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Pharmacological Treatment of Mental Disorders in Primary Health Care. Geneva: World Health Organization; 2009.

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Pharmacological Treatment of Mental Disorders in Primary Health Care.

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Chapter 8Medicines used in alcohol and opioid dependence

1. Definition of alcohol and opioid dependence

1.1.

Among the disorders due to psychoactive substance use, the dependence syndrome, the disorders of acute effects (intoxication and overdose), and the withdrawal states are the most common clinical conditions that may require pharmacological treatment. The scope of this section is limited to alcohol and opioid dependence and withdrawal.

1.2.

The term “dependence syndrome” refers to a cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.

1.3.

The term “withdrawal state” refers to a group of symptoms of variable clustering and severity occurring on absolute or relative withdrawal of a substance after repeated, and usually prolonged and/or high-dose, use of that substance. The withdrawal state in alcohol dependence usually presents with symptoms of sweating, tremor, nausea and vomiting, elevated blood pressure, tachycardia, anxiety and agitation, craving for alcohol, sleeplessness, and may be complicated by convulsions or delirium tremens. The duration of alcohol withdrawal, that usually develops after 24-48 hours after absolute or relative withdrawal from alcohol, lasts 1-3 and sometimes up to 5-7 days. Withdrawal state in opioid dependence is characterized by yawning, watering eyes, sweating, irritability, tremor, diarrhoea, chills, cramps and muscle aches, increased blood pressure and heart rate, and can lasts up to 7-10 days.

1.4.

Alcohol dependence is common, affecting approximately 6.5% of men and 1.5% of women. It often develops in early adulthood, but can start at any age after repeated continued exposure to alcohol beverages. It predominantly affects men, representing gender differences in drinking patterns among men and women in different cultures. The prevalence of alcohol dependence varies in different countries according to the prevalence and patterns of alcohol consumption, but in some countries, the 12-month prevalence of alcohol dependence among adult men is as high as 10-15%.

1.5.

Opioid dependence develops after a period of regular use of opioids, which is a necessary, but not sufficient, condition for developing opioid dependence. Common substances for opioid dependence are heroin and pharmaceutical opioids. To maximize their effect, opioids are often intravenously injected, but they can also be inhaled or taken orally. Heroin users have a mortality risk 13 times higher than the average in the same age group, even without taking into consideration increased mortality associated with HIV and other blood-borne infectious diseases, like hepatitis B and C. This increase in mortality is mainly due to opioid overdose, followed by violent deaths. The 12-month prevalence of opioid dependence in adult populations usually does not exceed 0.5%.

In some countries heroin injecting accounts for 25-33% of deaths in young adult males

2. Preliminary assessment and initial management strategies

2.1.

In populations where drinking of alcohol beverages is culturally acceptable, all patients should be asked about their alcohol use. The following question can be used: “How often do you have 6 or more drinks on one occasion?”. The objective of screening is to identify patients at higher risk of alcohol use disorders for further diagnosis and treatment.

2.2.

In health care settings in which drug use is common, or for presenting complaints for which drug use is a common precipitating factor, all patients should be asked about their drug use, or screened for drug use with instruments such as the WHO-ASSIST.

2.3.

Diagnosis of individual substance use disorders should be made on the basis of history, examination and investigations. The substance use history should examine the level and pattern of alcohol consumption, real and potential harms from substance use and the context in which substance use occurs. Health care providers may quantify the level of risk of harm from the consumption of alcohol and determine if any substance use disorders are present. The physical examination should check for the substance use effects of acute intoxication or withdrawal, and for effects of chronic substance use, and method of use (i.e. needle marks), and co-occurring conditions. If feasible, health care providers may investigate for substance-induced organ damage, and may include tests to determine the presence of substances in urine or other bodily fluids.

2.4.

Health care providers should take the medical history in a non-judgemental and non-confrontational way. The substance use history should examine the level and pattern of substance use, the context in which substance use occurs, harm that has occurred as a result of substance use, the patient's perspective on their substance use (including their motivations for continuing and motivations for changing their pattern of substance use), and their previous attempts to change their pattern of substance use.

2.5.

