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HEROIN ADDICTION &
Pacini Editore & AU CNS Heroin Addict Relat Clin Probl 2011; 13(2): 5-40 Basics on Addiction: a training package for medical practitioners or
psychiatrists who treat opioid dependence
Icro Maremmani 1, Matteo Pacini 2, Pier Paolo Pani 3, on behalf of the 'Basics on Addiction Group'
1 Vincent P. Dole Dual Diagnosis Unit, Santa Chiara University Hospital, Department of Psychiatry, NPB, University of Pisa, Italy 2 G. de Lisio Institute of Behavioural Sciences, Pisa, Italy 3 Social-Health Division, Health District 8 (ASL 8) Cagliari, Italy Opioid dependence is a chronic, relapsing brain disease that causes major medical, social and economic problems to both the individual and society. This seminar is intended to be a useful training resource to aid healthcare professionals – in particular, physicians who prescribe opioid pharmacotherapies – in assessing and treating opioid-dependent indi- viduals. Herein we describe the neurobiological basis of the condition; recommended approaches to patient assessment and monitoring; and the main principles and strategies underlying medically assisted approaches to treatment, including the pharmacology and clinical application of methadone, buprenorphine and buprenorphine–naloxone.
Key Words: Tolerance; physical dependence; addiction; clinical assessment; maintenance pharmacotherapies; methadone; buprenorphine; suboxone.
broader impact on other budgets (e.g., social wel- fare and criminal-justice services). In addition, Opioid dependence is a chronic, relapsing opioid dependence affects productivity, due to brain disease that causes major medical, social unemployment, absenteeism and premature mor- and economic problems to both the individual tality [111]. In West and Central Europe, there are and to society. Opioid-dependent individuals are estimated to be between 1 and 1.4 million opiate subject to substantial health risks including over- users, corresponding to a prevalence of between dose, transmission of infectious diseases, poor 0.4% and 0.5% of the population. physical and mental health and frequent hospi- Given the magnitude of these problems, it talization [44]. For society as a whole, opioid de- has become crucial to ensure medical practition- pendence incurs a significant economic burden, ers responsible for treating opioid dependence both in terms of direct healthcare costs (i.e., treat- have access to evidence-based training pack- ment and prevention services), and in terms of the ages. This supplement is intended to be a useful Correspondence: Icro Maremmani, MD; Vincent P. Dole Dual Diagnosis Unit, Santa Chiara University Hospital, Department of Psychiatry, University of Pisa, Via Roma, 67 56100 PISA, Italy, EU.
Phone +39 0584 790073 Fax +39 0584 72081 E-Mail: [email protected] Heroin Addiction and Related Clinical Problems 13 (2): 5-40 how each of these treatment options can be used Table 1. Actions of morphine [78]
to treat opioid dependence and the main efficacy Central nervous system depression and safety considerations that are relevant to the Respiratory depression (death) choice of treatment strategy.
2. Neurobiology of opioid dependence
Cough suppression Pupillary constriction Nausea and vomiting 2.1. Opioids and their mechanism of action
Increased respiratory tract secretions 2.1.1. What is an opioid?
training resource to aid healthcare professionals Opium has been used for social and medici- – in particular, physicians who prescribe opioid nal purposes for thousands of years to produce pharmacotherapies – in assessing and treating euphoria, analgesia and sleep and to prevent di- opioid-dependent individuals. It is based upon arrhoea [85]. Several pharmacologically active the ‘Basics on Addiction' training package de- compounds are derived from the opium poppy veloped as a collaborative initiative by leading Papaver somniferum, including morphine, co- treatment experts in Italy and led by Professor deine, papaverine, thebaine and noscapine [24]. Icro Maremmani (President of EUROPAD) and Opioids is the term given to natural or synthetic Professor Pier Paolo Pani (President of the Italian drugs that have certain pharmacological actions Society of Addiction Medicine) on behalf of the similar to those of morphine [84] by the interac- Basics on Addiction (BoA) Group.
tion with some or all opioid receptors. In order to optimally treat opioid-dependent individuals it is first necessary to understand the 2.1.2. Acute opioid effects
neurobiological basis of the condition as a chron- ic, relapsing disorder. The first article in this sup- Morphine, the archetypal opioid, is a power- plement, ‘Neurobiology of opioid dependence', ful analgesic and narcotic, and remains one of the gives an overview of the effects of opioids on the most valuable analgesics for relief of severe pain body at the cellular level and the physiological ef- [24]. It also induces a powerful sense of content- fects of opioids and neurobiological adaptations ment and well-being, which is an important part to opioids (including tolerance, physical depend- of its analgesic activity, as it reduces the anxiety ence, withdrawal, craving and relapse). Effective and agitation associated with a painful illness or treatment of opioid dependence requires thor- injury. Other opioid effects on the central nervous ough, ongoing assessment of patients to ensure system include respiratory depression, depres- therapeutic strategies are suited to their individu- sion of the cough reflex, nausea and vomiting and al needs and circumstances. The second article in pupillary constriction [85]. Morphine also acts this supplement describes approaches to clinical on the gut wall, reducing intestinal secretion and assessment and monitoring that should be con- motility and lengthening gut transit time [21]. ducted in drug-dependent individuals to inform The actions of morphine are shown in Table 1.
choices regarding appropriate treatment. The fi- Following elucidation of the chemical struc- nal article discusses the main principles, goals ture of morphine at the beginning of the 20th and strategies underlying medically assisted ap- century [95], many semi-synthetic and totally proaches to opioid-dependence treatment, the synthetic opioids have been produced (including unique pharmacological profiles of methadone, methadone, buprenorphine and pethidine) with buprenorphine and buprenorphine-naloxone, the aim of harnessing the clinically useful proper- I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence Table 2: Effects associated with the main types of opioid receptors [85]
mu (μ, MOP or OP3) delta (δ DOP or OP2) kappa (κ, KOP or OP1) Respiratory depression Pupil constriction Reduced GI motility Physical dependence +: denotes activity; −: denotes weak or no activity ties of the opioids without the less desirable side the brainstem, the medial thalamus, the spinal effects (i.e. habit-forming propensity or nausea cord, the hypothalamus and the limbic system. and vomiting) [24].
They have also been identified on peripheral sensory nerve fibres and their terminals and on 2.1.3. Opioid receptors
immune cells [36]. Each receptor type is associ- ated with specific functional effects, as shown Pharmacologic studies performed in the 1970s in Table 2. The best-studied receptor type is the had suggested the existence of three types of clas- mu receptor (also known as the μ, MOP or OP3 sic opioid receptor, termed mu, delta and kappa receptor), which is found in both spinal and su- [68], and this was subsequently confirmed by praspinal structures as well as in the periphery. receptor-cloning studies. Opioid receptors be- It plays an important role in nociception, as well long to the large family of receptors possessing as respiration, cardiovascular function, intestinal seven transmembrane domains of amino acids transit, feeding, learning and memory, locomotor and are coupled to guanine nucleotide-binding activity, thermoregulation, hormone secretion, proteins known as G-proteins [17]. They reduce and immune functions [25]. Kappa receptors the intracellular cyclic adenosine monophosphate (also known as κ, KOP or OP2 receptors) have (cAMP) content by inhibiting adenylate cyclase been implicated in the regulation of nociception, and also exert effects on ion channels through diuresis, feeding and neuroendocrine secretion. a direct G-protein coupling to the channel [85]. In addition, as kappa receptor agonists can pro- The main effects of opioids at the membrane duce dysphoria in humans [25], they appear to level are thus the promotion of the opening of play a role in regulation of mood. The olfactory potassium channels and inhibition of the opening bulb, neocortex, caudate putamen and nucleus of voltage-gated calcium channels [85]. These accumbens contain the highest densities of delta membrane effects reduce neuronal excitability (δ, DOP or OP1) receptors, with lower densities as the increased potassium conductance causes in the thalamus, hypothalamus and brainstem hyperpolarisation of the membrane and reduces [25]. A fourth opioid receptor has been discov- transmitter release due to inhibition of calcium ered more recently, the NOP receptor (formerly entry [85]. The overall effect is inhibitory at the referred to as opiate receptor-like 1 [ORL1], cellular level [85]. However, opioids do increase LC132 or OP4). Pharmacologically this is not a activity in some neuronal pathways by suppress- classical opioid receptor, as non-selective opioid ing the firing of inhibitory interneurones [85].
antagonists (e.g., naloxone) display negligible af- High densities of opioid receptors are present finity; the International Union of Basic and Clini- in five areas of the central nervous system (CNS): cal Pharmacology (IUPHAR) database of recep- Heroin Addiction and Related Clinical Problems 13 (2): 5-40 Table 3: Selectivity of opioid drugs and peptides for the three main opioid receptors [85]
mu (μ, MOP or OP3) delta (δ, DOP or OP2) kappa (κ, KOP or OP1) Endogenous peptides Morphine, codeine, Etorphine, bremazocine Fentanyl, sufentanil Partial/mixed agonists +: agonist activity; (): partial agonist activity; x: antagonist activity; −: weak or no activity tors proposes that the NOP receptor is considered way [13]. The classification of opioid drugs and as a non-opioid branch of the opioid receptor endogenous peptides in terms of their agonist, family [27].
partial agonist or antagonist activity and their selectivity for the three main opioid receptors is 2.1.4. Agonists and antagonists
shown in Table 3. The overall effect of an opioid depends on 2.1.5. Endogenous opioids
its activity at each of the opioid receptors; some opioids act as agonists on one type of receptor The search for endogenous compounds that and antagonists or partial agonists at another. Ag- mimicked the actions of morphine in the 1970s onist potency depends on two parameters: i) the led to the discovery of the endogenous opioids affinity of the agonist for the receptor, that is, its [43]. Four classes of endogenous opioids have tendency to bind to the receptor; and ii) the effi- now been identified: endorphins, enkephalins, cacy (commonly indicated as intrinsic activity) of dynorphins and endomorphins [56]. Endogenous the agonist, that is, its ability to initiate changes opioids function as neuromodulators to influ- which lead to effects once bound. Full agonists ence the actions of other neurotransmitters such (which can produce maximal effects) have high as dopamine or glutamate [94]. The endogenous efficacy whereas partial agonists (which can pro- opioid system has been found to be important in duce only submaximal effects) have intermedi- the modulation of pain, mood, blood-pressure ate efficacy [87]. The relationship of a drug with regulation and other cardiovascular functions, its receptor is often likened to that of the fit of a control of respiration, appetite, thirst and sexual key into its lock – the drug represents the key and activity [94]. There are high concentrations of re- the receptor represents the lock (Figure 1). Hor- ceptors for endorphins and enkephalins in many mones, neurotransmitters, drugs or intracellular areas of the CNS, particularly in the periaqueduc- messengers may all interact with receptors in this tal grey matter of the midbrain, in the limbic sys-

I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence Table 4: Clinical features of opioid intoxication and
Drowsiness, stupor or coma Symmetric, pinpoint, reactive pupils Decreased peristalsis Skin cool and moist Hypoventilation (respiratory slowing, irregular breathing, apnea) Reversal with naloxone Figure 1: Action of opioid agonists, antagonists
Anxiety, restlessness and partial agonists. A: Opioid agonist; B: Opioid
partial agonists; C: Opioid antagonists
Chills, hot flushes tem and at interneurones in the dorsal horn areas. Myalgias, arthralgias These areas are involved in pain transmission or perception and the endogenous opioids are Abdominal cramping Vomiting, diarrhoea thought to be the body's natural pain-relieving chemicals, which act by enhancing inhibitory ef- fects at opioid receptors. Opioid drugs elicit their Tachycardia, hypertension (mild) effects by mimicking the actions of the endog- Hyperthermia (mild), diaphoresis, lacrimation, enous opioids on opioid receptors [13].
