Alcohol Dependence in Women

US Pharm. 2008;33(9):Epub.

Alcoholism (or alcohol dependence) is a chronic disease of the brain.^1,2 Left untreated, alcoholism is progressive and may be life threatening.¹ This disease is characterized by relapse similar to other conditions such as diabetes, hypertension, or asthma.^2,3

According to the National Epidemiologic Survey on Alcohol Related Disorders, in a study conducted by the National Institute on Alcohol Abuse and Alcoholism, from 2001 through 2002, 5.42% of U.S. males and 2.32% of U.S. females suffered from this disorder.⁴ It is estimated that 10% to 20% of men and 5% to 10% of women will suffer from alcoholism sometime in their lives, depending which criteria are used to define alcoholism.⁵ The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) defines alcohol dependence based on the presence of several criteria, which are described in TABLE 1.⁶

Some of the nonspecific symptoms of alcoholism include insomnia, depression, anxiety, gastrointestinal problems, sexual dysfunction, and severe premenstrual syndrome. Upon physical examination, a physician might find hypertension, spider angiomata, acne rosacea, liver disease, and/or portal hypertension. An alcoholic's medical history may be positive for past trauma, eating disorders, depression, anxiety disorders, sexual or physical abuse, and/or gynecologic disorders.⁷

Risk Factors
A family history of alcoholism is a strong risk factor for the disease.⁸ Studies have shown that first-degree relatives (i.e., parents, siblings, children) of alcoholics are two to four times more likely to develop alcoholism than those who do not have relatives with the disease.⁸ The reason for this is twofold--a genetic component to alcoholism and the shared family environment.^4,8 There is evidence that points to a heritability rate of 50% to 60%.^4,8 Family dynamics and other shared features of a family's history (e.g., financial, social, educational) can contribute to developing an alcohol-use disorder.

Stress is a common denominator among female alcoholics.^1,9,10 Drinking to cope with stressors is a risk factor for developing alcoholism, and that should be examined in women who may have a propensity to progress to alcoholic drinking. Having a history of abuse of any sort--sexual, physical, or emotional--is another strong risk factor for developing alcohol dependence.^1,9

Troubled relationships with close family members may lead to alcoholism, particularly in women.^1,10 Peer pressure also contributes to the risk of developing alcohol dependence.⁹ Women whose significant others drink heavily are more likely to become alcoholics than women who are not exposed to heavy drinking.^1,10

Alcohol Dependence in Women
Female alcoholics experience a different course of disease development and suffer differing consequences than men.^11,12 Fewer women drink than men,^1,8,13 and women are more likely to be abstinent from alcohol throughout their lifetime than men.^14,15 However, this pattern is changing among young women.¹³ Binge drinking among adolescent and college-age females is on the rise, which is problematic because of the number of adverse events that result from this.¹⁵

The way women drink and the reasons women drink also differ from those of men.^14,15 Women often drink because of the stresses of the various roles they have in life, such as wife, mother, and employee.¹⁵ They often drink alone, binge less, have regular patterns of use (at different times of the day), and drink less alcohol than men.¹⁵ They will often consume a different type of alcoholic beverage than men as well.¹⁴

Alcoholism presents differently in women than in men.¹³ Women often start drinking at an older age, yet the progression from first drink to alcohol dependency progresses much more quickly in women than in men.^7,9,12,14,16 This phenomenon is known as telescoping.¹⁵ Women tend to start drinking at lower doses and consume less than men overall.^13,15 Despite this, women develop medical and psychological consequences more severely and more quickly after the beginning of heavy consumption of alcohol.^1,13,15 In fact, evidence shows that women suffer a 50% to 100% higher death rate from alcohol than men. Reasons for death include suicide, accidents, and medical complications, such as liver and/or heart disease.^1,15 Despite the greater frequency and severity of medical issues, women experience fewer and less severe withdrawal symptoms.

Women are more vulnerable to the effects of alcohol than men.^1,9,17 They are more likely to develop organ damage, even though they may have been drinking less or for a shorter time than men.^1,9,16,18 More women who were diagnosed with alcohol dependency also had dependency on another substance.¹⁵

Women suffer different psychosocial problems due to alcohol dependence. They are more likely to suffer damaged relationships and emotional problems than men. Emotional issues cause so much morbidity in the female alcoholic that a negative mood is highly associated with cravings and is an important risk factor for relapse.³ Much of this stems from the stigma attached to women and alcoholism.⁹ For this reason, alcoholic women are more likely to seek treatment in a primary care or psychiatric setting for physical illness and marital or emotional problems.^14,19

Pharmacokinetics: Women versus Men
The pharmacokinetics are different in women than in men.²⁰ When women and men are administered the same quantity of ethanol per kilogram of body weight, women show a higher blood alcohol concentration (BAC).^7,13,15,21 This increase in bioavailability may contribute to the higher vulnerability of women to the toxic effects of ethanol.¹⁷ There are several factors that may contribute to the higher BAC in women.

