Textbook of Psychiatry/Alcoholism and Psychoactive Substance Use Disorders
Substance use disorders or SUDs encompass a spectrum of conditions varying in severity from problematic use, abuse and varying grades of mild to more severe dependence. Over the last half century, various drug use epidemics have characterised different population groups worldwide. As the knowledge base of clinical neuroscience has expanded, the understanding of these disorders has developed from being viewed as a moral weakness to being viewed as complex biomedical disorders affecting the brain and manifesting clinically as chronic relapsing disorders. In addition, research has demonstrated equivalent rates of relapse for addictive disorders and non-compliance to treatment for medical disorders such as hypertension and diabetes.
- 1 Epidemiology
- 2 Pathogenesis
- 2.1 Biological Factors
- 2.1.1 Neuroanatomy and pathophysiology
- 2.1.2 Pathophysiology: Substance binge/intoxication phase and type 1 craving (Stage I addiction)
- 2.1.3 Pathophysiology: Withdrawal and protracted withdrawal/type 2 craving (Stage II addiction)
- 2.1.4 Pathophysiology: Relapsing recurring stage (Stage III addiction)
- 2.1.5 Pathophysiology: Genetic vulnerability
- 2.2 Psychological Factors
- 2.1 Biological Factors
- 3 Phenomenology
- 4 Treatment
- 5 Suggested reading
- 6 References
Trends in substance use vary from country to country and fluctuations occur in the prevalence rates across time periods. Epidemiology investigates the distribution and determinants of substance use disorders; as well as patterns of drug use over time and its association with age, gender and associated risk factors. Epidemiologists use various definitions for substance use and substance use disorders. Definitions of substance use can vary from substance use once in past month or year, life time use or use characterised by the fully developed syndrome of addiction. Life time prevalence refers to fulfilling the criteria for a specified pattern of use(i.e., abuse or dependence) at least once in a person’s lifetime. Depending on the nature of substance use disorders, the chronicity and the related mortality rates, prevalence and incidence rates can differ markedly. For example, due to the chronic nature of drug dependence, the prevalence rates of substance dependence can be significantly higher than incidence rates. Period prevalence measures, such as past year prevalence, records the rate of patients fulfilling diagnostic criteria over the past year form the total population at risk.
Total number of cases at time/period
Total population at risk at time/period
Incidence measures refer to the occurrence of newly diagnosed cases over a specified time period. Cumulative incidence or the incidence proportion is usually expressed as the total number of new cases per 10 000 or 100 000 patients over a period of time i.e., over a five year period. Alternatively, incidence rates or density can also be expressed as the number of new cases occurring in the at risk population, over the total number of person years of observation.
Number of new cases over period of time
Total population at risk (without the disease) over period of time
Most large epidemiological samples across countries have found that men are at least 2-3 times more likely than women to use illicit substances and develop substance use disorders such as abuse or dependence (Brady and Randall, 1999). In addition, whereas men start using drugs at a younger age and take longer to develop full blown dependency syndromes; women tend to develop problems with addiction later in life, but develop severe problems more rapidly. However, there is evidence of a trend toward lower differences in substance misuse rates, particularly alcohol abuse, in younger age cohorts; and between males and females in the context of more equal and less traditional gender roles (Grant, 1996; Seedat et al. 2009). Certain religious and ethnic groups also show differential patterns of use. In the UK Afro Caribbean’s and in the US black patients are less likely to abuse alcohol and illicit drugs.
In the National Comorbidity Replication Study (NCS-R)(Kessler et al. 2005), conducted between 2001-2003, the lifetime prevalence for alcohol abuse in the general US population was 13.2% and for alcohol dependence 5.4%. Lifetime drug abuse had a lifetime prevalence of 7.9% whereas dependence had a prevalence of 3 %.
Within the United States certain patterns of epidemics in the use of illicit substances have emerged over the past 30 years. Whereas cannabis use peaked in the mid 1970’s, there has been a decline in the early to mid 1990’s but a rapid upsurge in the mid 1990’s. The cocaine use epidemic reached a peak in the early to mid 1980’s and has been followed by a stimulant use epidemic dawning in the late early to mid 1990’s. Since the start of the new millennium an upsurge in methamphetamine use has plagued many countries among who include the USA, Japan, Australia, South East Asia, Eastern Europe and South Africa.
Epidemiological studies identified different developmental trends in the age of onset of first drug use to the development of dependence. Cocaine dependence follows a risk trajectory of average age of onset of use in early 20’s with a comparatively higher cumulative risk of developing dependence than other substances of up to 15-16% in the 10 years following the onset of first use. Whereas the high risk periods for development of dependence for illicit drugs after first use are confined to the late teen years for drugs such as cannabis, early twenties thorough to the early 30’s for cocaine, risk of the developing alcohol dependence continues throughout later life (Wagner and Anthony, 2002). Despite stringent drug legislation and law enforcement, substantive evidence that such measures are effective have not been forthcoming
Table 1. Lifetime prevalence of substance use disorders in the general population
|Alcohol abuse||ECA (1980)
|Alcohol dependence||ECA (1980)
|Illicit drug abuse||NCS (1992)
|Illicit drug dependence||NCS (1992)
ECA- Epidemiological Catchment Area- study (National Institute on Drug Abuse and Helzer, 1987)
NCS- National Comorbidity Survey (Kessler et al. 1994)
NCS-R- National Comorbidity Survey replication (Kessler et al. 2005)
Neuroanatomy and pathophysiology
The syndrome of drug dependence occurs as a result of a complex interplay of a variety biological mechanisms as well as psychological and social factors. Dependence is characterised by repeated use of a substance resulting that ultimately results in state of neural adaptation in the brain. Various drugs of abuse act on different receptor subsystems with many of these systems converging onto to the final common pathway involved in reward seeking behaviours, the mesolimbic dopamenergic pathway (Kalivas and Volkow, 2005; Koob and Volkow, 2009). Altogether a number of neuro-anatomical circuits are involved in the pathophysiology of addiction. These include:
a) The Reward-Seeking system consisting primarily mesolimbic dopamenergic pathway and its subcomponents. This pathway stretches from the cell bodies of the dopaminergic neurons in the ventral tegmental area of the brainstem (substantia nigra) which project their axons onto the nucleus accumbens in the ventral striatum. Pulsatile stimulation of these dopaminergic neurons result in highly a pleasurable sensations
b) The prefrontal cortex subcomponents are thought to be involved in impulse regulation and modulation of reward seeking behaviour. These components include the OFC orbitofrontal cortex, the DLPFC, and the ventro-medial cortex (VMC) as well as the loop circuits that stretch from the frontal cortex through the striatum to the thalamus and back to the cortex (cortico-striatal-thalamo-cortical circuits or CSTCC). These circuits that traverse the dorsal aspects of the striatum are also implicated in the compulsive aspects of drug addiction.
c) The extended amygdala (consisting of the central nucleus of the amygdala, the Bed Nuleus of the striae terminalis and the shell of the nAcc) and its connections with the VTA and Nu Accumbens, plays an important role in learning and conditioning of behaviours related to drug use.. The extended amygdala is sensitive to stress hormones such as cortisol, and plays a potentially important role in the triggering of relapses into drug taking behaviour caused by environmental and intrapsychic stressors.
d) The basolateral cortical amygdala. This structure represents the neocortical cellular layers of the amygdala and is thought to play an important role in environmental cue detection. This structure is therefore potentially important in cue induced drug taking behaviours. People, places and objects such as drug paraphranelia that has become conditioned with drug taking can potentially lead to stimulation this anatomical area to induce relapses.
e) Memory systems in the hippocampal formation, involved in the memory consolidation of events associated with substance use. This system is interconnected among others with the extended amygdala.
Pathophysiology: Substance binge/intoxication phase and type 1 craving (Stage I addiction)
The initial use of substances, in particular psychostimulants such as cocaine and methamphetamine, is associated with a surge in dopamine release in the mesolimbic dopaminergic pathway. The principal neurotransmitter in the reward pathway is dopamine which binds to D1 and D2 receptors. Whereas drug like cocaine and amphetamines result in a direct surge of dopamine release at dopaminergic synapses (via Dopamine re-uptake-DRI- inhibition in case of cocaine and increased release in case of amphetamines) other substances such as opoids and alcohol and cannabis are thought to indirectly result in increased dopamine release after affecting brain stem mu opoid, GABA inhibitory interneurions and CB1 (cannabinoid type one) receptors. In addition to the effects mediated indirectly via the dopaminargic system on learning, conditioning and reward-motivation, non stimulant drugs such opiates, cannabis and alcohol also exert effects on the glutamatergic, serotonergic, and cannabinoid systems that have been postulated to be crticial in the pathophysiology of addictive syndromes, independent of the effects of the dopaminergic system. The basolateral and extended amygadala is associated with craving, also known as type I craving, characterised by operant conditioning in the form of positive reinforcement of drug taking behaviour paired with rewarding sensations as well as classical conditioning by the pairing of neutral stimuli with the drug of abuse.
Pathophysiology: Withdrawal and protracted withdrawal/type 2 craving (Stage II addiction)
Prolonged use of a substance results in a state of neuroadaptation. Human Imaging studies have revealed decreased dopamine uptake activity in frontal striatal areas associated with chronic drug use. This downregulation of dopaminergic function results in a dampened reward system and the clinical phenomenon of tolerance. In addition repeated use and binging activates the hypothalamic pituitary axis (HPA axis) driven stress response and hormones such as corticotrophin releasing hormone (CRF) are mobilized. Anti stress hormones such as neuropeptide Y (NPY) levels also decrease. The activation of the stress response is has also been conceptualized as an anti-reward system. Whereas the presence of the substance is experienced as pleasurable the withdrawal is experienced as unpleasant and anhedonia frequently characterises protracted withdrawal states. In contrast to the positive emotional state of intoxication, withdrawal is associated with a negative emotional state. These negative emotional states are thought to drive increased drug taking. Increased drug use associated with stress/negative emotional states is termed type 2 craving or negative reinforcement (Koob, 2009).