Spontaneous ejaculation 2.2. Chronic opioid use: tolerance, physical de-
pendence and addiction
for effects such as constipation and miosis [85].
When the drug is stopped or when its effect 2.2.1. Effects of chronic opioid exposure
is counteracted by a specific antagonist [80], un- pleasant physical effects occur, which indicates Although possessing valuable properties (e.g., the occurrence of the withdrawal (abstinence) analgesia), repeated and chronic exposure to syndrome. Withdrawal symptoms generally rep- opioids can lead to development of tolerance and resent physiologic actions opposite to the acute physical dependence. The rate of development of actions of opioid drugs. For example, pupillary tolerance varies from one opioid to another.
constriction and constipation occur with opiate Tolerance describes the need to progressive- use, whereas pupillary dilatation and diarrhoea ly increase the drug dose to produce the effect occur in the withdrawal state [54]. The most originally achieved with smaller doses, following common symptoms of opioid intoxication and repeated exposure to opioid agonists. It may de- withdrawal are shown in Table 4. Individuals velop at different rates for the different effects of who abruptly stop taking morphine are extremely opioids and can occur over days, weeks or years restless and distressed and have a strong crav- [90]. Tolerance develops to the analgesic and ing for the drug. Although not life-threatening, euphoric effects of opioids, and to some of the opioid withdrawal is associated with severe psy- adverse effects such as respiratory depression, chological and moderate physical distress [54]. nausea and sedation, but does not fully develop The onset of withdrawal symptoms typically Heroin Addiction and Related Clinical Problems 13 (2): 5-40 Figure 2: Experience of the opioid-dependent individual depending on opioid
concentrations in the body. Reproduced with permission from Newman et al.,
1995 [78]
occurs 8–16 hours after cessation of the use of diction, and it is also referred to as ‘psychological heroin or morphine, with autonomic symptoms dependence' [86].
appearing first. By 36 hours, severe restlessness, piloerection, lacrimation, abdominal cramps and 2.2.2. Criteria for opioid dependence/addiction
diarrhoea become apparent. Symptoms reach their peak intensity at 48–72 hours and resolve The key criteria indicating that an individual over 7–10 days [54]. However, negative mood is addicted is when they no longer have control states and craving may persist for up to 2 years over their drug use and demonstrate a persistent after abstinence [37, 69]. Symptoms experienced change in reward-seeking behaviour, with an irre- by the opioid-dependent patient depend on the sistible desire to repeat the drug experience or to concentration of opioids in their body and their avoid the discontent of not having it. Such an in- own individual levels of tolerance: the patient stinctive drive is contrary to the person's declared will experience euphoria when the concentration intentions and underlies relapsing behaviour (re- of opioids in the body exceeds the tolerance level cidivism). It is the key aspect of addiction, and and will experience withdrawal symptoms when is also referred to as ‘psychological dependence' the concentration of opioids in the body is below [86]. A joint statement by the World Health Or- the dependence level. When the opioid concen- ganization (WHO), the United Nations Office on tration is in between these two levels the opioid- Drugs and Crime (UNDOC) and the Joint United dependent patient will look and feel normal (Fig- Nations Programme on HIV/AIDS (UNAIDS) ure 2) [78]. Evidence of tolerance/withdrawal is defines the key elements of opioid dependence as termed ‘physical dependence', although it is not a follows: a strong desire or sense of compulsion constant or exclusive feature of addiction. Addic- to take opioids; difficulties in controlling opioid- tion manifests with a persistent change in reward- taking behaviour; a withdrawal state when opioid seeking behaviour, with an irresistible desire to use has ceased or been reduced; evidence of tol- repeat the drug experience or to avoid the discon- erance, such that increased doses are required to tent of not having it. Such an instinctual drive is achieve effects originally produced by lower dos- contrary to the person's declared intentions and es; progressive neglect of alternative pleasures or underlies recidivism. It is the key aspect of ad- interests; and persistence with opioid use despite

I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence clear evidence of overtly harmful consequences bile organisms [35]. Drugs of abuse mediate their acute reinforcing effects by enhancing dopamine activity in this neural network, which consists 2.2.3. Neurobiology of opioid- and drug-addiction
of dopamine projections from cell bodies in the ventral tegmental area to limbic structures and Advances in knowledge of the neurobiological cortical areas of the brain [35]. It has been pro- processes that occur following acute and chronic posed that a network of four circuits within the opioid administration have helped to improve sci- mesolimbic system are involved in drug abuse entific understanding of how drug addiction de- and addiction: the nucleus accumbens and the velops, including the role of the specific neuronal ventral pallidum, which are associated with re- circuits in mediating the reinforcing effects of ward; the orbitofrontal cortex and the subcallosal opioids and the development of uncontrolled use cortex, which are associated with motivation/ drive; the amygdala and the hippocampus, which are associated with memory and learning; and the 2.2.3.1. The reward pathway
prefrontal cortex and the anterior cingulate gyrus, which are associated with control [101]. These Increased dopamine activity in the mesocorti- four circuits receive direct innervations from colimbic system (Figure 3) is intimately involved dopamine neurones but are also connected with in eliciting and reinforcing responses to natural one another through direct or indirect projections stimuli (e.g., food, drink and sex), which is impor- (mostly glutamatergic), confirming observations tant to drive behaviour necessary for survival and from preclinical studies indicating that modifica- reproduction [55]. From an evolutionary point of tions in glutamatergic projections mediate many view, the capacity to seek rewards as goals is es- of the adaptations observed with addiction [101]. sential for the survival and reproduction of mo- As may be expected from such a complex system, Figure 3: The mesolimbic reward system. Reproduced with permission from Kosten and George, 2002 [57]
Heroin Addiction and Related Clinical Problems 13 (2): 5-40 other brain regions are thought to be involved in [100]. For excellent reviews of the neurobiology these circuits (e.g., the thalamus and insula), one underpinning addiction, see Felkenstein, 2008 region may participate in more than one circuit and Volkow, 2003 [35, 101].
(e.g., the cingulate gyrus plays a role in both con- trol and motivation/drive circuits) and other brain 2.2.4. Relapse
regions (e.g., the cerebellum) and circuits (e.g., attention and emotion circuits) are likely to be A defining feature of drug dependence is the affected in drug addiction [101]. In the case of incidence of relapse to drug-seeking and drug- addiction to opioids it is predominantly the inter- taking behaviours following months or years of action of opioids with mu receptors in the meso- abstinence [116]. It has been estimated that be- corticolimbic system that appears to mediate the tween 40 and 60% of drug-addicted patients will behavioural and reinforcing properties [35]. relapse within a year [72] even though they may have achieved abstinence temporarily alone or 2.2.3.2. Uncontrolled use and craving
through detoxification or environmental interven- tions. Such a pattern is common to most chronic Tolerance may develop with repeated opioid relapsing disorders, such as diabetes or hyperten- use to the extent that the user no longer experi- sion. The relapsing course illustrates the chronic ences the euphoric effects once achieved with the nature of opioid addiction and the need for long- drug, despite ingesting higher and higher doses of term approaches to treatment. An important focus opioids [31]. Chronic opioid users will typically of addiction research has been to identify the be- continue to exhibit a strong drive to engage in havioural, environmental and neural mechanisms further drug-seeking and -using behaviours de- underlying drug relapse. Three types of trigger spite developing tolerance to the euphoric effects have been identified to cause craving and relapse of opioids. It has been postulated that repeated following extended periods of abstinence: a small exposure to drugs of abuse disrupts the function ‘priming' dose of the drug; cues previously asso- of the striato-thalamo-orbitofrontal circuit. This ciated with drug use (e.g., people, places, things, dysfunction leads to a conditioned response when moods); and stress (e.g., stressful life events as the addicted subject is exposed to the drug and/or well as anger, anxiety and depression) [114]. As drug-related stimuli that activates the circuit and opioid-using individuals invariably relapse fol- results in the intense drive to get the drug (con- lowing opioid withdrawal, detoxification alone sciously perceived as craving) and uncontrolled does not constitute an adequate intervention for self-administration of the drug (consciously per- substance dependence; maintenance treatment is ceived as loss of control). This model of addic- a more effective option for opioid-addicted in- tion postulates that the drug-induced perception dividuals to resume a normal life and achieve a of pleasure is particularly important for the initial favourable outcome [78]. Detoxification is, how- stage of drug self-administration but that with ever, a first step for many forms of shorter- or chronic administration, pleasure alone cannot longer-term abstinence-based approaches, i.e., account for the compulsive drug intake. Rather, those in which no opioid agonist pharmacother- dysfunction of the striato-thalamo-orbitofrontal apy is used. Both detoxification with subse- circuit, which is known to be involved in pers- quent abstinence-oriented treatment and agonist erverative behaviours, accounts for the compul- maintenance treatment are considered essential sive intake [100]. During withdrawal and without components of an effective treatment system for drug stimulation, the striato-thalamo-orbitofron- people with opioid dependence [113]. Overcom- tal circuit becomes hypofunctional, resulting in ing opioid dependence is not easy: at the cellular a decreased drive for goal-motivated behaviours level, the pathological changes that occur as a re- I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence sult of drug use can persist even after drug use lapse and results from enduring cellular changes. has ceased [45, 51] and the likelihood of relapse Changes in protein content and/or function often actually increases during a period of abstinence become greater with increasing periods of with- (a process called ‘incubation') as a result of the drawal, which is consistent with the possibility neuroadaptations that occur in drug dependence that the more temporary changes in protein ex- [40, 93]. Pharmacotherapies should ideally be ac- pression that mediate the transition to addiction companied with motivation, social support, and may induce changes in protein expression that positive coping strategies to fully achieve reha- convert vulnerability to relapse from a temporary bilitative goals [61].
and reversible phase into permanent features of addiction [52].
