Treatment, as well as maintenance of abstinence from alcohol and other drug-related disorders, involves the use of pharmacotherapy in combination with psychosocial interventions, such as cognitive behavioural therapy
Godwin Achunine BPharm MSc IP MRPharmS
Pharmacy Department
South London and Maudsley NHS Foundation Trust, London, UK
Email: [email protected]
Drug addiction or substance dependence, is a chronic relapsing medical condition which is characterised by a compulsion to seek and take a drug, a loss of control in limiting its intake, and the emergence of a negative emotional state when access to the drug is prevented.(1)
Alcohol is toxic to most organs of the body, and the level of consumption is strongly correlated with the risk for long-term morbidity and mortality.(2) Excessive alcohol consumption is common in many parts of the world, especially in Europe where more than 14 million people are alcohol dependent.(2,3)
Neurobiology
The areas in the brain rich in dopamine and collectively referred to as the brain’s ‘reward pathway’ include the ventral tegmental area, the nucleus accumbens and the prefrontal cortex (Table 1). Dopamine is increased by cocaine, amphetamines, opiates, alcohol, nicotine and cannabinoids. Increase in dopamine is linked with positive reinforcement.
Alcohol
Mode of action
Alcohol reduces N-methyl-D-aspartate (NMDA)-induced seizures, and enhances gamma-aminobutyric acid (GABA)A and glycine receptor function.
Neuronal membranes are high in lipids. Alcohol is an organic solvent that permeates neuronal membranes and also makes channel proteins more flexible. This makes it easier for GABA to open the chloride channel thereby increasing the rate of chloride entry.
The effects of alcohol include central nervous system (CNS) depression, disinhibited behaviour, euphoria, ataxia, clouded consciousness. The consequences of chronic alcohol abuse include physical health problems such as liver disease (fatty liver, liver cirrhosis), mental health problems such as Korsakoff’s syndrome (due to deficiency of thiamine), and risks to self/others.
Withdrawal syndrome
Following periods of excessive alcohol consumption, a drop in blood alcohol concentration may precipitate a withdrawal syndrome. The withdrawal syndrome includes autonomic hyperactivity (pulse rate > 100 beats per minute), increased hand tremor, insomnia, nausea and vomiting, hallucinations (visual, tactile, auditory), psychomotor agitation, anxiety and grand mal seizures. Individuals who regularly drink large amounts of alcohol may experience a withdrawal syndrome when ceasing or reducing their alcohol use. Chronic heavy drinkers who abstain from alcohol for more than a few hours may experience withdrawal symptoms. The first symptoms of alcohol withdrawal usually appear within hours of the last intake of alcohol and peak over 24–48 hours.(5)
The alcohol withdrawal syndrome may range from simple tremor with relatively mild signs/symptoms to hallucinations, seizures or the life-threatening delirium tremens. Delirium tremens occurs in about 5% of people during alcohol withdrawal but accounts for the highest morbidity and mortality. Delirium tremens is characterised by confusion, hallucinations (visual and auditory), and agitation and can be mistaken for psychosis.(5)
Rating scales, such as the Clinical Institute Withdrawal Assessment Scale-Alcohol Revised (CIWA-Ar), are used to quantify the alcohol withdrawal syndrome. The CIWA-Ar measures ten symptom categories, with a range of scores in each. The total maximum score is 67. Scores of less than ten indicate minimal-to-mild withdrawal (Table 2).
For moderate alcohol dependence (CIWA-Ar score 10–20) the following doses of chlordiazepoxide can be prescribed:(5)
Day 1 20mg four times a day
Day 2 15mg three times a day
Day 3 10mg four times a day
Day 4 5mg four times a day
Day 5 5mg twice a day
A full work up is recommended and should comprise:
- History
- Physical examination
- Time of most recent drink
- Concomitant drug (illicit and prescribed) intake
- Severity of withdrawal symptoms
- Co-existing medical/psychiatric disorders
- Lab investigation: FBC, U&E, LFTs, INR, PT and UDS.
Table 3 shows the treatment schedule for severe dependence.
Diazepam may also be used for moderate-to-severe withdrawal. Doses may be adjusted according to patient’s response, withdrawal severity and other medical conditions, for example, liver function. A typical withdrawal regimen could be:
Day 1: 10mg four times a day
Day 2: 10mg three times a day
Day 3: 10mg twice a day
Day 4: 5mg twice a day
Day 5: 5mg
In addition as required diazepam 10mg (oral; maximum four times a day) should be prescribed for ‘breakthrough’ withdrawal symptoms and diazepam 5–10mg PR (rectal); as required for seizures should also be prescribed.