Pathophysiology: Relapsing recurring stage (Stage III addiction)
In addition to neuro-adaptation at transmitter and receptor level, intracellular molecular changes also occur during the state of drug dependence. These include the activation of transcription factors such as CREB (cAMP response element binding protein) and delta Fosb. These transcription factors in turn lead to the switching on of genes that code for neurotransmitter receptors, enzymes involved in the synthesis of neurotransmitters and to altered neurotransmitter receptor numbers (up or down regulation). Increased cAMP in the nucleus accumbens associated with opoid, cocaine and alcohol use has also been linked to increased expression of the kappa opioid receptor that bind to the dysphoria inducing hormone dynorphine. This mechanism is thought to underlie the development of tolerance and is associated with the negative emotional state characterising withdrawal of the substance of abuse (Hyman, 2005). These molecular changes establish addiction and drive the relapsing and recurrent nature of addition.
Pathophysiology: Genetic vulnerability
Research into the genetics of alcohol dependence based on family, twin, and adoption studies have revealed that the heritability of alcohol dependence can be as high as 60%-80%. Genome wide association studies have implicated a number of genes in the development of alcoholism. In particular genes involved in the metabolism of alcohol are thought to play an important role. Asian populations are known to have low rates of alcoholism in comparison to Europeans. Persons from Asian descent experience highly unpleasant reactions upon alcohol ingestion such as severe nausea, flushing and tachycardia. This reaction is due to a rapid accumulation of the toxic breakdown and accumulation of the alcohol metabolite, acetaldehyde. This clinical observation lead to a search for associations with enzymes such as alcohol dehydrogenase (ADH) that converts alcohol into acetaldehyde and acetaldeyhe dehydrogenase which converts acetaldehyde to acetate. This search has revealed that variants in the alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) genes on chromosomes 4q and 12q respectively, are implicated. A variant of the ADH gene, ADH1B on chromosome 4q that encodes for a more robust ADH enzyme leading to higher levels of the toxic metabolite acetaldehyde, has been shown to protect against alcoholism in a Chinese population, reducing the rate of alcoholism with up to 80%. In turn a variant of the ALDH2 gene on chromosome 12q that produces weaker acetaldehyde dehydrogenase enzymes have been shown to reduce alcoholism with up to 67% in heterozygous subjects. As alcohol is an agonist on GABAA receptors, a search for genes encoding for the GABA receptor has revealed a strong relationship between alcoholism and the GABRA2 subunit gene on chromosome 4p that encodes for the ?2 subunit of the GABAA receptor. The GABAA receptor plays an important role in mediating the effects of alcohol intoxication as well as withdrawal (Hartz and Bierut, 2010).
Nicotine dependence carries a heritability estimated as high as 75%. Strong associations have been found between nicotine dependence and variants of genes coding for nicotinic cholinergic receptors (nAChR’s). In particular the gene CHRNA5, coding for the ?5 subunit of the nicotinic cholinergic receptor has been implicated. This gene is located on chromosome 15q. Nicotinic cholinergic receptors are distributed in the striatum on dopaminergic neurons and interact with these neurons in the dopaminergic reward pathways. In turn the CHRNA5 gene has also been implicated in cocaine dependence (Hartz and Bierut, 2010). Of recent interest has been the study of potential gene environment (GxE) interactions in the development of addictive disorders. Whereas many of these findings represent non specific risk factors for a variety of psychiatric disorders, they are also likely to play a role in addictive disorders. Gene environment interaction studies have demonstrated interactions between variants of genes such as the serotonin transporter gene (5-HTTLPR) short and long variants and childhood maltreatment and negative family relations; the monoamine oxidase (MAOA-LPR) gene and childhood maltreatment and sexual abuse, as well as the GABRA2 gene and marital status. Although the findings of GXE studies are intriguing, many of these studies await replication(van der Zwaluw and Engels, 2009).
Learning, conditioning and cognitive factors
The development of drug dependence is driven by two different types of associative learning behavioural psychologists refer to as classical and operant conditioning.
Classical (or Pavlovian conditioning-referring to Pavlov’s experiments with dogs) consists of the repeated pairing of a neutral stimulus with a particular stimulus (uncontioned stimulus) that elicits a physiological, reflexive response (unconditioned response) such as activation of salivary glands or activation of a sexual response. With repeated co-administration of the unconditioned stimulus with the neutral or conditioned stimulus the neutral stimulus becomes a conditioned stimulus (CS) and elicits a conditioned response (CR). People, places and objects associated with the drug use can become conditioned to elicit conditioned responses such as craving before using and therefore reactivate substance seeking behaviour.
Operant conditioning refers to a positive or negative reward that follows certain behaviour such as taking a drug. Thus the euphoriant effects of a drug will positively reinforce drug taking behaviour. Negative affective states associated with the absence of drug taking behaviour or withdrawal become a negative reinforce that also increase further substance use behaviours.
In addition to behavioural factors, cognitive styles of persons with addictions can also perpetuate addictive behaviours. Dysfunctional and irrational beliefs about drug taking, triggered by environmental cues or intrapsychic stressors, can also lead to craving and consequent relapses into drug taking cycles. These beliefs may include thoughts such as "I cannot socialize without drinking," "I need some drugs to enjoy myself," "I am able to control my drinking," "there is no life for me without drugs, as I am essentially a bad person."
Cycle of change and motivation
Prochaska and Diclemente have forwarded the cycle of change model of addiction (DiClemente et al. 2004). This model forms a useful framework of understanding motivation to change and forms the basis for motivational enhancement therapy. According to this model patients cycle through a number of stages throughout a recovery process. Patients can enter or exit at any stage of this cycle. These stages are:
a) Precontemplation stage: a stage where drugs are not considered problematic and dependence on the substance is denied.
b) Contemplation stage: Ambivalence is developed where the negative impacts of substances are weighed up against the perceived benefits, and change is contemplated.
c) Preparation: During this phase the person devises a plan for implementing change and strengthens their motivation to commit to such a plan c) Determination: The client is determined to seek help
d) Action: Advice is followed and a rehabilitation plan is followed
e) Maintenance phase: triggers for use are identified and new coping strategies are learnt, leading to a new lifestyle.
f) Relapse: Relapse into substance taking behaviour are viewed not in a negative light but as positive learning experiences for the future. Clients can cycle back and forth through these stages and recycle through these stages until a level of completion is reached that allows for a sustained change. Researchers also differentiate between readiness for change and readiness to engage in treatment. Whereas a client may show behaviours indicating a readiness to change, this does not necessarily translate into a willingness to follow a specific treatment program. Self-efficacy, the degree of confidence a client has in their ability to effect changes, plays an important role in shaping motivation and low self-efficacy can be an important predictor of relapse.
Understanding the psychodynamics of addiction
Although unmodified psychodynamic techniques play a limited direct role the treatment of most persons with addictions, psychodynamic theory is useful in understanding the behaviour and family interactions that characterise the lives of people with addiction. Psychodynamic understanding is also useful in informing other therapeutic modalities such as CBT, MET, and group therapy. Comorbidity with various personality disorders is common in patients with addictions, with as many as 73% of addicts receiving a diagnosis of a co-occuring personality disorder, a prevalence rate several times that in psychiatric patients or persons without any psychiatric disorder. The most common personality disorders are borderline and antisocial personality disorders with the later particularly prevalent in individuals with alcohol use disorders (Verheul, 2001).
The self medication hypothesis advanced by Khantzian has been put forward to explain substance taking behaviour (Khantzian, 1997). According to these theory patient abuse substances to aid in the regulation of strong affects and painful emotions that the person may experience as overwhelming. Furthermore the good, euphoriant effects of substances are used as a substitute for deficient positive affirmation of the self by significant others in the person’s past, leading to low self esteem and deficits in self care.
During the early stages of precontemplation and contemplation where substance dependence may not be considered problematic by the client, primitive ego defences characterise the defensive style of the individual. These defences include denial of the addiction, splitting objects, family members and loved ones into all good or bad and projective identification whereby family members often unconsciously identify with distressing internal self-representations that have been projected onto others by the client and therefore either become the good, "benevolent rescuer” or the "punitive, bad family member."
A subjective sense of overwhelming powerlessness characterises persons with addictions. Together with the roles of benevolent rescuer and malevolent punisher, feelings of helplessness are often projected onto family members who unconsciously identify with this sense of loss of control and power and may defensively insist on unhelpful, inappropriately restrictive and even punitive measures. Important distinction therefore need to be made between setting limits (a desirable therapeutic measure) and punishment (undesirable and may worsen the addiction) as well as rescuing behaviour which will take away the effects of the substance use on the lies of the addicted individual and absolve them of responsibility and therefore further enable substance taking behaviour. In addition to more primitive defences, more mature, neurotic defences such as rationalization and intellectualization also characterise certain individuals with addictive disorders. With substance use disorders, particularly higher are functioning personalities with more mature and neurotic defensive personality structures.
Symptoms and classification
The term addiction is not formally endorsed by the DSM-IV-TR or ICD-10 diagnostic classifications. A proposed revision to the DSM-IV-TR is that this term be reintroduced to differentiate benign dependence states on medication such as antidepressants and beta blockers from malignant and dysfunctional states that characterise drug and alcohol dependence. The term "addiction" is sometimes used interchangeably with the category described in diagnostic systems as substance dependence. The syndrome of substance dependence or addiction develops over time with repeated use of the substance and is accompanied by neuro-adaptive changes in the brain. The diagnosis of a substance use disorder is made clinically through patient and collateral interview and is based on a clustering together of various symptoms. The most used diagnostic systems used to diagnose addiction are the DSM-IV (American Psychiatric Association, 2005) and the ICD-10 (World Health Organization Geneva, 1992). See table X for the ICD-10 diagnostic criteria. These systems of disease classification sets out specified operational criteria that need to be present before a diagnosis can be made of drug abuse or dependence. Laboratory tests for substance use disorders can be used as confirmatory tool where the reliability of self report or collateral sources of information is questionable.
Substance abuse (as it is referred to in the DSM-IV) or harmful use (as referred to in the ICD-10) consists of the presence of behaviour whilst under the influence of the effects of a substance that result in adverse social, psychological, legal or physical consequences to the person involved. (See table 2 for ICD-10 Diagnostic Research Criteria) The ICD-10 differs from the DSM-IV in that abuse is termed "harmful use" and the criteria is less specific than the DSM-IV and requires symptoms to be present for at least one month or repeatedly within a twelve month period. The DSM-IV-TR specifies certain criteria to be present relating to failure to fulfil social and occupational responsibilities, using substances in circumstances that are physically hazardous such as driving under the influence, negative consequences in interpersonal relationships and being frequently in trouble with the law as a result of substance use.