2.2.5. Stages of addiction
2.2.6. Risk factors for opioid dependence
The development of addiction may be consid- ered to consist of three stages: (1) acute (immedi- Dependence is not an inevitable consequence ate) drug effects; (2) transition from recreational of opioid use, as demonstrated by their wide- use to patterns of use consistent with addiction; spread use as a treatment for chronic pain [79]. It and (3) end-stage addiction, which is character- has been proposed that addictive disease does not ised by an overwhelming desire to obtain the drug, begin with the onset of substance use, but that an a diminished ability to control drug seeking and individual's complex history of risk and protec- reduced pleasure from biological rewards [52]. tive factors increase or decrease the likelihood of These stages are associated with neurobiological their developing an addictive disorder when they adaptations, including a switch from dopamine- use a substance for the first time [12]. A large to glutamate-based behaviour as different parts number of risk and protective factors have been of the neural circuitry play the key role [52]. identified, the most important of which is genet- The first stage of addiction, acute drug effects, is ics, with some research suggesting that between caused by supraphysiological levels of dopamine 40% and 60% of the vulnerability to addictive being released throughout the motive circuit disease is accounted for by genetic factors [60]. which induces changes in cell signalling. These However, exposure to certain substances can be changes lead to short-term neuroplastic changes, sufficient to induce dependence in the absence persisting for a few hours or days after drug in- of risk factors. Associations have been found take, which initiate cellular events involved in the between substance abuse and polymorphisms in process of addiction. The second stage of addic- genes encoding opioid (OPRM1 and OPRK1), tion, the transition from recreational drug use to serotonin (5-hydroxytryptamine-1B [HTR1B] addiction, is associated with changes in neuronal and melanocortin (MC2R) receptors, endogenous function that accumulate with repeated drug use opioids (prodynorphin [PDYN]) and neurotrans- and diminish with drug discontinuation over days mitter enzymes (catechol-O-methyltransferase or weeks. There are also alterations in the con- [COMT] and tryptophan hydroxylase [TPH]) tent and function of various proteins that are in- [115]. Other factors known to play a role in the volved in dopamine transmission (e.g., tyrosine development of addictive disorders include an hydroxylase, dopamine transporters, RGS9-2 and individual's temperament, psychopathology, at- D2 autoreceptors) that persist for a few days af- titudes and perceptions. Society, including fam- ter drug discontinuation. However, these changes ily, peer group, school and community, also have appear to be compensatory and may not directly important implications for the development of mediate the transition to addiction. End-stage addictive disease [12]. Prevention strategies have addiction is characterised by vulnerability to re- been demonstrated to play an important part in Heroin Addiction and Related Clinical Problems 13 (2): 5-40 reducing the risk of opioid dependence among dependence in the same way, treatment success vulnerable groups [76].
may be defined as a decrease in drug use with only occasional relapses or abstinence from drug 2.2.7. Opioid dependence as a chronic, relapsing brain use with only occasional relapses rather than total
abstinence. Total abstinence develops gradually, is rarely achieved soon after initiating treatment, Individuals who are drug dependent have and depends on ongoing treatment rather than historically been considered to be ‘bad', ‘weak' being self-maintaining in the absence of chronic people who are unable to control their behav- treatment.
iour and do not deserve treatment. Among the Optimal management of opioid dependence scientific community, however, advances in our requires a multi-faceted approach in order to ad- understanding of the neurobiology of addiction, dress the neurobiological, social, behavioural and the pharmacology of opioids and their receptors, psychological aspects of the condition [62]. The and the discovery that some individuals may be pharmacotherapy of opioid dependence will be particularly susceptible to drug dependence have discussed in more detail in Part 3 of this supple- led to greater appreciation of the condition being ment.
a chronic, relapsing brain illness. In addition, the substantial changes in brain structure and func- 2.3. Conclusion
tion observed in drug dependence that persist after individuals have stopped drug use provide An understanding of the mechanisms respon- further evidence that the condition should be con- sible for opioid addiction is critical for optimal sidered a medical condition rather than a moral treatment of this chronic brain condition. Im- weakness. Viewing drug dependence as a chronic provements in our understanding of the cellular illness akin to diabetes or chronic hypertension processes responsible for opioid dependence, changes the way in which treatment success is addiction and relapse have helped to inform the recognised. In the case of diabetes, for example, now widespread view that opioid dependence complete cure is not currently a feasible outcome is a chronic disease requiring medical treatment and a decrease in blood glucose would therefore rather than a purely moral or social problem that be indicative of treatment success. Considering can be ‘cured' by criminal-justice solutions. Ulti- Key learning points
Opioids are drugs that share some of the pharmacological effects of opium Opioid receptors are widely distributed in the nervous system Mu-receptor activation produces direct opioid effects, including euphoria Opioids promote the release of dopamine in the reward pathway (ventral tegmental area, nu- cleus accumbens, prefrontal cortex) Opioids are classified as agonists (complete, partial) or antagonists according to their intrinsic activity at different receptors Neuroadaptations that occur in response to chronic opioid lead to: Tolerance: reduced effect of drug for a given dose Withdrawal: emergence of withdrawal syndrome upon abstinence or reduced drug levels Cravings and vulnerability to relapse Opioid dependence is a chronic, relapsing brain disorder Relapse is a symptom of the disorder and not a sign of abstinence failure I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence mately, increased understanding of the neurobiol- heterogeneity of the opioid-dependent popula- ogy of addiction should help to optimise the way tion makes treatment standardisation implausi- we manage drug-dependent individuals with the ble [108]. A comprehensive, long-term treatment treatment options we currently have at our dis- plan should be developed based on a multi-facto- posal and also inform the development of new rial assessment and the best available clinical evi- dence. All decisions should be made in concert with principles of medical ethics and considera- 3. Clinical assessment of opioid
tion of patient preferences [111].
3.1. Key components of patient assessment in
Effective management of opioid dependence includes a comprehensive patient assessment. The goals of the assessment are to confirm a A detailed patient assessment should consider diagnosis of opioid dependence, determine the specific physical, psychological and social fac- appropriate course of therapy and identify any tors, in addition to past and current drug use, in co-existing physical or psychosocial conditions order to assess the patient's condition and treat- that may affect treatment outcomes [108, 111]. ment options (Table 5). Psychological assess- As the number of options to treat opioid addic- ment of patients is critical as psychosocial fac- tion increases across a range of clinical settings, tors, including co-existing psychiatric disorders it becomes possible and desirable to tailor ther- and cognitive impairment, patient readiness and apy to individual needs [111]. Furthermore, the motivation for treatment, contribute to non-com- Table 5: Key features of patient assessment [108, 111]
Demographics and family history Psychiatric history Past and current drug use Past treatment experience Clinical examination Assessment of intoxication/withdrawal Presence of opportunistic infection(s) Presence of co-morbidities Lab investigation(s) Urine and plasma drug screen, LFTs, HIV, hepatitis B Co-existing conditions Infectious diseases HIV, hepatitis C and B, sexually-transmitted diseases, Other substance abuse Alcohol, benzodiazepines, stimulants, barbiturates, cocaine, marijuana, hallucinogens Psychiatric disturbance Depression, anxiety, personality disorders, cognitive Living conditions Extent of integration into drug community, Legal/criminal issues Past/present involvement with legal system and Occupational situation Current and past employment Social/cultural factors Language barriers, education level, religion Support for treatment and avoidance Patient motivation Short-term and long-term goals, and reason for seeking treatment LFT: liver function tests; TB: tuberculosis; CBC: complete blood count; HIV: human immunodeficiency virus Heroin Addiction and Related Clinical Problems 13 (2): 5-40 pliance and treatment failure [108].
it does not distinguish addictive use from thera- peutic dependence on prescribed drugs. We use 3.2. Diagnosis of opioid dependence
the term dependence here to mean addiction (i.e., a persistent change in reward-seeking behaviour, As of 1964, the World Health Organization with an irresistible desire to repeat the drug ex- has recommended the term ‘substance addiction' perience or avoid the discontent of not having it, be replaced by the term ‘substance dependence' which is contrary to the person's declared inten- [111] (www.who.int). The term ‘substance de- tions). Differentiating between opioid use, abuse pendence' is somewhat ambiguous, however, as and dependence is critical to establishing the Table 6: Definitions of substance abuse and dependence [2,109]
Substance abuse (DSM-IV-TR)(2)/Harmful use (ICD-10) (109)
A maladaptive pattern of substance use leading to clinically A pattern of psychoactive substance use that is causing significant impairment or distress, as manifested by one (or damage to physical or mental health; adverse social more) of the following, occurring at any time in the same consequences are also common, but not sufficient to 12-month period: establish a diagnosis of harmful use Recurrent substance use resulting in a failure to fulfil major role obligations at work, school, or home Recurrent substance use in situations in which it is physically hazardous Recurrent substance-related legal problems Continued substance use despite persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance In addition, the individual must never have met the criteria for substance dependence for the substance in question A maladaptive pattern of substance use leading to clinically A cluster of physiological, behavioural, and cognitive significant impairment or distress. Three (or more) of the phenomena in which the use of a substance or a class of following, occurring at any time in the same 12-month substances takes on a much higher priority for a given individual than other behaviours that once had greater value. Three or more of the following have been present together at some time during the previous year: Taking the substance in larger amounts or over a longer Strong desire or compulsion to take the substance period than was intended Difficulty controlling substance use (onset, termination, Persistent desire or unsuccessful efforts to cut down or or levels of use) control substance use A physiological withdrawal state when substance use is Spending a great deal of time in activities necessary to stopped or reduced obtain, use, or recover from the substance Evidence of tolerance (increased doses are required in Giving up or reducing important social, occupational, or order to achieve the effects originally produced by lower recreational activities because of substance use Continued use despite knowledge of having a persistent or Progressive neglect of alternative pleasures or interests recurrent physical or psychological problem likely to have because of time spent to obtain, use, or recover from the been caused or exacerbated by the substance Persisting with substance use despite clear evidence of overtly harmful consequences DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision; ICD, International Classification of Diseases I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence most effective course of treatment, if any. A diag- often a temporary stage of opioid usage; depend- nosis of any opioid disorder is made using criteria ence develops rapidly as a result of the powerful similar to other substance abuse disorders [108]. reinforcing qualities of the opioid and the emer- The Diagnostic and Statistical Manual of Mental gence of tolerance [28, 108].
