Other Substance use Disorders
4.2.3.1 Opioids: heroin, methadone, and buprenorphine
Soraya Mayet
Adam R. Winstock
John Strang
Opium is derived from the seed of the opium poppy (Papaver somniferum) and has been used for thousands of years for its analgesic and euphoriant effects.
What are opioids?
Opioids are drugs which mimic endogenous opioid peptides (e.g. endorphins and enkephalins) and activate opioid receptors. Opioids include both naturally occurring opiates extracted from opium (morphine and codeine) and synthetic opioids (heroin and methadone). Heroin is the most common opioid to be misused partly because of its distinctive euphoriant effects.
Neurobiology of opioids
Opioid receptors are widely distributed throughout the central nervous system. Activation of opioid receptors inhibits activity of the dorsal horn. The three most important opioid receptors are µ-receptor, δ-receptor, and κ-receptor. The µ-receptor is concentrated in brain areas and is mostly involved in nocioception (pain sensation). µ-receptor and δ-receptor activation cause hyperpolarization of neurones by activating K+ channels involving G-proteins. Exogenous opioids such as heroin and methadone act at all opioid receptors but particularly at µ-receptors. Opioid receptor antagonists such as naloxone reverse the effects of opioid agonists.(1)
The precise mechanisms of tolerance and dependence to opioids are not clear. Short term use of opioids causing intoxication may not lead to neuroadaption of opioid receptors. However, continued use of opioids may lead to opioid receptor desensitization and dependency. Acutely, opioids lead to the inhibition of adenylate cyclase with reduced conversion of ATP to cAMP, resulting in reduced firing at noradrenergic neurones located on the locus coeruleus. Chronic opioid administration leads to compensatory upregulation of cAMP, returning levels towards baseline. On cessation of opioid use (or following opioid receptor antagonism), withdrawal ensues, characterized by a massive surge in unopposed noradrenergic activity (termed the ‘noradrenergic storm’) from the locus coeruleus. This noradrenergic hyperactivity is thought to underlie many symptoms of opioid withdrawal, and explains some of the efficacy of the presynaptic α2 agonists in the treatment of the symptoms of acute opioid withdrawal. Opioid receptors can readapt back to normal in the absence of opioids.(2)
Both glutamate and γ-aminobutyric acid (GABA) are also likely to be involved. Positive reinforcement is thought to be mediated via the dopaminergic mesolimbic system. In the ventral tegmental area, GABA inhibits dopaminergic neurones, which in turn are inhibited via µ-opioid receptor activation. Consequently, opioid use leads to increased dopaminergic activity which is thought to mediate the drive to use and its positive reinforcement.
Route of administration
Heroin may be administered by a number of routes including injecting (intravenous, intramuscular and subcutaneous ‘skin popping’), snorting and ‘chasing the dragon’ (inhaling after heating on tin foil).(3) These different routes of administration have profound effects on bioavailability, speed of onset, severity of dependence and physical complications. Different types of heroin may be preferentially used by different routes of administration.(4) Brown heroin is poorly water soluble with a high oil content which ‘runs’ well on a heated foil making it better for ‘chasing’. In contrast, white heroin tends to be more water soluble and better suited for intravenous use, although it may still be snorted or smoked after preparation.
Whilst smoking heroin (‘chasing the dragon’) is probably the most commonly used route of self-administration, it is not as effective or efficient as injecting. Consequently, as heroin users develop tolerance, many subsequently change to the intravenous route. Injecting heroin use is also associated with a greater risk of fatal overdose and hence reducing the transition from smoking to injecting may be associated with reduced harms. Although injecting in the upper limbs is the most common site for administration, as venous access becomes compromised increasingly risky sites such as the groin or neck my be used. However, non-injecting routes of administration are not without risks and may still result in dependence and similar treatment outcomes.
Opioid metabolism
The oral bioavailability of heroin (Diacetylmorphine) itself is poor due to complete first pass metabolism, which is the reason it is often administered by alternative routes. Following administration, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM), which is the only metabolite that specifically indicates that heroin has been used. 6-MAM is metabolized to morphine, which is catalyzed in the liver. Morphine (either as a metabolite of heroin or given as a drug) is mostly metabolized by UDP-glucuronosyltransferase (UGT) to the inactive metabolite morphine-3-glucuronide (M3G) and in lesser amounts to the active morphine-6-glucuronide (M6G). Morphine is also N-demethylated to normorphine by hepatic CYP3A4 and CYP2C8 enzymes (Fig. 4.2.3.1.1). Heroin and its metabolites can be monitored in the blood, hair, saliva and urine. 6-MAM is detectable up to 12 h post administration, whilst morphine can be detected in the urine for several days after use.(5) Methadone is primarily metabolized in the liver by CYP3A4 to the inactive metabolite 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), then to 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP). Buprenorphine is metabolized to norbuprenorphine and to conjugated buprenorphine and norbuprenorphine. Codeine (3-methylmorphine) is synthesized from morphine and metabolized to codeine-6-glucuronide. Additionally codeine is
metabolized to morphine by CYP2D6. Therefore a morphine positive result is possible after consuming codeine only.(5) Dihydrocodeine is metabolized to nordihydrocodeine and dihydromorphine and cannot normally be metabolized to codeine or morphine.
metabolized to morphine by CYP2D6. Therefore a morphine positive result is possible after consuming codeine only.(5) Dihydrocodeine is metabolized to nordihydrocodeine and dihydromorphine and cannot normally be metabolized to codeine or morphine.
 Fig. 4.2.3.1.1 Major metabolic pathways of heroin and morphine in humans.(6) Reproduced from Maurer, H.H., Sauer, C., Theobald, D.S. (2006). Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine. The Drug Monit. 2006 June; 28(3), 447-53, copyright 2006, Lippincott Williams & Wilkins |
Epidemiology
The illicit nature of opioid use means that it is often difficult to estimate the exact prevalence. The European Monitoring Centre for Drugs and Drug Addiction reports that heroin use in the general population is less than one per cent.(6) Gender differences in opioid use have been reported with women accounting for approximately one third of all opioid users. Non-dependent recreational heroin use has been reported, but is rare. Dependence will often develop gradually over the first few years, most commonly in the late teens and early twenties. Treatment can alter the course of opioid dependence, by prolonging periods of abstinence and improving outcomes (see later sections). The risk of death from heroin dependence is approximately 12 times that of the general population, with most deaths occurring in males (>80 per cent). Opioid use has a major effect on crime and it has been estimated that half of all crime is drug related, with estimated costs within the UK criminal justice system at £1 billion per annum in 1996.
The effects of opioids
The effects of opioids are outlined in Table 4.2.3.2.1. The effects vary depending on dose and route.
Opioid dependence and withdrawal
Opioid dependence may be classified according to the ICD-10 criteria (see appendix). Continued use of heroin (or other opioids) tends to lead to physiological dependence with the development of tolerance and withdrawal symptoms on discontinuing heroin. Tolerance occurs when the same dose gives a reduced effect or conversely, an increased opioid dose is required to have the same effect. Once physiological dependence is established, abrupt cessation or a marked reduction in dose will result in a withdrawal syndrome. During this time there is an ‘undoing’ of the neuroadaptation which had occurred during the development of tolerance. Withdrawal leads to ‘gooseflesh’ (piloerection) of the skin (which is the reason behind the term ‘cold turkey’). Insomnia (with increase in Rapid Eye Movement sleep) and craving for the drug may persist for weeks. Most withdrawal symptoms appear within 4-12h and peak at 48-72h lasting 7-10 days. Longer acting opioids such as methadone may result in a more prolonged withdrawal. Opioid withdrawal is not usually considered to be life threatening.
Complications from opioid use
Complications may be biological, psychological, or social (Table 4.2.3.1.2).
Biological complications
Opioid overdose is the most common cause of death among opioid users, while blood-borne virus infection and other injecting related complications also contribute to increased morbidity and premature deaths.
(a) Opioid overdose
Opioid overdose occurs when the opioid dose exceeds the individual’s tolerance to the respiratory depressant effect of the drug.
It is more common when other Central Nervous System depressants are concurrently consumed. Respiratory depression is caused by the opioid action on the brain stem nuclei and death can follow within minutes of injecting excessive amounts. Risk factors for opioid overdose are injecting use, return to opioid use following recent abstinence (such as following detoxification and release from prison), during the early stages of dependence and starting opioid substitution treatment.(7) In addition, variability in opioid purity, increased central depressant effects following polysubstance use and high levels of psychiatric co-morbidity may increase the vulnerability for accidental or intentional overdose. Opioid overdose can be rapidly reversed if naloxone (opioid antagonist) is administered to the person who has overdosed. The management of an opioid overdose is described later in the chapter.
It is more common when other Central Nervous System depressants are concurrently consumed. Respiratory depression is caused by the opioid action on the brain stem nuclei and death can follow within minutes of injecting excessive amounts. Risk factors for opioid overdose are injecting use, return to opioid use following recent abstinence (such as following detoxification and release from prison), during the early stages of dependence and starting opioid substitution treatment.(7) In addition, variability in opioid purity, increased central depressant effects following polysubstance use and high levels of psychiatric co-morbidity may increase the vulnerability for accidental or intentional overdose. Opioid overdose can be rapidly reversed if naloxone (opioid antagonist) is administered to the person who has overdosed. The management of an opioid overdose is described later in the chapter.
