Substance (drug and alcohol) misuse

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chapter 62 Substance (drug and alcohol) misuse

INTRODUCTION AND OVERVIEW

We define a drug (substance) as a chemical entity, self-administered (non-medically) for its psychoactive effect. The effect usually includes a change in mood, arousal or perception, thinking (cognition) and/or behaviour. It may vary according to which drug is used, the amount used, the route of administration, the mixture of drugs used, the expectations of effect by the user, the setting of use and the personal characteristics of the user such as weight, gender and previous drug experience.

Drugs can be classified according to their physiological effects:

• depressants—lower inhibitions and impair consciousness, coordination and concentration
• opioids—are strong analgesics with euphoric properties that impair consciousness
• cannabinoids—have a mixture of mild hallucinogenic and depressant properties
• stimulants—increase nervous energy and suppress sleep and appetite
• hallucinogens—distort perception of reality.

In this chapter we briefly consider the more important drugs in most of the categories, and for each we consider the drug and its mode of action, use and clinical effects, and current medical and integrative treatments.

WHY PEOPLE USE DRUGS

Although there is no easy explanation for why people use drugs, the aim of using drugs may be broadly considered to be the pleasurable alteration of consciousness. The neural circuits that underlie the experience of pleasure clearly have high evolutionary value, as there is powerful survival value in repeating adaptive behaviour associated with pleasure or the relief of suffering. The ‘reward centre’ is the brain pathway responsible for the subjective experience related to natural reinforcers such as sexual activity and eating. These cells arise in the midbrain and extend to the nucleus accumbens, the amygdaloid nucleus, hippocampus, olfactory bulb and parts of the prefrontal cortex. Dopamine is released in anticipation of reinforcing activity and it facilitates approach behaviour (that is, feeling drawn to the things we find attractive or pleasurable). Dopamine release is necessary for associative conditioning, essentially enabling emotionally tagged information to be acquired and retained efficiently—in essence, dopamine has distinct motivational properties and important survival value in signalling reinforcement and in facilitating incentive learning. Anticipatory release of dopamine may assume an attentional role and be the biological basis of drug-related craving. Drugs of abuse may be thought of as increasing dopamine release (e.g. amphetamines), inhibiting post-synaptic dopamine reuptake (e.g. cocaine) or interfering with interneuron inhibition of dopaminergic pathways (e.g. opioids).

Not all effects of drugs on brain function are due to dopamine: dopamine modulates the presynaptic release of glutamate (the major excitatory neurotransmitter) and gamma aminobutyric acid (GABA, the major inhibitory neurotransmitter), both of which are implicated in reward pathways. Generally, the more efficiently a drug alters neurochemical function, the stronger its potential reward or reinforcing effect. And vice versa—with opioids, for example, use of a partial agonist (e.g. buprenorphine) or an antagonist (e.g. naltrexone) that blocks opioid receptors can be beneficial in treatment.

The collective impact of drugs of abuse is that neurotransmitter release is occurring as a result of direct stimulation of brain pathways, rather than their stimulation by sensory input. The ease, reliability, intensity and rapidity of such effects go a large way towards explaining the potential for such drugs to lead to abuse. The underlying brain structures and processes responsible for drug-related reinforcement are at least partially under genetic control. For example, studies suggest that the heritability of liability to alcohol abuse is 50%.

Studies also suggest that there are a myriad psychosocial influences on drug use patterns. For example, risk factors for heavy adolescent substance abuse include social environmental factors (e.g. high unemployment and liberal, cultural norms of use), family factors (e.g. family disruption), peer factors (e.g. greater attachment to peers than to parents) and individual factors (e.g. low self-esteem and depression).

The influence of genes is not static and can be expressed differently in the presence of differing environmental conditions.

DRUG USE AND HEALTH

The health effects of tobacco and alcohol dwarf those of all illicit drugs combined. Up to 25% of hospital medical admissions are directly due to the effects of excessive alcohol consumption, and an estimated 15–20% of all general practice attendees consume harmful amounts of alcohol. Alcohol-related injuries account for 3–4% of the annual global burden of disease and injury, and tobacco smoking is the major cause of preventable death and disability worldwide.

DOCTORS AND SUBSTANCE ABUSE

• Medical practitioners are well placed to influence, assess, diagnose and treat people whose drug and alcohol consumption contributes to their health problems.
• Doctors are particularly prone to the excesses of alcohol and drugs, and this is the most common cause of disciplinary measures in the profession.
• Doctors are also a major source of street or illicit prescription drugs that can be misused.

MEDICAL AND PSYCHOSOCIAL PROBLEMS

Drug and alcohol use is not an all-or-nothing phenomenon. It exists as a spectrum extending from abstinence through intermittent non-hazardous and sometimes beneficial use to risky, hazardous use, or harmful use, to dependence. There are four core diagnoses.

• Hazardous or risky use is a repetitive pattern of use that confers a risk of harmful physical and psychological consequences. Hazardous substance abuse is also definable in terms of at-risk behaviours, such as bingeing to severe intoxication or sharing intravenous needles. Brief interventions that provide information and advice are effective in reducing many forms of hazardous use.
• Harmful use is use that is actually causing physical or psychological harm to the individual, e.g. over 40 grams of alcohol per day for women.
• Substance abuse is use that disrupts prevailing social norms, which vary with culture, gender and generation.
• Dependence is present when there are any three of the following features:

• impaired control over use of a psychoactive substance
• a strong desire or craving to take it
• a priority given to substance use over other activities
• a stereotyped or predicable pattern of use, tolerance and withdrawal
• continued use despite harm. Severe dependence is typically associated with drug withdrawal on cessation of use.

SPECIFIC SUBSTANCE ABUSE

ALCOHOL

Excessive alcohol consumption is a major risk factor for morbidity and mortality. The WHO estimates that, worldwide in 2002, alcohol caused 3.2% of deaths (1.8 million) and 4.0% of the burden of disease.1 In Australia, for example, it has been estimated that harm from alcohol was the cause of 5.3% of the burden of disease for males and 2.2% for females.2 In Australia in 1998–99, the total tangible cost attributed to alcohol consumption (which includes lost productivity, healthcare costs, road accident-related costs and crime-related costs) was estimated at $5.5 billion. Nevertheless, some benefits are thought to arise in the longer term from low to moderate alcohol consumption, largely through reduced risk of stroke and ischaemic heart disease. The net harm associated with alcohol consumption, after taking these benefits into account, was around 2.0% of the total burden of disease in Australia in 2003.3

In most developed countries, around 10% of the population drink at levels considered low risk for long-term harm. Around one-third of people drink above safe limits for short-term harm. Groups with higher than average consumption include young people, people in rural and remote areas and certain occupational groups such as miners and hospitality workers.

Alcoholic beverages are made by yeast fermentation of sugars from different plant sources to give a variety of drinks. The alcoholic strength (expressed by volume) varies from 2–5% for beers to 10–15% for table wines, to 35–55% for spirits. A standard drink contains approximately 10 g alcohol. Compared with most other drugs, alcohol has low potency, and large doses are required to produce its toxic effects.

The effects of alcohol on the central nervous system (CNS) vary according to the blood alcohol concentration, starting with mild euphoria, muscle relaxation and pleasure, possibly through release of noradrenaline, dopamine and endogenous opioids; then impairment of performance, especially of complex tasks; then ataxia and slurred speech, intellectual impairment and amnesia; and finally, profound depression and progressive loss of consciousness, respiratory failure and death.

Alcohol enhances the effects of the inhibitory neurotransmitter GABA at the GABA-A receptor to produce anxiolytic, muscle-relaxant and sedative effects. Alcohol also blocks the NMDA receptors (N-methyl d-aspartate receptors), probably causing the amnesic and cerebral depressant effects. Alcohol dilates blood vessels, irritates the gastrointestinal tract and damages the liver and other organs.