Table 2. DSM-IV and equivalent ICD-10 substance use disorders
|"Substance use disorders"
Substance dependence syndrome
|"Disorders due to psychoactive substance abuse"
Substance dependence is a syndrome that is characterised by compulsive use of the substance and loss of control over substance using behaviour. It can be accompanied by the phenomenon of tolerance to the effects of the substance and substance specific withdrawal syndrome. Tolerance is characterised by the need for increased amounts of the substance to achieve the same desired effect or by the same dose not resulting in the desired effects. Withdrawal is characterised by a characteristic cluster of symptoms on cessation or reduction of the substance. If either tolerance or withdrawal is present ICD-10 and DSM-IV allow the subtype specification of physiological or physical dependence to be noted. Substance dependent individuals also spent increasing durations of time engaging in substance taking behaviour and may give up other activities previously enjoyed in order to use the substance. Substance use continues compulsively despite adverse consequences to the person’s psychological or physical health.
Table 3 sets out the key similarities and differences in ICD-10 and DSM-IV diagnostic criteria for substance dependence.
As noted the term "addiction" is often used interchangeably with substance dependence. Addiction can be defined as a chronic relapsing medical disorder characterised by
a) loss of control over substance intake
b) and compulsive drug use associated
c) with the development of neuro-adaptations that result in the presence of
d) negative affective states when the substance is withdrawn.
Table 3. ICD-10 criteria for harmful use and dependence
Mental or physical harm that may be associated with impaired judgement clearly caused by use of a substance within a 12 month period.
A) There must be clear evidence that the substance use was responsible for (or substantially contributed to) physical or psychological harm, including impaired judgement or dysfunctional behaviour.
B) The nature of the harm should be clearly identifiable (and specified).
C) The pattern of use has persisted for at least 1 month or has occurred repeatedly within a 12-month period.
D) The disorder does not meet criteria for any other mental or behavioural disorder related to the same drug in the same time period (except for acute intoxication).
Three or more of the following manifestations should have occurred together for at least one month or, if persisting for periods of less than 1 month, should have occurred repeatedly within a 12 month period:
1) A strong desire or sense of compulsion to take the substance.
2) Impaired capacity to control substance taking behaviour in terms of its onset, termination, or levels of use, as evidenced by the substance being often taken in larger amount s over a longer period than intended, or by a persistent desire or unsuccessful efforts to reduce or control substance use.
3) A physiological withdrawal state when substance use is reduced or ceased, as evidenced by the characteristic withdrawal syndrome for the substance or by use of the same (or closely related) substance with the intention of relieving or avoiding withdrawal symptoms.
4) Evidence of tolerance to the effects of the substance, such as that there is a need for significantly increased amounts of the substance to achieve intoxication or the desired effect, or a markedly diminished effect with continued use of the same amount of the substance.
5) Preoccupation with substance use, as manifested by important alternative pleasures or interests being given up or reduced because of substance use; or a great deal of time spent in activities necessary to obtain, take or recover from the effects of the substance.
6) Persistent use of substance despite clear evidence of harmful consequences, as evidenced by continued use when the individual is actually aware, or may be expected to be aware, of the nature and extent of harm.
Table 4. Differences and similarities between ICD-10 and DSM-IV criteria for substance abuse and dependence
|Harmful use: Psychological or physical harm that may be associated with impaired judgement clearly caused by use of a substance within a 12 month period.||Abuse: Defined operational criteria of which at least one out of 4 must be present within a 12 month period. Criteria refer to continued use despite harmful interpersonal consequences, failure to fulfil major social and occupational roles, using substances in hazardous circumstances and legal consequences such as arrests for behaving under the influence of substances.|
1. At least 3 symptom criteria have to be present concurrently for at least 1 month or repeatedly present if less than one month within a 12 month period.
2. Includes the concept of desire and craving with compulsive use.
3. Further criteria in ICD-10 and DSM-IV overlap with difference in which criteria are independent or present as the same construct.
1. Also specifies that at least 3 symptom criteria have to be present in a 12 month period from an operational set but not necessarily concurrently.
2. Does not refer to desire or compulsion to use (craving).
3. These are essentially the same with the exception that certain criteria treated independently rather than as one construct.
Substance intoxication syndromes:
Syndromes of intoxication that are specific to the substance of abuse characterise use of each substance. Intoxication is usually defined as a substance specific syndrome that develops during or immediately after the ingestion of a substance and is characterised by maladaptive behavioural or psychological changes as a result of the effect of the substance on the central nervous system. Drugs of abuse can broadly be classified into "uppers" and "downers" and often persons addicted to drugs of abuse use a combination of both stimulant and depressant substances. Classified within the "downer" group are substances such as alcohol, cannabis, heroin and sedative hypnotics. Uppers consist of stimulants such as amphetamines, methamphetamines, and cocaine and club drugs such as ecstasy. A third designated class of substances include the hallucinogens and consist of substances such as LSD, mescaline and psylopsiben. The specific features of each syndrome is determined by the unique effects of each substance on the receptor systems of the brain as well as the half life of the substance which determines the duration of the substance related effects.
Table 5 contains the details of various substance intoxication syndromes.
Table 5. Substance intoxication syndromes
|Substance of abuse||Behavorial, psychological and physical effects||Half life and onset and duration of effects||Principle receptor and neural systems affected|
|Alcohol||Disinhibition, impaired judgement, argumentativeness, aggression, lability of mood. Higher doses can lead to sedation, inco-ordination, slurred speech, flushed face and stuperous states.||Follows zero order kinetics with catabolic enzymes reaching saturation at certain levels and blood levels increasing exponentially. Effects more pronounced when blood levels are rising compared to when they are falling.||Allosteric modulator of GABAA receptors. Impacts on neural membrane integrity. Acts on opioid and dopamine systems.|
|Cannabis||Euphoria, disinhibition, anxiety, agitation, increased appetite, inco-ordination, mild euphoria, ,asedation, derealisation, depersonalization, temporal slowing (time passes slower) conjunctival injection.||Onset reaches peak 10 minutes after ingestion and declines after 1 hour. Due to uptake into fatty tissue effects can potentially be prolonged. Can be detected in urine for up to 4 weeks in heavy, chronic users.||Cannabinoid receptors (CB1, CB2 ), dopamine receptors|
|Amphetamines||Euphoria, elation, inflated self esteem, grandiosity, decreased appetite, abusiveness and aggression, argumentativeness, repetitive stereotypical movements, paranoid ideation, hallucinations with intact sensorium, tachycardia, dilated pupils, hypertension, cardiac arrhythmias.||"Rush" or high often more intense than other stimulants and can last from 8-12 hours. Half life up to 20 hours for methamphetamine.||Dopamine presynaptic neurons, Vesicular monoamine transporter (VMAT2), dopamine transporter (DAT) and receptors|
|Cocaine||Euphoria, increased energy, inflated self esteem, grandiosity, hallucinations usually with intact sensorium, hypervigilance, decreased appetite, abusiveness and aggression, argumentativeness, repetitive stereotypical behaviours, paranoid ideation, tachycardia, dilated pupils, hypertension, cardiac arrhythmias, weight loss.||"Rush" or high lasts few minutes after intake. Half life ranges from 30 to 90 minutes.||Dopamine transporter (DAT) and receptors|
|Heroin||Brief euphoric rush followed by apathy and sedation, psychomotor retardation, impaired attention and judgement, interference with personal functioning, pupillary constriction drowsiness.||Euphoric sensation lasts a few minutes only. Effects wear off in 4 hours with withdrawal symptoms and signs starting after 8 to 12 hours.||Mu (µ) opioid receptors, ?opioid receptors, dopamine neurons indirectly|
|Hallucinogens (LSD, mescaline)||Anxiety, visual, auditory or tactile hallucinations whilst awake and alert, depersonalization, derealisation, ideas of reference, paranoid ideation, lability of mood, impulsive acts, tachycardia, blurring of vision, palpitations, inco-ordination||Effects subside after 6 to 12 hours.||Serotonergic and dopamineric neural systems|
|Substituted amphetamines (MDMA, "ecstasy")||Combination of stimulant and hallucinogen effects: mood elevation, increased self confidence, sensory sensitivity, peaceful feelings coupled with insight, empathy and closeness to other people.||Effects last 4 to 8 hours.||Serotonergic and dopaminergic neural systems.|
Substance withdrawal syndromes
Depending on the severity of the dependency syndrome alcohol withdrawal can range from mild and spontaneously resolving states to severe, potentially life threatening states. Mild withdrawal is characterised by gastrointestinal symptoms such as nausea, retching and vomiting, sympathetic hyperactivity as manifested by sweatiness, tachycardia, tremor and insomnia. In the majority of cases mild to moderate withdrawal states can be managed with outpatient detoxification regimes. Less than 5-10% of patients with alcohol dependence will develop complicated withdrawal also termed delirium tremens. Risk factors for complicated withdrawal include:
a) Previous history of complicated withdrawal b) History of withdrawal seizures c) Severe nutritional deficiencies (Vit B and thiamine) d) Underlying medical complications such as pancreatitis, liver damage, peptic ulceration or oesophageal varices.
Delirium tremens typically develops 48 to 72 hours following cessation of drinking and is characterised by clouding of consciousness, severe tremor, visual and tactile hallucinations often in the form of small animal figures or insects, agitation and fidgetiness as well as nausea and vomiting. Withdrawal seizures can also develop 48 to 72 hours following the last drink. Delirium tremens is considered a medical emergency and treatment in a facility geared towards the management of medical ill patients is essential.
Wernicke’s encephalopathy is a further potential complication of alcohol withdrawal. This condition can arise due to nutritional depletion of thiamine leading to a cluster of neurological symptoms on the background of a delirium. Physical signs of Wernicke’s encephalopathy include opthalmoplegia with cranial nerve III and VI palsies as well as ataxia. Only 10% of patients with Wernicke's will have the classical triad of confusion, ataxia, and nystagmus. Cranial nerve signs also only occur in about 25% of patients. Therefore, a diagnosis of Wernicke's should always be considered in patients’ who present with alterations in level of consciousness in the context of alcohol withdrawal. Untreated Wernicke's can result in death in up to 20%, and as many as 20% of patients go on to develop neuronal damage in the diencaephalic brain regions such as the mediodorsal thalamus, periaquadauctal grey and mammilary bodies of the hypothalamus. Damage in these neuroanatomical regions can result in anterograde amnesia, characterised by the inability to learn new information. Also known as diencephalic amnesia, this form of memory loss is characteristic of Korsakoff’s psychosis, which is diagnosed according to the DSM-IV as "Alcohol induced persistent amnestic disorder."