Usually diazepam should not normally be continued beyond five-to-seven days. Doses should be withheld if a patient continues to drink. Other adjunct symptomatic (as required) medications may be prescribed, for example, paracetamol (headache), metoclopramide (nausea and vomiting), hyoscine butylbromide (abdominal cramps), loperamide (diarrhoea).
Anticonvulsants, chlormethiazole, antipsychotics and antidepressants are not usually recommended for alcohol withdrawal.
Pharmacological agents for alcohol detoxification
- Benzodiazepines, for example, chlordiazepoxide
- High-potency B-complex vitamins parenterally, that is, Pabrinex IM/IV; 1 pair ampoules daily for three-to-five days
- Thiamine 200–300mg IM daily (if Pabrinex unavailable)
- Long-term vitamin B compound strong: one tab orally three times a day.
Benzodiazepines are the cornerstone of alcohol withdrawal therapy. They have anticonvulsant effects and low toxicity, and attenuate the signs and symptoms of alcohol withdrawal.
Diazepam, chlordiazepoxide, lorazepam and oxazepam are the benzodiazepines used most frequently in the treatment of alcohol withdrawal.
Chlordiazepoxide has a lower potential for abuse than diazepam and is therefore the benzodiazepine of choice for the management of alcohol withdrawal.
chlordiazepoxide 30mg =
30mg oxazepam = diazepam 10mg
For patients with liver impairment, it is recommended to use a short acting benzodiazepine such as oxazepam.
In patients with liver impairment, low doses of a short or intermediate acting benzodiazepine such as oxazepam or chlordiazepoxide are preferable, and liver function should be carefully monitored.(6) Short-acting benzodiazepines may have a lower risk of oversedation. Benzodiazepines should be avoided in patients with severe liver impairment.
Longer-acting benzodiazepine such as diazepam may be preferable for the prevention of delirium and seizures. Caution is to be exercised in patients with liver failure.(6,7)
Thiamine deficiency is common in heavy drinkers with a poor diet, as vitamin B absorption is impaired by chronic alcoholism. Vitamin B1 (thiamine) acts a cofactor for metabolic enzymes.(7) Thiamine deficiency is a major cause of Wernicke’s encephalopathy (WE). Doses of long-term oral vitamin B compound strong tablets give the best absorption.
In healthy heavy drinkers at low risk seeking alcohol detox, oral thiamine should be prescribed at a dose of 300mg/day for seven days.(7) Patients at high risk of WE should be prescribed prophylactic treatment. It is suggested that one pair of ampoules of thiamine (Pabrinex) IM/IV should be prescribed once daily for three-to-five days days, until no further improvement is seen.(7) Patients are advised to drink plenty of fluids (at least two litres per day) and to have a light diet as opposed to heavy meals.
Patients with WE should initially be prescribed two pairs of Pabrinex ampoules three times daily for three days; this is then followed by one pair of ampoules once daily for a further three-to-five days, depending on the patient’s clinical response.(7)
Maintenance of abstinence
Various medications are effective in reducing/preventing alcohol use after withdrawal and these include:
- Naltrexone
- Nalmefene
- Acamprosate – to reduce craving
- Disulfiram – avoid if serious liver disease is present
- Psychosocial interventions (cognitive behavioural therapy, coping skills training, controlled drinking, couple therapy) kills training, controlled drinking,
Naltrexone
Naltrexone is a long-acting opiate antagonist used to prevent relapse in subjects who have remained opiate free for at least seven-to-ten days. It binds very tightly to opiate receptors and can block the effects of subsequently administered opiates for as long as three days.
Dopamine function is increased by opiates and alcohol, especially in the mesolimbic system. Increase in dopamine is linked with euphoria and positive reinforcement. Alcohol in turn causes the release of opiates. It is therefore postulated that by blocking the effects of opiates released by alcohol, naltrexone at the same time reduces the pleasurable effects of alcohol.
Naltrexone has a significant effect on reducing subsequent drinking by blocking the craving for, and reward from the next drink. Kranzler and Van Kirk8 conducted a meta-analysis comparing acamprosate and naltrexone. Nine naltrexone and 11 acamprosate studies were included. There were no differences between the drugs on a number of different outcomes (% abstinent, % retention) and both were better than placebo.
An open, non-blind, randomised comparison found that naltrexone was better than acamprosate in achieving abstinence, reducing craving, number of drinks and number of days to relapse.(9)
A Cochrane review(10) concluded that 50mg/day naltrexone was effective in the short-term treatment of alcohol dependence in improving drinking outcomes, that is, relapse rates, time to first drink, reduction in number of drinking days, reduction in craving and improvement in gamma-glutaryl transferase levels.