Regular intake of alcohol results in the development of tolerance, with larger amounts required to produce the same degree of intoxication. Tolerance develops in parallel with physical dependence.

A compulsive desire to use alcohol is attributed in part to its strong reinforcing properties—avoiding withdrawal symptoms and stimulation of the brain reward system with reduced anxiety and euphoria. Alcohol increases the firing of dopamine neurons in the ventral tegmental area and the release of dopamine in the nucleus accumbens. The alcohol-induced euphoria and stimulant effect in humans is antagonised, and craving for alcohol in chronic users is reduced by drugs that block the synthesis of catecholamines and deplete brain dopamine. Alcohol appears to increase endogenous opioid activity, and opioid receptor antagonists such as naltrexone decrease animal intake in both humans and animals and reduce the alcohol high and the number of relapses.

Clinical effects

Just as alcohol intake depresses the nervous system, its withdrawal produces over-excitation of the CNS. A mild acute withdrawal (hangover) can develop following a single intoxicating dose of alcohol or a short period of drinking, and manifests as headache, nausea, dehydration, tremulousness, lethargy and sleep disturbance.

Minor withdrawal syndrome

Minor withdrawal may cause symptoms within 24 hours of the last drink, including tremor, tachycardia, hypertension, sweating, nausea, diarrhoea, reduced appetite, anxiety, restlessness, headache, difficulty sleeping and bad dreams. The syndrome peaks on days 2–3 of abstinence and the major symptoms subside by day 4–5 or within a week. Fifteen per cent of withdrawing chronic alcohol users will experience withdrawal seizures 1–3 days after their last drink, and usually in the first 48 hours. These are usually grand mal in type, and between one and four seizures may occur.

Major withdrawal (delirium tremens)

Major withdrawal occurs 3–10 days after the last drink. Fewer than 5% of chronic alcohol patients (rarely under age 30 years) can suffer from agitation, disorientation, high fevers, sweating, paranoia and visual hallucinations. The patient gives a history of heavy alcohol use for at least 5 years and a recent episode of heavy drinking for two or more weeks.

Protracted withdrawal

Protracted withdrawal may be present, with symptoms of anxiety, irritability, hostility, depression, insomnia, fatigue and craving most severe in the first 5 days following the last drink. These may last for weeks or months following cessation of drinking and may be the major trigger for relapse.

Acute alcohol toxicity

The manifold manifestations of acute alcohol toxicity include acute alcohol hallucinosis or paranoia, pathological or idiosyncratic alcohol intoxication, blackouts, sleep disturbances, alcohol overdose, decreased myocardial contractility, peripheral vasodilatation with drop in blood pressure then systolic hypertension, atrial or ventricular arrythmias, oesophagitis, gastritis, subepithelial haemorrhages, increased small bowel motility and decreased water and electrolyte absorption, increased red cell volume, mild anaemia and leucopenia, hyperplasia of the bone marrow, mild thrombocytopenia and decreased platelet aggregation.

Chronic alcohol intoxication

Chronic alcohol use may affect almost every body system, and most of these effects are detrimental. Regular consumption of two drinks per day for men and one for women has been shown to be beneficial through decreased risk of atherosclerosis due to increased concentrations of circulating high-density lipoprotein cholesterol and inhibition of blood coagulation.

• Studies have linked high comorbidity of chronic alcohol dependence with mental disorders, especially anxiety disorders (25%), depression (20–40%) and alcohol-induced hallucinosis.
• Wernicke–Karsakoff syndrome is a neuropsychiatric condition found in the presence of ongoing carbohydrate load where thiamine is deficient.

Wernicke’s encephalopathy is an acute, reversible condition, seen in chronic alcohol-dependent individuals, characterised by ataxia, ophthalmoplegia and confusion. Not all of the classical triad of signs need be present for the diagnosis to be made. Indeed, it is underdiagnosed by up to a factor of 80% on this basis. Thiamine is required to act as an enzyme co-factor for pyruvate kinase, at the conclusion of glycolysis in the cytosol. It is mandatory for the production of high levels of ATP, produced via the Krebs cycle in mitochondria. Its absence causes significant under-utilisation of carbohydrates in the form of anaerobic over aerobic metabolism. Essentially the brain is starved of energy despite a high carbohydrate load. Despite the enormous variance of alcohol detoxification protocols and choice of detoxification agents used across the world, the single most important drug and the one common theme to all protocols is thiamine. In the absence of signs, parenteral (IV or IM) thiamine 100 mg q8h is thought to be sufficient prophylaxis.

Korsakoff syndrome (or Korsakoff’s psychosis) is the irreversible sequel to Wernicke’s, where thiamine is not administered quickly enough or in sufficient doses, and is characterised by inability to form new memories, loss of short-term memory and eventually long-term memory, confabulation and hallucinations. Treatment is with parenteral thiamine and is currently thought to require at least 500 mg per day, although resolution of symptoms is likely to be incomplete.

• Pancreatitis—inflammation of the pancreas (see Ch 30, Gastroenterology).
• Hepatic inflammation and cirrhosis (see Ch 30).
• Bones—chronic alcoholism is associated with other risk factors such as poor nutrition, leanness, liver disease, malabsorption, vitamin D deficiency, hypogonadism, haemosiderosis, parathyroid dysfunction and tobacco use, and these may contribute to the pathogenesis of bone disease related to alcoholism.4 Alcohol-related low bone density requires comprehensive lifestyle management in addition to alcohol reduction or abstinence in order to slow or prevent the development of osteoporosis.
• Poor immune function—alcohol has a deleterious effect on many immune system functions, and chronic alcoholism is associated with increased susceptibility to bacterial and viral infection. Assess immunisation status and arrange appropriate immunisation (e.g. influenza and pneumococcus, tuberculosis, hepatitis A and B).

Current guidelines5

• Low risk—less than 2 standard drinks per day on average for women and 4 per day for men, with 2 alcohol-free days per week in the long term. No more than 4 drinks for women and 6 for men on any one occasion, with consumption above long-term low-risk levels on more than 3 days per week. The guidelines suggest low-risk levels of < 25 g alcohol per day for women and up to 25–45 g per day for men.
• Hazardous—3–4 standard drinks for women and 5–6 for men per day in the long term. No more than 5–6 drinks per day for women and 7–10 for men on any one occasion.
• Harmful—5 or more standard drinks for women and 7 or more for men in the long term. More than 7 for women and 11 for men on any one occasion.
• No level is safe in pregnant women.

Without systematic screening, GPs are likely to miss up to 75% of risky drinking. A useful approach is to screen all patients annually and infrequent attenders opportunistically. The assessment should include:

• the level, frequency and pattern of alcohol consumption
• symptoms of alcohol dependence
• physical, psychological and social problems related to drinking.

Tools to assess alcohol intake:

• The WHO’s Alcohol Use Disorders Identification Test (AUDIT) is one of the most reliable to use.
• Another simple tool is the quantity–frequency index—on how many occasions in the past 30 days has the patient consumed more than 7 (women) or 10 (men) standard drinks?
• Physical examination and laboratory tests are not useful for identifying harmful drinking, and may be normal in alcohol dependence.

Management

1. Brief interventions—even as short as 5 minutes—have been shown to be effective. Compared to those receiving no intervention, those receiving any brief intervention show a 20–30% reduction in drinking and are at least twice as likely to modify their drinking. Brief interventions of 1–4 sessions can have an impact on drinking behaviour.
2. Follow-up is useful to reinforce changes and assess the need for further treatment.
3. Some patients find Alcoholics Anonymous (AA) helpful. A meta-analysis of AA and other 12-step programs found similar outcomes to other standard treatments including cognitive behaviour therapy (CBT).6
4. Motivational interviewing aims to motivate change in drinking behaviour by creating a discrepancy between the patient’s goals and their current actions. Evidence suggests that it is useful in risky and dependent drinkers.
5. Dependence and withdrawal management—patients who are physically dependent will require inpatient or outpatient withdrawal treatment, the latter being more common these days.