Discontinuation of heroin and other opioid derivatives is characterised by a pronounced withdrawal syndrome. Although highly unpleasant, unlike alcohol withdrawal heroin withdrawal is rarely associated with life threatening complications. The syndrome of withdrawal is characterised by severe dysphoria, craving for heroin, agitation, yawning, diaphoresis, lacrimation, piloerection (goose bumps) pupil dilatation, muscle and abdominal cramps as well as diarrhoea. For drugs such as heroin with a short duration of action, the acute withdrawal syndrome usually reaches a peak after 48 to 72 hours and subsides after 7 to 10 days.
Stimulant withdrawal (cocaine and methamphetamine)
Characteristic withdrawal syndromes have been described for stimulants such as cocaine, amphetamines and methamphetamine. The acute withdrawal syndrome usually has its onset within 12 to 24 hours of the last dose. The acute withdrawal syndrome is sometimes described as a "crash" after the period of a high. This syndrome is characterised by feelings of intense sadness and depression, severe fatigue and a tendency to oversleep and eat. The acute withdrawal syndrome typically subsides after 10 to 14 days. This is followed by a period from week 2 to week 8 post cessation that is characterised by renewed energy and a newfound confidence in abstinence. This period has also been described as the "honeymoon period" where persons typically feel confident that they are able to quit using stimulants on their own. In the treatment setting this can often be characterised by treatment drop-outs. By 2 months post drug cessation a third phase sometimes described as "the wall" is described. This phase is characterised by severe fatigue and a loss of the ability to experience pleasure (anhedonia). Usual routes to experience pleasure are often drug associated. Recovering addicts often experiences this stage is profoundly isolating.
Rates of substance use disorder have been reported as high as 75% in the treatment settings for patients with severe mental illness such as schizophrenia. The odds ratio for bipolar mood disorder in patients with substance use disorders in the NCS study has been reported to be as high as 6.8. Similarly major depressive disorder occurs in up to half of treatment seeking individuals with substance use disorders whereas the rates of substance use disorders in persons diagnosed with major depression is 2-3 times that of the general population (Kessler et al. 1996). Patients with anxiety disorders in particular panic disorder OCD and PTSD are also more likely to have a co-occurring substance or alcohol use disorder than persons from the general population. Whereas women with alcohol dependence are more likely to have co-occurring anxiety and mood disorders as compared to men, men are in turn more likely to have co-morbid ADHD, conduct disorder and antisocial personality disorder (Brady and Randall, 1999).
Substance use history and mental status examination:
In the routine clinical setting a thorough substance history should include the following:
a) The various different substances used including the substance of preference.
b) Age at first use, the frequency and amount of use over time.
c) Date of last use.
d) The amount of money spent on substances.
e) The amount of time spent daily on drug taking.
f) Attempts at trying to quit, as well as the duration of abstinent periods.
g) History of medical/physical complications including overdoses. This includes a history of risk taking behaviour placing the individual at risk of contracting transmissible conditions such as HIV or Hepatitis B.
h) An assessment of the social and relationship consequences of the substance.
i) Screening for mood, anxiety, psychotic and other psychological symptoms that may co-occur with drug use.
j) Family history of drug dependence and abuse.
k) A thorough forensic history and history of any legal involvement.
l) A detailed personal history and quality of relationship with important attachment figures as well as important developmental tasks.
Diagnostic and screening instruments:
The Alcohol Use Disorders Identification Test or AUDIT (Saunders et al. 1993) is a brief (2-3 minute) 10-item screening tool of particular use in primary care, general practice settings. It includes both a self report and clinician administered version that rate items relating to different aspects of drinking patterns, harmful use and dependency on a 4-point Likert-type scale ("never" to "daily or almost daily"). A total score of more than 8 on this scale is indicative of alcohol related problems that calls for further in-depth diagnostic interviewing. Lower cut-off scores than 8 are suggested for female populations. This instrument has demonstrated good sensitivities varying from 0.76 to 0.92 and specificities from 0.70 to 0.92 in various populations including psychiatric patients with severe mental illness and primary are patients (Reinert and Allen, 2002).
The Michigan Alcoholism Screening Test (MAST)(Selzer, 1971) is a slightly more comprehensive instrument that in addition to current alcohol use also assesses use over the subject’s entire lifetime. This self report screening instrument consists of 25 yes or no items and is available in two shorter 13 and 10 item versions. It is suitable for a variety of clinical and non-clinical settings. In addition to assessing alcohol use it also enquires about a number of related consequences of alcohol abuse such as medical, psychological, psychiatric, social, interpersonal, and occupational complications (Selzer, 2008). Despite its strength as regards comprehensiveness it is less likely to be suitable in busy time pressured clinical settings.
The Drug Abuse Screening Test (DAST)(Skinner, 1982) is a self report instrument based on the MAST but specific to illicit drug use. Similar to the MAST it assesses the presence of a variety of social, occupational, interpersonal and medical consequences relating to illicit non-medical drug use. Depending on the cut-off scores, the 20, 28 and 10- item versions of the DAST have a high sensitivity and specificity values for the detection of DSM-III-R diagnoses of substance use disorders diagnoses across a variety of settings including in patients with severe mental illness. This instrument is suitable for patients who are non-treatment seeking and assesses overall consequences of all, including polydrug use and does not specify which drugs are more likely to cause particular consequences. The test requires less than 10 minutes completing and scoring.
A brief and clinically useful tool to identify alcohol related disorders is the CAGE questionnaire (Ewing, 1984). This very brief instrument takes less than 1 minute to complete and consists of 4 brief questions as contained in the acronym "CAGE." Cut down- refers to the need to cut down or decrease drinking; Annoyed refers to feeling annoyed at criticism from others about drinking too much; Guilt refers to feeling bad or guilty about drinking; Eye opener refers to the need to have a drink first thing in the morning. The total score of the test is out of 4. A cut-off of 1 out of 4 has a high sensitivity varying from 0.86 to 0,90 but lower specificity (and hence higher false positive rate) ranging from as low as 0.52 to 0.53 to detect alcohol use disorders of clinical threshold (abuse and dependence as identified by DSM or ICD-10 criteria). Consequently some have recommended that a cut-off of ?2/4 be used to identify abuse or dependence as a result of the higher specificity and hence lower false positive rates. Clinicians also need to be aware of its limitations in certain populations as studies have shown to be a less accurate instrument in white women, pregnant women and college students who tend to binge drink (Dhalla and Kopec, 2007).
A similar test to the CAGE is the TWEAK test (Russell et al. 1991). This brief 5-item self or clinician rated instrument has been designed for and specifically validated in samples of females including pregnant women. The name of the scale is an acronym derived from the letters that represent the main constructs that are measured. In the TWEAK-HOLD version designed for the binge drinking population Tolerance refers to the amount of drinks a person can hold. In the TWEAK-HIGH version the question is phrased "does it take three or more drinks to feel high?" Worried refers to complaints or worries expressed by friends or close relatives about the patients drinking in the past year. Eye-openers refer to having a drink first thing in the morning. Amnesia refers to reports from others of blackouts where events or conversations are forgotten while drinking. The K refers to cut down or the need to cut down on drinking. The first two items are allocated a score of 2 if rate positive and the remaining items are all scored one to give a total for the entire test of 7 points. Cut–off scores of 2 or higher have been demonstrated to be associated with harmful drinking in pregnancy complicated by significantly lower birth weight, head circumference, APGAR scores and cognitive deficits by age 6 years. Cut-offs of 3 or higher are characterised by good levels of sensitivity and specificity to detect alcohol dependence in women in general population and emergency room settings (Russell et al. 2008). The TWEAK performs less well in primary care settings to detect harmful drinking where the AUDIT may be a more valid test (Bush et al. 2003).
In addition to non-structured clinical diagnostic classification systems such as the ICD-10 and DSM-IV, more structured instruments exist to aid in the diagnosis of substance abuse and dependence. The Structured Clinical Interview for DSM-IV or SCID-I (First et al. 1994) is a semi-structured clinical interview designed to generate categorical diagnoses based on DSM-IV diagnostic criteria. This interview is available in a clinician and research version and takes on average 90-120 minutes to complete depending on patient factors and clinician experience. Formal training is required and experience and background in clinical work is advantageous although not essential to conduct this interview successfully. The instrument consist of several modules that assess various mental disorders in addition to substance use disorders and depending on the needs and research designs or clinical need these modules included or excluded with the module assessing substance use disorders.
The Mini International Neuropsychiatric Interview (MINI)(Sheehan et al. 1998) is a briefer diagnostic instrument in comparison to the SCID-I and that generates a wide variety of diagnoses including substance and alcohol use disorder categories. The MINI is available in variety of languages including English and takes approximately 15 to 20 minutes to complete. Three versions the MINI, MINI-plus and MINI kid are available. The MINI evaluates the presence of 17 axis I disorders, with 8 additional disorders included in the MINI plus. The interviewers are required to have some training in its administration (2-3 hour training) with non clinicians requiring more extensive training. The MINI questions are structured to be delivered verbatim and have a yes no outcome. This instrument has been designed to maximise sensitivity introducing the possibility of false positives and therefore necessitating more in depth probing by clinicians in cases where positive predictive values need to be maximized (the likelihood that a positive screen represents a true positive). The most widely used scale in the measurement of addiction severity within addiction treatment settings is the addiction severity index or ASI (McLellan et al. 1992). This multidimensional instrument measures the consequences of drug use across 7 domains. These domains include the assessment of drug and alcohol use, medical consequences, psychiatric complications, impacts on employment and support, family history, family and social support and legal status. This scale requires training in its administration and takes 40-60 minutes to complete. Severity can be calculated by calculating composite scores and by means of clinician rated severity scale for each measured domain. It can be used to track treatment progress over time. Its limitations include low test retest reliability in some populations such as in dual disorder, severely mentally ill and homeless individuals, and lower inter-rater reliabilities among interviewers with less training. The calculation of composite scores has been recommended in follow up studies as opposed clinician rated severity scales (McLellan et al. 2008; Makela, 2004).