A double-blind, placebo controlled clinical trial with 70 male alcohol-dependent patients demonstrated that naltrexone significantly reduced craving, as well as the number of days during which alcohol was consumed.(11) Naltrexone also reduced the number of relapse events in the alcohol-treated group.(11)
A study reported that naltrexone treatment reduced the high produced by alcohol, as well as the amount of alcohol consumed during the first drinking episode. The authors of the study concluded that: “the lower alcohol consumption by naltrexone treated subjects may have resulted from naltrexone’s blockage of the pleasure produced by alcohol. Thus blockage of the opioid system appears to reduce the reinforcing or euphoric effects of alcohol”.(12)
The most common adverse drug reactions reported with naltrexone are abdominal cramps, nausea and vomiting, headache, sleep difficulties and dizziness. Liver function tests should be monitored before and during treatment with naltrexone, due to its potential hepatotoxic nature.
Dosing requirements: 25mg for two days, increasing to 50mg once daily. Initiate naltrexone three days after last drink. Naltrexone should be avoided in patients currently requiring opioid analgesia (opiate dependent). The most common adverse drug reactions with naltrexone are abdominal cramps, nausea and vomiting, headache, sleep difficulties and dizziness.
Nalmefene
Nalmefene is an opioid receptor antagonist used in the management of alcohol dependence. It is a selective opioid antagonist at the μ and δ receptors and partial agonist at the κ receptor.
Nalmefene is similar in structure and activity to naltrexone, but with a longer half-life, greater binding affinity to the µ-opioid receptor, greater oral bioavailability and no observed dose-dependent liver toxicity.
Nalmefene was licensed on the 28 February 2013 by the European Medicines Agency for use in the treatment of alcohol dependence. It was launched in the UK by Lundbeck in May 2013.
Nalmefene is indicated for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level (DRL), without physical withdrawal symptoms and who do not require immediate detoxification. Nalmefene should only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption. It should be initiated only in patients who continue to have a high DRL two weeks after initial assessment.(13)
Nalmefene is one of a first group of medications specifically developed for the reduction of alcohol consumption in patients with alcohol dependence who maintain a high level of alcohol consumption. It reduces the urge to continue drinking, reduces alcohol consumption and thus the consequences of harmful drinking, and offers a new treatment option for patients who might not have sought treatment before.
In the ESENSE 1 and 2 studies, nalmefene as-needed significantly reduced total alcohol consumption and number of heavy drinking days and significantly improved liver function and clinical status.(14) The study population comprised of a subgroup of men and women ≥ 18 years, with a primary diagnosis of DSM-IV alcohol dependence and alcohol consumption ≥ World Health Organization high drinking risk level (>60g/day for men and >40g/day for women) at both screening and randomisation. Patients received placebo or nalmefene (1:3). The as-needed dosing principle involved taking one tablet on each day that the patient perceived a risk of drinking alcohol. In ESENSE 1 (n=579), and 2 (n=655), 18% and 33%, of the total population, respectively, considerably reduced their alcohol consumption in the period between screening and randomisation. In vivo studies have demonstrated that nalmefene reduces alcohol consumption, possibly by modulating cortico-mesolimbic functions.(13)
At an initial visit, the patient’s clinical status, alcohol dependence, and level of alcohol consumption (based on patient reporting) should be evaluated. Thereafter, the patient should be asked to record his or her alcohol consumption for approximately two weeks. At the next visit, nalmefene may be initiated in patients who continued to have a high drinking risk level section over this two-week period, in conjunction with psychosocial intervention focused on treatment adherence and reducing alcohol consumption.
Oral doses used in clinical trials for the treatment of alcohol dependency were in the range of 20 to 80mg daily, with little observed differences in efficacy between the lower and higher dosage regimes.(15)
During pivotal trials, the greatest improvement was observed within the first four weeks. Nalmefene is to be taken as-needed: on each day the patient perceives a risk of drinking alcohol, one tablet should be taken, preferably one-to-two hours before the anticipated time of drinking. If the patient has started drinking alcohol without taking nalmefene, the patient should take one tablet as soon as possible. Nalmefene comes as 18mg film-coated tablets. The maximum dose of nalmefene is one tablet per day. Nalmefene can be taken with or without food.
No dose adjustment is recommended for the following:
- Elderly (≥65 years of age)
- Patients with mild or moderate renal impairment
- Patients with mild or moderate hepatic impairment
- Children and adolescents <18 years of age (data on safety and efficacy not available).
Interactions
Nalmefene with food and alcohol
Nalmefene does not prevent the intoxicating effects of alcohol.
Pregnancy and breast-feeding
It is not known whether nalmefene is safe to use during pregnancy and breast-feeding. Nalmefene is not recommended for use in pregnancy. In breastfeeding patients, a clinical decision needs to be made, taking into account the benefit of breastfeeding to the child and the benefit of therapy to the mother.