• Acamprosate (333 mg two tablets t.d.s. for patients < 60 kg and 4 tablets per day for patients > 60 kg) and naltrexone (50 mg daily) are generally well tolerated and can be continued if the patient is drinking. They are modestly effective in reducing relapse, delaying return to drinking and reducing drinking days.
• Disulphiram (Antabuse®) (200 mg daily) causes patients to become intensely unwell if they drink alcohol. It can be effective in patients when dosage is closely supervised. As reactions can be life threatening, it is not recommended as a first-line therapy.
• Psychosocial interventions have been shown to be effective in combination with anti-craving medications (acamprosate and naltrexone), and weekly follow-up may increase the effectiveness of pharmacotherapy.

Integrative approaches

Herbal medicines7

Herbal treatments such as St John’s wort (Hypericum perforatum), kudzu extracts (Pueraria lobata), panax ginseng, dried roots of S. militorrhiza (a Chinese medicine used for insomnia) and ibogaine (from a Central African root bark) may reduce alcohol consumption.8 While the mechanisms of action remain to be clarified, they probably act through several neurotransmitter systems. St John’s wort may provide some relief from comorbid depression.

Silybum marinarum (milk thistle)—silymarin, the flavonoid extracted from milk thistle, has been studied for treating all types of liver disease. Silymarin has the ability to block fibrosis, a process that contributes to the eventual development of cirrhosis in people with inflammatory liver conditions secondary to alcohol abuse.9

Nutrition

Nutritional deficiencies are common in people who chronically ingest excessive alcohol and may require dietary management and nutritional supplementation. Common deficiencies include vitamin B1, vitamin A, vitamin D, selenium, folate, riboflavin, zinc and vitamin B6.

Dietary advice

• Include foods high in B vitamins and iron, such as whole grains, dark leafy greens (such as spinach and kale) and sea vegetables.
• Include fruits (such as blueberries, cherries and tomatoes) and vegetables.
• Protein—alcohol causes both whole-body and tissue-specific changes in protein metabolism, resulting in loss of lean tissue mass. Clinical studies in alcoholic patients without overt liver disease show reduced rates of skeletal muscle protein synthesis. Ensure adequate protein with food sources (meat, chicken, fish, soy foods) and/or supplementation.
• Eliminate simple sugars and increase complex carbohydrates.
• Increase essential fatty acids, including omega-3 supplementation.
• Avoid caffeine.
• Recommend a multivitamin daily.

Acupuncture

Studies provide some evidence that acupuncture is more effective than placebo in:

• reducing alcohol intake over the subsequent 3 months and reducing the desire to drink
• reducing re-admissions for alcohol detoxification.

The studies have substantial methodological weaknesses, however, and there have been problems in finding appropriate control groups in blinded studies.7

It is claimed that complementary therapies may be effective in specific subgroups of alcohol abuse patients and that, in any case, acupuncture integrated with conventional treatment could represent a valid support treatment for some patients.

There are very few data on the effectiveness of homeopathy for alcohol dependence. Researchers generally agree on the need for more well-conducted studies.

TOBACCO

Smoking remains the most prevalent behavioural risk factor for disease and premature death. Daily smoking varies widely in different countries. For example, it is reported by nearly three-quarters of the male population in some Middle Eastern countries and by just over one-sixth of the population in Australia. A number of groups within the community, such as Indigenous Australians, those from specific ethnic groups, those with a mental health problem and those with other drug use problems have much higher rates. Nearly three-quarters of smokers report that they want to stop smoking, but the success rate of unaided attempts is low.

The process of drying, curing and ageing the tobacco leaf increases the concentration of the alkaloid nicotine and other constituents that contribute to the toxicity of tobacco. Substances added during manufacture to improve flavour, control burning and enhance nicotine delivery result in a complex cocktail of hundreds of biologically active substances in tobacco smoke.

Nicotine is selective for the nicotinic acetylcholine receptor. There are two major types of these receptors: at the skeletal neuromuscular junction, and at acetylcholine receptors in the brain and autonomic ganglia.

Nicotine increases arousal and attentiveness, and improves reaction time and psychomotor performance. It appears that nicotinic receptors have an important role in modulating higher brain functions; their effects on memory and learning are less clear. Nicotine can improve mood by relieving anxiety, and it reduces appetite. Autonomic effects include nausea and vomiting, tachycardia, vasoconstriction, increased blood pressure and cardiac output, and decreased gastrointestinal motility. It increases antidiuretic hormone secretion, reduces urine flow and suppresses the immune system via decreased T-cell activity. Smoking accelerates atherosclerosis and increases the risk of cardiovascular disease including angina, myocardial infarction and stroke.

The fastest route of absorption is by inhalation, which delivers a bolus of nicotine to the brain in about 10 seconds, leading to reinforcement. The rapid reinforcement probably contributes to the highly addictive nature of tobacco smoking. Absorption from nicotine gum is much slower, with a peak plasma level after 30 minutes of chewing compared with 5–10 minutes after smoking. Transdermal patches are even slower, with a peak level reached after 3–12 hours.

Smoking induces many liver enzymes responsible for the metabolism of nicotine itself and other drugs. There are therefore significant interactions, and nicotine seems to reduce the sedative effects of alcohol, possibly explaining their common consumption together.

Tolerance

Repeated exposure to nicotine results in neuronal adaptations that are reflected in tolerance, sensitisation and withdrawal. Tolerance of the cardiovascular and behavioural effects of nicotine develops during the course of one day, and smokers lose the tolerance overnight while sleeping and regain it the next day on resumption of smoking.

Dependence and withdrawal

Cessation of nicotine intake causes withdrawal: the symptoms can affect behaviour and provide strong motivation to continue smoking. Withdrawal symptoms start within a few hours of cessation and peak around 24–72 hours after the last cigarette. The DSM-IV criteria for nicotine withdrawal include four or more of eight symptoms and signs:

• dysphoria or depressed mood
• insomnia
• irritability, frustration, anger
• anxiety
• difficulty concentrating
• breathlessness
• decreased heart rate
• increased appetite or weight gain.

Craving, while not a diagnostic criterion, is an important element in withdrawal.

Smokers commonly maintain blood nicotine levels of 10–40 ng/mL. Withdrawal symptoms are believed to be mainly due to decreased nicotine concentration. Stress and anxiety affect nicotine tolerance and dependence because cortisol reduces the effect of nicotine. Elevated levels of cortisol mean that more nicotine needs to be consumed to achieve the same effect. Part of the reinforcement of smoking comes from relief of nicotine withdrawal (negative reinforcement). Nicotine also produces pleasurable effects that are important in positive reinforcement in that the smoker feels alert, yet relaxed. Nicotine activates the brain reward system with increased extracellular dopamine. Inhaled nicotine gets to the brain rapidly and each puff produces some discrete reinforcement.

Toxicity

The acute fatal dose of nicotine for an adult is about 60 mg of base. The average intake from a cigarette is 1–3 mg. The typical smoker obtains 20–40 mg nicotine per day. Acute tobacco poisoning results in symptoms of nausea, vomiting, dizziness and general weakness. Severe poisoning can result in convulsions, unconsciousness and possible death. Chronic tobacco exposure affects many organ systems. Nicotine, smoke tar and carbon monoxide play important roles in leading to atherosclerosis and cardiovascular disease, chronic obstructive airways disease, peptic ulceration, gastrointestinal tract cancers, impaired fertility, abortion, premature birth, low birth weight, SIDS, myopathy and osteoporosis.