Disorders, Fourth Edition, Text Revision (DSM- Notably, the DSM-IV-TR requires criteria for IV-TR) [2] describes two distinct categories for dependence to be fulfilled within a 12-month pe- substance-use disorders: abuse and dependence riod, although possibly on different occasions. In other words, a diagnosis can be based on a The most important feature that differentiates relatively recent period of physical dependence substance abuse from dependence is a loss of (e.g., in the past month) evidenced by signs of control (e.g., persistent or strong desire to take withdrawal and tolerance, as long as features of the substance, unsuccessful efforts to cut down previous escalating substance use or abuse have or control substance use, continued usage despite occurred in the same 12-month period. In addi- knowledge of harmful consequence and neglect tion, even if the pattern of use is not currently of other activities). It should be noted that toler- problematic, the recurrence of problems within ance and withdrawal are included in the potential the same 12-month period is (from a diagnostic criteria for substance dependence in both DSM- perspective) considered equivalent to a constant IV-TR and ICD definitions but neither tolerance problematic pattern of use. Conceptually, a diag- nor withdrawal are required to establish the diag- nosis of substance dependence can also be made nosis of abuse or dependence [2, 109]. Converse- for a past period, although the patient may be un- ly, the sole presence of tolerance and withdrawal dergoing a remission phase. Therefore, a progno- in the absence of other criteria, may indicate sis of long-lasting remission in the presence of a what might be termed a ‘normal', medical sta- retrospective diagnosis of drug addiction is unre- tus corresponding to habitual, controlled use of alistic.
a tolerance-inducing substance (e.g., nicotine or alcohol) or therapeutic dependence on a toler- 3.3. Assessing opioid intoxication and withdrawal
ance-inducing prescribed drug (e.g., methadone or buprenorphine). The DSM-IV-TR requires The documentation of the signs of opioid in- the clinician to specify whether the substance toxication or withdrawal is part of establishing a dependence is with or without physiological de- diagnosis of opioid dependence (Table 7). The de- pendence (manifested by evidence of tolerance or gree of opioid intoxication or withdrawal should withdrawal) [2]. be evaluated with the reported time of last use. A diagnosis of abuse is subordinate to that of Clinical assessment is complicated by the dependence: in other words, all dependent pa- fact that opioid users commonly abuse several tients are also abusers, whereas abusers can be substances including alcohol, benzodiazepines, assessed as such after ruling out a diagnosis of stimulants, marijuana, cocaine and nicotine, dependence. Furthermore, patients who do not which may result in additional symptoms such meet the criteria for abuse may fall into a cate- as tremors, delirium or seizures [1]. Care must gory of non-pathologic use, comprising irregular be taken to make a differential diagnosis against or habitual use, with possible features of toler- other conditions that may share similar symp- ance and dependence. Typically, dependence is toms [108], such as panic attack, gastroenteritis, the culmination of a pattern of abuse which starts peptic ulcer and pancreatitis. with occasional, social or recreational drug use or Injection sites are valuable indicators when as part of a legitimate medical regimen, such as determining the chronology of drug use [111]. with the treatment of pain [1]. Abuse is, however, The most common sites for injection include Heroin Addiction and Related Clinical Problems 13 (2): 5-40 Table 7: Signs of opioid intoxication and withdrawal [108, 111]
Signs of opioid intoxication Signs of opioid withdrawal Drooping eyelids Constricted pupils Muscle aches and abdominal cramps Reduced respiratory rate Itching and scratching Difficulty sleeping Dry mouth and nose Vomiting and diarrhoea Agitation and restlessness Elevated respiratory rate, blood pressure and pulse the cubital fossa (area on the inside of the elbow some form of immunoassay, are generally recom- joint) and the groin although superficial veins in mended before making treatment decisions. Gas– the extremities and neck are also used [28, 111]. liquid chromatography (GLC) and gas chroma- Recent injection marks are usually small and red tography–mass spectrometry (GC–MS) are very and are sometimes inflamed or surrounded by sensitive and specific tests, but are labour inten- slight bruising. Older injection sites are usually sive and expensive and are thus often reserved not inflamed, but may show pigmentation chang- for confirmation of other forms of testing, such as es (either lighter or darker) and the skin may have urinalysis [98, 108].
atrophied. A combination of recent and old injec- Urinalysis is an inexpensive, although not tion sites would normally be seen in an opioid- sensitive, form of screening for opioids and other dependent patient with current neuroadaptation. substances of abuse. Interpretation of urinalysis The visible injection sites should be consistent results requires knowledge of the specific test or with the reported history [111].
reagents used as well as the pharmacokinetics of the substance or substances being tested [98, 3.4. Assessment of co-existing conditions
111]. Heroin is metabolised to 6-monoacetylmor- phine (6-MAM), then to morphine and eventually Physical and biological assessment of the to codeine. Therefore, the presence of 6-MAM is patient not only confirms dependence, but also usually specific for recent heroin use. Morphine, provides important information on their overall with or without small amounts of codeine, can health, fitness and willingness to undertake treat- indicate either heroin or morphine use in the last ment. A trusting relationship between clinician few days. However, small amounts of morphine and patient is valuable to establish the free flow in the presence of large amounts of codeine can of information. A non-judgemental and affirm- suggest intake of high doses of codeine, as co- ing approach can help to alleviate the sense of deine is also metabolised to morphine [111].
shame and diminished self-esteem many patients A positive urine test for opioids must be feel that often leads to the withholding of critical judged cautiously. Although patients are usually information [38, 111] required to test positive for opioids in order to Although important, self-reporting by pa- be offered treatment, the presence of opioids in- tients often results in questionable validity and dicates recent use, but not necessarily abuse or reliability [111]. As a result, drug screens, using dependence [111]. On the other hand, the absence I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence of opioid does not exclude either abuse or addic- 3.5. Psychiatric co-morbidities
tion, but merely indicates that the individual has not used opioids in the previous week. Converse- In addition to physiological symptoms, as- ly, positive findings are possible after ingestion of sessment of a patient's behaviour, psychology large amounts of poppy seeds [111] or for people and cognitive functioning is important in the di- exposed to prescribed opioids. Urinalysis results agnosis of opioid dependence. Psychological as- should therefore always be used in the context of sessment includes determining the presence of a more comprehensive patient assessment to con- co-existing psychological conditions, cognitive firm a diagnosis of opioid dependence.
impairment, and consideration of the patient's Further serum testing can detect the presence motivation to treatment and short- and long-term of other substances of abuse (e.g., alcohol), HIV, goals. hepatitis C and other common infectious diseases. Several large-scale epidemiologic studies in- Voluntary testing for HIV and hepatitis C should dicate approximately 50% of patients with drug be offered as part of an individual assessment, or alcohol dependency also have psychiatric with counselling offered before and after the test. distress [82]. Mood and anxiety disorders are In particular, HIV testing should be routinely of- common in the opioid-dependent population, in fered to patients in areas with high HIV incidence addition to antisocial behaviour and other per- rates, particularly if they fall into multiple risk sonality disorders, all of which affect treatment Table 8. Examples of standardised questionnaires for patient assessment [6,48]
Severity of Opioid Dependence Questionnaire (SODQ) Physical aspects of opioid dependence Severity of Alcohol Dependence Questionnaire Physical aspects of alcohol dependence The Symptom Check List (SCL-90) and General Health Global assessment of mental health Questionnaire (GHQ) The Psychiatric Research Interview for Substance and Substance-induced major depression Mental Disorders (PRISM) categories. Research suggests opioid-dependent choices and outcomes [33]. It has been estimated HIV patients have decreased access to quality that up to 16% of opioid dependents suffer from HIV care and medication, and are more likely to major depression, which is more commonly as- be non-compliant with treatment [111]. Serology sociated with poly-drug use. Chronic, episodic testing and vaccination for hepatitis B is recom- low-grade depression or dysthymia can progress mended for all patients. To offset the risk of pa- to full-blown depression as a result of the stress tients neglecting to return for repeated treatments and trauma associated with opioid dependence to complete a hepatitis B vaccination program, [28, 82]. Acute mood disturbances (depressed vaccination could commence before serology mood, anxiety) are also apparent during opioid testing, and accelerated vaccination schedules withdrawal [46]. Consequently, when assessing should be considered [111]. As part of a complete patients, it is important for clinicians to establish assessment, screening for tuberculosis and sexu- any pre-existing psychological conditions and ally transmitted diseases should also be consid- recognise that the short- and long-term effects of ered [38, 111]. A pregnancy test for women with opioids, their withdrawal symptoms and the trau- reproductive potential should be offered, as early ma of addiction, can all produce symptoms that as possible in the course of treatment [108, 111]. are similar to those that characterise many mental disorders [82]. Nevertheless, clinicians should be Heroin Addiction and Related Clinical Problems 13 (2): 5-40 aware of unusual opioid-related symptoms, such the results should be interpreted in combination as psychosis or mania, which may require acute with a complete clinical assessment.
The tools for gathering social and cultural in- The presence of psychiatric conditions also has formation are not as well developed or widely important implications for treatment choices and available as for physical assessment. Although medication management. Pharmaceutical agents there is a lack of assessment tools, available re- such as methadone and buprenorphine have been search suggests that social assessment, e.g., pa- shown to have a beneficial effect on mental disor- tients' living conditions, occupational situation ders as well as addiction [82].
and legal issues, needs to be an on-going process, beyond the scope of a single interview [108].
3.6. Patient assessment tools
Several instruments and questionnaires have been developed to assist in the patient assessment A diagnosis of opioid dependence is contin- process when substance abuse is suspected (Ta- gent on an individualised, comprehensive patient ble 8). Standard questionnaires can be a useful assessment, which considers the particular risks adjunct to the assessment process, provided they of this patient population. When considered col- are delivered in the context of a relaxed patient lectively, the information gained from a complete interview [48]. The use of structured and semi- physical and psychosocial examination and his- structured interviews and standardised assess- tory will help to differentiate between substance ment tools has also improved the reliability of co- use, abuse or dependence, and identify the best morbid psychiatric diagnoses [82]. In every case, course of treatment.