Table 4.2.3.1.1 Effects of opioids | ||||||||||
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Table 4.2.3.1.2 Complications of opioid use | ||||||||||||||||||||||||||||||
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(b) Blood borne virus transmission
The risk of viral transmission is high among injecting drug users, and routine testing with counseling should be available to those at risk. Transmission of blood borne viruses is primarily related to sharing injecting equipment and involvement in the sex industry. Needle sharing appears to occur less frequently than sharing of spoons and filters, but any shared equipment may pose the risk of viral transmission. The prison population is particularly at risk, as injecting is more common likely to involve sharing injecting equipment.
Opioid substitution treatment is one of the most effective interventions for reducing the extent of injecting, thereby also reducing both the spread of and morbidity from blood borne viruses. Stabilization on methadone/buprenoprehine with abstinence from injecting, needle and other injecting equipment sharing, and unprotected sex should be encouraged among all dependent heroin users. Blood borne virus testing and referral to specialists for treatment is important. In addition, close liaison with medical and psychiatric services is important for improving outcomes and compliance with treatment.
(i) Human immunodeficiency virus (HIV)
Rates of HIV seropositivity amongst current injecting drug users in England and Wales although low, have recently increased, with an incidence of 1.5 per cent reported in 2004 (the highest since 1992), with higher rates reported in London.(8) The relatively low levels of HIV within the UK and elsewhere in Europe is believed to be due to the widespread availability of ‘needle-exchange’ services and provision of services focused towards ‘harm minimization’.(9)
(ii) Hepatitis B & C
Screening of drug users in treatment has revealed prevalence rates of 20 per cent for Hepatitis B and more than 50 per cent for Hepatitis C. Intravenous drug users are likely to have higher rates estimated at 30 to 50 per cent (Hepatitis B) and up to 90 per cent (Hepatitis C).(10) Prognosis is worsened by high levels of alcohol consumption and therefore liaison with hepatitis/gastroenterology services is important. Screening for Hepatitis B and C and targeted vaccination for Hepatitis B, in addition to education and harm-reduction provision, should be provided.
Psychological complications
Numerous large epidemiological studies have identified that co-morbid psychiatric illness is common among those with opioid dependence, with prevalence rates of about 50 per cent.(11) Concurrent use of benzodiazepines, alcohol, and especially stimulant drugs increases psychiatric morbidity in addition to female gender, poor physical function, and difficulties in personal relationships.(12) Many of those with opioid dependence will have had childhood behavioural problems such as conduct disorder which may be a marker for subsequent drug use.(13) The rate of suicide among heroin users is estimated at 14 times that of age matched peers with reports of 3-35 per cent of deaths related to suicide. Risk factors include a history of depression, poly substance use in addition to generic risk factors.(14)
At entry into treatment, it may be difficult to make an accurate determination of an opioid user’s psychiatric diagnosis and generally assessment should be repeated once stability on a substitution medication or detoxification has been achieved. Waiting to review a patient’s mental health once they are out of crisis can prevent early misdiagnosis since much of psychiatric distress dissipates rapidly on cessation of illicit use and stabilization. In one follow up study of opioid users entering treatment, baseline levels of depression fell from 25 per cent at baseline to 11 per cent at 12 month follow up, with the observed decline being strongly related to treatment exposure.(15) Follow-up and provision of treatment for co-morbid disorders are thus essential. Enhancing compliance with prescribed medications through supervised dispensing or engagement of carers is useful. Treatment can be effective in reducing psychiatric distress observed on entry to treatment in this group. However, in a significant proportion, even on cessation of use or abstinence, major psychiatric illnesses can persist. If left untreated, co-morbid conditions can lead to a poorer prognosis particularly in respect to relapse and suicide.
Social complications
The ramifications of heroin dependence upon individual functioning and that individual’s ability to relate and function within their family and community are immense. Although high rates of socioeconomic disadvantage often precede entry into heroin use, it is the other associated problems of relatively poorer premorbid functional and educational attainment that frequently compound later efforts at rehabilitation. High rates of criminal activity, homelessness, and unemployment are associated with opioid addiction, although treatment can improve socio-economic status.
Treatment of opioid dependence
Opioid maintenance treatment
Opioid maintenance treatment generally involves substituting heroin for an oral long-acting opioid, thereby reducing the plasma level variability and stopping injecting drug use. Oral methadone and buprenorphine have been licensed in several countries for use in the treatment of opioid dependence and both are approved in the UK.(16) The decision regarding whether methadone or buprenorphine is used should be based on individual factors estimating the risks and benefits and following discussion with the patient. If both drugs are equally suitable, cost-effectiveness examination by the National Institute of Clinical Excellence (NICE) concludes that methadone should be prescribed as the first choice.(16)
(a) Methadone maintenance treatment
Methadone is a synthetic orally active full opioid agonist with a half-life of 24-36 h, making it suitable for daily administration. This is an effective treatment for heroin dependence and has significantly better outcomes than non pharmacological substitution for retaining patients in treatment, decreasing heroin use, reducing crimes, reducing overdose deaths, reduced injecting and sharing of injecting equipment and consequent reduced risk behaviours leading to transmission of HIV.(17) Higher doses of methadone (60 to 120 mg/day) have been shown to be more effective than lower dosages(18) and doses greater than 80 mg daily are believed to provide a reasonable level of opioid receptor blockade such that euphoria from illicit opioids is diminished.
Methadone steady state plasma levels take approximately 4 to 5 days and so there is potential for methadone accumulation (and overdose) when initiating treatment. Deaths have been recorded during the induction phase onto methadone especially when the recipient is not as tolerant as believed or is using other opioids or substances.(19) Therefore, confirmation of the patient’s dependent status is paramount as described in the chapter and it is safer to start treatment at low doses (not more than 30 mg daily). Treatment should be initiated under supervision with oral methadone liquid where consumption can be easily monitored. Doses should generally be increased slowly, and titrated against withdrawal symptoms. As methadone can accumulate, there should be increased observation over the first few weeks of treatment. Doses can then gradually be increased to within therapeutic levels (60-120 mg daily). Prescribing should follow the guidelines outlined later in the chapter.
(b) Buprenorphine maintenance treatment
Buprenorphine (Subutex) is a synthetic partial opioid agonist which is given as a sublingual tablet and has a high affinity at µ-opioid receptors. It is an effective treatment for use in maintenance treatment for heroin addiction, but is not more effective than methadone at adequate dosages.(20)
Buprenorphine undergoes extensive first metabolism. Therefore, it is administered as sublingual tablets (2 mg and 8 mg) with bioavailability of between 30-40 per cent. Optimizing sublingual absorption while minimizing diversion is a practical challenge that supervised dispensing points still need to address. Taking 5-7 minutes to dissolve, buprenorphine reaches a plateau on most physiological subjective effect at a daily dose of 4-16 mg. At higher doses, the duration of action increases, permitting less than daily dosing in about one-third of patients. Because of its high affinity for the opioid receptor, buprenorphine will precipitate withdrawal if administered to someone with an opioid agonist on board (typically within 8 h of heroin use or 24-36 h of methadone use). Therefore, patients are advised to wait until they are in mild withdrawal before commencing treatment. Finally, it is thought to be safer in overdose (with a ‘ceiling’ in the respiratory depression, unlike with full opioid agonists) and so induction can be quite rapid aiming for doses of between 8-16 mg by day 3.
It is an effective analgesic but may be less suitable than methadone for those with chronic pain. Although safer in overdose than methadone, fatal overdose can occur especially when taken in combination with other substances. As with methadone dose, reduction in someone stable on maintenance should be done gradually (typically 2 mg ever 2 weeks) and only supported when there is evidence of continued abstinence from illicit opioid use. Continued dose reduction in the face of return to illicit use is likely to further destabilize the patient. In some countries (e.g. many European countries since 2007), another preparation has become available (Suboxone), in which buprenorphine has been combined with naloxone in a ratio of 4:1 to reduce the desirability of injecting diverted medication. When taken as directed (sublingual), the bioavailability of naloxone is very poor, whereas when injected by a dependent opiate user, a severe withdrawal reaction may be precipitated.
(c) Other opioid maintenance treatments
Injectable methadone and injectable heroin are rarely prescribed in the United Kingdom and at present there is insufficient evidence to guide this use.(21) However, it may be considered in some patients as a ‘second-line’ treatment option for whom an adequate trial (e.g. at least 6 months) of optimized methadone maintenance treatment (e.g. doses >80 mg daily, regular supervised dosing, regular appointments and appropriate management of medical or psychiatric co-morbidity) is ineffective in controlling illicit injecting heroin use. This should only be initiated by a specialist. Both long-acting morphine and dihyrocodeine have been compared to methadone in two randomized controlled trials which have revealed broadly equivalent outcomes between the groups.(23,23)
Opioid detoxification
Detoxification may be based on suppression of the ‘nor-adrenergic storm’ that accompanies opioid withdrawal, by prescribing either α2-receptor agonists or a gradual reduction of an opioid agonist. When a patient is stable and motivated, a gradual reduction in the dose of opioid maintenance dose can be an effective means for attaining abstinence. However, it must be noted that detoxification is generally associated with poor long term rates of abstinence and retention in treatment.