Helping smokers to quit

There is good evidence that brief advice from healthcare providers to quit has a small effect: 2–3% of quitters one year later. This effect can be increased by adding other strategies including pharmacotherapy, active follow-up, and referral to quit-smoking services. The 5 A’s approach10 is recommended:

• Ask—being aware of who the smokers are in practice is important for effective management of chronic diseases. About one in three smokers attending their GP have not been correctly identified.
• Assess—assessment of interest in quitting is helpful in tailoring relevant advice to help motivate a quit attempt. Nicotine dependence can be rapidly assessed by asking about time to first cigarette after waking, the number of cigarettes smoked per day, and whether the patient had cravings or withdrawal symptoms in previous attempts to quit. Yes to any of these suggests nicotine dependence.
• Advise—brief assessment and advice to quit, often taking as little as three minutes, acts as a prompt to quit attempts and has a measurable effect on quit rates.
• Assist—all smokers interested in quitting should be given counselling and support by a GP or a trained practice nurse. A quit kit and referral to a Quitline should be provided.
• Arrange—a follow-up visit one week and one month after quit date to check for relapse has been shown to increase the likelihood of successful long-term abstinence.

Pharmacotherapy

Several drugs have been shown to assist smoking cessation but they are not a substitute for motivational and professional counselling support. Three pharmacotherapy agents have been licensed for smoking therapy: nicotine replacement therapy (NRT), bupropion and varenicline.

Nicotine replacement therapy

All forms of NRT are effective in aiding cessation, nearly doubling the cessation rate at 12 months compared to placebo. Combination therapy (patch and gum) should be recommended to smokers who are not able to quit or who experience craving when using one form of NRT. NRT can also help smokers who are unwilling or unable to stop smoking to reduce their nicotine consumption. Some of these smokers will go on to attempt to quit. Some points to note:

• More than one form of NRT can be used concurrently.
• NRT can be used by pregnant and lactating women.
• All forms of NRT can be used by patients with cardiovascular disease.
• All forms of NRT can be used by smokers aged 12–17 years.
• There is a high likelihood of persistent addiction to NRT.

Bupropion

The mode of action of this antidepressant is not known but may be due to inhibition of reuptake of dopamine and noradrenaline. Bupropion doubles the cessation rate at 12 months compared with placebo. It has been shown to be effective in patients with chronic conditions—depression, cardiac disease, pulmonary disease and schizophrenia. It is not as effective as varenicline and should be used if the latter is contraindicated. The dose is 150 mg once a day for 3 days, then b.i.d.

Varenicline

Varenicline is a partial agonist of the alpha-4 beta-2 nicotinic acetylcholine receptor, where it acts to alleviate symptoms of craving and withdrawal. At the same time it blocks nicotine from binding to the alpha-4 beta-2 receptor, reducing the intensity of the rewarding effects of smoking. A 12-week course of varenicline produced a continuous abstinence rate of nearly one-quarter at 12 months, significantly more effective than bupropion and placebo. The main adverse effects include nausea (30%) and abnormal dreams (13%).

People should set a date to stop smoking. Start varenicline 1–2 weeks before their quit date.11 Titrate the dose as follows:

• days 1–3: 0.5 mg daily
• days 4–7: increase to 0.5 mg twice daily
• continue with 1 mg twice daily from day 8 to the end of a 12-week treatment course.

Nortryptyline

This antidepressant drug is not registered for smoking cessation but a 12-week course appears to double cessation rates compared with placebo. Its use is limited by its potential to produce serious side effects including arrythmias in those with cardiovascular disease, and it can be dangerous in overdose.

Integrative approaches

Acupuncture and hypnotherapy are used in some patients to aid smoking cessation but only a limited number of studies have tested these approaches. In controlled trials, acupuncture does not increase quit rates over sham acupuncture.

CANNABIS

Cannabis, used for over 4000 years, is the most popular drug used worldwide after caffeine, alcohol and tobacco. There is a popular perception that it is a soft drug and perhaps less addictive than harder drugs such as stimulants and opioids.

Australia has the highest rate of use in the OECD countries, with 10% of adult males current users and 4% of adult females. Twenty-five per cent of adolescents have used cannabis and nearly 20% of these exposures occurred before the age of 12 years. Earlier onset of cannabis use predicts greater addiction severity and morbidity.

Cannabis sativa (hemp) produces a resin with about 60 cannabinoids, of which one, tetrahydrocannabinol (THC), is principally responsible for the psychoactive effects of cannabis. The drug is usually smoked, to deliver the vaporised THC and other pyrolysis products rapidly to the lungs, blood and brain. Lipophilic THC is taken up by the body lipids and the metabolites are excreted slowly in the urine over the next several days.

There are two types of cannabinoid receptors: CB1 (brain and peripheral tissues such as testes and endothelial cells) and CB2 (in the immune system, especially T-cells). The CB1 receptors mediate most of the well-known effects of cannabis, and among these is the facilitation of mesolimbic dopaminergic pathways.

Cannabis produces a feeling of euphoria, relaxation and wellbeing, perceptual distortions such as apparently sharpened senses, and psychomotor and cognitive impairment. Peripheral effects include tachycardia, vasodilatation (especially in the conjunctivae), hypotension, reduced intraocular pressure, and bronchodilation. It stimulates the appetite and is antiemetic, being used in some countries to treat nausea from cancer chemotherapy. Blood concentrations of THC do not correlate well with effects, and the presence of THC metabolites in urine may not necessarily reflect recent usage.

Tolerance, dependence and withdrawal syndromes occur with cannabis, and there is concern that dependence may develop rapidly in some younger people and that it may be more severe than previously thought. Two joints a day for 3 weeks is sufficient to induce withdrawal symptoms after cessation in some people. Symptoms of withdrawal include:

• anxiety
• anorexia
• disturbed sleep and vivid dreams
• nausea
• salivation
• increased body temperature
• tremor
• weight loss
• irritability
• stomach pain.

Acute toxicity is characterised by:

• anxiety, panic attacks, delusions (persecutory), visual hallucinations, overt psychotic reactions in vulnerable people
• impairment of short-term memory and attention
• impairment of motor skills, reaction time and ability to perform skilled activities
• a shortlived psychotic state—has been reported associated with high-dose use
• slight increase in heart rate.

Chronic toxicity is characterised by:

• impairment of short-term memory, attention and the organisation and integration of complex information
• effects on major mental illnesses, such as precipitation and relapse of schizophrenia
• chronic respiratory disease
• effect on pregnancy—low birth weight
• other problems possibly related to chronic cannabis use—precipitation and aggravation of chronic psychosis; amotivational syndrome; reduced fertility; respiratory cancers; impaired immune function.

Cannabis and psychosis:

• Cannabinoids increase dopamine release.
• Cannabis precipitates relapses of schizophrenia.
• Heavy use can cause an acute toxic psychosis.
• There is little evidence for chronic toxic psychosis.

Patient assessment

Patient assessment should focus on:

• form of cannabis and method of administration
• amount used and money spent each week
• number of hours per day spent using, being intoxicated and recovering from use
• activities undertaken while intoxicated
• withdrawal symptoms
• age when first tried and started to use regularly
• other substances used
• comorbid—physical and mental health
• insight and motivation to change.

Medical treatment

• Develop therapeutic rapport—cannabis dependence rarely occurs in isolation from other drug use.
• Cognitive behavioural therapy (CBT) interventions that include motivational interviewing techniques are effective in reducing problematic cannabis use (see below).
• Treatment of overdose is rarely required.
• Provide information handouts.
• Set a ‘quit date’.
• ‘Detoxification’.
• Although there are no specific pharmacological treatments, associated psychological conditions may benefit from symptomatic treatment:

• bupropion valproate—exacerbate withdrawal symptoms
• antidepressant—side effects may limit use (e.g. SSRIs exacerbate insomnia)
• benzodiazepines—risk of abuse; use temazepam 10–20 mg nocte, maximum 1 week
• mirtazapine—30 mg nocte; may help with sleep disturbance. Initial reports suggesting reduced cannabis intake have not been supported with one small clinical trial to date
• rimonabant—20 mg mane; possible role in abstinence-based treatment.