Patients with alcohol or opioid dependence may also be taking other psychoactive substances, like benzodiazepines or cannabis, and often have tobacco dependence as well. It is necessary to explore, in addition to the history of taking opioids or alcohol consumption, other substance use, particularly when pharmacotherapy involving methadone or buprenorphine is planned, in view of their interaction with other substances with a potential to cause a respiratory depression.

2.6.

Patients with substance use disorders frequently also have other mental disorders. Health care providers should look for these disorders, exploring the link with the substance use disorders.

2.7.

Health care providers should diagnose and treat any comorbid medical and psychiatric conditions. In some situations, substance use may be in response to some painful conditions.

2.8.

The diagnosis of harmful use of alcohol or opioids require interventions from health care professionals, but pharmacological treatment is justified only for treatment of alcohol or opioid dependence, management of withdrawal states, and some substance induced clinical conditions.

Patients with substance use disorders are at increased risk of a range of medical and psychiatric disorders

3. Short-term treatment (management of alcohol withdrawal, Wernicke-Korsokoff syndrome and commencement of relapse prevention medication for alcohol dependence)

3.1.

Health care providers should consider that people with alcohol dependence usually find it very difficult to return to low levels of alcohol consumption, and that even these low levels of consumption can still contribute to end organ (i.e. brain and liver) damage. Consequently, the target level of alcohol consumption for people with alcohol dependence should be zero alcohol.

3.2.

Not all people dependent on alcohol experience alcohol withdrawal symptoms. Many will experience only mild withdrawal symptoms such as anxiety, insomnia, headache and agitation that resolve without need for medication. Some people, on the other hand, will experience severe anxiety, agitation, insomnia, headache, tremors, sweating, tachycardia, hypertension, and hallucinations, seizures and delirium (delirium tremens). People more likely to experience severe withdrawal are those who drink higher amounts, such as greater than 100 grams alcohol per day, have had multiple episodes of alcohol withdrawal in the past, have concomitant benzodiazepine or other sedative drug use, and have concomitant medical illnesses.

3.3.

Benzodiazepines are the main treatment for alcohol withdrawal. Used in the 5 days following the cessation of alcohol, in doses proportional to the severity of the withdrawal syndrome, they reduce the discomfort and complications of alcohol withdrawal, including seizures and delirium. Long acting benzodiazepines such as diazepam are preferable to short acting benzodiazepines.

3.4.

People with mild or moderate alcohol dependence can be withdrawn from alcohol at home. In this setting, patients should receive 5-20 mg diazepam three to four times daily, depending on the severity of withdrawal, tapering to zero over 4-5 days. Patients needing higher doses of diazepam should be treated in a residential setting. Because of their abuse potential, benzodiazepines should not be continued for more than a week. The initial prescription should not be for more than 40 mg diazepam per day, unless the patient is known to experience severe withdrawal symptoms and can tolerate high doses of benzodiazepines.

3.5.

In residential settings, patients can be given 20 mg diazepam every 1-2 hours until the patient is calm and mildly sedated, with reducing doses given as needed over the following 4-7 days. Use of more than 120 mg diazepam in a 24 hours period warrants the involvement of a specialist in the treatment of alcohol use disorders.

3.6.

Health care providers should correct nutritional and electrolyte deficiencies. This typically involves: 100 mg thiamine intramuscularly daily for five days followed by 100 mg daily orally indefinitely; and oral potassium, magnesiuim and zinc supplementation during withdrawal.

3.7.

Patients should be placed in low stimulus environments (i.e quiet and dimly lit) and given adequate rehydration. Patients should not be given dextrose before thiamine.

3.8.

Health care providers should consider that Wernicke-Korsakoff encephalopathy is common and does not always present with the classic triad of ataxia, confusion and ophthalmoplegia; any altered mental state, ataxia, ophthalmoplegia, or memory disturbance should be provisionally considered Wernicke-Korsakoff encephalopathy. Health care providers should be treated with diluted infusions of high dose thiamine 3 times daily for 2 days, and continued daily for 5 days if there is any response to treatment.

3.9.