Key learning points
A comprehensive and individualised patient assessment is critical for the diagnosis of opioid dependence The key components for a comprehensive patient assessment include: Physical/biological evaluation and patient history – drug use, abuse and dependence, Co-existing somatic and psychiatric conditions Psychological/social functioning The potential for tolerance and withdrawal is common to non-pathologic (controlled) use, abuse and dependence, but is not required to diagnose drug dependence Documentation of opioid intoxication or withdrawal is important in diagnosis, and should be made in the context of reported time of last drug usage Examination of new and old injection sites aids the determination of drug-use chronology Serum and urine testing is recommended to detect opioids and substances of abuse, as well as co-existing infectious diseases and conditions A thorough psychiatric assessment is recommended to detect mental symptoms and to identify psychiatric co-morbidities, which affect a substantial proportion of the opioid-de- pendent population Numerous standardised assessment tools and questionnaires are available to assess de- pendence, physical and mental health I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence In addition to confirming the presence or ab- practices [111]. Harms to society associated with sence of opioids and other substances of abuse, opioid dependence include criminal activity and clinicians should ensure the necessary serum and the economic burden associated with healthcare urine testing is undertaken to detect co-existing costs (treatment and prevention services, costs conditions that may affect treatment. Importantly, incurred due to additional health problems), so- the patient's psychological health must be con- cial welfare and criminal-justice services [111]. sidered, given the high incidence of psychiatric The objectives of treatment for opioid-dependent co-morbidity and the implications for treatment patients are, therefore, to: reduce dependence on choice and outcome. A number of standardised abused drugs; reduce the morbidity and mortality patient assessment tools may aid in the assess- caused by the use of opioids of abuse, or associat- ment and diagnostic process.
ed with their use, such as infectious diseases; im- As with other chronic conditions, treatment prove physical and psychological health; reduce should be structured in such a way as to provide criminal behaviour; facilitate reintegration into long-term support to patients. Assessment of the the workforce and education system and improve patient's response to therapy should be undertak- social functioning [113]. Achieving these objec- en on a regular basis, with a continued focus on tives has clear medical, economic and social ben- outcome-oriented and individualised treatment. efits [113]. Accordingly, the World Health Organ- ization (WHO) has included the opioid agonists 4. Maintenance pharmacotherapies:
methadone and buprenorphine on their model list treatment principles and clinical
of essential medicines as a result of their strong evidence base [112]. Essential medicines are de- fined as those that satisfy the priority healthcare This section outlines the main principles, needs of the population and they are selected with goals and strategies underlying medically as- due regard to public-health relevance, evidence sisted approaches to opioid-dependence treat- on efficacy and safety and comparative cost-ef- ment, the unique pharmacological profiles of the fectiveness [112]. Access to essential medicines therapies available to treat opioid dependence, is considered a fulfilment of the human right to and the safety and efficacy considerations that health according to international law [42].
are relevant to the use of these pharmacological interventions throughout the different stages of 4.1.2. Elements of drug-dependence treatment
Treatment of opioid dependence must address 4.1. Principles, goals and strategies for treating the multiple needs of the patient. Pharmacologi-
cal treatments (which are discussed in detail here) are the critical component of the treatment proc- 4.1.1. Overal aims of drug-dependence treatment
ess but behavioural interventions and/or coun- selling therapies to address underlying mental Opioid dependence is a chronic and relaps- disorders and impaired psychosocial functioning ing medical disorder [62] with consequences also play a key role [77]. Comprehensive pro- that primarily affect the individual but also have grammes, involving access to psychosocial and broader effects. Harms to the individual include counselling services and referral to vocational, an increased risk of mortality as a result of over- financial, housing and family assistance, can help doses, violence, suicide and smoking- and alco- address the broader aspects of addiction. Indeed, hol-related diseases; and an increased risk of HIV combining pharmacological treatments with and hepatitis C infection through unsafe injection counselling aimed at promoting treatment adher- Heroin Addiction and Related Clinical Problems 13 (2): 5-40 ence and lifestyle change can greatly enhance the is defined as the administration of thoroughly effectiveness of treatment [92]. Pharmacological evaluated opioid agonists, by accredited profes- maintenance treatment also helps to initiate and sionals, in the framework of recognised medical retain contact between patients and substance- practice, to people with opioid dependence, for abuse specialists, thus enabling these other inter- achieving defined treatment aims [110]. The pri- ventions to be delivered.
mary aims of maintenance pharmacotherapy are Due to the complexity of drug dependence, to reduce drug craving and illicit opioid use, and one treatment approach is not appropriate for eve- where necessary, to prevent withdrawal symp- ry patient. Pharmacological interventions such toms. By reducing the drive to engage in contin- as opioid agonist treatments should be initiated ual addictive-drug-seeking and -using behaviour, according to evidence-based quality standards maintenance treatment can provide an opportu- to ensure safety and efficacy. Over time, the ap- nity to address the broader ramifications of each propriate dose and other aspects of treatment can individual's dependence-related problems (e.g., be individualised to the patient's needs, without impaired psychosocial functioning and physical losing the critical factors of success. Treatment health), reduce associated risks (e.g., overdose plans must be continually assessed and modified mortality, infectious-disease transmission), and to ensure they meet the patient's changing needs minimise the socio-economic burden imposed on wider society (e.g., criminality, lost productivity, healthcare costs of untreated opioid dependence). 4.1.3. Overview of treatment pathways
The medications most frequently used as mainte- nance therapies are the opioid agonists methadone The primary pharmacological approach to (typically administered as an oral syrup) and bu- treating heroin dependence involves opioid ago- prenorphine (administered as a sublingual tablet). nist maintenance treatment – also known as medi- Buprenorphine is available in two formulations: a cally assisted treatment, and less appropriately as monotherapy and a buprenorphine–naloxone (4:1 opioid replacement therapy or opioid substitution ratio) combination product designed to reduce the therapy. Opioid agonist maintenance treatment potential for misuse and diversion. Additional op- drug to an opioid agonist for long- Medically supervised withdrawal
Slow reduction of agonist dose until the The patient remains on a consistent patient is completely drug free; typically in agonist dose level that allows him/her association with psychosocial support to function properly Figure 4. Phases of heroin dependence treatment
I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence tions that are used less frequently and have been tion alone cannot be regarded as a viable treat- less thoroughly evaluated include slow-release ment approach for drug dependence. Rather than oral morphine and injectable therapies including a first step into long-term treatment, it has been injectable methadone and diamorphine. The main likened to a ‘revolving door'; many individuals phases of maintenance treatment are summarised who begin detoxification do not complete it and in Figure 4. Following induction and stabilisa- many individuals who complete detoxification do tion, patients typically need to be maintained on not go on to more definitive treatment [70]. Re- opioid agonist therapy for at least 12 months in sults from a placebo-controlled, randomised trial order to achieve enduring positive treatment out- of buprenorphine maintenance versus a tapered comes [41]. Opioid maintenance treatment is as- 6-day regimen of buprenorphine subsequently sociated with a substantial reduction in the use followed by placebo (individuals in both arms re- of heroin and other illicit opioids, crime and the ceived cognitive behavioural therapy to prevent risk of death through overdose. A WHO posi- relapse plus weekly counselling), demonstrated tion paper on maintenance treatment states it to that buprenorphine maintenance was far superior be an effective, safe and cost-effective modality to detoxification (1-year retention rates of 75% for the management of opioid dependence [113]. vs 0% and negative urine screens for illicit opi- Compared to detoxification or no treatment, both ates, central stimulants, cannabinoids and benzo- methadone and buprenorphine significantly re- diazepines in 75% of patients remaining in treat- duce drug use and improve treatment retention ment) [50].
Although maintenance treatment is consid- 4.2. Maintenance treatment of opioid dependence
ered the gold-standard therapeutic strategy (and is the focus of this article), a popular approach is There are multiple determinants of the ef- that of assisting opioid-dependent individuals to fectiveness of maintenance treatment for opioid medically withdraw from opioids, a process also dependence, including characteristics of the pa- referred to as opioid detoxification (Figure 4). tient, the medications used and the way treat- Both methadone and buprenorphine can be used ment is implemented. The primary focus of this in reducing doses to assist in achieving medical educational supplement will be to highlight the withdrawal from opioids. Gradual dose reduc- basic pharmacological considerations that are rel- tions help to minimise the likelihood of signifi- evant in selecting an appropriate medication and cant withdrawal and allow time for neuronal re- implementing this option to achieve the goals of adaptation. Alpha-2 adrenergic agonists such as therapy. According to the WHO, the following clonidine can also be used to reduce the severity attributes are essential for treatments to be used of opioid withdrawal symptoms. In non-tolerant as maintenance therapy in opioid-dependent pa- patients, the long-acting opioid antagonist nal- tients [113]: trexone can be used to prevent relapse to opioids Opioid properties in order to prevent with- [111]. Both naltrexone and its active metabolite drawal symptoms and reduce craving 6-β-naltrexol are competitive antagonists at the Affinity for opioid receptors in the brain in or- mu and kappa opioid receptors, reversibly block- der to diminish or block the effects of heroin or ing or attenuating the effects of opioids [91]. As other opioids a result, a person maintained on naltrexone will Longer duration of action than abused opioid not experience any of the sought-after positive drugs to delay the emergence of withdrawal and effects of heroin. Naltrexone maintenance may reduce the frequency of administration be effective for selected, mildly ill and highly Oral administration to reduce the risk of infec- motivated individuals [90]. However, detoxifica- tions associated with injections Heroin Addiction and Related Clinical Problems 13 (2): 5-40 The following sections present an overview of 4.2.1.2. Treatment – induction
the basic pharmacological and clinical considera- tions applicable to the use of the three main main- Induction describes the initial stage of treat- tenance pharmacotherapy options: methadone, ment when an individual dependent on street buprenorphine and buprenorphine–naloxone. heroin or other non-prescribed opioids is initiated The local manufacturer's prescribing information on maintenance treatment. The primary objec- should be consulted for comprehensive infor- tives of the induction stage are to ensure safety mation on dosage, administration, precautions, and to retain patients in treatment by preventing warnings and contraindications.
or reducing the signs and symptoms of opioid withdrawal, or preventing relapse in non-tolerant 4.2.1. Methadone treatment
individuals or treatment re-starters in the early phase of use. It is important to carefully explain intoxicating effects and withdrawal symptoms to patients, observe them frequently and ensure safe Methadone was the first widely used opioid- dosing in seeking to achieve these aims. Once in- maintenance therapy for the treatment of patients ducted safely, the goal is to achieve an optimal with opioid dependency [29] and its use assisted dose for longer-term maintenance that prevents a shift in treatment targets for opioid dependency cravings and addictive opioid use. from total abstinence to long-term maintenance A comprehensive assessment of patient drug [106]. Methadone is a synthetic, lipid-soluble, use, medical, psychological and social conditions, opioid agonist, which acts with similar affinity previous treatment history and current treatment to heroin at the mu-receptor [47]. Usually ad- goals should be conducted and documented prior ministered orally, methadone is readily absorbed to initiating therapy. Corroborative evidence of via the gastrointestinal tract resulting in a high opioid dependence – observed signs of opioid but variable bioavailability of 40–100% depend- withdrawal or a history of previous treatment ing on the individual patient [74]. The onset of for dependence – should be established before therapeutic benefit with methadone is within 30 initiating treatment. Responses to previous treat- minutes after ingestion, with an average time to ments can also guide treatment decisions, form- peak of 2.5 hours [41, 67]. Plasma-methadone ing the basis of the initial treatment plan. Such concentrations continue to rise for 3–4 hours fol- assessments can also be used to monitor progress lowing oral ingestion and then decline gradually. during treatment [41, 67].