• Antipsychotic drugs are occasionally needed for cannabis-induced psychotic states—these states are usually shortlived and resolve within a week of cessation of cannabis use:

• drug abstinence, rehydration, sleep hygiene, regular review
• olanzapine 5–10 mg nocte or quetiapine 50–100 mg nocte for the first 2 nights, then 100–200 mg nocte depending on degree of sedation, or temazepam 10–20 mg nocte, up to 1 week
• admission when uncooperative and risk to self or others.

• Other medication may be required for coexisting conditions such as depression, anxiety or phobias (see below).
• Relapses are not uncommon—treat as an opportunity to learn, rather than as a failure.

Psychological interventions

Most interventions have been developed from those used for alcohol.

• Usually follow brief intervention format, including motivational interviewing.
• Psychological interventions—even one session of CBT has been shown to be of value compared with no treatment. No difference has yet been demonstrated between CBT, motivational therapy and social support sessions.
• CBT includes management of withdrawal symptoms, motivational interviewing, cognitive restructuring, coping skills training, lifestyle modification and relapse prevention, including management of urges and triggers.
• Marijuana Anonymous exists in some countries.

Cannabis and mood disorders

• Pre-existing symptoms may initially be alleviated through self-medication with cannabis (poor evidence).
• Cannabis use is more common in certain social groups that are also at a higher risk of depression (good evidence).
• Cannabis use may carry a direct risk for depression and anxiety (good evidence).

Amotivational syndrome:

• Described in chronic users—may be due to chronic intoxication.
• Loss of ambition, drive, motivation.
• Affective restriction.
• Reduced capacity to complete complex tasks, including those at school or work.

Cannabis and physical health

The effects of cannabis are difficult to differentiate from the effects of smoking. They include:

• carcinoma of head and neck, respiratory and upper digestive tracts
• chronic airways disease
• coronary artery disease
• hypertension
• infertility in men and women.

Key points

• Cannabis use is common, and cannabis dependence is relatively uncommon.
• There is good evidence for the efficacy of psychological treatment (especially CBT).
• In managing cannabis abuse, it is important to treat comorbidity (e.g. psychosis, other drug-use disorders).

PHARMACEUTICALS

Benzodiazepines

Benzodiazepines were discovered in 1954. Chlordiazepoxide (Librium®) was the first patented benzodiazepine drug, in 1960. Diazepam (Valium®) was introduced in 1963, and was found to be not only sedative but also a useful muscle relaxant. Other agents followed, from the mid-1960s with nitrazepam (Mogadon®), through to the 1980s with alprazolam (Xanax®). Benzodiazepines rapidly became popular because they were superior to barbiturates in having decreased tissue toxicity and a vastly improved safety profile in overdose.

Indications

Benzodiazepines are primarily used as anxiolytic, sedative/hypnotic, anticonvulsant, antispasmodic, anaesthesia and amnesia agents for medical procedures and for drug and alcohol withdrawal.

Prevalence

Benzodiazepines such as temazepam, diazepam, oxazepam and nitrazepam tend to rate as some of the most widely prescribed medications.

Mode of action

Benzodiazepines appear to modulate the effect of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter of the CNS, via the GABA receptor complex. The GABA receptor complex includes binding sites for benzodiazepines, barbiturates and steroids.

Short-term effects

Low-dose benzodiazepines cause loss of motor coordination, drowsiness, lethargy, fatigue, cognitive impairment, memory loss, confusion, depression, blurred vision, slurred speech, vertigo, tremors and respiratory depression. High doses can cause extreme drowsiness. In high-dose intoxication, the above symptoms may be observed as well as mood swings, hostile, violent and erratic behaviour, and euphoria.

Long-term effects

Because some benzodiazepines have long half-lives, exceeding 24 hours, and as a result of their lipid solubility, accumulation may occur in body fat stores. The symptoms of over-sedation may not appear for several days. These include: cognitive impairment, memory loss, poor judgment, disorientation, delirium, confusion, slurred speech, muscle weakness and lack of coordination.

Tolerance

Long-term benzodiazepine use can result in neuro-adaptation and dependence. The mechanism is unclear but may be due to altered sensitivity of GABA NMDA or other receptors. Benzodiazepine dependence may also be due to the unfixed sensitivity of the GABA receptor to various neurotransmitters. In this model, the set-point where drugs can bind but are not effective appears to shift with long-term use.

Common benzodiazepine withdrawal symptoms include: perceptual distortions, sense of movement, depersonalisation, derealisation, hallucinations (visual, auditory), distortion of body image, tingling, numbness, altered sensation, formication, sensory hypersensitivity (light, sound, taste, smell), muscle twitches, jerks, fasciculation, tinnitus. In addition, rapid withdrawal from high doses has been associated with psychosis, delirium and convulsions.

Dependence

Time from first dose to the development of dependence is based on the dosage, potency and duration of habit. For example, in someone who is taking a high dosage of alprazolam, dependency can develop within one to two months. Short-acting benzodiazepines are popular among opiate-dependent individuals as they have a rapid onset of sedation. As dependence develops, increased doses are required to invoke and maintain a therapeutic effect.

Detoxification

Detoxification regimens are broadly divided into two main scenarios:

• those where a client’s daily intake is either at or near a therapeutic dose—such clients can usually be managed as outpatients with a modest detoxification program
• those where a client’s daily intake is extremely high and very erratic—this is often seen in the context of poly-drug use with heroin, for example, where benzodiazepines are used between heroin injections to manage withdrawal and insomnia. These clients may at times be managed as outpatients, but may also require inpatient management.

In assessing suitability for home or ambulatory detoxification, the following points should be considered:

• The patient is not ‘doctor shopping’.
• There is no evidence of severe and high dose dependence.
• There is no history of seizures.
• Doses are either therapeutic or only slightly above.
• There is no psychiatric or medical comorbidity.
• There has been no previous treatment failure in this setting.
• The home environment is stable and there is a carer.
• There is no poly-substance abuse/dependence.
• The patient is highly motivated.

Patients considered unsuitable for home detoxification and therefore possibly requiring inpatient specialist unit care may exhibit the following:

• previous complicated withdrawal
• moderate–severe dependence
• ingestion of non-therapeutic, high doses of benzodiazepines
• chaotic ingestion patterns
• significant use of other psychotropic drugs
• physical or psychiatric comorbidity
• absence of care or an unstable household
• access/exposure to benzodiazepines in the home environment.

Ambulatory/home detoxification

For low (therapeutic) dose dependence, home detox can be considered. This has been adapted from Queensland Health Detoxification Protocols.12

• 2 days diazepam 5–10 mg at 6 am, midday and 6 pm, and 10 mg at bedtime
• 2 days diazepam 5 mg at 6 am, midday and 6 pm, and 10 mg at bedtime
• 2 days diazepam 5 mg at lunchtime and at bedtime
• then diazepam 5 mg at bedtime for one night.

The doses required to begin the detoxification should not exceed those admitted by the patient. It may be necessary to reduce doses much slower than suggested by weeks or even months, particularly at the lower end of the dose scale.

Symptomatic therapy can include metoclopramide for nausea, antacids for reflux, antidiarrhoeals, and paracetamol for headache.

Inpatient detoxification

Patients who have been on high doses of benzodiazepines for long periods are more likely to experience withdrawal reactions than those on lower doses, particularly if withdrawal is abrupt.

Patients should be commenced on a dose of diazepam which safely prevents seizures and delirium, and then steadily reduced over time. There is avid debate regarding the cases for and against structured detoxification from benzodiazepines on several grounds. Safety is the most notable issue, but efficacy is also questionable, with high relapse rates described. If undertaken, current recommendations suggest management of patients at a dose which prevents withdrawal seizures, between 40 and 60 mg per day in divided doses. Reductions should be gradual and should not exceed 10% of the total dose per week. This is particularly important at the lower end of the dose range and towards the conclusion of the detoxification, where flexibility is essential. Given the high relapse rate of patients to uncontrolled benzodiazepine use in this group, it is useful to explore other mental health comorbidity and other addictions, e.g alcohol and opioids, which may be drivers of ongoing chaotic substance use among this group of patients.