There are several medications which have been shown to be effective in reducing relapse to alcohol dependence, noteably: acamprosate, disulfiram and naltrexone. These medicines are not included in the WHO Model list of Essential Medicines.

3.10.

Acamprosate inhibits transmission at NMDA - glutamatergic receptors and stimulates, to a lesser extent, GABAA receptors which are both involved in alcohol dependence and alcohol withdrawal. In this way it is thought to reduce cravings associated with alcohol dependence.

3.11.

Disulfiram inhibits the action of the enzyme acetaldehyde dehydrogenase, thus inhibiting the main metabolic pathway of alcohol. If alcohol is consumed, the build up of toxic acetaldehyde leads to an unpleasant reaction including throbbing headache, facial flushing, nausea, vomiting, tachycardia, hypotension, dyspnoea, blurred vision, weakness and confusion. In severe cases it can be fatal, particularly in the elderly, and those with ischaemic heart disease. The knowledge of these severe adverse reaction is enough to prevent alcohol consumption in some people. In others, the first experience of the alcohol-disulfiram reaction will prevent relapse. Patients who relapse usually stop taking their disulfiram and should not be encouraged to recommence until they have ceased alcohol consumption. Treatment with disulfiram should be supervised and regularly reviewed.

3.12.

Naltrexone is a high affinity opioid antagonist. It is thought to act by reducing both the craving for alcohol and the enjoyment of alcohol as medicated by opioid receptors. Naltrexone can cause nausea when commenced, although this normally resolves in the first week of treatment.

Untreated delirium tremens has been reported to have up to a 30% mortality

4. Short-term treatment (management of opioid withdrawal and commencement of agonist maintenance treatment)

4.1.

The goals of the treatment of opioid dependence more broadly include preventing the health and social problems associated with non-prescribed opioid use and reducing non-prescribed opioid use.

4.2.

The most effective pharmacological treatment of opioid dependence is opioid agonist maintenance therapy with methadone, followed by opioid agonist maintenance therapy with buprenorphine. Before commencing opioid agonist maintenance therapy, patients should be assessed to confirm the diagnosis of opioid dependence. It is important to make a correct diagnosis because opioid agonist maintenance treatment can cause harm in people who are not opioid dependent. The diagnosis should be made firstly on the basis of the history and supported by evidence from physical examination, investigations, or by confirmation of the history from other sources.

4.3.

Opioid withdrawal symptoms include nausea, stomach cramps, muscular tension, muscular spasm/twitching, aches and pains, and insomnia. Symptoms usually reach their peak 32-72 hours after the last dose. Treatment of opioid withdrawal reduces the severity of the opioid withdrawal syndrome, increasing the chances of completing opioid withdrawal and of commencing subsequent treatment options.

4.4.

According to the WHO EML, essential medicine for opioid dependence are methadone and buprenorphine. These agents can be used for both opioid withdrawal and maintenance treatment. Maintenance treatment must be provided in combination with services which can provide psychosocial support.

4.5.

Methadone is subject to international control under the Single Convention on Narcotic Drugs (1961). Buprenorphine is subject to international control under the Convention on Psychotropic Substances (1971). The International Narcotics Control Board (INCB) is charged with monitoring the compliance by Governments with the above international treaties, ensuring on the one hand that controlled substances are available for medical and scientific use and on the other hand that diversion from licit sources to illicit traffic does not occur.

4.6.

Health care providers should warn patients about the risk of toxicity and overdose associated with methadone use. While opioid withdrawal is not a life-threatening condition, opioid toxicity is.

Opioid agonist maintenance therapy reduces drug use, criminal activity and reduces the risk of contracting HIV

5. Long-term treatment

5.1.

The optimal duration of therapy with acamprosate, disulfiram and naltrexone is uncertain. The continued use should be assessed on an individual basis. In people who are abstinent, there is little data to support their ongoing use beyond one year of abstinence. By contrast, those who do relapse to alcohol dependence, statistically the majority, should not consider that they are unresponsive to the medication, and should still consider either the same or a different relapse prevention medication on future attempts to stop drinking.

5.2.