With ongoing dosing, the half-life of methadone is extended to 13–47 hours, with a mean of 24 4.2.1.2.1. Treatment-naïve patients Due to its combination of mu-opioid-receptor- New patients should be dosed with caution agonist properties, high oral bioavailability and when using methadone in order to safely uptitrate a prolonged half-life, once-daily oral methadone to a satisfactory dose and achieve steady-state provides effective long-lasting suppression of plasma concentrations. This approach is neces- opioid withdrawal symptoms and cravings for sary to mitigate the risks of methadone accumula- many patients. In addition, as a result of the phe- tion across dosing intervals (due to its prolonged nomenon of cross tolerance, tolerance to other half-life) and consequent toxicity (including res- opioids is produced. This means that diminished piratory depression and sedation). The first dose intensity of opioid effects will be observed, which should be determined for each patient based on contributes to the reduction in heroin abuse dur- the severity of dependence and level of tolerance ing methadone maintenance [58].
to opioids, and, if possible, patients should be ob- I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence served for 3–4 hours after the first dose. The first ment. Patients transferring from buprenorphine 2 weeks of treatment are the greatest risk period treatment should be stabilised on 16mg/day or for methadone toxicity and overdose. During this less for several days prior to transfer. Metha- time, patients should be observed daily prior to done can be commenced 24 hours after the last dosing and assessed for signs of intoxication or buprenorphine dose, and the initial methadone withdrawal. Deaths in the first 2 weeks have been dose should not exceed 40mg. Patients transfer- associated with methadone doses in the range of ring from naltrexone should be treated as opioid- 25–100mg/day, with most occurring at doses of naïve, as tolerance to opioids is lost after a few 40–60mg/day. Whilst therapeutic maintenance days of naltrexone treatment. Methadone should doses are typically in the range of 60mg/day or not be administered for at least 72 hours after the more, the risk of toxicity during methadone in- last naltrexone dose, and the commencing dose duction requires the use of lower starting doses. should be no more than 20mg [41, 105].
An initial methadone dose of ≤20mg for a 70kg patient can be presumed safe, even in opioid- 4.2.1.3. Treatment – maintenance
naïve users; this dose will alleviate withdrawal symptoms in most patients. Caution should be Typically, effective methadone maintenance exercised with doses of 30mg or more, and ex- doses are 80–120mg/day. Maintenance doses treme caution and specialist involvement are higher than 120mg/day may be necessary in some advisable for doses of 40mg or more [41, 105]. patients, such as those who have a fast metha- Dose increments of 5–10mg can be considered done metabolism or dual-diagnosis patients, every 5–7 days as required, with overall weekly while a minority of patients can be maintained increases no larger than 40mg [41] until a stable effectively on doses less than 60mg/day [15, 32, maintenance dose is achieved. For individuals 41]. Methadone maintenance doses should be de- starting treatment who are presumed to have no termined on an individual basis. Patient input to tolerance, or irregular use at time of treatment treatment decisions, including determination of initiation, dosages should be low, dose increases dose levels, helps promote a good therapeutic re- should take not place more often than weekly (at lationship. The optimal maintenance dose should least until blocking dosages are reached), and reduce opioid cravings and use without produc- overall increases in daily dose should not be more ing euphoria. Daily administration of methadone than 10mg. This may be the case for: a) patients is required in order to maintain adequate plasma who have discontinued treatment recently, and levels and avoid opioid withdrawal. Monitoring have not yet relapsed into regular drug use; b) pa- drug use can also help assess treatment progress tients who have just been returned to their natural and may be useful for clinical decision making environment, with free availability of the opiate [41, 105].
of abuse, without having been started on any ag- Patients who miss their daily methadone dose onist treatment while in a protected environment; may be engaging in other drug use or are at risk c) patients who are not currently tolerant to opi- for leaving treatment. Tolerance to opioids may ates, but are willing to start some effective treat- be reduced after more than 3 days of missed ment, or who ask for advice about how to prevent methadone, placing patients at risk of overdose relapses (diagnostic criteria should be satisfied).
when methadone is reintroduced. If missed for more than 3 days, methadone should be reintro- 4.2.1.2.2. Patients transferring from other pharmacotherapies duced at half dose, while for more than 5 days of missed treatment, reintroduction of methadone When another pharmacotherapy has failed, should be regarded as a new induction [41, 105].
patients may be transferred to methadone treat- Heroin Addiction and Related Clinical Problems 13 (2): 5-40 4.2.1.4. Cessation of methadone treatment
safety consideration for methadone given its doc- umented association with QT-interval prolonga- Patients should be encouraged to remain in tion. On the basis of available evidence, an expert treatment for at least 12 months to achieve en- panel convened by the United States Center for during lifestyle changes, with some patients re- Substance Abuse Treatment developed a series of quiring considerably longer periods. Beyond this safety recommendations for physicians prescrib- point, no pre-determined treatment-term suits all ing methadone, specifically addressing the need cases, but benefits are maintained and stability to inform patients about the risk of arrhythmia, guaranteed by ongoing treatment, while with- assess cardiac history, use electrocardiography drawal from treatment, no matter how gradual, is for baseline and follow-up assessment, manage associated with a higher risk of relapse.
risk factors, and be aware of interactions between Withdrawal from methadone treatment should methadone and other drugs that prolong the QT be completed slowly and safely, and dose reduc- interval [59].
tions should be made in consultation with pa- In addition to direct methadone side effects, tients. Doses should be reduced by 10mg/week some studies have reported that a significant to a level of 40mg/day, then by 5mg/week. Signs subset of patients (up to a third) may experience and symptoms of withdrawal may become appar- symptoms of breakthrough withdrawal during ent as the methadone dose falls below 20mg/day, the 24-hour inter-dosing interval [34]. Failure with a peak at 2–3 days after cessation of metha- to achieve satisfactory 24-hour withdrawal sup- done. Supportive care reduces the risk of relapse pression has been linked to individual variation in the short-term and should be offered for at in methadone pharmacokinetics and the rate of least 6 months post-methadone treatment [41, decline in plasma concentrations between peak 105]. Clinical monitoring and follow-up is also and trough [32]. Withdrawal symptoms may also advisable in patients who have been drug-free for indicate that the current dose is inadequate.
a long period and are not receiving treatment.
4.2.1.6. Drug interactions
4.2.1.5. Side effects and symptom complaints
Pharmacodynamic and pharmacokinetic inter- Many effects of methadone are similar to actions can alter the safety and efficacy of metha- those of morphine and other opioid agonists. Tol- done for maintenance treatment. Methadone is erance can develop to some side effects, however metabolised in the liver by CYP450 3A4, 2B6 some side effects (e.g., constipation, increased and 2D6. CYP450-inducing drugs reduce plas- sweating) can continue to be troubling for some ma methadone levels and can cause withdrawal patients for the duration of methadone treatment symptoms; these drugs should be avoided in [3]. The primary hazard of methadone treatment methadone patients if possible. CYP450 3A in- is the risk of overdose, particularly during induc- hibitors can decrease the metabolism of metha- tion and when used in combination with other done and cause overdose; specialist advice should sedative drugs. The relatively slow onset of ac- be sought regarding the use of these drugs [41, tion and long half-life of methadone mean that 71]. Some psychotropic drugs may increase the opioid overdose can be deceptive and toxic ef- actions of methadone because they have overlap- fects may become life threatening many hours ping, additive effects (e.g., benzodiazepines and after ingestion of methadone. Most deaths during alcohol add to the respiratory depressant effects the induction period have occurred on the third of methadone) [41]. Similarly, given the associa- and fourth day of treatment [41]. tion between methadone and QT interval prolon- Cardiac safety also represents an important gation, there is a need for vigilance in prescribing I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence other agents that have QT prolongation effects in lower intrinsic activity than full-agonist opioids combination with methadone. For details refer to but a high binding affinity, buprenorphine com- Pacini et al., 2009 [81].
petes with other agonists, such as methadone, heroin, morphine and hydromorphone, at the 4.2.2. Buprenorphine treatment
mu-opioid site [10, 49, 103, 107]. As a result, in the short term, it may not produce sufficient com- pensatory agonist effects, leading to precipitated opioid withdrawal. This can largely be avoided During the initial development of buprenor- by the use of suitable initial dosing and rapid titra- phine as an analgesic in the 1970s its potential tion to an appropriate maintenance dose [65]. The utility as a treatment for opioid dependence was lower intrinsic activity of buprenorphine results recognised [49]. The high-dose sublingual tablet in a lower level of maximum tolerance, which preparation of buprenorphine was introduced in does not increase over a certain dose threshold the 1990s and has since been marketed world- (ceiling effect), and its long duration of action wide for the management of heroin dependence. leads to milder withdrawal symptoms than those Full agonist
Methadone, heroin Fatal respiratory % of maximal effect
Naloxone, naltrexone Figure 5. Risk of respiratory depression with opioid agonists, partial agonists and antagonists. Reproduced
from Walsh et al., 1994 [104]
Buprenorphine is a highly lipophilic [20] partial seen with morphine or methadone [49].