There is evidence to support the use of brief interventions. In addition, evidence is quite strong for the use of CBT in this setting.

Self Management and Recovery Training (SMART) has been shown to be of benefit as a self-help strategy. It is a group-based therapy based on the principles of CBT and rational emotive therapy.

Integrative approaches

The first step in the integrated management of benzodiazepine use is to assess the underlying reasons for the drug abuse. It is also important to exclude adverse drug reactions from other prescribed and illicit drugs—for example, SSRIs can cause anxiety and patients may be using benzodiazepines to manage that side effect.

Management of underlying anxiety

Vitamin and mineral supplements that may assist include thiamine, magnesium, phosphate, folate, zinc and vitamins A, C, D, E and B group.

While there have been case reports and uncontrolled series involving auricular acupuncture, there is a lack of randomised trials and systematic reviews to support its use widely.

Neither valerian nor melatonin has been found to have a significant effect on benzodiazepines consumed by those trying to detoxify, nor have they had a reproducible effect on sleep quality among those who have successfully stopped using benzodiazepines.

PRESCRIPTION OPIATES AND OVERTHE-COUNTER MEDICATIONS

A prescription is written by an approved medical, dental, optometric or nursing practitioner, and medications are dispensed to the consumer or patient at hospitals, pharmacies or clinics. Doctors occasionally dispense drugs to patients directly, in the form of samples, in remote areas in lieu of a dispensing chemist or via the doctor’s bag.

There are a number of other avenues by which people may obtain prescription medications. Online outlets have become popular in the past 5–10 years. In some cases, highly addictive and dangerous drugs are available via the internet without medical assessment or prescription. In a number of cases, drugs may not have been formally approved for sale in the country of purchase. An example of this is oxycodone (Endone®), an opioid analgesic, commonly marketed in many countries as a sustained-release preparation (e.g. OxyContin® in Australia). In the United States, oxycodone is available in combination with paracetamol in an over-the-counter (OTC) formulation.

The range of agents in the opiate category is very broad, ranging from codeine available OTC, to morphine available on prescription. Recently, hydromorphone (Dilaudit®) has become popular again after a long absence. These opiate preparations are all highly addictive and their long-term use results in significant problems for both the prescriber and the patient.

In addition to these narcotics, a number of other drugs have significant abuse and dependence potential. Table 62.1 provides a list of the classes and names of drugs that may be addictive or have potential for abuse. Use of these drugs has increased dramatically in the past decade.

TABLE 62.1 Common prescription and OTC drugs, classified by organ system, action and name, and matched to adverse effects

Organ system Action and drug name Adverse effect/dependence
Gastrointestinal Antispasmodics

• Hyoscine

Drowsiness, intoxication Cardiovascular Beta-blockers

• Propanolol

Reduce tremor, calmative Caffeine

• coffee, cafergot, No-doze
Increase alertness, stay awake, performance enhancing, dependence Diuretics

• Frusemide
Short-term weight loss, Masking agent
Neurological Sedative/anxiolytics

• Benzodiazepines
Intoxication, withdrawal, self-medication, respiratory depression, overdose, death Anticonvulsants

• Clonazepam
• Phenobarbitone
As above, cardiac, respiratory and renal failure, death Neurological, other Movement disorders

• Benztropine
Drowsiness, intoxication Travel sickness

• Antihistamines
Drowsiness, intoxication Analgesics
Narcotic analgesics
Oxycodone, morphine, pethidine, codeine, hydromorphone
Drowsiness, intoxication, respiratory depression, death, dependence Endocrine Human growth hormone

• Erythropoietin
• Anabolic steroids
Performance enhancement in sport, increased strength and stamina, improved recovery Genitourinary Erectile dysfunction

• Tadalafil
• Sildenafil
• Vardenafil
Crushed and injected at dance parties with psychostimulants and hallucinogens; no actual benefit from this technique; causes embolism, increases BBV Paediatric
Treatment of ADD/ADHD
Psychostimulants
• Methylphenidate
• Dexamphetamine
CNS and CVS hyper-stimulation, mood changes, psychosis, dependence Dietary Anorectics

• Phentermine
• Diethylpropion
As for psychostimulants Respiratory Antitussives

• Codeine
• Dextromethorphan
As for narcotics Antihistamines

• Chlorphenphiramine
Drowsiness, intoxication Decongestants

• Pseudoephedrine
As for psychostimulants

In the United States, it is currently estimated that 20% of the population have at some time in their lives used a prescription drug for indications not recommended by the prescriber. A US national survey on drug use13 found that 6.4 million Americans over the age of 12 years, or 2.6% of the population, had used a psychotherapeutic drug for non-medical reasons in the previous month, with the main three categories being analgesics, tranquillisers and stimulants. Retail sales of opioid medications in the United States had increased from 1997 for various medications listed in Table 62.1. Methadone was the most common, with a 933% increase in sales over the eight-year period. Over the same time, retail sales of oxycodone increased by 588%. The US Department of Justice reported that pharmaceutical drug abuse exceeded that of all other drugs except cannabis and accounted for the high annual number of pharmaceutical deaths.

In many countries there have been reports of increased prescribing of opiates for non-cancer pain. For example, in Australia, the Department of Health and Ageing reported a rise of greater than 800% in the use of oxycodone between 2001 and 2006.14 In 5 years, oxycodone has moved from being insignificant to being in the top ten fastest-rising rates of prescription drug, and it was seventh for volume of drug and sixteenth for cost.

US internet suppliers of prescription drugs sell to consumers worldwide. Although the sale of opioids is controlled in the United States and in Australia, this is difficult to enforce, because a third-party country where such laws do not exist is often used to supply the drugs. Internet providers rarely give detailed warnings regarding use, contraindications and precautions while taking medication. This is particularly true of warnings about addiction.

Treatment options

A careful history, examination and review of previous investigations is required. If prescriptions were given previously by other doctors, try to locate the source of the original diagnosis and verify the presence or absence of the condition for which the patient claims to need the drug in question.

Be completely transparent with the patient in an empathic, non-judgmental way. If their diagnosis cannot be confirmed, it is reasonable to establish the diagnosis by referrals and special tests, as long as they can be justified on clinical grounds. Too many investigations can have the effect of magnifying the patient’s concerns, while too few may leave an important diagnosis undiscovered.

Once dependence has been established, use treatments for the same class of illicit drug—for example methadone or buprenorphine for opioid dependence. This will not be possible in all cases, and may be prohibited in certain jurisdictions. This is particularly relevant for psychostimulants, where specialist evaluation is necessary. It may be worthwhile to consider other treatments depending upon the patient’s mental state, such as antidepressants and CBT.

Where no direct drug-receptor combination and effect exists, brief intervention, CBT and long-term follow-up are required, as relapse is common. Factors affecting relapse include lack of desire to change, hyperalgesia and the ready availability of prescription and OTC drugs.

It is important to remember that there is no compelling evidence to support the long-term use of opiates for chronic back pain or chronic headache.

Opiate and stimulant prescribing patterns by doctors are monitored by state health regulatory bodies. If they are found to be abnormal, action can be brought against the doctor to counsel and ameliorate such practices. In some cases medical boards limit or prohibit prescribing privileges.

Integrative approaches

As with other drug groups, it is important to assess the cause of opiate use and abuse, and this includes appropriate pain management. Psychosocial interventions such as those mentioned above can help to treat dependence on prescription or OTC preparations.