(a) Buprenorphine detoxification
Buprenorphine has been found to be more effective than clonidine (below) for the management of opioid withdrawal. In addition, there is no significant difference between buprenorphine and methadone in terms of completion of treatment, but withdrawal symptoms may resolve more quickly with buprenorphine.(24) This can be undertaken as an inpatient or outpatient. Buprenorphine should only be taken after cessation of heroin use as it can precipitate withdrawal. Withdrawal may be achieved by the burpenorphine dose being stabilized according to withdrawal over
a 24-48 h period, after which a gradual dose reduction should occur over 5-21 days in the inpatient or outpatient setting.
a 24-48 h period, after which a gradual dose reduction should occur over 5-21 days in the inpatient or outpatient setting.
(b) Methadone detoxification
Methadone detoxification can be used for pharmacologically assisted opioid detoxifications. A review revealed that withdrawal programs vary widely with regard to duration, design and treatment objectives. This review confirmed that slow tapering with temporary substitution of methadone accompanied by medical supervision and ancillary medications can reduce withdrawal severity. Nevertheless, the majority of patients relapsed to heroin use.(25)
(c) α2-Agonist assisted detoxification
α2-agonists, such as lofexidine and clonidine, reduce pre-synaptic nor adrenaline release alleviating many withdrawal symptoms associated with opioid withdrawal. The dose is titrated against the symptoms and signs of withdrawal whilst also avoiding hypotensive episodes. Detoxification can occur in both outpatient and inpatient settings. Lofexidine that has a lower incidence of hypotension than clonidine is the preferred non-opioid method of assisting opioid withdrawal. A review has concluded that there is no significant difference in efficacy for treatment regimes based on clonidine and lofexidine, compared to reducing doses of methadone over a period of around 10 days, for the management of opioid withdrawal.(26)
(d) Naltrexone assisted detoxification
Some research has been published suggesting that withdrawal may also be completed more quickly by additionally administering the long-acting opioid antagonist naltrexone. However, further research is still needed to confirm effectiveness and safety of this treatment.
Naltrexone for relapse prevention
Oral naltrexone has recently been recommended in the UK for the management of opioid dependence. Naltrexone is relevant for highly motivated patients who have completed an opioid detoxification. This may be combined with arrangements for supervision and should be given as part of a programme of supportive care. Regular reviews of effectiveness of naltrexone should be undertaken by the clinician and discontinuation of treatment should be considered if there is evidence of continued opiate misuse.(27)
Psychosocial interventions for opioid dependence
There are numerous psychosocial approaches that are currently used in the management of substance misuse. Treatment based on a holistic approach encompassing biological, psychological and social aspects of care is likely to improve outcomes. Psychosocial treatments such as relapse prevention, motivational interviewing and contingency management are often used in the addiction setting. Cognitive behaviour therapy and other types of psychotherapy are also used particularly for those with a specific psychiatric disorder such as depression and can be referenced elsewhere in the book.
Relapse Prevention looks at identification of triggers for craving (e.g. people, places, or moods) and uses learning techniques (distraction, relaxation) to handle high-risk situations.(28) Motivational interviewing techniques can help patients move along a ‘cycle of change’ from pre-contemplation (no interest in changing behaviour) to contemplator, to determination and action without confrontation.(29) This is based on five key principles (Table 4.2.3.1.3) which are often used in both addiction and eating disorders, but may also be used in any aspect of the doctor-patient relationship where the patient is ambivalent about change.(30) Although used rarely in the UK, Contingency Management (CM) has a stronger evidence base. This behavioural treatment uses rewards or other reinforcers to promote abstinence or other selected goals. Narcotics Anonymous is based on the 12-step program (the philosophy behind Alcoholics Anonymous) where the individual accepts they have a drug problem and uses 12 steps (Table 4.2.3.1.4) within the group setting, to attain abstinence.(31)
Table 4.2.3.1.3 Principles of motivational interviewing(30) | ||||||
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Psychosocial interventions alone have not been shown to be more effective than no treatment.(32) However psychosocial interventions combined with pharmacological interventions have been shown to lead to better outcomes.(33)
Educating the drug user about safe practices (including safer injecting, not sharing equipment) and harm-reduction techniques is important, as is appropriate liaison with other agencies such as social services or voluntary sector supports. Therapeutic communities, residential rehabilitation and ‘concept houses’ based on a religious or abstinent theme offer longer-term care.
Management of opioid dependence
The treatment plan should be made jointly between the clinician and patient. The actual management plan depends on whether the person has opioid dependence, the amount of opioids used, and the outcome of the mutually agreed treatment objectives and
treatment plan. Opioid dependence management is sometimes based on ‘abstinence’, where the person refrains from taking drugs, but also needs to be based on the principles of harm reduction. Harm reduction aims to reduce harms from opioid use often in terms of reducing deaths, spread of blood-borne viruses or improving psychosocial outcomes. This may optimally be achieved through cessation of injecting illicit opioid use by stabilizing the person on an opioid replacement.
treatment plan. Opioid dependence management is sometimes based on ‘abstinence’, where the person refrains from taking drugs, but also needs to be based on the principles of harm reduction. Harm reduction aims to reduce harms from opioid use often in terms of reducing deaths, spread of blood-borne viruses or improving psychosocial outcomes. This may optimally be achieved through cessation of injecting illicit opioid use by stabilizing the person on an opioid replacement.
Table 4.2.3.1.4 12 Steps of Narcotics Anonymous(31) | ||||||||||||||||||||||||||
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Assessment of opioid use and dependence
A comprehensive assessment of opioid use patterns and associated risks forms the basis of any treatment plan. A suggested plan of enquiry that allows both accurate diagnosis and risk assessment is outlined below.
(a) Clinical assessment
1 Current consumption: How much heroin (or other opioid) is consumed on a typical day, in terms of either weight or money spent, and for how long has consumption been at this level? Are opioids taken daily? What happens when no opioids are taken? The route of use (smoking, intravenous injection), number of administrations per day, and the minimum amount of opioid required each day to avoid withdrawal symptoms should also be assessed. Enquiry should be made to determine if more than one type of opioid is being used (e.g. prescribed medication or street methadone). All other substances being used should be identified (e.g. cocaine, benzodiazepines and alcohol) and their patterns of use.
2 Typical day: A systematic enquiry of the person’s typical day and the use of opioids and other substances is particularly important for assessing evidence of withdrawal. This can also be useful for identifying risk activities that the user engages in to support their ongoing use, including criminal activity, high risk sex, or injecting practices.
3 Drug use history: A careful enquiry needs to be made to determine the temporal relationship between the onset of drug use and any psychological behaviors. The age of first use and the psychosocial precipitants of use should be established, as should the development of tolerance and craving through increased frequency of use, escalating dose, and where relevant, the onset of injecting.
4 Biopsychosocial complications: This should assess episodes of overdose (intentional or accidental), viral screening status and injecting behaviour including use of needle exchanges, sharing equipment and use of high-risk injection sites such as the groin and neck. Effects on family relationships, employment and criminal activity, and co-morbid psychiatric conditions related to opioid use should be assessed.
5 Past treatments and abstinent periods: Have they ever been in contact with treatment services, maintained on substitute medication or undertaken a detoxification? What was their longest period of abstinence? What has helped in the past? When and why did relapses occur? What are high-risk situations and other triggers for use?
6 Motivation for change: Why seek treatment now? What support is needed? Thinking of Livelihood (financial), Life (physical health), Love life, Legal problems and Losing it (loss of control) can be helpful as these are often precipitants for seeking treatment and can be used to encourage behavioural change.
(b) Confirmation of dependence
Although a diagnosis of opioid dependence can be made by taking a full history; dependence and tolerance to opioids should be corroborated before commencing substitute treatment. Confirmation of dependence and tolerance prior to commencing treatment is important since the greatest risk associated with prescribing methadone is the possibility of overdose following consumption of methadone by a non-tolerant individual. Corroborative information may come from urine drug screens and other health care practitioners such as the GP or criminal justice worker. Physical examination is essential and may reveal stigmata of injecting drug use such as evidence of recent intravenous injection sites or the more long-term ‘track marks’ (linear scarring along veins from repeated intravenous use) on the drug user’s limbs. All patients should be asked where they usually inject and recent injection sites should be examined. In those with poor upper limb veins, with evidence suggestive of ongoing illicit use, it may be appropriate to examine groin or neck sites.
Urines tests are supportive of use but not confirmatory of dependence. Sequential urine testing over a few days may allow the confirmation of regular opioid (although not necessarily heroin) consumption. Measurement of withdrawal by using withdrawal scales (Table 4.2.3.1.5) in addition to examining for presence of tachycardia and hypertension, following a period of abstinence, is helpful in confirming withdrawal. The Objective Opiate Withdrawal Scale (Table 4.2.3.1.5) is useful when assessing whether a person is in withdrawal before commencing opioid substitution treatment and useful after commencing treatment to aid assessing whether the opioid substitute dose is adequate. Partial or full reversal of withdrawal following a measured dose of opioids administered on site will provide some information of the patient’s level of tolerance.
Table 4.2.3.1.5 Objective opiate withdrawal scale(27) | ||||||||||||||||||||||||||||||||||
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Investigations for patients with opioid dependence
Heroin dependence is associated with high rates of physical and psychiatric morbidity. Since access to primary health care may be difficult, basic physical health checks should be a fundamental part of all drug treatment. The core assessment should include history, physical examination, routine blood tests, blood borne virus screening and vaccination where appropriate, and assessment of nutritional status, mental and dental health. Referral to appropriate specialist services should be facilitated through coordinated care planning which should form the cornerstone of structured drug treatment delivery.