In the clinical setting it is important to realize that laboratory tests merely detect recent use of substances and are not diagnostic of abuse, dependence or addiction. During the diagnostic work-up laboratory tests should only be used when the reliability of the patient’s account of use is in doubt. In turn routine random, unannounced testing does from an important part in treatment settings, where rewards or limit setting may be contingent upon urine test results.
Laboratory tests are routinely based on urine samples but hair, blood, saliva and sweat samples can also be used. The availability of inexpensive on-site, point of collection rapid urine drug tests has made routine testing much more practically useful to many treatment facilities. Urine immune-essay tests typically a have shorter detection range, varying from 1-3 days with all the typical drugs of abuse usually eliminated from the body within 48 hours. One exception is in chronic heavy users of cannabis where detection in the urine can be present for up to 1 month. Hair analysis by means of gas chromatography, mass spectrometry (GCMS) has a much wider detection range vary from 7-90+ days. Hair analysis, although prone to false positives in cases of passive ingestion of substances, can also quantify severity of drug use as the length of hair containing drugs of abuse correlates with frequency of use. In addition hair testing may be useful in opiate addicts in patients claiming false positive urine test due to poppy seeds, or in patients who are cheating or evading urine drug testing (Dolan et al. 2004).
Blood tests are also useful in the treatment of patients with alcohol dependence. The most sensitive and specific tests are serum gamma glutamyl transferase (GGT) and carbohydrate deficient transferrin (CDT). Although the most sensitive of markers, GGT is also influenced by age and obesity and can be false positive as a result of a number of chronic illnesses such as liver disease and medication treatments .CDT, although less reliable in female patients, is specific to high levels of alcohol intake and when done in combination with GGT increases sensitivity and specificity. These markers will remain positive for up to 2-3 weeks following cessation of alcohol use. Mean corpuscular volume of red blood cells (MCV) is another sensitive marker, particularly in female patients and remains positive for up to 2-4 months following the start of abstinence (Niemela, 2007).
Treatment setting and level of care
The consequences of addictive disorders span across a wide array of potential biopsychosocial complications. Consequently the treatment needs of individuals with addictions span across medical, psychiatric, psychological, legal, social occupational and financial domains. Due to this multidimensional nature of treatment needs many health providers are likely to be involved in the treatment process. Treatment providers can include medical services, specialized psychiatric services, social services, the criminal justice system and psychological services. As the treatment needs of patients are highly heterogeneous, treatment intensity and treatment modalities needs to be matched to the individual patients needs. This requires frequent and effective interaction between various role players in the addiction treatment process. A standardized intake assessment procedure that determines the level and intensity of the required treatment needed is essential to ensure integrated and appropriate treatments. Research has demonstrated that patients who are not appropriately matched in terms of the intensity of treatment are more likely to drop out of treatment and relapse earlier (Deck et al. 2003). One such standardized assessment procedure is the revised version of Patient Placement Criteria (PPC-2R) for the treatment of substance related conditions endorsed by the American Society of Addiction Medicine (ASAM)(Mee-Lee et al. 2001). This system allows for placement in five main levels of care with further specifications in the revised system. These levels consist of an early intervention level (level 0.5), outpatient based care (level I), intensive outpatient or partial hospitalization care (level II), inpatients residential care (level III) and medically managed inpatients services (level IV). In addition the type of care is further determined along six dimensions: acute intoxication or withdrawal potential; biomedical conditions or complications; emotional, behavioural or cognitive conditions and complications; readiness to change; relapse, continued use or continued problem potential and recovery environment.
Stages of treatment
Treatment can be conceptualized in phases according to the stage of readiness of a client. However, these stages should not be regarded as rigid as therapeutic interventions may be applicable across different stages of motivation. Both psychological and pharmacological interventions differ across the various stages of change.
a) Precontemplative, contemplative and early determination stages:
During the early phases the dependence syndrome, denial of the fact that drug use is problematic may be the rule rather than the exception. Interventions such as motivational enhancement therapy and its related interventions such as brief interventions are particularly effective in patients who display high levels of resistance to change and manifest denial of drug and alcohol problems. During this early phase two techniques are useful to motivate patients towards recovery:
Brief motivational interventions:
This is a suitable intervention for primary care and emergency room practitioners who often can only spend a few minutes with a client. Key principles in counselling patients with addiction problems are non-judgementality and empathy. Described by Bien at.al (Bien et al. 1993), it is summarized by the mnemonic "FRAMES" which entail the following:
F- Feedback: The practitioner provides feedback regarding the negative effects the substance has had on the physical health, interpersonal relations and occupational roles of the client.
R- Responsibility: It is emphasised that the responsibility to stop using remains that of the client.
A-Advice- Advice is given that the cause for many problems relate to drug use and that abstinence or cutting down is advised. Possible options that will facilitate recovery are explored and practical advice is given.
M-Menu for change: Interest is expressed to aid the recovery of the patient and the various options and pathways are discussed such as referral to specialist centres for recovery.
E-Empathy: The counselling style is characterised by a warm and caring style that is empathic and non-judgemental.
S-Self-Efficacy: Hope is instilled by encouragement and emphasising that the patient has the ability and power to change.
Motivational Enhancement Therapy (MET):
This is a counselling intervention that requires a greater deal of skill and training than brief interventions. It is primarily a client-centred approach that emphasizes a non-judgemental empathic style of interviewing and communicating. In this respect it differs from more confrontational techniques such as Minnesota model and 12-step facilitation, although should not be seen as incompatible with such techniques but in fact complementary. The role of the therapist in addiction treatments may vary according to the stage of readiness for change, treatment setting and context and therapists need to be comfortable in adapting this role within the network of role players in addiction treatment that may include the therapist but also family members, employers and other professionals. Motivational enhancement therapies are aimed particularly at persons with high levels of denial and resistance to change. Although client centred, motivational enhancement therapy is not passive but in fact subtly directive in its selective attention to particulars in the clients’ communication. Practitioners trained within the medical model often find this approach difficult in the beginning as medical model interviewing often requires more closed ended questioning and more active information gathering exercises.
The following are principles of this technique:
a) Expressing empathy
b) Avoiding argumentation
c) Developing discrepancy
d) Rolling with resistance
e) Enhancing self-efficacy
The aim of this interview technique or communication style is to reflect empathically on the consequences drug taking behaviour has had on the person’s life and to develop and point out discrepancies between what the person’s life is currently like and what the person aspires to be like. The ultimate goal is to increase the client’s ambivalence and develop a sense of discrepancy and cognitive dissonance that in turn will drive motivation to change. A cardinal principal in this communication style is the avoidance of argumentation (i.e., when patients deny or rationalize their drug taking behaviour). Instead resistance to change is met with reflective and empathic listening. Various techniques of reflective listening are used to mobilise initial resistance and thus transforming resistance via self reflection into motivation to change. Self motivating statements are elicited and the therapist empathises with both the part of the client that wants to change and the resistant part, whilst at the same time pointing out discrepancies in the between the clients goals and actual behaviour. It is important to instil hope as self efficacy or the confidence the client has in their ability to effect change, is an important factor in successful recovery.
b) Precontemplative, contemplative and early determination stages:
The cessation of drug use is accompanied by substance specific withdrawal syndromes. These syndromes typically consist of highly unpleasant symptoms. For certain substances such as alcohol, benzodiazepines, sedative-hypnotics and opioids these syndrome are often more pronounced and requires pharmacological treatment within an inpatient or, in less severe cases, outpatient settings. Most withdrawal regimes consists of substituting the drug of abuse with a agonist medications that act on similar receptor sites as the drug of abuse but that does not have the typical euphoriant side effect profiles. Although several withdrawal regimes exist it is important to measure the presence of a withdrawal syndrome objectively with rating scales and to titrate the dosages of the replacement therapy according to the symptom severity of the withdrawal.
Alcohol withdrawal: Uncomplicated, mild alcohol withdrawal:
Most patients (75-85%) will only experience milder forms of alcohol withdrawal. Symptoms typically consist of nausea, tremors, sweating and tachycardia. Uncomplicated, mild withdrawal can be managed without medication and may only require as needed benzodiazepine treatment on an outpatient basis. Medication should be limited to 5-7 day course of decreasing dose regime. Long acting benzodiazepines are preferable such as chlordiazepoxide or diazepam, with shorter acting agents such as lorazepam and oxazepam reserved only for patients with impaired liver functions. Thiamine replacement therapy should always accompany withdrawal treatment.
Alcohol withdrawal: moderate, severe and complicated alcohol withdrawal. Of all patients with alcohol dependence as many as 25 % of patients may experience symptomatically severe withdrawal syndromes, whilst 5-15% of all alcohol dependence patients may experience complicated withdrawal syndromes. A past history of withdrawal seizures, physical illness such as liver, cardiac or pancreatic disease, hallucinations and psychotic symptoms or delirium tremens should be regarded as indicators of potential complicated withdrawal. Complicated alcohol withdrawal carries a high mortality, is potentially dangerous and is best managed in an inpatient setting equipped and staffed to monitor patients physically on a regular basis. Three approaches on the initiation of benzodiazepine withdrawal regimes are described in the literature (Saitz and O'Malley, 1997). The frontloading approach involves starting the patient on high initial doses (20mg of diazepam) repeated every 2 hours in order to prevent withdrawal. A second approach, the fixed dose regime, involves the prescription of 6hly benzodiazepines (usually 20mg of diazepam), with as needed doses for breakthrough symptoms in between. Alternatively a third approach the "symptom trigger" method involves the regular monitoring for withdrawal symptoms and the administration of benzodiazepines when clinical symptoms reach a threshold above 8 on the CIWA-Ar scale. There is some evidence that initiation of pharmacotherapy after the emergence of symptoms (symptoms trigger approach) produces superior (yet non-significant) outcomes in terms of symptoms relief (Ntais et al. 2005). Practitioners should however be flexible and treat patients according to the severity of symptoms. Under or over treatment with benzodiazepines should be avoided. Intravenous or intramuscular thiamine replacement with additional vitamin B complex should always accompany withdrawal prior to administration of glucose as the administration of glucose prior to thiamine can precipitate a rapid depletion of neuronal thiamine and lead to Wernicke’s encephalopathy. Intravenous thiamine administration should be monitored due to the rare potential complication of an anaphylactic reaction. Antipsychotics should be avoided during the acute withdrawal stage as they can precipitate withdrawal seizures by lowering seizure threshold. In certain circumstances such as delirium tremens antipsychotics can be used cautiously for severe agitation and hallucinations, but care should be taken not to use lower potency agents as these are more likely to precipitate seizures.