The optimal duration of opioid agonist maintenance treatment is not known, but it can be continued in the long-term. Cessation of opioid agonist maintenance treatment is associated with a high risk of relapse and overdose and the timing of withdrawal from opioid agonist maintenance treatment should be made on a case-by-case basis.

5.3.

When withdrawing from opioid agonist maintenance treatment, health care providers should establish with the patient a flexible plan of gradual dose decreases. This plan needs to be regularly reviewed, taking into consideration the patient's readiness for total abstinence.

5.4.

Health care providers should consider that psychosocial interventions play an important role in the treatment of alcohol and opioid dependence. Basic social support includes addressing the many specific social needs that patients may have, including housing, food, company, recreation, employment, and legal assistance. Exploring the psychosocial needs and linking with services available in the community to meet those needs is one of the key roles of psychosocial assistance.

6. Administration

6.1.

For adults 18-65 years weighing 60 kg and over, the starting dose of acamprosate is 666 mg three times daily; for adults less than 60 kg, the dose should be reduced to 666 mg (morning), 333 mg (midday) and 333 mg (night).

6.2.

Health care providers, before starting treatment with disulfiram, must ensure that no alcohol has been consumed for at least 24 hours. Disulfiram should be started at 800 mg as a single dose on first day, reducing over 5 days to 100-200 mg daily. Patients should ideally have supervision during treatment, by a family member or by someone who knows the patient well.

6.3.

Naltrexone is usually commenced after detoxification at a standard dose of 50 mg daily, although doses from 25 to 100 mg have been used. Higher doses may result in liver damage.

6.4.

Health care providers should consider that the use of methadone and buprenorphine for opioid dependence should be supervised during the first three months or until stability is achieved. Daily dispensing is usually recommended.

6.5.

Health care providers should prescribe methadone in the oral liquid formulation. Tablets should not be prescribed because they may be crushed and inappropriately injected.

6.6.

Health care providers may initially prescribe methadone in the range of 10-20 mg daily, depending on the level of tolerance. Observing patients 2-3 hours after their dose enables the best assessment of the degree of tolerance to opioids. If patients have significant opioid withdrawal symptoms 2-3 hours after their dose of methadone, then they should be given an additional 5-10 mg methadone and a corresponding increase in their next daily dose. If patients are sedated after their dose of methadone, then the next daily dose should be reduced, and patients should be observed until the patient is no longer sedated. Dose increases should not exceed 5-10 mg daily and 30 mg per week. Treatment stabilisation is usually achieved within 6 weeks but may take longer. In the treatment of opioid withdrawal, the dose on the first day is the same, with subsequent doses reducing over 1-3 weeks.

6.7.

If one of two doses of methadone are missed the patient can be maintained on the same dose. If three doses are missed the next methadone dose should be reduced by 25% to adjust for the possible reduction in tolerance. If it is well tolerated, doses can return to previous dose levels. If four doses are missed the next dose should be reduced by 50% to adjust for the potential reduction in tolerance. If the dose is well tolerated doses can be increased over several days to previous levels. If more than four doses are missed, patients should resume induction from baseline.

6.8.

Methadone can be administered daily for most patients. In approximately 20% of patients, methadone is metabolized more quickly and does not produce stable opioid effects over the 24 hours between doses. In such cases methadone can be administered twice a day, dividing the dose in two. When it is too difficult to pick up the medication twice a day, or when take home doses are not suitable, then buprenorphine should be considered as an alternative.

6.9.

In heroin users, health care providers may initially prescribe 8 mg buprenorphine in patients experiencing some opioid withdrawal symptoms. If no withdrawal symptoms are present, 4 mg buprenorphine may be prescribed. Dose increases should not exceed 2-4 mg at a time, up to a maximum daily dose of 32 mg. Maintenance dose is usually in the range of 12-24 mg daily.

6.10.