Management options for opioid dependence
Following a careful and thorough assessment which allows confirmation of dependence as outlined above, there are several treatment options. In the short term, opioid substitution treatments with methadone or buprenorphine may be offered. Opioid substitution treatment should be monitored closely, especially during the initial phase of treatment. Initiation of opioid substitution treatment usually takes place in the community setting, but may occur in an inpatient setting if there is a complicated history involving medical or psychiatric morbidity. Opioid maintenance treatment is continued in the community setting and can be continued as maintenance for the long term, with some patients continuing treatment for over 50 years. Treatment for opioid dependence is likely to be improved when framed within a comprehensive treatment package including psychosocial and pharmacological interventions.(32) Relapse prevention and motivational interviewing can be carried out during regular appointments with health professionals. Community substance misuse teams often use keyworking as a model of care for opioid dependent patients. This is where one healthcare professional looks after the patients care and provides the main source of contact, often following up referrals and ensuring medical and psychosocial needs are met. Opioid maintenance treatment within the community substance team may continue in the long term or be a prelude to starting abstinence based treatments, with the aim of stopping all illicit heroin use.
Abstinence can be achieved by pharmacologically assisted withdrawal from the opioid via a detoxification with either lofexidine or an opioid substitute such as methadone or buprenorphine (as above). This usually takes 10-21 days but may be longer if withdrawal from a longer acting opioid is required. Opioid detoxification may take place in the inpatient or community setting, depending on the level of medical and psychiatric morbidity. Following opioid detoxification patients may benefit from treatment within a therapeutic community or residential rehabilitation centre where life skills for dealing with a world without opioids may be developed. For patients who do not enter rehabilitation centres, regular sessions with keyworkers using relapse prevention and motivational interviewing may also be beneficial. Highly motivated patients may also benefit from naltrexone to prevent relapse (described above).
Prescribing opioids for opioid dependence
In the United Kingdom, all doctors may prescribe methadone or buprenorphine for the treatment of dependence, although prescribing should generally be initiated by a specialist or special interest general practitioner. Prescriptions for opioid dependence should ideally be dispensed daily with supervised doses, particularly for the first three months of treatment. After about three months, if a patient is stable (based on psychosocial outcomes and illicit substance use) the number of dispensings per week and level of supervision may be reduced, although this may be varied when there are extenuating circumstances. UK guidelines advocate that no more than a week’s medication is dispensed at a time.
Liaison between the pharmacist, the general practitioner and the specialist is important to prevent double scripting, reduce diversion and improve safety. Clinicians in all specialties should be aware of the potential for all opioid-containing analgesics to be diverted for abuse or develop into iatrogenic dependence. Repeat prescriptions of such analgesics should be carefully reviewed. Prescriptions for controlled drugs can only be for 28 days in total and the total prescribed amount must be written in words and figures. It is recommended that the prescription should state the name of the pharmacy where the prescription is to be dispensed, how often the prescription should be dispensed and whether the dose should be consumed under supervision. Installment prescriptions for daily dispensing are available in the UK for burpenorphine and methadone. Only doctors in possession of a Home Office license are able to prescribe heroin for the treatment of opioid dependence.(34)
Opioid overdose management
Opioid overdose management training is particularly important as early recognition (Table 4.2.3.1.6) of an opioid overdose and prompt action (Table 4.2.3.1.7) can save lives. The antidote to heroin is naloxone and this should be given if an opioid overdose is suspected. Although intravenous naloxone is quicker acting, venous access may be difficult and therefore, intramuscular injection may be preferable and also results in a more gradual reversal of the overdose which may be less likely to provoke aggression. Hospital monitoring should always be recommended, since the plasma half-life of naloxone is shorter (<1 h) than the physiological effects of heroin (4-6 h) and methadone (24-36 h). In addition many overdoses are a result of concomitant substance use—the effects of which will not be reversed by naloxone alone. Opioid overdoses involving buprenorphine (partial agonist) will not be readily be reversed by naloxone; however buprenorphine is believed to have much less respiratory depressant effects.
The supply of ‘take home’ emergency naloxone may help reduce opioid related overdose deaths. It has, therefore, been advocated that providing take-home naloxone in combination with opioid overdose management training to opioid using patients and their families may help reduce deaths.(35)
Table 4.2.3.1.6 Recognition of an opioid overdose | |||||||
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Table 4.2.3.1.7 Management of an opioid overdose | |||||||||
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Special groups
Young people
Young people with opioid problems often have other emotional and/or behavioural problems, and frequently fall between the adult and child psychiatric services as well as addiction services, compounding the difficulties in providing effective services to this group. Increasingly dedicated services have recently been developed and these integrated services focus as much on the family and re-integration with education as they do on substance use issues. Approaches effective for the adult population may be less effective in a group with less developed emotional and cognitive abilities. Separation of such a service from adult providers would also assist in preventing experienced drug users from influencing more naive users. Ultimately, a tiered approach would appear appropriate, since it would allow maximum utility of current services and focused development of new services. Generic services in primary health care could provide accurate screening with initial referral to youth-oriented services within existing departments. Beyond this, referral to specialist and super-specialist regional services could be employed to provide secure environments with the option of residential rehabilitation and therapeutic communities. Once engaged they may benefit from a range of possible therapies from family work and cognitive behavioural therapy to pharmacotherapy and self-help groups.
Pregnancy and breastfeeding
Maternal opioid use poses a risk to both the mother and foetus. Pregnancy can be a specific point when women try to address their opioid use problem. The management of the pregnant opioid user should follow the same guiding principles as for other opioid users; additionally, there should be close liaison between addictions and maternity services, the general practitioner and other relevant agencies (Table 4.2.3.1.8).
Women who are already on methadone maintenance treatment can remain on methadone but should be encouraged to stop illicit opioid use. For women who are not prescribed methadone, the first step is to initiate stabilization on methadone. Methadone maintenance may continue at a stable dose throughout pregnancy. During the third trimester, maternal metabolism may increase the need for methadone and so the dose may need to be increased or alternatively the daily dose could be split. Methadone increases the risk of respiratory depression in the neonate and should always be pre-considered for the delivery plan. Women prescribed opioids may also need increased pain relief during delivery. The long-term outcome in women who enter methadone treatment programmes during pregnancy is better in terms of their pregnancy, childbirth, and infant development, irrespective of continuing illicit drug use.(36) Methadone is not contraindicated for breast feeding.
Table 4.2.3.1.8 Aims of managing the pregnant drug user | ||||||||||||||
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Some women prefer to be abstinent from opioids during pregnancy. These women will often need a gradual pharmacologically assisted detoxification, which should be avoided in the first trimester, ideally undertaken in the second trimester and undertaken with caution in the third trimester. Detoxification is best undertaken within a dedicated inpatient facility, however, this may not always be possible and therefore community detoxification can be undertaken. During stabilization on methadone or detoxification, it is important to prevent the pregnant woman experiencing opioid withdrawal as this is dangerous for both mother and fetus.
Currently, there is insufficient evidence regarding the use of buprenorphine during pregnancy or breastfeeding to be able to define its safety profile. However, women well maintained on buprenorphine prior to pregnancy refusing alternative pharmacotherapy could be kept on buprenorphine following full informed consent.
Forensic
It has been estimated that up to two-thirds of people arrested have taken substances prior to arrest, whilst approximately 15-50 per cent of the prison population were previously dependent on drugs or alcohol. It is difficult to estimate exact opioid use and dependence, but approximately one-fifth of the prison population injects drugs. Access to illicit substances is not prevented by imprisonment; indeed some users may increase or start using drugs whilst imprisoned.(37) Improving identification of drug users before sentencing is important. In addition, identification of drug related crimes and offering court diversion schemes with drug treatment interventions can be an alternative to a custodial sentence. Prisoners will benefit from education, good primary health care, blood borne virus testing, and hepatitis vaccination. In addition, prisoners can undertake opioid detoxification or commence/continue opioid maintenance treatment whilst in prison. Release from prison is associated with extremely high risk of opioid overdose death, particularly in the first few weeks, and therefore quick access to drug services following release (or prior to release) may reduce deaths.
Accessing treatment and the range of services
Those who experience problems with opioids may present to a wide range of professionals within the health-care, social, and legal systems. The range of treatment options available from statutory and non-statutory agencies in any particular area will vary, as will the provision of either maintenance or detoxification for opioid dependents depending upon differing treatment philosophies and treatment settings.
Outcomes
Heroin dependence is a chronic relapsing condition and opioid use reduces morbidity and mortality more than any other drug use.(38) Treatment saves lives and improves psychosocial function as well as reducing risk to both the individual and the community. Outcomes are broadly comparable to those seen with other chronic medical conditions.(39) Abstinence rates following treatment vary widely, but 10 to 40 per cent of treated patients are still drug free at 6 months.(40) The majority of those who relapse following treatment do so within 3 months of discharge. Longer treatment is associated with better outcomes and greater pre-treatment severity of psychopathology is associated with worse outcomes. Long-term follow-up studies suggest that successful and lasting cessation of opioid use can be a very slow process and becomes increasingly unlikely if users continue into their late thirties.