OPIOIDS

It is estimated that there are over 74,000 dependent heroin users in Australia. Use of illicit opioids is associated with a substantially higher mortality and morbidity than use of prescription opioids. Complications of intravenous use of opioids include infectious conditions: hepatitis B, C, HIV, bacterial endocarditis and tetanus. Users may suffer injection site infections and vascular and nerve damage. Environmental factors including poor living conditions, exposure to violence and accidents increase the likelihood of poor health, with regular illicit opioid injectors having 13 times the mortality rate of the general population.

Opium is named after the juice of the opium poppy; morphine is the major active ingredient of the poppy. Morphine and codeine are derived from the poppy juice. Opioids are a class of substances with morphine-like effects that can be reversed by the specific antagonist naloxone. Some opioids are semi-synthetic chemical derivatives of morphine (e.g. heroin, acetylated morphine) and some, such as pethidine and methadone, are fully synthetic and share a common core structure that enables them to bind to opioid receptors. Opioid peptides and their receptors are widely distributed in the brain and spinal cord and in many non-neuronal tissues including the gastrointestinal tract. The endogenous opioid system is activated by stress, and is involved in the modulation of pain perception and mood and in the regulation of physiological systems such as respiration and immune function.

The principal effects of morphine include miosis, drowsiness, contentment, euphoria, analgesia (through altered perception of pain), respiratory depression, cough suppression, nausea and vomiting, constipation and increased bladder and urethral tone. Morphine activates receptors in the reward pathway, causing increased dopamine release. Tolerance develops after the first dose. Strong agonists such as morphine and methadone activate opioid receptors to elicit a full response, whereas partial agonists such as buprenorphine do not elicit a full response. Antagonists such as naloxone occupy the receptors and block agonist effects.

The acute toxic effects of opioids involve many body systems: pruritis, constipation, nausea, vomiting, confusion, delirium, stupor, miosis, urine retention, hypothermia, pulmonary oedema, hypotension, coma and death due to respiratory depression.

Tolerance is characterised by a shortened duration and reduced intensity of the euphoric, analgesic and sedative effects. There is marked variation between individuals in the development of tolerance, perhaps due to genetic variation in receptor characteristics.

Opioid withdrawal is unpleasant but not life threatening. It is characterised by insomnia, irritability, restlessness, malaise, bone and joint pain, fatigue and increased gastrointestinal motility.

Clinical assessment

A non-judgmental interviewing style should be used, and observation for signs of intoxication or withdrawal and their timing in relation to last dose of the drug is vital. The patient may appear malnourished and underweight.

The psychosocial history is often complex, with substantial disadvantage, and the assessment should include personality, comorbid psychopathology, employment and treatment history, and history of illegal activities.

Physical examination should include inspection of limbs for increased pigmentation, track marks, thrombosed veins and injection site abscesses. It is important to check for sexually transmitted infections, HIV infection and hepatitis C, endocarditis and tuberculosis.

Investigations should include tests to exclude the above. Urine drug screens for opioids and metabolites are often performed.

Treatment

Treatment for opioid use takes many forms. It is most important that clinicians treating opioid-dependent patients adopt a non-judgmental attitude and a treatment philosophy that incorporates the principles of harm reduction or harm minimisation.

Opioid overdose is a medical emergency that should be treated immediately with cardiopulmonary resuscitation, clearance and maintenance of airways, and urgent call for paramedical services. Naloxone 0.4–1.2 mg should be given IV or IMI titrated to support respiratory function. Treatment for the impact of other sedative drugs may also be required for complicated opioid overdose.

Opioid dependence is a chronic relapsing disorder. While opioid withdrawal can be effectively treated with well-researched agents, relapse is common. Pharmacotherapies for opioid withdrawal management include:

• oral methadone—tapering by 1–2 mg/day from an initial dose of 30–40 mg per day; the rate of reduction should be slowed towards the end
• buprenorphine—given sublingually at least 6 hours after the last heroin dose and 24 hours after last methadone dose, in a dose of 4, 8, 12, 12, 12 mg on days 1–5 sequentially and then stopped or reduced by 2 mg per day.
• adrenergic agonists and adjunctive medications—can be used, such as clonidine (75–150 μg t.d.s.) to reduce withdrawal symptoms and then tapered over 1–2 weeks. Other agents that are sometimes used for symptom relief include: benzodiazepines or hypnotics to reduce anxiety or the former in tapering regimen for coexisting benzodiazepine dependence; loperamide for diarrhoea; quinine sulfate for cramps; non-steroidal anti-inflammatories for pain management; metoclopramide for nausea; and neuroleptics for agitation and insomnia
• psychological therapies—can improve the effectiveness of pharmacotherapies and be used in the treatment of those who do not wish to undertake such treatments. Only a minority of patients will participate in psychological therapy for extended periods.

Integrative approaches

Studies comparing acupuncture to methadone detoxification found that acupuncture produced comparable clinical outcomes or superior outcomes relative to methadone detoxification regimens. One study also found acupuncture plus methadone detoxification produced greater alleviation of withdrawal symptoms than methadone detoxification alone. Some studies provide evidence that acupuncture has clinical value as a component of detoxification treatment for opiate abuse. Correct site acupuncture appears to have greater therapeutic effect than incorrect site acupuncture. Reported studies have methodological problems, however, and reveal conflicting results, making interpretation difficult.11

Meta-analyses have not demonstrated a significant efficacy of other complementary therapies, including pharmacological and biological treatments such as herbal therapies, dietary supplements, natural hormones, health and healing practices (e.g. hypnosis, meditation, yoga, biofeedback, exercise, chiropractic or massage therapy) or acupuncture.

PSYCHOSTIMULANTS AND OTHER DRUGS

Psychostimulants are the group of chemicals that affect the CNS monoamine transmitters, such as dopamine, noradrenaline and serotonin. Although they have greatest effect on dopamine, most have some effect on the other two, which often results in complications and significant health risks.

Psychostimulants are a heterogeneous collection of chemicals including cocaine, amphetamines, ecstasy and ‘club’ or ‘party’ drugs. In many ways, these names are misplaced, as all drugs can be taken at parties, but these are also often taken alone, in solitude and under very dangerous conditions. It is important to remember that alcohol and nicotine are also party drugs, and kill more people per year than all other drugs combined.

Cocaine is an alkaloid derived from the leaves of the plant Erthroxylan coca. It is not as common in Australia as other stimulants. Cocaine blocks the reuptake of dopamine into the terminal neuronal bouton, causing increased concentrations to be present in the synapse for longer periods of time. This results in a pleasurable experience for the user. It has a very short half-life, about 60 minutes, which results in binge use of the drug. It is commonly inhaled intranasally, but is also very effective if injected.

In 1927 Gordon Alles discovered that amphetamine ameliorated fatigue and improved nasal and airway passages. It was marketed as Benzedrine in the 1930s, during which time it became extremely popular. Soon after, other compounds such as methamphetamine were developed.

Amphetamines promote the release of dopamine, noradrenaline and serotonin from the terminal boutons of neurons. With repeated use, they lead to an exhaustion of endogenous monoamine neurotransmitters, causing reduced effects and a ‘crash’ depression. They can be used in a variety of ways owing to their chemistry, including orally, intranasally, smoked and injected. While there are differences in bioavailablity and absorption with different methods of administration, the effects are fairly similar.

Ecstasy, or 3,4-methylenedioxy-methamphetamine (MDMA), first became apparent as a recreational drug in the late 1960s but did not come to prominence until the 1990s. The methylenedioxy side-chain has the effect of raising its boiling point, and therefore this chemical is usually not smoked but taken orally, usually in tablet form. It can, however, be injected, although this is rarely done.

More recent side-chain variation has resulted in a variety of drugs being illicitly produced and marketed as stimulants. Among these has been paramethoxyamphetamine (PMA), also known as ‘red Mitsubishi’ as it is a red-coloured tablet. A more recent addition, 4-bromo-2,5-dimethoxy-phenethylamine (2CB) has a side-chain bromine substation and is a powerful hallucinogen. It is usually swallowed as a red or white tablet. One of the more worrying trends with MDMA is that it may contain varying levels of impurities or other stimulants such as these, creating powerful and unwanted effects. In addition, these tablets may contain caffeine, pseudoephedrine or ketamine. Indeed, it is estimated that at least 10% of ecstasy tablets may not contain any MDMA.