After a satisfactory period of stabilization has been achieved the frequency of buprenorphine dosing may be decreased to dosing every other day at twice the individually titrated daily dose. For example, a patient stabilized to receive a daily dose of 8 mg may be given 16 mg on alternate days, with no medication on the intervening days. However, the dose given on any one day should not exceed 32 mg. In some patients, after a satisfactory period of stabilization has been achieved, the frequency of dosing may be decreased to three times a week (for example on Monday, Wednesday and Friday). The dose on Monday and Wednesday should be twice the individually titrated daily dose, and the dose on Friday should be three times the individually titrated daily dose, with no medication on the intervening days. However, the dose given on any one day should not exceed 32 mg. In the management of opioid withdrawal using buprenorphine, the dose over the first 3 days should be similar to opioid maintenance treatment, tapering rapidly thereafter. One suggested schedule is Day 1 – 6 mg, day 2-3 – 10+/−2 mg, day 4 – 8+/−2 mg, day 5 – 4 mg.

6.11.

Health care providers may need to switch from buprenorphine to methadone. Methadone should be started 24 hours after the last dose of buprenorphine. When commencing methadone from buprenorphine doses of 8 mg daily and above, commence with 30 mg methadone daily. From buprenorphine doses of 4-8 mg daily, commence with 20-30 mg methadone daily. With buprenorphine doses below 4 mg daily, commence with less than 20 mg methadone daily.

Starting doses of methadone above 20 mg should be prescribed with caution because of the risk of overdose and death

7. Adverse reactions

7.1.

Adverse reactions associated with acamprosate treatment include diarrhoea, nausea, vomiting, abdominal pain, pruritus, occasionally maculopapular rash, rarely bullous skin reactions, fluctuation in libido.

7.2.

Adverse reactions associated with disulfiram treatment include drowsiness, fatigue, nausea, vomiting, halitosis, reduced libido, rarely psychotic reactions, allergic dermatitis, peripheral neuritis, hepatic cell damage.

7.3.

Adverse reactions associated with naltrexone treatment include nausea, vomiting, abdominal pain, anxiety, nervousness, sleeping difficulties, headache, reduced energy, joint and muscle pain; less frequently, loss of appetite, diarrhoea, constipation, increased thirst, chest pain, increased sweating and lacrimation, irritability, dizziness, chills, delayed ejaculation, rash; occasionally, liver function abnormalities.

7.4.

Methadone use is a risk factor for QT interval prolongation. It is additionally possible that methadone combined with other QT-prolonging agents may increase the likelihood of QT prolongation. Health care providers may consider an ECG at baseline and during treatment in individuals with other risk factors for QT prolongation.

7.5.

Buprenorphine may cause changes in liver function in individuals with hepatic impairment. Monitoring of hepatic function should be considered in individuals at risk.

8. Overdosage

8.1.

Health care providers should consider that methadone should not be given to patients showing signs of intoxication, especially due to alcohol or other CNS depressant drugs. Risk of fatal overdose is enhanced when methadone is combined with alcohol or other respiratory depressant drugs.

8.2.

Health care providers should consider that buprenorphine should not be given to patients showing signs of intoxication, especially due to alcohol or other CNS depressant drugs. Risk of fatal overdose is enhanced when buprenorphine is combined with alcohol or other respiratory depressant drugs. Overdose of buprenorphine is usually safer than overdose of methadone.

8.3.

High doses of naltrexone have resulted in tremors, tachycardia, dizziness, insomnia, fatigue and agitation. High doses of naltrexone have been associated with elevations of liver transaminases.

8.4.

In limited cases of overdose, doses of up to 56 grams of acamprosate (normal dose approximately 2 g/day) were generally well tolerated, and the only associated symptom was diarrhoea.

8.5.

Lethargy, ataxia, seizures, and coma have occurred after acute ingestion of 2.5 to 3 grams of disulfiram in children. These may be preceded by vomiting, lethargy, tachypnoea, tachycardia, EEG abnormalities, and ketosis.

8.6.

High doses of buprenorphine have resulted in transient changes in hepatic transaminases.

9. Special patient populations

9.1.

Acamprosate should be used with caution and at lower doses in individuals with renal or hepatic impairment.

9.2.

Acamprosate is not recommended in individuals who are pregnant or breastfeeding.

9.3.

Disulfiram is contra-indicated in individuals with coronary heart disease, cardiac failure, history of cerebrovascular accidents, hypertension, psychosis, severe personality disorders, suicide risk.