Results from three longitudinal studies ranging from 3-5 years based in the United Kingdom, Australia and United States of America have shown that treatment leads to better outcomes against all parameters as compared to no treatment.(41,42,43) Patients who enter drug treatment are more likely to significantly reduce use of heroin and other illicit drugs and longer treatment times have been associated with better treatment outcomes. Reductions in heroin use have also been mirrored by reductions in heroin overdose rates. Therefore opioid treatment increases morbidity and mortality in opioid users.
The Australian Treatment Outcome Study (ATOS) reported that half the number of opioid overdoses occurred in the participants in treatment at 1 year as compared to the same participants prior to entering treatment. In addition this study showed that levels of psychopathology reduced, physical health improved and crime rates in this population reduced following treatment.(43) The National Treatment Outcome Research Study (NTORS) based in the UK had increased rates of abstinence, reduced heroin use and reduced injecting and sharing of injecting related equipment with both residential and community treatment.(42) Findings from the Drug Abuse Treatment Outcome Studies (DATOS) based in the USA were similar to both the UK and Australia studies.(41)
Longer term outcomes have been observed in a study following up 581 male heroin users since 1962. At the 33-year follow up, 284 subjects were dead and 242 were interviewed. Over a fifth were still using heroin and 40.5 per cent admitted to using heroin in the last year. There were high rates of health problems, mental health problems, and criminal justice system involvement. Heroin abstinence was associated with improved outcomes in all these domains. Deaths increased steadily over time with a relatively stable pattern of heroin use in the subjects.(44) A further analysis of the results assessed years of life lost through heroin use and concluded that on average, 18.3 years of potential life were lost before the age 65, which is significantly higher than that of US population.(45)
Conclusion
Opioid dependence is a chronic relapsing and remitting disorder affecting a large proportion of people throughout the world with severe physical, psychological, and social consequences. Opioid overdose and spread of blood borne viruses are major causes of morbidity and mortality. Assessment of opioid use and dependence should be systematic and confirmation of dependence is of paramount importance before initiating treatment. The prescription of substitute opioids should be managed carefully to prevent harm, diversion to others and improve safety. Management of opioid dependence can greatly improve outcomes and may be based on opioid maintenance stabilization or detoxification combined with psychosocial interventions.
Further information
Department of Health (England) and the developed administrations. Drug misuse and dependence: UK guidelines on clinical management. 1999. HMSO, London. http://www.dh.gov.uk/prod_consum_dh/groups/dh_ digitalassets/@dh/@en/documents/digitalasset/dh_4078198.pdf
National Treatment Agency for Substance Misuse website for guidelines. http://www.nta.nhs.uk/
The Cochrane Library for Cochrane Systematic Reviews on Opioids. http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME
National Institute for Clinical Excellence. www.nice.org.uk/
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4.2.3.2 Disorders relating to the use of amphetamine and cocaine
Nicholas Seivewright
Robert Fung
Introduction
Amphetamine and cocaine are classed as stimulant drugs, although the distinction between stimulants and depressants can be criticized on the grounds that the same drug may have both actions in turn. This does indeed occur with amphetamine and cocaine, but the initial desired effects are increased energy and activity, and elevation in mood. These appear to be mainly due to enhanced central transmission of dopamine and noradrenaline (norepinephrine), with a similar enhancement of serotonin playing a less certain role.
Pharmaceutical preparations of amphetamine were previously widely used for treatment of depression and obesity, with some misuse of these occurring. In the period since the 1970s of increasing recreational drug use, the powder preparation of ‘street’
amphetamine (commonly known as ‘speed’ or ‘whizz’) has largely displaced the pharmaceutical forms to become a common drug of misuse in many countries. The powder is typically very impure and constitutes a racemic mixture of d- and l-isomers, with the l-form being relatively inactive. A stronger street preparation is the ‘base’, sometimes more a moist paste, and both these forms of the drug may be swallowed (either on their own or in a drink), snorted, or injected. (For the methylated forms ‘ecstasy’ and ‘crystal meth’, see Chapter 4.2.3.5.)
amphetamine (commonly known as ‘speed’ or ‘whizz’) has largely displaced the pharmaceutical forms to become a common drug of misuse in many countries. The powder is typically very impure and constitutes a racemic mixture of d- and l-isomers, with the l-form being relatively inactive. A stronger street preparation is the ‘base’, sometimes more a moist paste, and both these forms of the drug may be swallowed (either on their own or in a drink), snorted, or injected. (For the methylated forms ‘ecstasy’ and ‘crystal meth’, see Chapter 4.2.3.5.)
The coca shrub is indigenous to countries in South America, where the leaf is chewed, and use of the derived cocaine powder has spread extensively to the United States and elsewhere. The powder may be injected, sometimes along with heroin, by polydrug users, or snorted, the image of which is sometimes linked with executive lifestyles. Cocaine has become more dangerous as usage has gradually transferred in many countries to the ‘crack’ form, which is made from cocaine hydrochloride powder in a simple chemical process, and is more potent in its effects and withdrawal effects. Very rapid increases in blood levels of the drug can be achieved by smoking crack, and this is the usual route, although it is injected by committed intravenous drug users.
Clinical features
The effects and withdrawal effects of amphetamine and cocaine can be considered together, as the main features are equivalent. However, amphetamine has a slower onset of action than cocaine and longer elimination half-life, while crack is the most quickly absorbed of the cocaine preparations. This is reflected not only in the generally more intense effects of cocaine than amphetamine, but in the timescales involved. Thus an amphetamine user may experience desired effects, unwanted mental effects, and withdrawal features over the course of a few days, while a crack user can report the same sequence occurring in a matter of hours or even less. The main effects and withdrawal effects of these two stimulant drugs are shown in Table 4.2.3.2.1.
The list of effects can be seen as merging from the desired to the undesired. These drugs are typically taken in situations where stimulation is the aim, with sleep and eating regarded as hindrances. Mood is elevated, but characteristically this progresses to suspicion, in which true paranoid symptoms may be experienced. This is usually recognized by the individual as indicating that the episode of use should be terminated, but if use persists symptoms may become severe, or a more confused state develop. After stopping the drugs there are typically withdrawal effects of depressed mood, hyperphagia, and hypersomnia; no consensus exists as to whether such features are best viewed as ‘rebound’ symptoms, a truer withdrawal syndrome, or simply users catching up on sleeping and eating after a period without either.
Table 4.2.3.2.1 Effects and withdrawal effects of amphetamine and cocaine | ||||||||||||||||
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Such withdrawal features have been delineated most closely in relation to cocaine. A three-stage process has long been recognized(1): initially agitation, anorexia, and acute craving; second, excessive tiredness, depression, and hyperphagia; finally, a normalization of most features, but a return of craving when triggered by environmental cues. This description is from before the escalation in crack use, and depression, craving, and agitation especially are often much more severe with this form of the drug. While environmental cues are clearly relevant in precipitating the use of any drug, a powerful surge of craving on encountering situations associated with previous use appears particularly characteristic of cocaine and crack.(2) The three-stage description of withdrawal features suggests that this phenomenon may occur after months or even years of abstinence.
Are amphetamine and cocaine addictive?
It is commonly observed that amphetamine and cocaine are non-addictive, or cause psychological but not physical dependence. Such observations rest on a distinction in which the condition of addiction, or physical dependence, requires visible bodily withdrawal symptoms, but critics claim this is of limited meaning now that there is an understanding of the neurobiological basis of drug withdrawal states. The current classification systems do retain some distinctions between physical and psychological dependence, and the issue is largely one of definition and semantics. The credibility of the label ‘non-addictive’ is certainly tested by individuals who have injected amphetamine 10 or more times every day for many years, or who spend vast amounts of money using crack in a highly compulsive manner.
Classification
Table 4.2.3.2.2 shows the classification within ICD-10 and DSM-IV-TR of disorders that may relate to the use of cocaine. In both systems the same diagnoses can be applied to amphetamine, in ICD-10 within a category ‘other stimulants’.
Importantly, the list of diagnoses in ICD-10 is a standard one to be used across all psychoactive substances, with the second digit of the code number simply changed according to substance, and so does not imply that all those conditions can be caused by amphetamine or cocaine. The DSM-IV-TR listing is somewhat more specific, in that the diagnoses are selected from a wider general list of conditions which can apply to the range of substances. In this way the DSM-IV-TR classification recognizes that cocaine and amphetamine can produce states of dependence and withdrawal, as well as psychosis, affective disorders, and the other conditions included.
Diagnosis
The use of amphetamine or cocaine can be detected by drug screening of a plain urine sample, in laboratory testing or with instant kits. The importance of urine testing as a relatively simple procedure to employ, in any setting, in cases where drug use is suspected must be emphasized, as it is surprisingly often neglected. The two main limitations are possible doubts about authenticity, where mouth swabs for oral mucosal transudate can be a useful
alternative, and the short time for which drugs remain detectable in urine—as little as 24 h for cocaine. By contrast drugs remain in hair from the head or other parts of the body for the whole period of growth, but this technique which gives much longer-term information is a specialized one.
alternative, and the short time for which drugs remain detectable in urine—as little as 24 h for cocaine. By contrast drugs remain in hair from the head or other parts of the body for the whole period of growth, but this technique which gives much longer-term information is a specialized one.