Opiate withdrawal and detoxification:
Cessation of opioid use in individuals dependent on opioids is characterised by a highly unpleasant withdrawal syndrome consisting of anxiety, increased sweating, dysphoria, restlessness, craving, irritability, pupillary dilation, lacrimation, rhinorhea, muscle cramps, abdominal cramps, nausea, vomiting, diarrhea, raised blood pressure and increased heart rate (American Psychiatric Association, 2005). Whereas less severe withdrawal syndromes can occur with opioids other than heroin, the following discussion will focus on the detoxification of heroin. In contrast to alcohol withdrawal that represents a condition with considerable morbidity and mortality, opioid withdrawal is rarely ever dangerous. The acute syndrome reaches a peak 48-72 hours after the last dose of opioids and resolves within 7 to 10 days (Mattick and Hall, 1996) The aim of medically assisted opoid withdrawal should always be to prepare patients for ongoing inpatient or outpatient psychosocial rehabilitation. Detoxification of opioids without concomitant rehabilitation serves little purpose. Medications used in the detoxification of opioids are full or partial agonists at the mu opioid receptor site. The most commonly used medications with a good evidence base to support its efficacy are buprenorphine and methadone. Whereas buprenorphine is a partial agonist at mu opioid receptor sites, methadone acts as a full agonist. Both these drugs are long acting and ameliorate the unpleasant withdrawal symptoms associated with cessation of opioid use. Buphrenorphine has a long duration of action making once or even alternate day dosing possible. In contrast to methadone buprenorphine is less sedative and interferes little with QTc interval and cardiac conduction at higher doses. This property together with its ceiling effect at higher dosages (due to lower intrinsic activity as a result of its partial agonist activities) renders this drug safer in overdose and makes it an attractive medication for outpatient, office based detoxification treatment. As buprenorphine can precipitate withdrawal due to its partial agonist actions it is important that this medication be initiated only after symptoms of withdrawal have manifested, usually 12 hours after the last use of heroin.
c) Determination, action and maintenance stages:
Twelve-Step Facilitation (TSF):
Twelve step facilitation is a manual based therapy that is aimed at facilitating and encouraging the involvement of patients into community based self-help twelve step programmes such as alcoholics anonymous and narcotics anonymous. Twelve-step facilitation can be delivered in a time limited manner on a weekly basis over 12 weeks or, as in many cases as an ongoing intervention over months to years. The twelve step facilitator therapists are required to have an excellent working knowledge of the twelve step manual as well as the principles that underlie twelve step programs such as AA and NA. This entails reading the AA handbook, twelve step manuals as well as attending several 12 step meetings as a professional guest (in cases where therapists are not recovering addicts). Therapists function as educators that introduce patients to the 12 step principles, elucidating the structure and functioning of 12-step meetings, the importance of regular attendance and the role of sponsors. Therapists should be actively encouraging participation in 12-step meetings and explore patient’s views of 12-step principles such as the pertinent role of spirituality and the notion of a higher power. Central to twelve step facilitation is the notion that addiction is a disease with a physical, emotional as well as spiritual component. In the 12-step model cure from addiction is not viewed as a realistic option but rather management of an ongoing chronic illness, with abstinence from drugs and alcohol viewed as a central treatment goal. Surrender to a higher power, which may be symbolized by treatment principles, structures and philosophy or more spiritual notions such as God, is viewed as a critical step in treatment. Patients are required to keep a diary of their attendance of meetings and the issues discussed at meetings. In turn therapists confront patients in a non-judgemental manner should there be signs of resistance or denial of drug and alcohol related problems. Denial may manifest in non attendance of meetings and rationalizations as to why attendance is not possible. It is important for therapist to explore patient’s experiences of 12-step meetings in order to identify each patient’s unique views and beliefs about twelve step programs. This will enable therapists to explore problems relating to denial or irrational or erroneous beliefs about 12-step programs and make suggestions as to how this can be addressed. Twelve step programs have been found to be as effective as cognitive behavioural and motivational enhancement treatments in reducing alcohol intake at 1 and 3 years follow up in the large multisite randomized controlled trial, project MATCH. In turn twelve step facilitation has shown somewhat superior outcomes in promoting abstinence and higher AA and NA attendance rates in aftercare settings (Humphreys, 1999).
CBT for relapse prevention:
Cognitive behavioural therapy is based on the principles of learning theory and has as one of its main targets to promote cognitions and behaviour that disrupt the cycle of learned drug taking behaviours that is encoded via the mechanisms of classical and operant conditioning. It is a highly structured; time limited (12-24 weeks) therapy in characterised by a collaborative client therapist relationship. It forms part of the active treatment and maintenance phases of the treatment cycle, with the principal objective being that of acquiring the necessary skills to prevent relapses into drug taking behaviour. Sessions are highly structured in that time is devoted first on feedback and homework assignments, then on didactic discussion of skills and behaviour followed by setting goals and targets. An important tool in therapy is functional analysis of behaviour that is associated with drug taking. In this analysis internal (emotional and cognitive) and external (environmental) triggers are identified and skills and techniques are then acquired on how to manage and deal with these triggers. Aspects of the functional analysis include identifying thoughts and feelings associated with internal triggers such as craving as well as environmental triggers that may drive dysfunctional beliefs about drug use. Skills training involve the learning of techniques to cope with craving and social pressures and may include distraction techniques and assertiveness training. CBT has been demonstrated to be effective as a relapse prevention treatment across a wide variety of substance use disorders including cocaine, alcohol, cannabis, nicotine and heroin addictions (Magill and Ray, 2009). CBT has also been shown to offer additional benefits for patients with co-occurring psychiatric disorders such as depression. Findings from Project Match, a large multicentre randomised controlled trail in patients with alcohol dependence investigating the efficacy of twelve step facilitation (TSF), cognitive behaviour therapy (CBT) and motivational enhancement therapy (MET), demonstrated CBT to be efficacious in reducing drinking (Project MATCH Research Group, 1998a; Project MATCH Research Group, 1998b). An important effect demonstrated by earlier studies of CBT for drug addiction is the lingering effect after therapy has been terminated (Carroll et al. 1994). This effect is particularly useful when CBT is used in combination with behavioural treatments such as contingency management that often show potent effects early on in treatment, which subsides wanes as treatment is discontinued (Rawson et al. 2006). In addition recent research has demonstrated superior outcomes for CBT in comparison to interpersonal therapy (IPT) in patient with cocaine dependence (Carroll et al. 2004). An important potential active ingredient for CBT efficacy has been shown to be high compliance with additional session and homework assignments. Thus patients who comply more diligently with home work assignments have been shown to have superior outcome in CBT (Carroll et al. 1994; Carroll et al. 2005). Although treatment programs may be eager to roll out manualized forms of CBT treatment, therapist training associated with active session to session direct personal supervision has been demonstrated to be associated significantly higher fidelity to CBT criterion standards.
Combined psychosocial modalities: matrix model
The matrix model of treatment is an intensive, manualized, outpatient based treatment model for addictive disorders. Although it originated during the cocaine epidemic during the 1980’s in the United States, it has been developed as a treatment for methamphetamine addiction as well as other non-stimulant addictions (Obert et al. 2000; Rawson et al. 1995). This eclectic treatment model incorporates various evidence based psychosocial interventions such as motivational enhancement therapy, 12-step facilitation, cognitive behavioural therapy, contingency management and family therapy. A typical treatment program consists of a highly structured 4 month, 3 times per week intensive outpatient based program followed by somewhat less structured 8 month continuing care program. Treatments are structured according to the stage of recovery and include early recovery groups in the early recovery stages and relapse prevention and social support groups in the more advanced stages. Information about the nature of addiction and the recovery process is also given early on in the treatment and a family psycho-education group forms a critical part of treatment. Early recovery groups focus on ways patients can attain abstinence early on in treatment. Relapse prevention groups focus on identifying external and internal triggers for relapse as well as methods to cope with such triggers. Social support groups are aimed at helping clients develop of social and interpersonal supports that are non drug users. An important part of the program involves facilitation into 12-step self help groups. Individual counselling and support is also received in parallel with group therapy. In contrast to more confrontational inpatient based models, the therapist style is non-confrontational and firmly based on motivational interviewing principles. Therapists are however not passive and actively pursue non-compliant patients in a non-confrontational caring manner. Weekly urine tests are conducted and negative tests are positively re-inforced with rewards. Some programs also make use of structures contingency management schedules of reward (Obert et al. 2002).
d) Determination, action and maintenance stages:
Disulfiram is an irreversible inhibitor of the enzyme acetaldehyde dehydrogenase. Administration of disulfiram causes an accumulation of acetaldehyde, a toxic breakdown product of in the metabolism of alcohol. This results in a highly unpleasant reaction characterised by facial flushing, severe nausea and vomiting, hypotension and headaches. This reaction is thought to be a powerful negative reinforcer promoting abstinence. Studies have however shown that the efficacy of this medication is highly dependent on compliance with this drug, which can be very poor (Fuller et al. 1986). More recent research has shown that supervised consumption of disulfiram by family members of addicts has improved outcomes (De Sousa et al. 2008; Laaksonen et al. 2008). Therapy with disulfiram has to be initiated cautiously as this medication is contraindicated in alcohol dependent individuals with liver, kidney and cardiac conditions. Disulfiram treatment has also been reported to be associated with the development of psychotic symptoms.
