focused on helping the patient develop her or his own internal motivation for change. • Attention is given to recognize and empower each patient’s innate capability for change. Behavioral Treatment

Twelve Step Facilitation Therapy (TSF)1 • Engages patients in the fellowship of Alcoholics Anonymous. • Alcoholism is viewed as a medical disease and results from spiritual imbalance. • Complete the 12 steps of Alcoholics Anonymous. • Attend group sessions and develop member cohesion. • Active participation is the primary focus in recovery. Behavioral Treatment

Project MATCH was the largest clinical treatment trial conducted with alcoholics in 1997. 1 • Participants followed for one year at three-month intervals. 1 • Evaluated for changes in drinking patterns, functional status/quality of life, and treatment services utilization. 1 Patients randomly assigned to 1 of 3 groups for 12 week manual-guided individual treatment: 1 • Cognitive Behavioral Coping Skills Therapy (CBST) • Motivational Enhancement Therapy (MET) • Twelve-Step Facilitation Therapy (TSF) Project MATCH

* Little difference across treatments as all showed sustained improvement in drinking frequency and severity. 1 Further analysis suggested: 2 • Those with high alcohol dependence had better posttreatment outcomes with TSF. • Low dependence clients did best with CBST. • Outpatients who rated high in anger had best outcomes with MET. Project MATCH Results

At three-year follow-up: 1 • Overall, reductions in drinking that were observed in the first year were sustained over the three-year follow-up period. • TSF showed a slight advantage. • Clients high in anger fared better in MET as compared to CBST and TSF. Project MATCH Results

FDA-approved drugs for the treatment of alcohol dependence: 1 • Disulfiram- Inhibitor of aldehyde dehydrogenase (ALDH). • Acamprosate- Reduces dopamine output in the mesolimbic reward pathway. • Naltrexone- Mu-opioid receptor antagonist. Alcohol Pharmacotherapies

In addition to the FDA-approved drugs, a number of other medications are used off-label for treating AUD: • Mood stabilizers: Gabapentin, 1 Topiramate, 1 Lamotrigine. 2 • Antidepressants: SSRIs (Fluoxetine and Sertraline), 3 TCAs (Desipramine and Doxepin), 4 Trazodone. 5 • Others: Baclofen, 1 Risperidone, 4 Varenicline. 6 Alcohol Pharmacotherapies

General: • Less than 10% of patients receive medications to help with reducing alcohol use. 1 • Barriers to prescribing meds: 1 • Lack of knowledge/comfort by the prescriber. • Lack of prescriber's confidence in efficacy of medication. • Inability to offer psychological intervention along with the prescription. • Patient reluctance. Alcohol Pharmacotherapies

Behavioral counseling is recommended along with drug therapy for best treatment outcomes. 1, 2 Despite available treatments, there are currently no guidelines for sex-specific treatment using alcohol pharmacotherapy! Limited available research suggests that gender-specific treatment is no more effective than mixed-gender treatment. 3 • Further research needs to be completed before we can come to a consensus on the matter of sex and genderspecific treatment. Sex and Gender Differences in Treatment

Future research should examine: 1 • Improving care for women who seek help in primary care or mental health settings. • Increasing the referral of women to specialized addiction treatment. • Identifying subgroups of women and men who may benefit from gender-specific interventions. • Addressing sex and gender-specific risk factors for reduced treatment initiation, continuation, and treatment outcomes. Sex and Gender Differences in Treatment

1. Alcohol Use Disorder (AUD) is a common problem in the United States. 2. Alcohol abuse leads to significant health problems that differ in men and women. 3. It is important to consider sex and gender differences when screening for AUD. 4. More research on sex and gender differences in treatment is needed. 5. Research needs to continue in this area to further our understanding of AUD as it relates to sex and gender. Conclusions