When an equivalent dose of alcohol is administered to both sexes IV, the BAC is identical. However, when an equivalent dose is administered orally, the resulting BAC is higher in women.^18,21 This suggests that first-pass metabolism (FPM) is smaller in females.

Unlike other drugs, FPM of ethanol is not dependent solely on the liver, but rather on metabolism in the gastric mucosa.^18,21 Ethanol is metabolized by alcohol dehydrogenase (ADH) into acetaldehyde, which is toxic.^15,18,21 (A hangover is due in part to a buildup of acetaldehyde.) Acetaldehyde is further metabolized to acetate by ADH in the liver.¹⁸ Lower levels of ADH in women, particularly in the stomach, result in a lower FPM.^7,9,15,21,22 A decreased FPM is one factor contributing to an increased BAC in women compared to men.

Another reason for the observed higher ethanol concentration in women versus men may be the volume of distribution (VD). Baraona et al found the VD to be 7.3% lower in women, although they concluded that the lower VD is not large enough to account for the higher BAC.²¹ Despite Baraona's conclusion, it appears that the smaller VD in women may contribute to higher alcohol concentrations.^9,12,15 Ethanol is a water-soluble molecule.¹⁸ Because women have more fatty tissue and 12% less body water than men, the VD is smaller in women.^9,12,15,18

Gastric emptying influences the concentration of ethanol. Accelerated gastric emptying results in less exposure to ADH in the gastric mucosa, thus decreasing the FPM effect. In both sexes, fasting results in an increased rate of gastric emptying and consequently a smaller FPM. Women have a 43% faster gastric emptying in response to alcohol than men.¹⁸ This decreases exposure to ADH in the stomach, thereby decreasing the FPM.

A final difference in the pharmacokinetics of ethanol in women is the rate of metabolism and elimination. Women eliminate alcohol from their body faster than men.^15,20,21 This seems counterintuitive to resulting in an increased concentration of alcohol, but it may partially explain the higher toxicity women experience from the drug. Since the first metabolite of ethanol breakdown (acetaldehyde) is toxic, a faster metabolism may result in greater medical sequelae. Longer exposure to acetaldehyde may contribute to the greater toxicity in women.^18,20 Although the actual mechanism responsible for the higher rate of elimination in women remains unknown, it is postulated that gonadal hormones (i.e., progesterone, testosterone, estrogen) may play a role.²⁰

Alcohol's Effects on Physical and Mental Health
Women's increased vulnerability to alcohol leads to quicker and, in many cases, more severe consequences. Their risk of morbidity and mortality is increased.^9,15,16 Alcoholics are at a higher risk of developing heart disease, brain disease, liver disease, muscle wasting, bone disease, hypertension, stroke, and cancer, as well as metabolic disorders.^{1,13,14,16,18}

Both male and female alcoholics are at an increased risk of cardiomyopathy.^7,12,15 This may be due to alcoholic-induced hypertension or free radicals.⁷ The incidence of cardiomyopathy is the same in men and women. However, women develop heart disease after a shorter exposure time to, and overall lower consumption of, alcohol.^12,15

Both men and women who abuse alcohol experience a decrease in cognitive performance. With women, though, it appears earlier and with less alcohol exposure than with men.^9,11,12,15 CT scans have revealed a decreased brain volume in alcoholics.¹¹ A study conducted by Mann et al demonstrated a decrease in brain volume and an increase in cerebrospinal fluid.¹² Again, with female alcoholics, this brain pathology develops after a shorter period of heavy drinking and an overall lower alcohol exposure than with male alcoholics.¹¹ Evidence shows that the "brain shrinkage" is reversible upon abstinence from alcohol.^11,12

Alcohol-induced liver damage may occur in any alcoholic. Both men and women are susceptible to liver injury. In women, alcoholic liver disease may be more severe with less alcohol consumption.^9,12,14 It is estimated that women who drink 20 to 40 g of ethanol (approximately 2-4 drinks) per day are at the same risk as men who drink 60 to 80 g per day.¹¹