agonist at mu-opioid receptors and opioid-recep- Due to its partial agonist action, there is a tor-like (ORL-1) receptors and has mixed but ‘ceiling' effect to the respiratory depression that primarily antagonistic actions on kappa and delta occurs with buprenorphine; higher doses do not opioid receptors [99]. Buprenorphine has a high increase respiratory depression to a significant affinity for mu-opioid receptors [11] and dissoci- degree [104]. This translates into a lower risk of ates from the receptor slowly [39], thus produc- fatal overdose by comparison with full agonists ing powerful opioid agonist effects whilst also such as methadone (Figure 5). However, there is providing blockade against the effects of other no ceiling effect on buprenorphine's clinical ef- opiates in a dose-dependent fashion [102]. ficacy, as higher doses have increasing effective- As a partial mu-opioid-receptor agonist with ness with regard to treatment retention, heroin use Heroin Addiction and Related Clinical Problems 13 (2): 5-40 and withdrawal suppression [26, 53, 63]. Avail- 6 hours after last opioid use or when objective ability of mu-opioid receptors is correlated with and clear signs of withdrawal are evident [88]. buprenorphine plasma concentration, withdrawal In contrast with the approach recommended for symptoms and opioid blockade, with 50–60% methadone induction (‘start low, go slow'), most receptor occupancy required for adequate with- guidelines recommend buprenorphine induction drawal symptom suppression [39] and 80–90% should proceed rapidly [16, 23, 65]. It has been receptor inactivation required for significant re- shown that faster buprenorphine induction im- ductions in heroin-induced effects [19]. Comer et proves early treatment retention in subsequent al. reported that 2, 8 and 32 mg of buprenorphine buprenorphine maintenance treatment and higher (using the buprenorphine–naloxone combina- doses reduce craving [30] (Figure 6). tion) dose-dependently reduced the available mu- receptor population by 74, 83, and 91%, respec- 4.2.2.2.2. Patients transferring from other pharmacotherapies tively [19]. In addition to buprenorphine dose, receptor blockade also varies with time since ad- Patients can be inducted onto buprenorphine ministration. Receptor-binding studies conducted maintenance treatment from either current de- using PET scanning at 4, 28, 52 and 72 hours post pendent heroin use, or can transfer from metha- administration of buprenorphine 16mg to heroin- done. As methadone and buprenorphine have dependent volunteers demonstrated its duration comparable effectiveness in reducing cravings of action at receptors: 70% of mu-opioid recep- and illicit opioid use, transfer from methadone to tors were occupied at 4 hours, 46% at 28 hours, buprenorphine may be appropriate when patients 33% at 52 hours and 18% at 72 hours [39].
have not met their treatment goals or have devel- Buprenorphine is a long-acting drug with an oped intolerable side effects to methadone, or in elimination half-life of 24–36 hours. The onset patients who wish to change pharmacotherapies, of effects can be measured within 30–60 minutes e.g. to enable reduced-frequency dosing. Patients of administration and peak clinical effects occur on low doses of methadone (<40mg) generally within 1–4 hours. Effects are experienced for up tolerate this transition with minimal discomfort. to 12 hours at low doses (2mg) and for as long as However, patients on higher methadone doses 48–72 hours at higher doses (16 or 32mg). The may find that buprenorphine precipitates tran- prolonged duration of effect at high doses ena- sient opiate withdrawal [16, 23, 65]. The first bu- bles alternate day or three times a week dispens- prenorphine dose should be administered at least ing regimens [9, 83].
24 hours after the last methadone dose to mini- mise the likelihood of precipitated withdrawal, 4.2.2.2. Treatment – induction
ideally waiting until patients experience a mild degree of opioid withdrawal symptoms. Patient 4.2.2.2.1. Treatment-naïve patients assessment and communication are important during this phase [65]. The general principle is to The initial aims of buprenorphine induction cease methadone and delay buprenorphine until are to control possible physical symptoms quick- patients experience observable withdrawal [16, ly while avoiding precipitated withdrawal. Suc- 23], generally 2–4 days after the last methadone cessful induction can be achieved by assessing dose. Symptomatic medication may be used to patients for opioid tolerance, observable signs of ease withdrawal discomfort. mild opioid withdrawal, concurrent drug abuse and concurrent medical conditions. To prevent 4.2.2.3. Treatment – maintenance
precipitated withdrawal with buprenorphine, the first dose (2–4mg) should be administered at least The aims and principles of buprenorphine

I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence Figure 6. Association of retention rate with intensity of buprenorphine induction. Reproduced from
Bacha, Reast and Pearlstone, 2010 [7]
maintenance treatment are generally equivalent to riod is double the normal daily buprenorphine those of methadone maintenance treatment and to dose, and the dose for a 72-hour period is three addiction treatment in general. The optimal main- times the daily dose, up to a maximum of 32mg tenance dose needs to be individualised according at a time [88].
to the patient's response to buprenorphine. Dur- Patients who have missed fewer than 5 con- ing the stabilisation phase, buprenorphine doses secutive days since their last buprenorphine dose should be titrated according to clinical effect by must be reviewed prior to receiving a further dose increments of 2–4mg, to reach the recommended to ensure safety (i.e., reduction in tolerance may target dose of 12–24mg/day by the end of the first have occurred), while patients who have missed week. Several guidelines recommend aiming to more than 5 days need to recommence treatment reach doses of 12–16 mg within 2–3 days, subject at a dose no greater than 8mg [65].
to patient response [16, 23]. At each dose review, patients should be assessed for features of intoxi- 4.2.2.4. Cessation of buprenorphine treatment
cation or withdrawal, craving, additional drug use, adverse events, adherence to dosing regimen The decision to withdraw from opioid main- and satisfaction with buprenorphine treatment tenance treatment should not be made lightly: re- [65]. Effective maintenance, resulting in reduced lapse to illicit opioid use and treatment dropout is heroin use and improved treatment retention, high following interruption of a long-term treat- may be achieved with buprenorphine doses in the ment programme. Patients should be reminded range of 8–24mg per day, with a maximum daily that the ultimate goal of treatment is to continue recommended dose of 32mg [88].
not to relapse into addictive use and to achieve, Alternate-day dosing can be considered in maintain and consolidate other life goals (e.g. patients who are first stabilised on daily dosing employment, meaningful relationships) and that [16, 23, 65]. Duration of buprenorphine effects there is no restriction to the length of time they is dose-dependent, allowing for twice a week can receive maintenance treatment in order to or three times a week dosing schedules [9, 83]; achieve this goal [97].
however, not all patients can be stabilised on such A gradual process of treatment withdrawal was regimens. The dose dispensed for a 48-hour pe- historically believed to result in better outcomes Heroin Addiction and Related Clinical Problems 13 (2): 5-40 [4]; however, a buprenorphine–naloxone tapering quences [65].
schedule of 7 days was reported to be compara- Buprenorphine-maintained patients may have ble to 28 days in terms of opioid-free urine speci- a diminished response to opiates prescribed for mens at 1- and 3-month assessments in a study analgesia [75]. This can be managed by tempo- by the National Drug Abuse Treatment Clinical rarily increasing the buprenorphine dose, using Trials Network (NIDA CTN) [64]. The signs and higher potency opioids such as sufentanil (which symptoms of buprenorphine withdrawal are qual- is approximately 1000 times more potent than itatively similar to withdrawal from other opiates morphine) or using non-opioid analgesics [65, although the withdrawal syndrome experience on 66]. Which option is appropriate depends on the cessation of buprenorphine is delayed and may severity, onset and duration of pain. In addition, be milder than withdrawal from heroin, morphine some options may require management in spe- or methadone [4]. The onset of symptoms is usu- cialist settings [23; 65].
ally around 24–72 hours after the last dose and the peak is between days 3 and 5 (days 5 and 14 4.2.3. Buprenorphine–naloxone
following long-term maintenance treatment).
Frequent monitoring and review, including 4.2.3.1. Pharmacology
the use of withdrawal scales, counselling and symptomatic medication should occur regularly Buprenorphine–naloxone (Suboxone®) is a during the withdrawal phase. Patients who feel sublingual tablet containing buprenorphine hy- at risk for relapse should be allowed to return to drochloride and naloxone hydrochloride dihy- maintenance treatment at any time during taper. drate in a ratio of 4:1. It is available in two dosage Psychosocial counselling should continue and strengths: 2mg buprenorphine/0.5mg naloxone, possibly be increased during and after medical and 8mg buprenorphine/2mg naloxone. The phar- withdrawal [65].
macology of buprenorphine has been described above. Naloxone is a competitive mu-opioid- 4.2.2.5. Side effects and drug interactions
receptor antagonist, which displaces receptor- bound opioid molecules and produces a rapid re- Buprenorphine is principally metabolised by versal of the effects of opioids. The main clinical CYP450 3A4. Although buprenorphine metabo- use of naloxone is to treat respiratory depression lism can be influenced by medications that are caused by opioid overdose [85]. Naloxone has also metabolised by or alter the activity of the cy- low oral bioavailability but has rapid access to tochrome P450 system, it is less affected by drug mu receptors if administered intravenously. It is interactions or hepatic disease than other opioids metabolised in the liver, with a short half-life of such as methadone. Of particular interest in light about 1 hour [85].
of the increased incidence of HIV among inject- The buprenorphine–naloxone combination ing drug users, buprenorphine is less likely to be product was developed to decrease the potential associated with adverse events when given with for diversion and abuse of buprenorphine [73]. efavirenz-containing highly active anti-retroviral The presence of naloxone is intended to deter in- therapy (HAART) compared with methadone travenous abuse by persons dependent on other [14]. The combination of buprenorphine with opioids; if administered sublingually, naloxone benzodiazepines, alcohol or other sedatives has does not cause significant effects due to the poor been associated with fatal overdoses, due to ad- absorption of naloxone via this route. However, ditive effects. Appropriate prescription of these if the product is used intravenously or nasally, the therapeutics, combined with responsible use by antagonistic effect of naloxone elicits an acute patients, is unlikely to lead to adverse conse- but non-life-threatening withdrawal syndrome I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence in opioid-dependent subjects [73]. Therefore, the oid-dependent volunteers were maintained on a combination of buprenorphine and naloxone for 40mg dose of hydromorphone and then tested sublingual administration should diminish the with intramuscular and sublingual buprenor- parenteral abuse liability of buprenorphine by phine/naloxone (1.0/0.25, 2.0/0.5, 4/1, 8/2 and opioid-dependent individuals [73]. Notably, bu- 16/4mg); intramuscular hydromorphone (10mg) prenorphine time to onset, time to peak effect and and naloxone (0.25mg); both intramuscular and duration of action remain unaltered.