9.4.

Naltrexone is contra-indicated in individuals with acute hepatitis or liver failure. Health care providers should cautiously prescribe naltrexone in individuals with hepatic and renal impairment. If feasible, liver function tests should be routinely carried out.

9.5.

Disulfiram is contra-indicated in individuals who are pregnant or breastfeeding.

9.6.

Naltrexone is not recommended in individuals who are pregnant or breastfeeding.

9.7.

Methadone and buprenorphine should not be given to patients showing signs of intoxication or sedation, due to the risk of sedative overdose. The risks of methadone and buprenorphine use in opioid dependent patients who are frequently intoxicated with sedatives such as alcohol and benzodiazepines, needs to be balanced against the benefits of treatment.

9.8.

The metabolism and elimination of methadone and buprenorphine may be affected by either hepatic or renal dysfunction in which case the dose or dosing frequency should be reduced accordingly.

9.9.

In patients with respiratory insufficiency, methadone and buprenorphine may reduce the respiratory drive.

9.10.

Methadone and buprenorphine can be used in individuals who are pregnant or breastfeeding.

10. Potentially relevant interactions

Alcohol and disulfiram. See above.

Warfarin and disulfiram. Decreased prothrombin time.

Medications that prolong the QT interval and methadone. Increased risk of QT prolongation-associated cardiac arrhythmias

Antiretrovirals and methadone. Altered plasma levels of methadone and antiretrovirals. Dose adjustment may be required.

Antiretrovirals and buprenorphine. Altered plasma levels of buprenorphine and antiretrovirals. Dose adjustment may be required.

11. Essential medicines for opioid dependence

Methadone hydrochloride

  • Starting dose: The initial dose of methadone should not be more than 20 mg a day and should be determined for each patient based on the severity of dependence, the level of tolerance to opioids, use of other psychoactive substances such as benzodiazepines or alcohol, as well as on the other relevant clinical factors.
  • Therapeutic dose: Once it has been established that the initial dose is well tolerated, the methadone dose should be gradually increased until the patient is comfortable and not using heroin or other illicit opioids. The rate of increase should be individually assessed, and should generally not be faster that 10 mg every few days. On average, methadone maintenance doses range from 60 to 120 mg daily, sometimes higher dosage is required.
  • Adverse effects: anorexia, nausea, vomiting (particularly in initial stages), constipation; euphoria, hallucinations, dizziness, drowsiness, confusion, headache; dry mouth, spasm of urinary or biliary tract; hypotension, postural hypotension, vertigo, bradycardia, tachycardia, palpitations, headache, sweating, miosis, hypothermia; decreased libido; rash, facial flushing, urticaria, pruritus.
  • Serious adverse effects: respiratory depression.
  • WHO Model List: Oral solution, concentrate (Powder for oral concentrate), methadone hydrochloride 5 mg/ml, 10 mg/ml; Oral solution, methadone hydrochloride 5 mg/5 ml, 10 mg/5 ml.

Buprenorphine hydrochloride

  • Starting dose: 2-8 mg a day, sublingually, and the dose should be determined for each patient based on the severity of dependence, the level of tolerance to opioids, the presence or absence of opioid withdrawal features, the use of other psychoactive substances such as benzodiazepines or alcohol, as well as on the other relevant clinical factors.
  • Therapeutic dose: For management of opioid withdrawal state, 4-32 mg a day, sublingually, with subsequent reduction of dosage by 1-4 mg over three to fourteen days. Average buprenorphine maintenance dose should be at least 8 mg per day.
  • Adverse effects: anorexia, nausea, vomiting (particularly in initial stages), constipation; euphoria, hallucinations, dizziness, drowsiness, confusion, headache; dry mouth, spasm of urinary or biliary tract; hypotension, postural hypotension, vertigo, bradycardia, tachycardia, palpitations, headache, sweating, miosis, hypothermia; decreased libido; rash, facial flushing, urticaria, pruritus.
  • Serious adverse effects: respiratory depression.
  • WHO Model List: Sublingual Tablets, buprenorphine hydrochloride 2 mg, 8 mg.
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