Chronic heavy drinking is associated with an increased risk of bone fracture.^7,17 This may be due to a greater risk of falling and/or to ethanol's effects on bone.⁷ Evidence shows that both male and female alcoholics have a higher risk of osteoporosis than nonalcoholics. The mechanisms involved appear to be due to both direct effects on the bone and bone marrow cells and indirect effects via endocrine disruption.¹⁷ Evidence shows that in females, ethanol-induced bone loss results from both the inhibition of bone formation (via inhibition of osteoblastogenesis) and the induction of bone resorption (via stimulated osteoclastogenesis).¹⁷

Heavy alcohol consumption may result in muscle wasting. The degree of muscle atrophy that results from chronic ethanol consumption is directly related to the duration and amount of alcohol ingested. Fortunately, like brain atrophy, alcohol-induced muscle atrophy is reversible once abstinence from alcohol is achieved.¹

Alcohol use promotes the development of certain cancers.¹ Cancers of the digestive system, head and neck (especially in smokers), and breast have been associated with ethanol consumption.¹ Alcohol disrupts hormonal cycles in males and in females.¹⁷ As a result, the female sex hormone balance becomes altered and an increased risk in breast cancer results.^7,9,15,23 One study showed that women who drank 2.5 to 5 drinks daily (on average) had a 40% higher incidence of breast cancer than nondrinkers. In fact, this risk climbed by 9% for each 10-g increase (about 1 drink) in daily alcohol consumption up to 60 g per day.⁷ The mechanism for increased risk of breast cancer may be ethanol's effect on estradiol after acute ingestion.^9,2

The hormonal imbalances created by chronic alcohol abuse create reproductive dysfunction as well.^9,15,17,23 In females, the gonadal hormone imbalance may lead to infertility, miscarriage, and spontaneous abortion.^9,15,23 The menstrual cycle may become irregular, resulting in anovulation, amenorrhea, luteal phase dysfunction, and hyperprolactemia.^15,23

Women present with a higher incidence of psychosocial problems than men, and female alcoholics' comorbid psychiatric diagnoses differ from those of men.^7,8,14,19 Female alcoholics are at a higher risk for being victims of domestic violence and rape, which may result in posttraumatic stress disorder.^7,15,19 This may be why they are four times more likely to attempt suicide than nonalcoholic women.⁷ Women who abuse alcohol experience more relationship problems, including marital issues.^7,14 Compared to men, who suffer more from antisocial behavior and comorbid abuse of other drugs,^8,19 women are more likely to suffer from depression, anxiety, mania, phobic disorders, and eating disorders.^7,9,12,19

Fetal Alcohol Syndrome
Alcohol consumption during pregnancy is the leading preventable cause of birth defects and mental/developmental problems.^1,7,15,24 Many women, from all walks of life, drink during pregnancy. It is estimated that anywhere from 14% to 22.5% of women report some alcohol use while pregnant.²⁵ These figures are likely to be low, as the stigma of drinking during pregnancy may prevent women from reporting it. Heavy binge or chronic prenatal exposure to alcohol causes fetal alcohol syndrome (FAS).^15,18 There is evidence that suggests that in the early weeks of gestation, the fetus may be more vulnerable to developing FAS.¹⁵ Since the "safe" amount of alcohol and the "safe" stage of pregnancy to drink are unknown (if they exist at all), pregnant women are urged not to drink at all during pregnancy.¹

FAS is defined by four criteria: 1) maternal drinking, 2) low birth weight, 3) characteristic facial anomalies, and 4) abnormal neurologic development.^15,24 The facial features on FAS individuals may include any combination of the following: thin upper lip, smooth philtrum, flat midface, small eyes, and epicanthal folds.^15,24 The brain damage that results from FAS may lead to lifelong problems with learning, memory, attention, and problem solving.¹

There may be some mental, behavioral, and physical problems due to prenatal alcohol exposure, even without an FAS diagnosis. The terms alcohol-related neurodevelopmental disorder (ARND) and fetal alcohol spectrum disorder (FASD) have been used to describe the presence of abnormalities caused by drinking while pregnant.^15,24 Defects in the bone, heart, kidney, and vision or hearing systems are symptoms of FASD.¹⁵ Low IQ scores and learning disabilities result from maternal drinking prenatally. Behavioral problems such as overactive disorders and attention-deficit disorders have been associated with fetal alcohol exposure.²⁴

Medications
Alcoholism is still viewed by some as a character defect and not a treatable disease.³ In addition to psycho­ behavioral therapy, there are medications being used to treat alcoholism. Medications are used for acute withdrawal as well as for maintaining sobriety.²²