Contraindications
- Hypersensitivity to the active substance or to any of the excipients of the drug
- Not recommended during pregnancy
- Patients taking opioid analgesics
- Patients with current or recent opioid addiction.
- Patients with acute symptoms of opioid withdrawal.
- Patients for whom recent use of opioids is suspected.
- Patients with severe hepatic impairment (Child-Pugh classification).
- Patients with severe renal impairment (estimated glomerular filtration rate <30ml/min per 1.73m2).
- Nalmefene is not for patients for whom the treatment goal is immediate abstinence. Reduction of alcohol consumption is an intermediate goal on the way to abstinence.
- Patients with a recent history of acute alcohol withdrawal syndrome (including hallucinations, seizures, and delirium tremens).
The most common side effects associated with nalmefene include nausea, dizziness, insomnia, headache, drowsiness, vomiting and dry mouth. The majority of these reactions were mild or moderate, occurred at the beginning of treatment and lasted for a few hours to a few days.
In a study in patients diagnosed with pathological gambling, doses of nalmefene up to 90mg/day for 16 weeks were investigated. In a study in patients with interstitial cystitis, 20 patients received 108mg/day of nalmefene for more than two years. Intake of a single dose of 450mg nalmefene has been reported without changes in blood pressure, heart rate, respiration rate, or body temperature. No unusual pattern of adverse reactions was observed in these settings, but experience is limited. Management of an overdose should be observational and symptomatic.(13)
Acamprosate
Acamprosate works via glutamate pathways to reduce alcohol cravings. Acamprosate inhibits glutamatergic NMDA receptor (NMDA receptor system is upregulated in alcoholism), thereby suppressing the ‘urge to drink’ in response to learned cues. Treatment should be commenced as soon as possible after assisted withdrawal.
Acamprosate can be initiated three days after the last drink. Acamprosate comes as 333mg tablets and the dosing schedule for patients 60kg and over is two tablets tds; and for patients <60kg, it is two in the morning, one at noon and one at night.
Acamprosate is generally well tolerated, with gastrointestinal disturbances such as diarrhoea, nausea, vomiting and abdominal pain being the most common side effects reported.
Acamprosate should be avoided in pregnancy, breastfeeding and severe hepatic and renal impairment (serum creatinine >120micromol/litre).
Disulfiram
Patients with no contraindications who wish to remain abstinent from alcohol may also be considered for treatment with the alcohol dehydrogenase inhibitor, disulfiram.(7) Disulfiram inhibits aldehyde dehydrogenase, leading to acetaldehyde accumulation after drinking alcohol. This in turn can lead to signs and symptoms such as flushing, nausea, vomiting, headache, abdominal discomfort, tachycardia and palpitations. Continued drinking can lead to arrhythmias, hypotension and collapse.
Disulfiram should only be initiated under specialist supervision. It should be avoided in patients with cardiac failure, hypertension, psychosis, breastfeeding and in the first trimester of pregnancy. It may be used with caution in hepatic and renal impairment.
The dosing schedule is 200mg per day, started at least seven days after alcohol detox or 48 hours after the last drink. It is also possible to start with a loading dose, that is, 800mg as a single dose on the first day of treatment, then reducing over five days to 100–200mg mg daily. Disulfiram should not be discontinued following relapse. Three to six months duration of treatment is advocated, then reviewed, or for as long as benefits are maintained.
Conclusions
Drug addiction manifests as a compulsive drive to take a drug despite serious adverse consequences. It can manifest as psychological as well as physical. In psychological dependence, there is a compulsion or a craving to continue taking a drug for stimulation or to relieve anxiety or depression. Physical dependence is characterised by the need to take a psychoactive substance to avoid physical disturbance or withdrawal symptoms following cessation of use.
Alcohol and drug disorders are major problems for individuals and society. They have profound effects on individual users, their families, the society and account for a significant disease burden worldwide.
People take drugs for euphoric effects, alleviation of withdrawal effects of other drugs and coping with life difficulties.
Treatment as well as maintenance of abstinence from alcohol and other drug related disorders involves the use of pharmacotherapy in combination with psychosocial interventions such as cognitive behavioural therapy.
Key points
- Alcohol dependence is a chronic relapsing remitting disorder.
- Alcohol withdrawal syndrome may range from simple tremor with relatively mild signs/symptoms to hallucinations, seizures or the life-threatening delirium tremens.
- Mild alcohol dependence may be managed with supportive care or with small doses of an appropriate benzodiazepoxide.
- In moderate-to-severe alcohol dependence, larger doses of an appropriate benzodiazepine are usually required.
- Patients with severe alcohol dependence should be given medical assistance in order to prevent seizures, delirium tremens and death.
- Various medications are effective in reducing/preventing alcohol use after withdrawal and these include: naltrexone, nalmefene, acamprosate and disulfiram.
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