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:
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 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.
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.
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.
Current guidelines5
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:
Management
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
Acupuncture
Studies provide some evidence that acupuncture is more effective than placebo in:
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:
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:
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:
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:
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.
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:
Acute toxicity is characterised by:
Chronic toxicity is characterised by:
Medical treatment
Psychological interventions
Most interventions have been developed from those used for alcohol.
Cannabis and mood 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:
In assessing suitability for home or ambulatory detoxification, the following points should be considered:
Patients considered unsuitable for home detoxification and therefore possibly requiring inpatient specialist unit care may exhibit the following:
Ambulatory/home detoxification
For low (therapeutic) dose dependence, home detox can be considered. This has been adapted from Queensland Health Detoxification Protocols.12
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 |
Drowsiness, intoxicationCardiovascularBeta-blockers
Reduce tremor, calmative
Caffeine
Increase alertness, stay awake, performance enhancing, dependenceDiuretics
NeurologicalSedative/anxiolytics
Intoxication, withdrawal, self-medication, respiratory depression, overdose, deathAnticonvulsants
As above, cardiac, respiratory and renal failure, deathNeurological, otherMovement disorders
Drowsiness, intoxicationTravel sickness
Drowsiness, intoxicationAnalgesics
Drowsiness, intoxication, respiratory depression, death, dependenceEndocrineHuman growth hormone
Performance enhancement in sport, increased strength and stamina, improved recoveryGenitourinaryErectile dysfunction
Crushed and injected at dance parties with psychostimulants and hallucinogens; no actual benefit from this technique; causes embolism, increases BBVPaediatric
CNS and CVS hyper-stimulation, mood changes, psychosis, dependenceDietaryAnorectics
As for psychostimulantsRespiratoryAntitussives
As for narcoticsAntihistamines
Drowsiness, intoxicationDecongestants
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:
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.
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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