Acute alcohol withdrawal (AW) is characterized by many symptoms. They are not always all present, but they may occur in any combination. They are "disturbance of consciousness, change in cognition or perceptual disturbance developing in a short period," hyperpyrexia, hypertension, tachycardia, diaphoresis, nausea, headache, and delirium tremens (DTs).^22,26 These symptoms occur during withdrawal or slightly after.²⁶ However, DTs do not develop for two to three days after acute withdrawal, and they usually last for 48 to 72 hours. DTs are serious and may result in death; however, with the proper medical management, mortality rates have fallen to 0% to 1%.²

The first-line treatment of AW is sedative hypnotics, particularly benzodiazepines.^22,26 Women have a robust response to benzodiazepines and may require lower doses; however, for AW the doses are larger than those prescribed for anxiety.^22,26 Although not recommended as sole pharmacotherapy for AW, neuroleptics (i.e., haloperidol, chlorpromazine, and promazine) may be used in conjunction with benzodiazepines.²⁶ Adrenergic agonists, such as clonidine, may be used in conjunction as well, especially for controlling hypertension and tachycardia.²⁶

There are three FDA-approved medications for maintaining sobriety: disulfiram, naltrexone, and acamprosate (TABLE 2). Disulfiram is an aversive agent. It inhibits aldehyde dehydrogenase and prevents acetaldehyde from being further metabolized.^2,3,22 Disulfiram does not decrease cravings, so the motivation to continue abstinence is due to the resultant adverse effects when alcohol is consumed.^2,27 The buildup of acetaldehyde causes flushing, sweating, dyspnea, tachycardia, headache, and nausea.^2,3 Side effects are usually fatigue and metallic taste, but they can be serious and include elevated hepatic enzymes or hepatotoxicity, depression, and psychotic reactions.^2,22,27

Naltrexone is an anticraving medication that antagonizes the mu opioid receptors.^2,3,22,28,29 Alcohol releases the endogenous opioid peptides, thereby stimulating opioid receptors.^3,22 Naltrexone decreases the incidence of relapse and heavy drinking. However, it is associated with adverse effects that may affect compliance rates.^28,29 Side effects include nausea, abdominal cramps, tearfulness, restlessness, bone or joint pain, myalgia, and nasal symptoms. Because naltrexone has been known to cause hepatocellular injury, it is contraindicated in patients with acute hepatitis or liver failure.^28,29

A depot formulation of naltrexone was developed and released in 2006 under the promise of reducing adverse events, improving compliance, and improving therapeutic outcome through constant therapeutic levels.^2,3,27,28 Contrary to expectations, the naltrexone depot formulation caused the same, and possibly more severe, adverse events as the oral formulation.^2,28 In addition to the side effects caused by oral naltrexone, the depot injection also causes tenderness, pain, induration, angioedema, inflammation, and contusion in approximately 15% of patients.²⁸

Acamprosate may benefit alcoholic patients with anxiety, a negative family history of alcoholism, and late age of onset.² Acamprosate is used to alleviate craving and restore brain function.³ Acamprosate was approved by the FDA based largely on efficacy data from European studies.² However, the efficacy of acamprosate has come into question. There have been U.S. studies that have not demonstrated the efficacy of the drug.^2,30 The common side effects of acamprosate are diarrhea, nervousness, and fatigue.²

Even though these three drugs have been known to be effective in maintaining abstinence, behavioral intervention along with drug therapy results in a more favorable outcome. Psychotherapy combined with medical management increases abstinence by approximately 20%.³⁰

Role of the Pharmacist
Since alcoholism is associated with high morbidity and mortality rates, it is imperative that pharmacists take advantage of their role in the health care continuum to improve patients' treatment outcomes. As noncompliance is a problem with alcoholism treatments,²⁷ the pharmacist can monitor refills and counsel patients on the need to take their medications as prescribed. If the patient is experiencing adverse effects that may affect compliance, the pharmacist can help the patient and physician choose an alternative treatment that is more tolerable. Of equal importance to compliance is the prevention of FAS. The pharmacist must tactfully discuss FAS with women, stressing the importance of avoiding alcohol while pregnant or avoiding pregnancy while drinking.