A number of other drugs are often associated with psychostimulants and party drugs, and also have varying degrees of hallucinogenic effect. These include gamma-hydroxybutyrate (GHB), ketamine and LSD. Most of these agents are either sedative or depressant drugs, rather than stimulants, and all have the potential to be hallucinogenic. They can be quite dangerous and, along with benzodiazepines, are associated with sex-based crimes, such as ‘date rape’.

The typical age of first use of these types of drugs is quite late compared with other drugs. On average, adolescents start to smoke when aged between 15 and 16 years, and drink alcohol when aged between 16 and 17 years. Psychostimulants and other drugs are mostly first used by people when aged in their twenties, rather than in their teens.

Clinical effects

The effects, both wanted and unwanted, are essentially driven by increased, prolonged agonistic monoamine activity in the synapse. There is no simple drug–receptor reaction as is seen with opiates. As a result, withdrawal and detoxification is more complex, and not simply driven by replacement therapy, as is the case with heroin and methadone or buprenorphine.

The popular (positive) effects sought by stimulant users are: euphoria, increased energy; improved social interaction; increased confidence; perceived improvement in sexual performance/prowess; improved concentration, productivity and creativity; and reduced fatigue and anorexia.

The negative effects of stimulants include anxiety, anger, agitation, impaired judgment and hypervigilance. In addition, users often experience stereotyped or repetitive behaviours, nausea, vomiting, confusion, psychosis or convulsions. Bingeing is associated with poor sleep and self-care, irritability, paranoia and strong cravings. Users often report an inability to achieve the original high, causing frustration and unstable behaviour. Increased violence, crimes and accidents are common among heavy amphetamine users.

With ongoing binge use, dopamine levels are exhausted and higher doses of stimulants are taken, in a vain attempt to increase or prolong the desired effect. Without endogenous monoamine neurotransmitters, psychostimulant drugs have little capacity for augmenting the euphoria, causing frustration to the user. As the dose of drugs increases, so does the danger of unwanted effects.

Stimulants may impair the thermoregulatory system, leading to increased body temperature. This is a major component of a condition known as serotonin syndrome. It is a constellation of signs present after the ingestion of a serotonergic agent. Autonomic signs include tremor, fever and sweats. Agitation is usually present. In addition there is a neuromuscular component, consisting of hypertonia, hyperreflexia and clonus. This is a medical emergency, requiring urgent resuscitation and transfer to hospital. Patients will require advanced life support. In severe cases, rhabdomyolysis, elevated creatine kinase and metabolic acidosis may ensue, along with multi-organ failure. The mortality from this condition is about 11%.

Stimulant withdrawal, amphetamines in particular, can be separated into three phases—crash phase, acute phase and chronic phase—and these may blend into one another. The ‘crash’ occurs after depletion of dopamine stores in the presynaptic bouton and lasts from a few hours to 2–3 days. It occurs more frequently after prolonged or heavy binge use and is characterised by excessive sleeping, eating, and depression and irritability. It is described as a separate entity from acute withdrawal and is thought to be more like a hangover, as seen with alcohol use. The acute phase lasts for 5–7 days. Common complaints include mood swings, emotional lability, anger, aggression and intense cravings. The chronic phase can last for weeks to months. Symptoms include depression, dysphoria, lethargy and cravings. Relapse is common in this group as symptoms of depression and boredom are set in a context of fairly ready availability of this class of drugs.

Treatment options

Mood disorders and dysphoria count heavily among the symptoms seen in stimulant users. Depression follows binge or heavy use. It is reasonable to use an antidepressant such as an SSRI to assist. Mirtazapine has been trialled in 15–30 mg doses at night to assist with night-time anxiety in short periods of up to 4 weeks. Early results are promising.

Psychosis can occur with heavy or binge-style use and requires urgent treatment. The hallucinations that occur in this context are often referred to as ‘pseudo-hallucinations’ as the patient is aware of the difference between fantasy and reality. It is common for such patients to have hallucinations about their drug use and getting caught. If mild, treatment can be initiated as an outpatient using an atypical antipsychotic. If the psychosis is severe, or if harm is likely to the patient or others, admission to a psychiatric emergency facility should be undertaken for stabilisation.

While some patients will require long-term treatment with antipsychotics, they are in the minority, as drug-induced psychosis is usually a self-limiting condition. Those requiring permanent treatment may have had previously undiagnosed schizophrenia. This group will usually require lifelong care.

As drinking alcohol is often associated with stimulant use, there is good evidence to demonstrate that using aversive drugs such as disulfiram (Antabuse®), as well as anti-craving medications such as naltrexone, will concomitantly reduce alcohol and stimulant use. It is vital that adequate counselling be given to the patient prior to prescribing. If the patient has recently drunk alcohol or has some while taking disulfiram, profound vomiting, headache, hypotension and loss of consciousness will almost certainly ensue. If opiates are taken in significant amounts by an opiate-dependent individual, withdrawal may be precipitated by naltrexone.

Psychosocial interventions are the mainstay of treatment in this group. There is good evidence to support the use of CBT and brief interventions in the management of stimulant dependence. CBT-based interventions indicate that the retention rate of patients in treatment, urine test results and self-reported drug use are all significantly better than self-help strategies.

Integrative approaches

There is no evidence for effectiveness of treatment by herbal treatments or acupuncture for stimulant use or dependence.

FUTURE DIRECTIONS

Vaccines for cocaine are being trialled, on the pretext of making antibodies to cocaine and thus reducing the available free drug for the brain. Replacement therapy for amphetamines has been trialled with dexamphetamine in fairly modest doses. The results remain inconclusive, possibly because limits must be placed on therapeutic doses to prevent unwanted side effects, such as psychosis in treatment.

A newer form of medication—modafinil—used in sleep apnoea and narcolepsy is in trial at the moment. This drug improves wakefulness without euphoria or positive reinforcement for abuse potential. It has been used successfully off-licence for shift work sleep–wake disturbance in France and the United States, and is currently under evaluation for this condition in amphetamine use. Results of this and other trials are eagerly awaited.

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Oude Voshaar RC, Couvee JE, Vanbalkom AJLM, et al. Strategies for discontinuing long-term benzodiazepine use. Br J Psychiatry. 2006;189:213-220.

Peles E, Hetzroni T, Bar-Hamburger R, et al. Melatonin for perceived sleep disturbances associated with benzodiazepine withdrawal among patients in methadone maintenance treatment: a double-blind randomized clinical trial. Addiction. 2007;102(12):1947-1953.

Prescription and OTC

Australian Institute of Health and Welfare. Statistics on drug use in Australia, 2004. Canberra: AIHW, 2005;18.

Bell JR. Australian trends in opioid prescribing for chronic non-cancer pain, 1986–1996. Med J Aust. 1997;167(1):26-29.

New drugs. Australian Prescriber 1999, 22(5):125–127; 2001, 24(2):43–47; 2004, 27(1):21–23.

NSW Therapeutic Assessment Group. Low back pain. Rational use of opioids in chronic or recurrent non-malignant pain. http://www.ciap.health.nsw.gov.au/nswtag/publications/guidelines/LowBackPain41202.pdf.

US Department of Health and Human Services. Results from the 2005 National Survey on Drug Use and Health: National Findings. http://www.oas.samhsa.gov/nsduh/2k5nsduh/2k5Results.pdf.

Psychostimulants

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Khong E. The growing challenge of party drugs in general practice. Aust Family Physician. 2004;33:709-713.

Sidis A, Haber P. Psychostimulants and party drugs. Australian Doctor, March 2005: 25–32.

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