One postulated mechanism whereby alcohol produces its reinforcing effects is via the increased release of endogenous opioids. Endogenous opioid secretion increases the release of dopamine directly via stimulation of the nucleus accumbens or indirectly by inhibiting the tonically inhibitory effect of GABA neurons on dopamine neurons within the nucleus accumbens (Gianoulakis, 2009). Evidence from randomized controlled trials and meta-analyses has supported the use of naltrexone a mu opiate receptor antagonist in the maintenance treatment of alcohol dependence (Srisurapanont and Jarusuraisin, 2005). There is also evidence that naltrexone can help to prevent a lapse into drinking from turning into a full blown relapse. As an antagonist of mu opiate receptors naltrexone blocks the stimulation of opiate receptors by beta endorphins which in turn is postulated to result in less dopamine release in the nucleus accumbens. Via this mechanism the positive reinforcing euphoriant effects of alcohol is attenuated and type I craving is diminished. Naltrexone is well tolerated in the majority of patients. Contraindications include abnormalities in liver function and the comorbid presence of opioid dependence. Monitoring requirements include baseline and follow up liver enzymes. Concurrent use of medications that are potentially hepatotoxic should be avoided (such as disulfiram). Use with opioid containing analgesics is contraindicated. Naltrexone is also available in long acting depot formulation (XR-NLX) for once monthly administration.
Acamprosate is related to the amino acid taurine. Acamprosate modulates hyperglutamatergic states characteristic of acute and protracted alcohol withdrawal via its inhibitory action on excitatory NMDA receptors and facilatatory action on GABA function. The prolonged withdrawal stage is characterised by increased excitatatory glutamatergic neurotransmission due to NMDA receptor upregulation that takes place during the intoxication phases in the presence of high alchohol levels. Via its inhibitory action on NMDA receptors acamprosate curbs negative or type 2 craving associated with unpleasant withdrawal symptoms. Studies have demonstrated that acamprosate is effective in preventing relapse into heavy drinking. This effect may be more pronounced in patients who are more motivated to remain abstinent (Johnson et al. 2007; Johnson et al. 2008).
Other candidate drugs in the maintenance treatment of alcohol dependence include topiramate, a drug that is thought to both enhance GABAA inhibitory activity over the positive reinforcing effects of dopamine in the nucleus accumbens (type I craving) and at the same time attenuates glutamatergic hyperactivity via its action on AMPA glutamatergic receptors (type 2 craving). In turn it is thought that the decrease of glutamatergic activity results in decreased dopamine release in the nucleus accumbens (Kenna et al. 2009). Two randomized controlled trials, one of which is a multisite trial, have demonstrated the superior efficacy of topiramate over placebo on a number of outcome measures such as time abstinent from drinking, level of self reported drinking, compulsive cravings for alcohol and improved physical and psychosocial wellbeing (Johnson et al. 2003; Johnson et al. 2007; Johnson et al. 2008).
In recent years baclofen, a GABAB receptor agonist, has received increasing attention in pharmacotherapy trials for alcohol maintenance (Addolorato et al. 2009). Due to the fact that it is not metabolized in the liver makes it an attractive alternative for patients with alcohol dependence and existing liver damage (Garbutt and Flannery, 2007). Three randomized controlled trails have been conducted to date with two showing significant superiority over placebo in reducing alcohol intake and prolonging periods of abstinence from alcohol (Addolorato et al. 2002; Addolorato et al. 2007; Garbutt et al. 2007). A third trial conducted in the US failed to replicate these findings and further research is necessary to clarify the role of baclofen in the treatment of alcohol dependence (Garbutt et al. 2007).
Prospective cohort studies have demonstrated that long term abstinence based community residential rehabilitation programmes can be successful for opioid dependent patients with up to 50% achieving abstinence at 5 year follow up (Gossop et al. 2003). Nevertheless a subgroup of patients with severe heroin dependence is unlikely to succeed with traditional abstinence based approaches and may require harm reduction approaches that consist of opioid substitution maintenance prescribing. The primary aim of substitution maintenance treatment is to reduce the use of illicit heroin and in turn the associated morbidity and criminal behaviours that often accompany heroin addiction. Table 6 summarizes some of the goals of opioid substitution therapies.
Table 6. Aims of opioid substitution prescribing
|1. Reduction of illicit heroin use|
|2. Reduction of criminal behaviour accompanying heroin use|
|3. Reduction of morbidity associated with heroin use such as risky sexual practices and needle sharing (HIV, Hepatitis B and C transmission)|
|4. Reduction of mortality associated with heroin overdoses|
|5. Creation of a environment conducive to addressing social and occupational problems|
During substitution maintenance treatment patients are given the opportunity to reconstruct their lives and improve their psychosocial and occupational functioning in order to obtain greater stability. Maintenance treatments can be time limited over 12 to 24 months but may be a treatment option over many years.
The main medications used in substitution maintenance programs are methadone, a full mu receptor agonist and buprenorphine, a partial mu receptor agonist. Research has shown that methadone, in particular high dose methadone maintenance is somewhat superior to buprenorphine in reducing illicit heroin use. Nevertheless as the side effect profile of methadone includes mild oversedation and somnolence; both agents are recommended as treatment options in maintenance programs. Substitution maintenance programs have to adhere to certain standards to be effective. These standards include staff trained and experienced in prescribing substitution medications. Daily supervised consumption including a full pre-treatment medical workup (including HIV and Hepatitis testing) is mandatory for all patients initiated on substitution therapies. Daily supervised consumption is less critical in patients treated with burprenorphine or buprenorphine-naloxone combinations, however still recommended in the early stabilization phase of treatment. Random urine tests testing for heroin is also mandatory. A pre-treatment contract between the treating doctor and patients stipulating the consequences of a positive urine tests is also important. One particular clinical problem is the injection of substitution medicines to obtain a high or the selling of these medicines (called diversion) to raise funds for illicit heroin. In some countries electronic methadone prescription monitoring services have been launched to prevent patients from obtaining prescriptions more than once at different pharmacies. Another strategy to counter diversion and injection practice is the use of Suboxone, a combination of buprenorphine (opioid agonist) and naloxone (opioid antagonist) in a 4:1 ratio. When taken sublingually the bioavailability of naloxone is not sufficient to lead to any clinical effect. However in the context of diversion practices and intravenous abuse of substitution medicines, naloxone has a high bioavailability leading to the induction of unpleasant withdrawal reactions and therefore acts as a discouragement for injection practices.
Patients on maintenance treatment may prematurely want to discontinue their opioid substitution medication in order to become drug free and independent. Each individual case needs to be carefully reviewed in terms of the particular clients’ strengths and ongoing risks of relapse. Factors that can contribute to relapse such as instability in interpersonal, occupational or living circumstances need to borne in mind when considering suitability to wean patients from opioid substitution medications.
Johnson, Bankole A. Addiction medicine. Science and practice. Volumes 1 &2. Springer Science+ Business media, New York., 2011.
Galanter Marc, Kleber Herbert D. The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition. Arlington, VA, American Psychiatric Publishing, 2008.
Sadock BJ, Sadock VA. Kaplan and Sadock’s comprehensive textbook of psychiatry, 8th edition, vol 1&2.Lippinicott Williams & Wilkins, 2005.
Addolorato, G., Caputo, F., Capristo, E., Domenicali, M., Bernardi, M., Janiri, L., Agabio, R., Colombo, G., Gessa, G. L. & Gasbarrini, G. (2002). Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol 37, 504-508.
Addolorato, G., Leggio, L., Cardone, S., Ferrulli, A. & Gasbarrini, G. (2009). Role of the GABA(B) receptor system in alcoholism and stress: focus on clinical studies and treatment perspectives. Alcohol 43, 559-563.
Addolorato, G., Leggio, L., Ferrulli, A., Cardone, S., Vonghia, L., Mirijello, A., Abenavoli, L., D'Angelo, C., Caputo, F., Zambon, A., Haber, P. S. & Gasbarrini, G. (2007). Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 370, 1915-1922.
American Psychiatric Association (2005). Diagnostic and statistical manual of mental disorders., DSM-IV Task force and working group. 4th edition. text revision. In (Anonymous), American Psychiatric Association: Washington DC. AT McLellan, H Kushner, D Metzger, R Peters, I Smith, G Grissom, H Pettinati & M Argeriou (2008). Substance Use Disorders Measures: Addiction Severity Index (ASI). In Handbook of Psychiatric Measures, (ed. A John Rush, Michael B First and Deborah Blacker), pp. 454-457. American Psychiatric Publishing: Washington DC, London England.
Bien, T. H., Miller, W. R. & Tonigan, J. S. (1993). Brief interventions for alcohol problems: a review. Addiction 88, 315-335.
Brady, K. T. & Randall, C. L. (1999). Gender differences in substance use disorders. Psychiatr. Clin. North Am. 22, 241-252.
Bush, K. R., Kivlahan, D. R., Davis, T. M., Dobie, D. J., Sporleder, J. L., Epler, A. J. & Bradley, K. A. (2003). The TWEAK is weak for alcohol screening among female Veterans Affairs outpatients. Alcohol Clin. Exp. Res. 27, 1971-1978.
Carroll, K. M., Fenton, L. R., Ball, S. A., Nich, C., Frankforter, T. L., Shi, J. & Rounsaville, B. J. (2004). Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial. Arch. Gen. Psychiatry 61, 264-272.
Carroll, K. M., Nich, C. & Ball, S. A. (2005). Practice makes progress? Homework assignments and outcome in treatment of cocaine dependence. J. Consult Clin. Psychol. 73, 749-755.
Carroll, K. M., Rounsaville, B. J., Nich, C., Gordon, L. T., Wirtz, P. W. & Gawin, F. (1994). One-year follow-up of psychotherapy and pharmacotherapy for cocaine dependence. Delayed emergence of psychotherapy effects. Arch. Gen. Psychiatry 51, 989-997.
De Sousa, A. A., De, S. J. & Kapoor, H. (2008). An open randomized trial comparing disulfiram and topiramate in the treatment of alcohol dependence. J. Subst. Abuse Treat. 34, 460-463.
Deck, D., Gabriel, R., Knudsen, J. & Grams, G. (2003). Impact of patient placement criteria on substance abuse treatment under the Oregon Health Plan. J. Addict. Dis. 22 Suppl 1, 27-44.
Dhalla, S. & Kopec, J. A. (2007). The CAGE questionnaire for alcohol misuse: a review of reliability and validity studies. Clin. Invest Med. 30, 33-41. DiClemente, C. C., Schlundt, D. & Gemmell, L. (2004). Readiness and stages of change in addiction treatment. Am. J. Addict. 13, 103-119.
Dolan, K., Rouen, D. & Kimber, J. (2004). An overview of the use of urine, hair, sweat and saliva to detect drug use. Drug Alcohol Rev. 23, 213-217. Ewing, J. A. (1984). Detecting alcoholism. The CAGE questionnaire. JAMA 252, 1905-1907.