Table 4.2.3.2.2 Classification of disorders relating to cocaine in ICD-10 and DSM-IV-TR | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Obtaining a history and compliance with sampling may be particularly problematic in psychotic states. In such conditions it is also important to recognize that detected drug use may be incidental rather than necessarily causative.
Epidemiology
In most countries, the use of illicit drugs is commonest among young males of lower socio-economic status. Stimulant use overall reflects this, although of the various drugs of misuse, cocaine powder has been exceptional in the extent of usage also by more affluent individuals.
The biggest epidemic of cocaine use outside South America has been in the United States, where it peaked in the mid-1980s.(3) Household surveys at that time estimated that approximately one-tenth of the population had used the drug; the same epidemiological method has charted the subsequent general decline in occasional use, but an increase in more dependent use of crack. Cocaine use in other countries has not generally spread as widely as was predicted from the United States experience. In Europe the population lifetime prevalence of cocaine use has remained in low single-figure percentages,(4) much of it among inner-city polydrug users, although snorting cocaine powder is seemingly increasing among young people, rather displacing the recreational use of ‘ecstasy’.
Even in areas where stimulant use is common, such users tend to present relatively rarely to treatment services. Priority is generally given to opioid substitution treatment of heroin addicts, and so service statistics will nearly always underestimate stimulant problems.
Aetiology
Broadly the same familial, social, and psychological factors are relevant in the aetiology of amphetamine and cocaine misuse as in other forms of drug misuse. Approximately half of the drug misusers are deemed in studies to have an underlying personality disorder,(5) usually of the antisocial type, although the figure has sometimes been found to be lower for stimulant misusers than for those dependent on opiates. This may be partly methodological, to do with the difficulty in distinguishing true personality characteristics from behaviours inherent in the activity of highly dependent drug misuse, but is probably also a reflection of the use of stimulant drugs by a generally broader population.
Course and prognosis
Course
A far greater proportion of amphetamine and cocaine misuse than opiate misuse is recreational in nature, with few significant complications if the medical harms are avoided. It is assumed that the vast majority of those who are identified in school and teenage surveys as having used stimulants simply give them up in due course, although little systematic data is available. Complications and involvement with treatment services are more likely where there is dependent usage, and there may be psychiatric contact in episodes of psychosis. A very small proportion of amphetamine injectors progress to high-dose daily usage, while the heavy use of cocaine appears to be less sustainable and is therefore usually periodic in nature.
Other drug use
After being stimulated with amphetamine or cocaine, many individuals will use sedatives such as alcohol, benzodiazepines, or cannabis to ‘come down’ from their drug. Increasingly heroin is being used for this purpose, sometimes to the point of becoming dependent on the opiate and requiring substitution treatment. The use of cocaine in particular is commonly encountered as a secondary form of drug misuse in methadone patients,(6) with some individuals undoubtedly switching their preferred illicit drug from heroin to cocaine when treatment is established.
Prognosis
The drug misuse literature in general would suggest that stimulant use is more likely to progress and become problematic in individuals with associated personal or social difficulties or psychiatric disorder. Usage by individuals with severe mental illness, which often contains an element of ‘self-medication’ of distress even though in the long run stimulants will render symptoms worse, can be particularly entrenched.(7)
Complications
Many of the complications of amphetamine and cocaine misuse are complications of drug misuse in general, including those related to injecting. The range includes general physical decline,
weight loss, dental problems, infective complications ranging from abscesses to hepatitis and infection with the human immunodeficiency virus (HIV), reduced foetal growth in pregnancy, mood disturbances, and various social problems. Complications in the following areas are somewhat more specific to stimulant misuse:
weight loss, dental problems, infective complications ranging from abscesses to hepatitis and infection with the human immunodeficiency virus (HIV), reduced foetal growth in pregnancy, mood disturbances, and various social problems. Complications in the following areas are somewhat more specific to stimulant misuse:
Cardiovascular—hypertension, arrhythmias, myocardial infarction, cerebrovascular accident
Obstetric—premature labour, placental abruption
Psychiatric—anxiety, depression, aggressive behaviours, psychosis
Other—perforation of nasal septum (cocaine snorting)
The cardiovascular problems relate to increased catecholamine secretion, and represent the most serious hazard of cocaine abuse.(8) With obstetric complications, it is difficult to separate the effects of drugs from other risk factors such as poor diet, smoking, or adverse social conditions, but there appears to be a particular link between stimulants and placental abruption.
There are also various psychiatric disorders that are particularly associated with amphetamine and cocaine misuse. Anxiety as a symptom is common in relation to the agitation produced by the drugs, while depression is a classic withdrawal effect. An assessment of the true clinical significance of these features therefore requires withdrawal from drugs, while in acute presentations both can be extremely distressing. Aggressive behaviour may be due to an underlying personality disorder, but it is also characteristic of withdrawal from crack cocaine when severe craving is experienced. Paranoid psychosis, sometimes indistinguishable from an acute schizophrenic episode, is the best-known complication of stimulant misuse. The earliest descriptions were of cases where symptoms quickly subsided after withdrawal of the drugs, but it is now recognized that through mechanisms which represent a kind of sensitization, symptoms which are drug-induced can persist and recur even with avoidance of substance use.(9)
Treatment
Evidence
A very large number of medications have been investigated in cocaine misuse, mainly compounds which through actions on catecholamines or serotonin could be expected to alleviate withdrawal effects. After decades of such work the evidence is very discouraging, with no medications consistently found to reduce stimulant abuse.(10) Inpatient programmes and psychological treatments basically represent modifications of those approaches used across all forms of drug misuse, although cocaine abuse appears particularly amenable to the ‘contingency management’ approach of providing material incentives for abstinence.(11)
Management
Faced with the limitations in treatment for these forms of drug misuse that have high morbidity and mortality, drug services have had to consider how best to achieve some benefits in terms of very practical management.(12) The factors that appear important in such provision are:
specific outreach programmes
harm-reduction approaches
rapid response where necessary
targeted use of treatments
admission in severe cases
To engage stimulant users at all can require outreach aimed at the subcultural groups in whom usage is common. Basic harm-reduction measures must be offered, including drug information, education about health risks, advice to reduce damaging injecting practices, and the provision of clean equipment. Counselling of a supportive or more behavioural kind may be provided by various types of agency.
The periodic nature of stimulant problems means that rapid response can be important, for instance in states of acute crack withdrawal or psychiatric disturbance. Use of tranquillizers and antipsychotic medications may be necessary for some presentations, while fluoxetine appears to be increasingly favoured over other antidepressants, due to a possible anticraving effect and good acceptability. Inpatient admission can be required in cases where no long-term measure is able to make much impact between acute crises. The possibility of any substitute prescribing in stimulant misuse is highly controversial, with some services seeing a role for oral dexamphetamine in heavily dependent amphetamine users experiencing extreme problems from injecting.(13)
Drug-induced psychosis
The two aspects of management of this complication are the treatment of psychotic symptoms and the withdrawal of the drug which is thought to be causative. The latter can be very problematic other than as an inpatient, and is not guaranteed even then. In practice, ongoing low-grade psychotic states in individuals who have not completely stopped drug use are common, and treatment may have to be attempted in such circumstances. The use of antipsychotic medications does not differ significantly from that in psychoses not produced by drugs.
Prevention
The prevention of drug misuse lies largely outside the clinical domain, in the areas of education, enforcement and social improvement. A more biological development in cocaine misuse of vaccination, whereby limited exposure produces antibodies to subsequently block the drug’s effects, remains experimental.
Further information
National Institute of Drug Addiction-Research Report for Cocaine Addiction: www.nida.nih.gov/ResearchReports/cocaine.html
Amphetamine Dependence: www.mentalhealth.com/dis/p20-sb02.html
Sadock, B.J. and Sadock, V.A. (2003). Kaplan and Sadock’s synopsis of psychiatry; Substance-related disorders, Chap. 12. Lippincott, Williams & Wilkins, Philadelphia.
European Monitoring Centre for Drugs and Drug Addiction. (2006). Annual report: the state of the drugs problem in Europe. Office for Official Publications of the European Communities, Luxembourg. Chapter 4, Amphetamines, ecstasy and other psychotropic drugs, and Chapter 5, Cocaine and crack cocaine.
References
1. Gawin, F.H. and Kleber, H.D. (1986). Abstinence symptomatology and psychiatric diagnoses in cocaine abusers: clinical observations. Archives of General Psychiatry, 43, 107-13.
2. van de Laar, M.C., Licht, R., Franken, I.H.A., et al. (2004). Event-related potentials indicate motivational relevance of cocaine use in abstinent cocaine addicts. Psychopharmacology, 177, 121-9.
3. Withers, N.W., Pulvirenti, L., Koob, G.F., et al. (1995). Cocaine abuse and dependence. Journal of Clinical Psychopharmacology, 15, 63-73.
4. European Monitoring Centre for Drugs and Drug Addiction. (2006). Cocaine and crack cocaine. In Annual report: the state of the drugs problem in Europe. Office for Official Publications of the European Communities, Luxembourg.
5. Grant, B.F., Stinson, F.S., Dawson, D.A., et al. (2004). Co-occurrence of 12-month alcohol and drug use disorders and personality disorders in the United States. Archives of General Psychiatry, 61, 361-8.
6. Williamson, A., Darke, S., Ross, J., et al. (2006). The association between cocaine use and short-term outcomes for the treatment of heroin dependence: findings from the Australian treatment outcome study. Drug and Alcohol Review, 25, 141-8.