REFERENCES
1. Alcohol: A Women's Health Issue. Rockville, MD: National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism; 2003. NIH publication No. 03-4956. http://pubs.niaaa.nih.gov/publications/brochurewomen/women.htm. Accessed July 1, 2008.
2. Johnson BA. Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Biochem Pharmacol. 2008;75:34-56.
3. Hellig M, Egli M. Pharmacologic treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther. 2006;111:855-876.
4. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). National Institute on Alcohol Abuse and Alcoholism. www.nesarc.niaaa.nih.gov. Accessed July 16, 2008.
5. Alcoholism. Encyclopedia Britannica Online. 2008. http://original.britannica.com/eb/article-251754/alcoholism. Accessed July 16, 2008.
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000.
7. Cyr MG, McGarry KA. Alcohol use disorders in women. Screening methods and approaches to treatment. Postgrad Med.2002;112:31-32,39-40,43-47.
8. Prescott CA. Sex differences in the genetic risk for alcoholism. Alcohol Res Health. 2002;26:264-273.
9. Van der Walde H, Urgenson FT, Weltz SH, Hanna FJ. Women and alcoholism: a biopsychosocial perspective and treatment approaches. J Counsel Dev. 2002;80:145-153.
10. Timko C, Finney JW, Moos RH. The 8-year course of alcohol abuse: gender differences in social context and coping. Alcohol Clin Exp Res. 2005;29:612-621.
11. Mann K, Batra A, Günthner, Schroth G. Do women develop alcohol brain damage more readily than men? Alcohol Clin Exp Res. 1992;16:1052-1056.
12. Mann K, Ackermann K, Croissant B, et al. Neuroimaging of differences in alcohol dependence: are women more vulnerable than men? Alcohol Clin Exp Res. 2005;29:896-901.
13. Becker JB, Hu M. Sex differences in drug abuse. Front Neuroendocrinol. 2008;29:36-47.
14. Green CA, Perrin NA, Polen MR. Gender differences in relationships between multiple measures of alcohol consumption and physical and mental health. Alcohol Clin Exp Res. 2004;28:754-764.
15. Greenfield SF, Manwani SG, Nargiso JE. Epidemiology of substance use disorders in women. Obstet Gynecol Clin North Am.2003;30:413-446.
16. Diehl A, Croissant B, Batra A, et al. Alcoholism in women: is it different in onset and outcome compared to men? Eur Arch Psychiatry Clin Neurosci. 2007;257:344-351.
17. Ronis MJ, Wands JR, Badger TM, et al. Alcohol-induced disruption of endocrine signaling. Alcohol Clin Exp Res. 2007;31:1269-1285.
18. Lieber C, Abittan C. Pharmacology and metabolism of alcohol, including its metabolic effects and interactions with other drugs. Clin Derm. 1999;17:365-379.
19. Zilberman ML, Tavares H, Blume SB, el-Guebaly N. Substance use disorders: sex differences and psychiatric comorbidity. Can J Psychiatry. 2003;48:1-13.
20. Dettling A, Skopp G, Graw M, Haffner HT. The influence of sex hormones on the elimination kinetics of ethanol. Forensic Sci Int. 2008;177:85-89.
21. Baraona E, Abittan CS, Dohmen K, et al. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res. 2001;25:502-507.
22. Bogenschutz MP, Geppert CM. Pharmacologic treatments for women with addictions. Obstet Gynecol Clin North Am. 2003;30:523-544.
23. Sarkola T, Mäkisalo H, Fukunaga T, Erikson CJ. Acute effect of alcohol on estradiol, estrone, progesterone, prolactin, cortisol, and luteinizing hormone in premenopausal women. Alcohol Clin Exp Res. 1999;23:976-982.
24. Bailey BA, Sokol RJ. Pregnancy and alcohol use: evidence and recommendations for prenatal care. Clin Obstet Gynecol. 2008;51:436-444.
25. Screening for alcohol use and alcohol-related problems. Alcohol Alert. 2005;65:1-8. Rockville, MD: National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. http://pubs.niaaa.nih.gov/publications/aa65/AA65.htm. Accessed July 14, 2008.
26. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium. Arch Intern Med. 2004;164:1405-1412.
27. Peterson AM. Improving adherence in patients with alcohol dependence: a new role for pharmacists. Am J Health Syst Pharm. 2007;64(suppl 3):S23-S29.
28. Roozen H, de Waart R, van den Brink W. Efficacy and tolerability of naltrexone in the treatment of alcohol dependence: oral versus injectable delivery. Eur Addict Res. 2007;13:201-206.
29. Naltrexone hydrochloride tablets package insert. St. Louis, MO: Mallinckrodt; September 2003.
30. Anton RF, O'Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study. JAMA. 2006;295:2003-2017.
31. Rakel R, Bope E. Conn's Current Therapy. 60th ed. St. Louis, MO: WB Saunders; 2008.

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