First MB, Spitzer RL, Gibbon M & Williams JBW (1994). Structured Clinical Interview for DSM-IV Axis I disorders-Patient Edition (SCID-I-P, version 2). In (Anonymous), Biometrics Research Department.
Fuller, R. K., Branchey, L., Brightwell, D. R., Derman, R. M., Emrick, C. D., Iber, F. L., James, K. E., Lacoursiere, R. B., Lee, K. K., Lowenstam, I. & . (1986). Disulfiram treatment of alcoholism. A Veterans Administration cooperative study. JAMA 256, 1449-1455. Garbutt, J. C. & Flannery, B. (2007). Baclofen for alcoholism. Lancet 370, 1884-1885.
Garbutt, J. C., Kampov-Polevoy, A., Flannery, B., Kalka-Juhl, L. & Gallop, R. (2007). Placebo-controlled trial of baclofen in alcohol dependence. In (Anonymous), Research Society on Alcoholism Annual Meeting, Chicago, Illinois. Gianoulakis, C. (2009). Endogenous opioids and addiction to alcohol and other drugs of abuse. Curr. Top. Med. Chem. 9, 999-1015.
Gossop, M., Marsden, J., Stewart, D. & Kidd, T. (2003). The National Treatment Outcome Research Study (NTORS): 4-5 year follow-up results. Addiction 98, 291-303.
Grant, B. F. (1996). Prevalence and correlates of drug use and DSM-IV drug dependence in the United States: results of the National Longitudinal Alcohol Epidemiologic Survey. J. Subst. Abuse 8, 195-210.
Hartz, S. M. & Bierut, L. J. (2010). Genetics of addictions. Psychiatr. Clin. North Am. 33, 107-124.
Humphreys, K. (1999). Professional interventions that facilitate 12-step self-help group involvement. Alcohol Res. Health 23, 93-98. Hyman, S. E. (2005). Addiction: a disease of learning and memory. Am. J. Psychiatry 162, 1414-1422.
Johnson, B. A., it-Daoud, N., Bowden, C. L., DiClemente, C. C., Roache, J. D., Lawson, K., Javors, M. A. & Ma, J. Z. (2003). Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 361, 1677-1685.
Johnson, B. A., Rosenthal, N., Capece, J. A., Wiegand, F., Mao, L., Beyers, K., McKay, A., it-Daoud, N., Addolorato, G., Anton, R. F., Ciraulo, D. A., Kranzler, H. R., Mann, K., O'Malley, S. S. & Swift, R. M. (2008). Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial. Arch. Intern. Med. 168, 1188-1199.
Johnson, B. A., Rosenthal, N., Capece, J. A., Wiegand, F., Mao, L., Beyers, K., McKay, A., it-Daoud, N., Anton, R. F., Ciraulo, D. A., Kranzler, H. R., Mann, K., O'Malley, S. S. & Swift, R. M. (2007). Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 298, 1641-1651.
Kalivas, P. W. & Volkow, N. D. (2005). The neural basis of addiction: a pathology of motivation and choice. Am. J. Psychiatry 162, 1403-1413.
Kenna, G. A., Lomastro, T. L., Schiesl, A., Leggio, L. & Swift, R. M. (2009). Review of topiramate: an antiepileptic for the treatment of alcohol dependence. Curr. Drug Abuse Rev. 2, 135-142.
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R. & Walters, E. E. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593-602.
Kessler, R. C., McGonagle, K. A., Zhao, S., Nelson, C. B., Hughes, M., Eshleman, S., Wittchen, H. U. & Kendler, K. S. (1994). Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch. Gen. Psychiatry 51, 8-19. Kessler, R. C., Nelson, C. B., McGonagle, K. A., Edlund, M. J., Frank, R. G. & Leaf, P. J. (1996). The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization. Am. J. Orthopsychiatry 66, 17-31.
Khantzian, E. J. (1997). The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harv. Rev. Psychiatry 4, 231-244.
Koob, G. F. (2009). Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology 56 Suppl 1, 18-31. Koob, G. F. & Volkow, N. D. (2009). Neurocircuitry of Addiction. Neuropsychopharmacology .
Laaksonen, E., Koski-Jannes, A., Salaspuro, M., Ahtinen, H. & Alho, H. (2008). A randomized, multicentre, open-label, comparative trial of disulfiram, naltrexone and acamprosate in the treatment of alcohol dependence. Alcohol Alcohol 43, 53-61.
M Russell, D.M Czarnecki, R Cowan, E McPherson & PJ Mudar (2008). Substance Use Disorder Measures: TWEAK Test. In Handbook of Psychiatric Measures, (ed. A John Rush, Michael B First and Deborah Blacker), pp. 453-454. American Psychiatric Publishing.
Magill, M. & Ray, L. A. (2009). Cognitive-behavioral treatment with adult alcohol and illicit drug users: a meta-analysis of randomized controlled trials. J. Stud. Alcohol Drugs 70, 516-527.
Makela, K. (2004). Studies of the reliability and validity of the Addiction Severity Index. Addiction 99, 398-410.
Mattick, R. P. & Hall, W. (1996). Are detoxification programmes effective? Lancet 347, 97-100.
McLellan, A. T., Kushner, H., Metzger, D., Peters, R., Smith, I., Grissom, G., Pettinati, H. & Argeriou, M. (1992). The Fifth Edition of the Addiction Severity Index. J. Subst. Abuse Treat. 9, 199-213.
Mee-Lee D, Shulman GD & Fishman M, et. a. (2001). ASAM Patient Placement Criteria for the Treatment of Substance Related Disorders , 2nd Edition, Revised (ASAM PPC-2R). Chevy Chase, MD, American Society of Addiction medicine.
ML Selzer (2008). Substance Use Disorder Measures: Michigan Alcoholism Screening Test (MAST). In Handbook of Psychiatric Measures, (ed. A John Rush, Michael B First and Deborah Blacker), pp. 450-451. American Psychiatric Publishing. Inc.: Washington DC, London England.
National Institute on Drug Abuse, R. & Helzer J (1987). Proceedings of the 49th Annual Scientific Meeting. Problems on drug abuse: Monograph Series 81. In (Anonymous).
Niemela, O. (2007). Biomarkers in alcoholism. Clin. Chim. Acta 377, 39-49. Ntais, C., Pakos, E., Kyzas, P. & Ioannidis, J. P. (2005). Benzodiazepines for alcohol withdrawal. Cochrane. Database. Syst. Rev. CD005063.
Obert, J. L., London, E. D. & Rawson, R. A. (2002). Incorporating brain research findings into standard treatment: an example using the Matrix Model. J. Subst. Abuse Treat. 23, 107-113.
Obert, J. L., McCann, M. J., Marinelli-Casey, P., Weiner, A., Minsky, S., Brethen, P. & Rawson, R. (2000). The matrix model of outpatient stimulant abuse treatment: history and description. J. Psychoactive Drugs 32, 157-164.
Project MATCH Research Group (1998a). Matching alcoholism treatments to client heterogeneity: Project MATCH three-year drinking outcomes. Alcohol Clin. Exp. Res. 22, 1300-1311.
Project MATCH Research Group (1998b). Matching alcoholism treatments to client heterogeneity: treatment main effects and matching effects on drinking during treatment. J. Stud. Alcohol 59, 631-639.
Rawson, R. A., McCann, M. J., Flammino, F., Shoptaw, S., Miotto, K., Reiber, C. & Ling, W. (2006). A comparison of contingency management and cognitive-behavioral approaches for stimulant-dependent individuals. Addiction 101, 267-274.
Rawson, R. A., Shoptaw, S. J., Obert, J. L., McCann, M. J., Hasson, A. L., Marinelli-Casey, P. J., Brethen, P. R. & Ling, W. (1995). An intensive outpatient approach for cocaine abuse treatment. The Matrix model. J. Subst. Abuse Treat. 12, 117-127.
Reinert, D. F. & Allen, J. P. (2002). The Alcohol Use Disorders Identification Test (AUDIT): a review of recent research. Alcohol Clin. Exp. Res. 26, 272-279. Russell, M., Czarnecki, D. M., Cowan, R., McPherson, E. & Mudar, P. J. (1991). Measures of maternal alcohol use as predictors of development in early childhood. Alcohol Clin. Exp. Res. 15, 991-1000.
Saitz, R. & O'Malley, S. S. (1997). Pharmacotherapies for alcohol abuse. Withdrawal and treatment. Med. Clin. North Am. 81, 881-907. Saunders, J. B., Aasland, O. G., Babor, T. F., de, l. F., Jr. & Grant, M. (1993). Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption--II. Addiction 88, 791-804.
Seedat, S., Scott, K. M., Angermeyer, M. C., Berglund, P., Bromet, E. J., Brugha, T. S., Demyttenaere, K., de, G. G., Haro, J. M., Jin, R., Karam, E. G., Kovess-Masfety, V., Levinson, D., Medina Mora, M. E., Ono, Y., Ormel, J., Pennell, B. E., Posada-Villa, J., Sampson, N. A., Williams, D. & Kessler, R. C. (2009). Cross-national associations between gender and mental disorders in the World Health Organization World Mental Health Surveys. Arch. Gen. Psychiatry 66, 785-795.
Selzer, M. L. (1971). The Michigan alcoholism screening test: the quest for a new diagnostic instrument. Am. J. Psychiatry 127, 1653-1658. Sheehan, D. V., Lecrubier, Y., Sheehan, K. H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R. & Dunbar, G. C. (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59 Suppl 20, 22-33.
Skinner, H. A. (1982). The drug abuse screening test. Addict. Behav. 7, 363-371.
Srisurapanont, M. & Jarusuraisin, N. (2005). Opioid antagonists for alcohol dependence. Cochrane. Database. Syst. Rev. CD001867.
van der Zwaluw, C. S. & Engels, R. C. (2009). Gene-environment interactions and alcohol use and dependence: current status and future challenges. Addiction 104, 907-914.
Verheul, R. (2001). Co-morbidity of personality disorders in individuals with substance use disorders. Eur. Psychiatry 16, 274-282.
Wagner, F. A. & Anthony, J. C. (2002). From first drug use to drug dependence; developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology 26, 479-488.
World Health Organization Geneva (1992). WHO ICD-10 Classification of mental and behavorial disorders. Clinical descriptions and diagnostic guidelines. In (Anonymous).