7. Seivewright, N., Iqbal, M.Z., and Bourne, H. (2004). Treating patients with comorbidities. In Drug treatment: what works? (eds. P. Bean and T. Nemitz), pp. 123-41. Routledge, London.
8. Edgred, M. and Davis, G.K. (2005). Cocaine and the heart. Postgraduate Medical Journal, 81, 568-71.
9. Curran, C., Byrappa, N., and McBride, A. (2004). Stimulant psychosis: systematic review. The British Journal of Psychiatry, 185, 196-204.
10. de Lima, M.S., de Oliveira Soares, B.G., Alves, A., et al. (2002). Pharmacological treatment of cocaine dependence: a systematic review. Addiction, 97, 931-49.
11. Higgins, S.T., Heil, S.H., Dantona, R., et al. (2007). Effects of varying the monetary value of voucher-based incentives on abstinence achieved during and following treatment among cocaine-dependent outpatients. Addiction, 102, 271-81.
12. Seivewright, N., McMahon, C., and Egleston, P. (2005). Stimulant use still going strong. Advances in Psychiatric Treatment, 2, 262-9.
13. Grabowski, J., Shearer, J., Merrill, J., et al. (2004). Agonist-like replacement pharmacotherapy for stimulant abuse dependence. Addictive Behaviors, 29, 1439-64.
4.2.3.3 Disorders relating to use of PCP and hallucinogens
Henry David Abraham
PCP
Introduction
Phencyclidine (PCP, ‘angel dust’) is an arylcyclohexylamine dissociative anaesthetic. It was first abused in the United States in New York and San Francisco in the 1960s, but abuse declined when a broad range of adverse complications was noted.(1)
Epidemiology
While use of the unadulterated drug occurs, PCP is more frequently mixed with LSD or cannabis. The drug may be ingested or injected, but is more commonly smoked or snorted. Data suggest use in the United States and Europe. In the United States, a stable trend of 3 per cent of high school seniors have tried PCP at least once.(2) It traffics under a long and colourful list of street names. It has been suggested that any illicit smoked drug with an unrecognized street name (dust, mist, THC, embalming fluid, inter alia) should be considered PCP until proven otherwise.
Acute physiological effects
The drug has a delayed onset of activity when taken orally. Unlike the major hallucinogens, PCP requires doses in milligrams to be effective, a factor facilitating toxicological identification. When smoked, the onset of its main effects occurs immediately. The drug has particular affinity for the sigma opioid receptor, and non-competitively blocks the N-methyl-d-aspartate-type excitatory amino acid receptor. Other effects appear to be mediated indirectly by catecholamine release, cholinergic stimulation, and serotonergic receptors.
DSM-IV lists as criteria for acute PCP intoxication the following:
agitation
belligerence
impaired judgement
nystagmus
hyperacusis
hypertension
tachycardia
numbness
ataxia
dysarthria
rigidity
salivation
seizures
coma
It is clear from this daunting inventory that impaired judgement is likely to be present beforehand in any person intentionally choosing to abuse this drug.
Adverse effects
PCP affects not only adults, but fetuses and nursing infants.(3) Neurological consequences in infants include poor attention, hypertonia, and depressed neonatal reflexes.(4) In vitro studies show that PCP causes inhibited axon outgrowth, degeneration, and death in human fetal cerebral cortical neurones.(5)
In adults signs of severe PCP toxicity include:
hyperthermia
opisthotonus
cardiac arrhythmia
stroke
PCP is capable of provoking extreme muscular agitation, rhabdomyolysis and renal failure in 2.5 per cent of users.(6) DSM-IV lists psychiatric effects of PCP including intoxication, delirium, PCP-induced psychotic, mood, and anxiety disorders, and PCP abuse and dependence. A criterion for diagnosis is the emergence of the disorder within a month of drug use.
PCP delirium
Unlike acute intoxication with other hallucinogens, PCP delirium is associated with neurological disturbances. A continuum of effects is noted depending on dose.(7) Psychiatric symptoms occur early in
drug use, with stupor and coma occurring later. Shortly after drug use, patients appear confused and ataxic. Analgesia in fingers and toes may be described. PCP can produce complex hallucinations resembling LSD intoxication. Differentiating the two drugs in emergencies is important, since high-potency neuroleptics, which are useful in PCP toxicity, may exacerbate LSD, while the use of benzodiazepines, helpful in acute LSD toxicity, may disinhibit an assaultive PCP patient. Unlike LSD, PCP is readily identified in routine toxicological screening of blood and urine, but such data may not be readily available. One rapid bedside technique to differentiate the two drugs is the palm sign. The examiner asks the patient to describe the names of all the colours seen in the examiner’s outstretch palm. A typical LSD patient reports a vision of multiple colours and images. A PCP patient simply attacks the hand. Dexterity of the examiner is suggested. Unfocused aggression makes PCP delirium a particularly dangerous disorder. The spectrum of violence includes both suicide and homicide.(8) The technique of ‘talking down’ acutely toxic patients is contraindicated. Environmental stimuli should be minimized, and the patient provided with protective supervision. The use of physical restraints is relatively contraindicated because of the potential for rhabdomyolysis.
drug use, with stupor and coma occurring later. Shortly after drug use, patients appear confused and ataxic. Analgesia in fingers and toes may be described. PCP can produce complex hallucinations resembling LSD intoxication. Differentiating the two drugs in emergencies is important, since high-potency neuroleptics, which are useful in PCP toxicity, may exacerbate LSD, while the use of benzodiazepines, helpful in acute LSD toxicity, may disinhibit an assaultive PCP patient. Unlike LSD, PCP is readily identified in routine toxicological screening of blood and urine, but such data may not be readily available. One rapid bedside technique to differentiate the two drugs is the palm sign. The examiner asks the patient to describe the names of all the colours seen in the examiner’s outstretch palm. A typical LSD patient reports a vision of multiple colours and images. A PCP patient simply attacks the hand. Dexterity of the examiner is suggested. Unfocused aggression makes PCP delirium a particularly dangerous disorder. The spectrum of violence includes both suicide and homicide.(8) The technique of ‘talking down’ acutely toxic patients is contraindicated. Environmental stimuli should be minimized, and the patient provided with protective supervision. The use of physical restraints is relatively contraindicated because of the potential for rhabdomyolysis.
Specific treatments involve:
intravenous naloxone to rule out narcotics overdose
activated charcoal
acidification of the patient’s urine with vitamin C, ammonium chloride, cranberry juice
diuresis with frusemide (furosemide, Lasix)
antihypertensives
high-potency neuroleptics or barbiturates
PCP has mixed agonist and antagonist effects at cholinergic receptors. Anticholinergic drugs may precipitate a synergistic reaction with PCP, worsening delirium. Thus, low-potency neuroleptics, tricyclic antidepressants, and the anticholinergic antiparkinsonian drugs should be avoided.
PCP-induced psychotic disorder
PCP delirium may evolve into a chronic PCP psychosis that is differentiated from schizophrenia only with difficulty. Alternatively, a PCP delirium may clear, only to be replaced by the insidious onset of a post-PCP psychotic disorder. Certain features of PCP psychosis, namely neurological abnormalities, dose-related severity of symptoms, and regularity of the length of illness, are not noted with other psychedelic drugs, leading to the suggestion that PCP psychosis is a toxic drug effect rather than a functional illness. Four classes of agents are reported to help PCP psychosis:
benzodiazepines
neuroleptics
acetylcholinesterase inhibitors (physostigmine)
catecholamine depleters (reserpine)
Otherwise, treatment considerations are those for PCP delirium. The long-term prognosis for this disorder appears to be poor, according to data from an 8-year follow-up of 10 patients.(9)
PCP abuse, dependence, and organic mental disorder
Rhesus monkeys will self-administer PCP in a dose-dependent way,(10) suggesting that repeated abuse in humans may be associated with psychophysiological dependence. This in turn is likely to be associated with a decline in social and occupational function characteristic of other forms of addiction. Because of its widespread neuropsychological effects, any intentional, informed use of PCP should be considered maladaptive. For the habituated patient, long-term treatment is indicated. Issues that should be addressed in the process are:
emotional lability
cognitive defects
depression
possible PCP withdrawal
nutritional status
Many of the treatments applicable to patients addicted to the opiates, alcohol, and cocaine apply to this population. Several aspects of treating the PCP patient depart from the more conventional addiction treatments. A triad of confusion, decreased cognitive function, and assaultiveness mark an organic mental disorder associated with PCP use. Reduced cognition is a barrier to recovery that must be recognized and addressed in any prospective treatment plan. Neuropsychological assessment is helpful in this regard. Secondly, there is murine evidence that PCP is sequestered in fat and by melanin for at least 3 weeks following a single exposure.(11) Conditions associated with weight loss are likely to release longheld PCP into the blood and brain.
Hallucinogens
Introduction
Agents that alter perception and mood without disorientation typify hallucinogenic drugs. They have been known and used for millennia for purposes ranging from magical to medical. Anthropologists trace back the earliest use of hallucinogens to Paleolithic Europe, although 80 per cent of extant hallucinogenic plants are to be found in the New World. Galen (ad 130-200) wrote that it was customary to give dinner guests hemp seeds to promote the evening’s proceedings. The ergot-bearing fungus Claviceps purpurea infected rye in tenthcentury France and claimed 40 000 lives. Despite such calamities, ergot continued to be used by midwives in medieval Europe. In search of a benign ergot derivative for use in childbirth, Albert Hofmann synthesized lysergic acid diethylamide (LSD-25) in 1938, described in his classic monograph, LSD: my problem child.