sublingual buprenorphine alone (8mg); and pla- cebo found that the combination produced dose- 4.2.3.2. Reduced abuse liability
related opioid antagonist effects when admin- istered intramuscularly but that the same doses Numerous controlled and observational stud- produced neither significant agonist or antago- Figure 7. Mean ‘willing to take the drug again' responses across all buprenorphine maintenance
doses in the study by Comer et al., 2010 [18]
ies have confirmed the reduced abuse liability of nist effects when administered by the sublingual buprenorphine–naloxone relative to buprenor- route [96]. Results from a study of 12 intravenous phine. The findings of a study in which 12 opi- heroin users maintained on each of three different oid-dependent volunteers were stabilised on a sublingual buprenorphine levels (2, 8 and 24mg) 60mg daily dose of morphine and then received showed that the subjective ratings of ‘drug liking' a series of challenges with buprenorphine alone and ‘desire to take the drug again' were signifi- (2mg intravenous dose), or in combination with cantly lower for buprenorphine–naloxone than naloxone (ratios of 2:1, 4:1 and 8:1) were that bu- for buprenorphine or heroin (Figure 7). Similar prenorphine alone did not precipitate withdrawal results were found for the amount of money that and had similar agonist effects to those of mor- participants were willing to pay for each drug. phine; buprenorphine plus naloxone at ratios of Subjects were most likely to self-administer drug 2:1 and 4:1 produced moderate to high increases when maintained on the lowest sublingual bu- in global opiate withdrawal, bad drug effect and prenorphine dose [18]. Retrospective, real-world sickness; while the 8:1 ratio produced only mild data collected from interviews with injecting drug withdrawal symptoms [73]. A study in which opi- users from the Australian Illicit Drug Reporting Heroin Addiction and Related Clinical Problems 13 (2): 5-40 System (IDRS) indicated that buprenorphine– centage of opioid-free urine samples over time naloxone was less likely to be injected than either did not differ by drug or dosage. The percentage methadone or buprenorphine [22].
of patients with ≥12 consecutive opioid-negative urine samples did not differ by drug and was sig- 4.2.3.3. Treatment – induction
nificantly greater for patients receiving higher doses of either agent. Induction success, compli- The rationale for induction onto buprenor- ance, non-opioid drug use, retention and Addic- phine–naloxone is similar to that for buprenor- tion Severity Index scores did not differ among phine. To avoid precipitated opioid withdrawal, the groups [53].
the first dose of buprenorphine–naloxone is de- layed by 12–24 hours from the last opioid use, 4.2.3.5. Buprenorphine–naloxone and take-home dos-
upon presentation of observable withdrawal ing
signs. Induction on buprenorphine–naloxone from illicit opioid use has been shown to be ef- Due to its favourable safety profile and reduced fective and well tolerated in a NIDA CTN trial of abuse liability, buprenorphine–naloxone may 234 opioid-dependent subjects. The study found hold particular value for patients in whom unsu- that 90% of participants successfully completed pervised ‘take-home' dosing is used. In an Aus- the 3-day induction period, reaching the target tralian 3-month trial of 119 subjects randomised dose of 16mg buprenorphine/4mg naloxone, and to observed or unobserved (weekly take-home) 68% completed the 13-day taper program [5].
administration of buprenorphine–naloxone, re- tention and heroin use were not significantly dif- 4.2.3.4. Treatment – maintenance
ferent between the two dosing groups. Treatment with close clinical monitoring, but no observation EU prescribing information recommends of dosing, was significantly cheaper (AU$ 1663 that the dose of buprenorphine/naloxone be in- compared with AU$ 2138) and therefore signifi- creased progressively according to the clinical cantly more cost-effective [8]. Buprenorphine– effect and should not exceed a maximum single naloxone might therefore help to alleviate pres- daily dose of 24mg/6mg [89], although adopting sure on resources by allowing safe ‘take-home' a best-practice approach by titrating individu- dosing.
al doses according to clinical effect means that some patients may require higher or lower dos- 5. Conclusion
age for optimum response. As for buprenorphine, patients should be assessed at least weekly dur- Opioid dependence is a chronic metabolic ing the stabilisation phase to allow assessment brain disease manifesting with several biological, of patient response to therapy and appropriate sociological and individual effects. Treatment dose adjustment. EU prescribing information for opioid dependence aims to improve the well- states that following satisfactory stabilisation, being and social functioning of individuals and buprenorphine/naloxone may be administered on to reduce the associated health and social conse- alternate days or thrice weekly in some patients quences. Given the complexity of this condition, (the buprenorphine/naloxone dose given on any no single treatment approach is effective for all 1 day should not exceed 24mg/6mg) [89]. In a individuals, and people with opioid dependence 17-week, double-blind, double-dummy trial, dai- should therefore be offered access to a range of ly dosing of buprenorphine–naloxone (8mg/2mg high-quality treatments to respond to their vary- and 16mg/4mg) was compared with methadone ing retention and response-related needs [113].
(45mg and 90mg) in 268 participants. The per- Opioid agonist maintenance treatment has be- I. Maremmani et al.: Basics on Addiction: a training package for medical practitioners or psychiatrists who treat opioid dependence come the first-line treatment for opioid depend- Decisions should be informed by a sound under- ence. Agonist maintenance treatment benefits standing of the basics of addiction, the principles individuals with opioid dependence through re- of opioid maintenance treatment, and the clinical ductions in addictive drug use and associated application of available options. Whilst treatment mortality risks, increased stability, improved with methadone, buprenorphine and buprenor- well-being and social functioning; benefits to phine–naloxone has the same therapeutic aims, society include reductions in the incidence of these products/compounds have unique pharma- criminal behaviour, reduced health and criminal- cological properties and safety profiles that need justice costs and increased productivity [113].
to be considered when formulating treatment In order to realise the full benefits of opioid plans. This supplement provides an overview of maintenance treatment, it is necessary that clini- the basic knowledge required to deliver mainte- cians deliver treatment in a manner that meets nance treatment in a safe and effective manner.
certain quality standards, as derived from the available scientific evidence base, while tailoring the treatment to the individual in order to meet the complex and unique needs of different patients. Key learning points
Opioid dependence is a chronic metabolic brain disease and several biological, sociologi- cal and individual factors are implicated in its development Effective treatment Is accessible for as many people as possible Involves a set of pharmacological and psychosocial interventions Aims to reduce or cease addictive opioid use, prevent harms associated with opioid use, improve quality of life for the patient and benefit the wider community Opioid agonist maintenance treatment is the most cost-effective form of treatment Primary options are methadone, buprenorphine and buprenorphine–naloxone Access to psychosocial interventions can significantly enhance success The benefits of maintenance programmes increase the longer the person remains in treat- Many people do need to receive treatment for a number of years Methadone, buprenorphine and buprenorphine/naloxone: Are broadly comparable in terms of retention and effectiveness in reducing addictive opioid use or any opioid use Buprenorphine is preferred for detoxification/short-term programmes Methadone is associated with specific side effects Respiratory depression and QT prolongation Fewer drug interactions with buprenorphine and HAART Methadone is associated with greater overdose risk with benzodiazepines Buprenorphine–naloxone is associated with the lowest abuse potential Regular monitoring allows the clinician to evaluate and adapt therapy to meet the needs Heroin Addiction and Related Clinical Problems 13 (2): 5-40 effectiveness of observed versus unobserved administration of buprenorphine-naloxone for heroin dependence. Addiction. 102:(12) 1. A.P.A. (2000): Desk Reference to the Diagnostic Criteria from DSM-IV-TR. American 9. Bickel W. K., Amass L., Crean J. P., Badger Psychiatric Association, Washington, DC.
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111. Who (2009): Guidelines for the Psychosocially Icro Maremmani, Matteo Pacini and Pier Pao- Assisted Pharmacological Treatment of Opioid lo Pani contributed equally to this work.
Dependence. Available at: wwwwhoint. Accessed on May 28, 2010.
Conflict of interest
112. Who (2010): WHO Model List of Essential Medicines. Available at: http://wwwwhoint/ The authors disclose the following relevant fi- medicines. Accessed on Febr 10, 2011.
nancial relationships: Icro Maremmani: [None], 113. Who, Unodc, Unaids (2004): WHO/UNODC/ Matteo Pacini [None], Pier Paolo Pani: [None].
UNAIDS position paper: Substitution Acknowledgements
maintenance therapy in the management of opioid dependence and HIV/AIDS This seminar summarises a training resource prevention. Available at: wwwwhoint/ developed by Professor Icro Maremmani (Presi- substance_abuse/publications/treatment/en/ dent of EUROPAD and AU-CNS) and Professor indexhtml. Accessed on May 28, 2010.
Pier Paolo Pani (President of the Italian Society 114. Yahyavi-Firouz-Abadi N., See R. E. (2009): of Addiction Medicine) on behalf of the Basics Anti-relapse medications: preclinical models on Addiction (BoA) Group: Francesco Auriem- for drug addiction treatment. Pharmacol Ther. ma (Napoli), Jacopo Bizzarri (Bolzano), Pietro 124:(2) 235-247.
Casella (Roma), Lucia D'Ambrosio (Matera), 115. Yuferov V., Levran O., Proudnikov D., Nielsen Giovanna De Cerce (Campobasso), Stefano D. A., Kreek M. J. (2010): Search for genetic Dell'Aera (Enna), Fernando Fantini (Lanciano), markers and functional variants involved in the Paola Fasciani (Chieti), Michele Ferdici (Agri- development of opiate and cocaine addiction gento), Giuseppe Filippone (Palermo), Piero Fun- and treatment. Ann N Y Acad Sci. 1187 184- done (Melfi), Riccardo Gionfriddo (Siracusa), Guido Intaschi (Viareggio), Francesco Lamanna 116. Zahm D. S. (2010): Pharmacotherapeutic (Pisa), Claudio Leonardi (Roma), Angelo Gio- approach to the treatment of addiction: vanni Icro Maremmani (Pisa), Icro Maremmani persistent challenges. MoMed. 107:(4) 276- (Pisa), Andrea Michelazzi (Trieste), Carlo Mine- strini (Città di Castello), Franco Montesano (Ca- tanzaro), Matteo Pacini (Pisa), Pier Paolo Pani Role of the funding source
(Cagliari), Maria Chiara Pieri (Bologna), Vico This initiative was supported by an unre- Rosolino Ricci (La Spezia), Francesco Ruffa stricted educational grant from Reckitt Benckiser (Firenze), Alberto Santa Maria (Bari), Carmelo Pharmaceuticals to the European Opiate Addic- Siragusa (Caserta), Lorenzo Somaini (Biella), tion Treatment Association (EUROPAD) and the Luigi Stella (Napoli), Enrico Teta (Torino), And- Association for the Application of Neuroscien- rea Vendramin (Padova). Editorial assistance was tific Knowledge to Social Aims (AUCNS).
provided by Real Science Communications.
Received April 2, 2011 - Accepted May 3, 2011

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