In 1947, Stoll in Switzerland published the first experimental use of LSD in psychiatry. Intelligence agencies worldwide seized on the misnomer of LSD as an instrument of ‘mind control’. Academicians including Sandison and Elkes in England, Cohen and Eisner in the United States, Leuner in Germany, and Grof in Czechoslovakia engaged in human studies. But within a decade the drug the genie was out of the bottle, as the drug moved from the hands of scientists to clinicians, clergy, curious professors, and a widening number of students on both sides of the Atlantic. Military investigators in the United States gave the drug surreptitiously to recruits. By the late 1960s LSD and cannabis led the way to a pandemic of drug abuse among the young.
Drug preparations
Hallucinogenic drugs comprise not so much a single class of compounds, but a multiple classes affecting different neuronal receptors. Hofmann and Schultes describe 11 classes of hallucinogenic compounds which can be isolated from botanicals.(12) Hallucinogens are readily available. Botanicals are easily grown. Indole and phenethylamines can be easily synthesized, especially with the rise of the Internet. Chemically pure hallucinogens are psychoactive in microgram quantities, and are easily concealed, transported and sold, accounting for their enduring role as abusable substances.
LSD is psychoactive in a single droplet of solvent. The drug is easily dissolved in an aqueous solution. Drops of the drug are placed on sugar cubes or blotting paper stamped with coloured cartoon figures to mark the drug’s location. Sheets of the paper are then distributed, and the figures ingested. Dosages commonly range from 25 to 100 µg. A hallucinogenic trip can occur after 75 µg. Other hallucinogens, such as dimethyltryptamine, are injected. The serotonin-2A receptor has been shown to bind strongly to many hallucinogenic drugs, and these drugs appear to act as partial agonists.(13)
Common botanical hallucinogens include fungi and angiosperms (flower-bearing plants), of which approximately 100 are recognized with hallucinogenic properties. Ibogaine is derived from the root of the Tabernanthe iboga plant cultivated in Gabon and eaten as a rite of passage. Ayahuasca is a tea of dimethyltryptamine from the Amazon vine, Banisteriopsis, potentiated by beta-carbolines which inhibit monoamine oxidase. Mescaline is a predominant hallucinogen in the cactus Lophophora williamsii. Strips of cactus are cut from the plant, dried, and eaten. The Mexican mint, Salvia divinorum, contains a diterpene kappaopioid agonist. Salvia is easily bought from the Internet from scores of Websites in the United States and Europe.(14)
Hallucinogenic mushrooms contain psilocybin and psilocin, which are phosphorylated hydroxylated congeners of dimethyltryptamine. Mushrooms are ingested for their effect, or brewed first and the broth consumed. Responses vary widely between individuals and occasions. The American psychologist William James reported ingesting several dozen hallucinogenic mushrooms and only experiencing headache. Shulgin has synthesized and tested 179 phenylethylamines for hallucinogenic properties. Their effects on the human brain are complex and largely unknown.
Epidemiology
Annual surveys in United States college students indicate that LSD use fell from 1995 to 2005 from a lifetime prevalence of 11.5 to 3.7 per cent. This was offset by an increase in the lifetime use of psilocybin mushrooms, from 6.5 to 10.6 per cent. This increase in the use of non-LSD hallucinogens is reflected across secondary grades and young adults between 19 and 28 as well,(1) and follows a period of rising LSD use in Germany, the United Kingdom, and the United States in the 1990s. Factors which may explain this decrease in LSD use include student reports of less availability, greater perceptions of risk, and the substitution of psilocybin and MDMA for LSD. A cross-sectional study of 904 women from 14 to 26 found that LSD users were more often Caucasian, victims of physical abuse, and suffering depression.(15)
Acute effects
The characteristic LSD trip comprises:
autonomic arousal
marked mydriasis
sensory disturbances
emotional lability
Progressive modulations of visual imagery appear to be generated both from external objects and distortions of eidetic sources. Ordinarily benign objects may take on new emotional meanings. Geometric imagery may rise and fall before one’s eyes. A prevalent feeling one experiences is a sense of helplessness to control one’s streaming images and emotions, hence the hippie advice of ‘going with the flow’. The loss of cognitive, perceptual, and affective control for some users leads to panic, which in turn results in the so-called ‘bad trip’. As these effects decline, they may be replaced with a sense of oceanic well-being or residual paranoia.
Adverse effects
Adverse reactions to hallucinogens include panic reactions associated with a bad trip, hallucinogen persisting perception disorder, and prolonged psychoses.
(a) Panic reaction
Panic may arise during the acute drug experience. It is characterized by a crescendo of rising anxiety accompanied by autonomic arousal in the context of streaming emotions and imagery. Mydriasis is greater than that seen in non-drug-induced panic. The use of an oral benzodiazepine such as diazepam 20 mg is utterly effective in stopping the panic within minutes.
(b) Hallucinogen persisting perception disorder (HPPD)
It became apparent within the first few years of experimentation with LSD that this class of drugs was capable of inducing visual disturbances days to weeks following drug exposure. Subsequent research found that these disturbances, dubbed ‘flashbacks’ because of their evanescent visual appearance, appeared to be an intermittent form of post-drug visual disorder that in its extreme form was experienced continually. Thus, HPPD patients are capable of describing a range of visual disturbances that fluctuate in intensity, but are observable from moment to moment (Abraham, 1983). Such imagery includes:
geometric hallucinations
false perceptions of movement
afterimagery
the perception of trails behind moving images
pinpoint dots in the air (aeropsia)
Symptoms drawn by HPPD patients have been published on the Internet.(16) Patients also describe derealization and depersonalization. Symptoms are intensified by stimulation from:
emergence into a dark environment
marijuana
amphetamines
cocaine
anxiety
the stress of intercurrent illnesses
While recovery may occur over months and years following last drug use, approximately half of the patients so afflicted appear to develop a permanent alteration of the visual apparatus. Studies of psychophysics in HPPD patients reveal quantified prolongations in afterimagery.(17) Neurophysiological studies confirm cerebral disinhibition involving those regions of the cortex processing visual information.(18)
Management: Because the disorder is exacerbated by psychological and physiological conditions of arousal, benzodiazepines have been helpful for management of visual symptoms.(19) The results of these efforts are palliative at best, and complicated by the prospect of treating a drug abuser with an abusable substance. Recent case reports of treatment with sertraline, naltrexone, and clonidine are encouraging.
In addition to pharmacotherapy, HPPD patients often require supportive psychotherapy to deal with the issues of learning to cope with what may be a permanent alteration in perception. Therapy is also indicated to educate the patient, and prevent the development of common comorbid disorders in HPPD. These are:
major depression
panic disorder
alcohol dependence from self-medication
(c) Psychosis
Evidence supporting the hypothesis that the use of potent hallucinogens can trigger prolonged psychotic episodes is found in multiple longitudinal, cross-sectional, and case studies (Abraham et al. 1996). Psychiatric patienthood appears to be a risk factor for the development of psychosis following LSD. The clinical picture of post-LSD psychosis resembles schizoaffective disorder more than it does schizophrenia, with the commonly added feature of chronic visual disturbances. Clinically such patients resemble those with good-prognosis schizophrenia, since they possess more affect than those with poor prognosis, have less thought disorder, are more socially related, and appear to have fewer signs of negative schizophrenia. Mystical preoccupations reminiscent of acute drug experiences can predominate. Visual hallucinations often are of the variety that are seen in HPPD, although in contradistinction to such patients, psychotic patients may describe delusions and auditory hallucinations as well.(20)
Management: Atypical pharmacotherapies appear to have an important role in treatment, and in selected cases are preferable to dopamine-blocking neuroleptics. Reports in the literature describe cases responding to electroconvulsive therapy, lithium, anticonvulsants, and the serotonin precursor, l-5-hydroxytryptophan. Long-term supportive psychotherapy is almost always indicated to help the patient and his family make painful adjustments to the patient’s chronic disappointments in relationships and employment, frequently made all the more poignant by the illness’ propensity to preserve the patient’s insight as it progresses. This last factor may partially explain the apparently high risk for suicide.
Human experimentation with hallucinogens
The discovery of the effects of LSD in 1943 led to a flurry of experimental activity with the drug in humans, at its worst with dubious methodology and indifferent to the protection of human subjects. But the ability of this unique class of drugs to alter perception, cognition, and affect has prompted a new wave of research with selected hallucinogens with regulatory oversight. Studies have examined the safety of peyote in religious use(21); the psychological effects of psilocybin, dimethyltryptamine, and ketamine(22); their use as a tool in modelling the pathophysiology of psychosis,(23) and possible therapeutic uses.
Hallucinogens have been used as experimental psychoses. Vollenweider et al. have found increased metabolic activity in the frontal cortex of subjects on the dissociative anaesthetic ketamine,(24) and in subjects during an experimental psychosis from psilocybin, increased serotonin-2 agonist activity.(25) Finally, the study of treatment with hallucinogens for psychiatric disorders has cautiously reemerged. In a randomized trial of ketamine for depression, Zarate et al. found that the drug had benefits for a week following a single dose.(26)
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